Primary polycythemia. Wakez disease: what is it, causes, symptoms, blood test, treatment. What is polycythemia

Polycythemia is a tumor process in which the cellular elements of the bone marrow increase (hyperplasia). The overwhelming majority of the process is benign, although under certain conditions a transition to a malignant form is possible.

This pathology, called erythremia, is singled out as a separate nosological form (disease). The name Wakez's disease is also used, after the doctor who first described it in 1892.

More often the disease is diagnosed in older men. But for young and middle age, the predominance of women is characteristic. Polycythemia manifests itself in different ways, but in terms of external effects, skin veins dilate and skin color changes. Changes in the neck, on the face and hands are especially clearly visible.

The disease is dangerous, in particular, thrombosis and increased bleeding (for example, from the gums).

Polycythemia (erythremia, Wakez's disease, polycythemia vera) is a chronic neoplastic myeloproliferative clonal disease in which there is an uncontrolled proliferation of erythroid, megakaryocytic, granulocytic myelopoiesis sprouts with predominant proliferation of erythroid sprout (panmyelosis), an increase in the concentration of erythrocytes, an increase in hemoglobin levels, a high content of platelets, leukocytes (pancytosis).

Important! With erythremia, erythropoiesis does not depend on normal regulatory mechanisms.

The most common disease occurs in men in middle and old age, but in general, erythremia is a rare disease.

For reference. True polycythemia is most common among Jews, and the most “resistant” inhabitants of our planet to such a disease are the Negroid race and the inhabitants of Japan (the exception is those who survived atomic attacks).

Erythremia - cancer or not

Polycythemia vera belongs to the group of chronic leukemias, the course of which can be either benign or malignant. Since the blood system is affected, this disease cannot be called cancer, since cancer is a malignant neoplasm that develops from the epithelial tissues of various organs.

However, erythremia is a highly differentiated neoplastic process that affects the human hematopoietic system.

Wakez disease - causes and risk factors

The main cause of true (primary) polycythemia is hereditary genetic mutations, which is proved by the fact that almost all patients with this disease are carriers of the JAK2V617F mutation or other functionally similar mutations.

In such cases, specific genes are determined that are responsible for the synthesis of red blood cells and show high sensitivity to erythropoietin. This phenomenon is often recorded in relatives and is family.

Another option for a genetic mutation is that pathological genes begin to capture a lot of oxygen without giving it to the tissues.

Secondary polycythemia is the result of pathological changes in chronic long-term diseases that stimulate the production of erythropoietin. These diseases and conditions include:

• Emphysema of the lungs.
• Bronchial asthma.
• Obstructive bronchitis.
• Heart defects in the stage of compensation and decompensation.
• Thromboembolism of any localization.
• Increased pressure in the pulmonary artery.
• Heart rhythm disorders.
• Heart failure.
• Cardiac ischemia.
• Kidney cysts.
• Renal ischemia due to atherosclerotic lesions of the vessels of the kidneys.
• Tumors of the red bone marrow.
• Renal cell carcinoma.
• Liver carcinoma.
• Tumor processes in the uterus.
• Tumors of the adrenal glands.
• Smoking.
• Ionizing radiation.
• Exposure to toxic and chemical substances.
• Some drugs - chloramphenicol, azathioprine, methotrexate, cyclophosphamide.

There are also a number of genetic diseases that increase the risk of developing polycythemia. Such diseases have nothing to do with the blood system, but gene instability leads to the fact that blood cells become more susceptible to various external and internal influences, which can cause the development of erythremia. Such diseases are:

• Down Syndrome.
• Klinefelter syndrome.
• Bloom Syndrome.
• Marfan syndrome.

With polycythemia, the leading manifestation is an increase in the number of red blood cells in the blood plasma, but the causes of this process directly depend on the type of erythremia:

• Absolute type- in this case, there is an increase in the concentration of erythrocytes in the bloodstream due to their increased formation. This phenomenon is typical for:
  • True polycythemia.
  • Polycythemia in case of hypoxia.
  • Lung obstructions.
  • Hypoxia that occurs with damage to the kidneys, adrenal glands.
• Relative type- at the same time, the volume of erythrocytes increases due to a decrease in plasma volume. The indicators of erythrocytes do not change at the same time, but the ratio of erythrocytes / plasma changes and therefore this phenomenon is called relative. This type of process occurs due to the occurrence of the following diseases:
  • Salmonellosis.
  • Cholera.
  • Dysentery, as well as other infectious diseases, which are accompanied by severe vomiting and diarrhea.
  • Burns.
  • Exposure to high temperatures, which is accompanied by increased sweating.

In addition to the immediate causes of the development of Wakez's disease, there are also risk factors that can, under certain conditions, trigger the pathological process:

• Stressful situations, prolonged exposure to stress.
• Activities associated with constant exposure to carbon dioxide, which leads to changes in the gas composition of the blood.
• Living in the highlands for a long time.

How the disease develops

Pathogenetic mechanisms for the development of polycythemia are based on mutations in the pluripotent hematopoietic stem cell, from which the development of the pathological process begins:

• The V617F point mutation occurs in the Jak2 gene, which leads to a disruption in the structure of the gene itself.
• As a result, the activity of tyrosine kinase significantly increases, which is transformed into increased proliferation of mature cells of myeloid germs. In this case, a complete blockade of apoptosis (natural cell death) occurs.
• In addition, an increased sensitivity of pathological precursor cells to erythropoietin, even at its lower concentrations, leads to an increased synthesis of formed elements, in particular, erythrocytes. Moreover, there is also a second type of cells - the precursors of erythrocytes, which behave absolutely independently and autonomously, their division does not depend on erythropoietin. This population is mutant and is one of the main substrates of erythremia.
• As a result of such a reaction, hyperplasia of hematopoietic germs occurs with a significant increase in the production of red blood cells in the bone marrow in the first place, as well as platelets and granulocytes. At the same time, absolute erythrocytosis develops, the rheological properties of the blood are disturbed.
• Organs and tissues overflow with blood, the viscosity of which increases significantly, which leads to the development of blood clots inside the vessels, changes in the liver, spleen of varying severity (myeloid metaplasia of the spleen and liver), hypoxia and hypervolemia.
• In the final stages, hematopoiesis is depleted, myelofibrosis develops.

Important! An abnormal cell clone is able to transform into any blood cell - erythrocyte, leukocyte and / or platelet.

The result of all pathogenetic reactions is the emergence of two types of cells - precursors:

• Normal.
• Mutant.

Since the process of formation of mutant cells is uncontrollable, the number of erythrocytes significantly exceeds the body's needs for them. This leads to inhibition of the synthesis of erythropoietin in the kidneys, which further aggravates the pathological process, since erythropoietin loses its effect on normal erythropoiesis, and it has no effect on tumor cells.

In addition, the constant growth of mutant cells leads to the displacement of normal ones, which at a certain point in time leads to the fact that all erythrocytes are produced from mutant precursor cells.

Disease classification

As mentioned above, depending on the reasons that led to the development of polycythemia, it is divided into two types:

• True polycythemia.
• Relative.

True erythremia, in turn, can be:

• Primary - the basis of this process is the defeat of the myeloid germ of hematopoiesis.
• Secondary - the basis of this variety - an increase in the activity of erythropoietin.

The disease goes through three stages of development:

• Stage 1 - oligosymptomatic, initial, height - during this period, there are practically no clinical manifestations of erythremia. This stage lasts for a long time, up to 5 years or more. During this period, the following processes develop:
  • Moderate hypervolemia.
  • moderate erythrocytosis.
  • Changes in the size of the spleen are not detected.
• Stage 2 - deployed, erythremic - at this stage, all relevant clinical signs are expressed. This period of the disease is divided in turn into 2 stages:
  • IA - no myeloid degeneration of the spleen. Erythrocytosis, thrombocytosis, and in some cases pancytosis develops. The myelogram shows hyperplasia of all hematopoietic lineages and severe megakaryocytosis. This stage can last up to 20 years.
  • IIB - here the spleen is already actively involved, which undergoes myeloid metaplasia. Severe hypervolemia develops, the spleen and liver increase in size, and pancytosis is recorded in the blood plasma.
• Stage 3 - terminal, anemic, posterythremic - the final stage of the disease. It develops:
  • Anemia.
  • thrombocytopenia.
  • Leukopenia.
  • Myeloid transformation of the liver, spleen.
  • Secondary myelofibrosis.
  • It is possible to degenerate into other hemoblastoses, much more dangerous than polycythemia itself.

Important! At the last stage of the disease, cells lose their ability to differentiate, which in most cases leads to the development of acute leukemia.

Polycythemia. Symptoms

The main clinical manifestations of erythremia are two leading syndromes:

• Plethoric (plethora) The main symptoms of this syndrome are:
  • Change in the volume of erythrocytes in the circulating blood in the direction of increase.
  • The occurrence of dizziness, headaches.
  • Visual disorder.
  • Development of itchy skin.
  • Angina pectoris.
  • The appearance of a bluish tint on the skin and visible mucous membranes, which is called a positive symptom of Cooperman.
  • Thrombosis of any level of localization.
  • Redness of the fingers of the upper and lower extremities, which is accompanied by extremely painful attacks and a burning sensation, which is called erythromelalgia.
• Myeloproliferative- occurs due to hyperplasia of all three hematopoietic sprouts, with which there are:
  • Sweating.
  • Skin itching.
  • Marked weakness.
  • Increase in body temperature.
  • Violation of purine metabolism, which causes uric acid diathesis, the occurrence of kidney stones, gout and gouty arthritis.
  • The development of extramedullary hematopoiesis (foci of the formation of pathological blood cells no longer appear in the bone marrow, but outside it).
  • Enlargement of the spleen.
  • Frequent infections.

If we talk about each stage of polycythemia, then they are characterized by their own special clinical signs, which are signs of the stages of the disease:

• initial stage- there are practically no manifestations here, they are nonspecific and can be attributed to many other diseases of various organs and systems:
  • Redness of the mucous membranes and skin - this symptom occurs due to an increase in the concentration of red blood cells. It appears in all parts of the human body. at the beginning of the disease may be mild.
  • Headaches - develop in violation of microcirculation processes in the vessels of the brain of small caliber.
  • Soreness in the toes, hands - since during this period the blood flow through small vessels is already disturbed, this leads to an increase in blood viscosity, which leads to a decrease in oxygen delivery to the organs. This leads to the development of ischemia and the appearance of ischemic pain.
• Expanded stage- at this stage of the disease, polycythemia causes a significant increase in the number of blood cells, which leads to an increase in its viscosity, their increased destruction in the spleen and disturbances in the activity of the blood coagulation system. Clinically, this is manifested by such signs:
  • Redness of the skin and mucous membranes intensifies up to the appearance of a purple, blue tint.
  • Teleaniectasias (spot hemorrhages on the skin).
  • Bilateral erythromelalgia intensifies, which is complicated by necrosis of the fingers of the upper and lower extremities. Such a process with the progression of polycythemia can completely cover the entire hand and foot. Attacks of acute pain can last up to several hours, and exposure to cold water may provide some relief.
  • An increase in the liver (sometimes up to 10 kg) is expressed by the development of pain in the right hypochondrium, a disorder in the act of breathing and disorders of the digestive process.
  • Enlargement of the spleen - excessive filling of the spleen with blood leads not only to its enlargement, but also to the thickening of the spleen.
  • Arterial hypertension appears due to an increased volume of circulating blood, high blood viscosity. This causes the development of vascular resistance to blood flow.
  • The severity of skin itching becomes stronger - this is because the increased formation of blood elements, in particular, leukocytes, leads to their high concentrations. This leads to their massive destruction, as a result of which histamine is actively released from them, which is the culprit of skin itching, which is further enhanced by contact with water.
  • Increased bleeding - even minor cuts and injuries can lead to bleeding due to high blood pressure, increased blood volume and excessive platelet activity.
  • Ulcerative lesions of the digestive tract, which is accompanied by such dyspeptic symptoms of varying severity.
  • Pain in the joints of any localization.
  • Ischemic stroke due to massive thrombosis.
  • Myocardial infarction.
  • Signs of iron deficiency - exfoliating nails, dry skin and mucous membranes, cracks in the corners of the mouth, poor appetite, impaired smell, taste, increased susceptibility to the development of infectious diseases.
  • Dilated cardiomyopathy - gradually all the chambers of the heart are more and more filled. The heart is stretched. This occurs as a protective, compensatory reaction of the body to maintain a sufficient level of blood circulation. Gradually, the constant stretching of the heart leads to the loss of its ability to contract normally. Clinically, this is expressed by rhythm and conduction disturbances, edematous syndrome, pain in the heart, fatigue and severe general weakness.
• anemic stage- the main symptom of this stage is a decrease in the production of all blood cells, which transforms into the following symptoms:
  • Aplastic iron deficiency anemia - develops as a result of inhibition of hematopoietic processes in the bone marrow due to myelofibrosis - displacement of hematopoietic cells from the bone marrow by the connective tissue. Paleness of the skin, increased fatigue, general pronounced weakness, fainting, a feeling of lack of air appear.
  • Bleeding - occurs with the smallest injuries on the skin and mucous membranes due to reduced production of platelets and the synthesis of platelets that lose their functions.

Important! In the absence of treatment, the terminal stage occurs very quickly with the development of a lethal outcome.

Erythremia in children, features

True polycythemia in newborns and young children is not typical. If the child has symptoms of the disease, they indicate the development of a secondary process that may occur due to:

• Hypoxia.
• Toxic dyspepsia.
• Feto - placental insufficiency.

Important! Twins have congenital polycythemia due to genetic defects, which manifests itself from birth.

Basically, the disease manifests itself at 2 weeks of a child's life.

The staging of the disease in children is completely identical to that in adults, but in children the disease is much more severe, with the development of severe bacterial infections, heart defects, bone marrow sclerosis, which leads to early death. Treatment for polycythemia is the same as for adults, as discussed below.

Diagnosis of Wakez disease

When diagnosing polycythemia, a well-defined diagnostic plan is used, which includes the following steps:

• Collection of anamnestic data.
• Visual inspection.
• Blood test, which should include:
  • The number of red blood cells and other blood cells.
  • Hematocrit.
  • Mean volume of erythrocytes - MCV.
  • The average content of hemoglobin in erythrocytes - MCH.
  • The average concentration of hemoglobin in erythrocytes is MCHC.
  • The distribution width of erythrocytes by volume is RDW.
  • Erythropoietin in blood serum.
  • Molecular genetic testing of blood to detect mutations.
• Ultrasound examination of the abdominal organs.
• A biochemical blood test, especially for uric acid, an increase in the levels of which indicates the development of gout.
• Fibrogastroduodenoscopy.
• Abdominal CT scan in vascular mode.
• Bone marrow biopsy.
• Assessment of the functions of external respiration.
• Determination of the content of oxygen and carbon dioxide in the blood.
• large arteries.
• EchoCG.
• General urine analysis.

To make a diagnosis of true polycythemia, after all the manipulations, certain criteria are applied, according to which the diagnosis of polycythemia is made:

• Big Criteria:
  • Hemoglobin levels above 185 g/l for men and 165 g/l for women, as well as other signs of increased mass of red blood cells - hematocrit > 52% in men, > 48% in women.
  • Detection of mutations in the JAK2V617F gene.
• Small Criteria:
  • Panmyelosis in a bone marrow biopsy is an increase in the proliferation of erythroid, granulocytic and megakaryocytic hematopoietic sprouts.
  • Low erythropoietin values.
  • The formation of endogenous erythrocyte colonies without the participation of erythropoietin in the study of biopsy of bone marrow cultures.

Important! The diagnosis is fully confirmed in the presence of two major and one minor criteria.

Treatment

Treatment of patients with polycythemia takes place in the conditions of the hematology department. For the treatment of this condition, the following measures are used:

• Bloodletting - performed to reduce the number of red blood cells and hemoglobin. The procedure is carried out once every 1-2 days with the collection of up to 500 ml of blood.
• Cytopheresis is the passage of blood through special filters, with the help of which some of the red blood cells are eliminated.
• Reception of cytostatics - cyclophosan, cyclophosphamide, hydroxyurea, etc.
• Antiplatelet therapy with aspirin, dipyridamole.
• Interferons.
• symptomatic treatment.

Important! It is strictly forbidden to independently treat the disease without medical intervention, as well as to use dubious methods and types of treatment.

Important in the treatment of polycythemia is a diet that completely excludes the intake of foods that increase blood formation. With the addition of gout, meat and fish in general can be excluded from the diet of patients and replaced with plant foods.

In general, the basis of treatment is the distinction between the primary process and the secondary, since in secondary polycythemia, the condition that caused the development of erythremia is primarily treated.

Complications

Polycythemia is characterized by a high probability of such formidable complications as:

• Arterial hypertension in severe form.
• Hemorrhagic strokes.
• Myocardial infarction.
• Acute myeloid leukemia.
• Chronic myeloid leukemia.
• Erythromyelosis.

In some cases, even timely treatment leads to the development of such dangerous situations that can end in death at any time.

Forecast

The prognosis of polycythemia directly depends on its type, course, timeliness and correctness of treatment.

Important! Without appropriate treatment, about 50% of patients die within a year and a half from the time of diagnosis.

With timely therapy, the prognosis in patients with erythremia is quite favorable and demonstrates a 10-year survival rate in more than 75% of cases.

Content

Hematologists know that this disease is difficult to treat and has dangerous complications. Polycythemia is characterized by changes in the composition of the blood that affect the health of the patient. How does the pathology develop, what are the symptoms? Find out diagnostic methods, methods of treatment, medicines, life forecasts for the patient.

What is polycythemia

Men are more susceptible to the disease than women, middle-aged people are more likely to get sick. Polycythemia is an autosomal recessive pathology in which, for various reasons, the number of red blood cells, or blood cells, increases in the blood. The disease has other names - erythrocytosis, polyhemorrhage, Wakez's disease, erythremia, its ICD-10 code is D45. The disease is characterized by:

• splenomegaly - a significant increase in the size of the spleen;
• increased blood viscosity;
• significant production of leukocytes, platelets;
• an increase in circulating blood volume (CBV).

Polycythemia belongs to the group of chronic leukemias and is considered a rare form of leukemia. True erythremia (polycythemia vera) is divided into types:

• Primary - a malignant disease with a progressive form associated with hyperplasia of the cellular components of the bone marrow - myeloproliferation. Pathology affects the erythroblastic germ, which causes an increase in the number of red blood cells.
• Secondary polycythemia is a compensatory reaction to hypoxia caused by smoking, alpine climbing, adrenal tumors, and pulmonary pathology.

Wakez's disease is dangerous with complications. Due to the high viscosity, blood circulation in the peripheral vessels is disturbed. Uric acid is excreted in large quantities. All this is fraught with:

• bleeding;
• thrombosis;
• oxygen starvation of tissues;
• hemorrhages;
• hyperemia;
• hemorrhage;
• trophic ulcers;
• renal colic;
• ulcers in the digestive tract;
• kidney stones;
• splenomegaly;
• gout;
• myelofibrosis;
• iron deficiency anemia;
• myocardial infarction;
• stroke
• lethal outcome.

Types of disease

Wakez's disease, depending on developmental factors, is divided into types. Each has its own symptoms and treatment options. Physicians distinguish:

• true polycythemia, which is caused by the appearance of a tumor substrate in the red bone marrow, leading to an increase in the production of red blood cells;
• secondary erythremia - its cause is oxygen starvation, pathological processes occurring in the patient's body and causing a compensatory reaction.

Primary

The disease is characterized by tumor origin. Primary polycythemia is a myeloproliferative blood cancer that occurs when pluripotent stem cells in the bone marrow are damaged. When a disease occurs in the patient's body:

• increases the activity of erythropoietin, which regulates the production of blood cells;
• the number of erythrocytes, leukocytes, platelets increases;
• there is a synthesis of mutated brain cells;
• proliferation of infected tissues is formed;
• there is a compensatory reaction to hypoxia - there is an additional increase in the number of erythrocytes.

With this type of pathology, it is difficult to influence mutated cells that have a high ability to divide. Thrombotic, hemorrhagic lesions appear. Wakez's disease has developmental features:

• changes occur in the liver, spleen;
• tissues are filled with viscous blood, prone to the formation of blood clots;
• plethoric syndrome develops - cherry-red color of the skin;
• severe itching occurs;
• increased blood pressure (BP);
• hypoxia develops.

True polycythemia is dangerous for its malignant development, causing severe complications. For this form of pathology, the following stages are characteristic:

• Initial - lasts about five years, is asymptomatic, the size of the spleen is not changed. BCC increased slightly.
• Extended stage - duration up to 20 years. It is characterized by an increased content of erythrocytes, platelets, leukocytes. It has two substages - without changes in the spleen and with the presence of myeloid metaplasia.

The last stage of the disease - posterythremic (anemic) - is characterized by complications:

• secondary myelofibrosis;
• leukopenia;
• thrombocytopenia;
• myeloid transformation of the liver, spleen;
• cholelithiasis, urolithiasis;
• transient ischemic attacks;
• anemia - the result of depletion of the bone marrow;
• pulmonary embolism;
• myocardial infarction;
• nephrosclerosis;
• leukemia in acute, chronic form;
• hemorrhages in the brain.

Secondary polycythemia (relative)

This form of Wakez disease is provoked by external and internal factors. With the development of secondary polycythemia, viscous blood, which has increased volumes, fills the vessels, provoking the formation of blood clots. With oxygen starvation of tissues, a compensation process develops:

• the kidneys begin to intensively produce the hormone erythropoietin;
• active synthesis of erythrocytes in the bone marrow is launched.

Secondary polycythemia occurs in two forms. Each of them has features. The following varieties are distinguished:

• stressful - caused by an unhealthy lifestyle, prolonged overvoltage, nervous breakdowns, unfavorable working conditions;
• false, in which the total number of erythrocytes, leukocytes, platelets in the analyzes is within the normal range, an increase in ESR causes a decrease in plasma volume.

Causes

The provoking factors for the development of the disease depend on the form of the disease. Primary polycythemia occurs as a result of a neoplasm of the red bone marrow. The predetermining causes of true erythrocytosis are:

• genetic failures in the body - a mutation of the tyrosine kinase enzyme, when the amino acid valine is replaced by phenylalanine;
• hereditary predisposition;
• cancerous tumors of the bone marrow;
• oxygen deficiency - hypoxia.

The secondary form of erythrocytosis is caused by external causes. Concomitant diseases play an equally important role in development. The provoking factors are:

• climatic conditions;
• living in highlands;
• congestive heart failure;
• cancerous tumors of internal organs;
• pulmonary hypertension;
• the action of toxic substances;
• overstrain of the body;
• x-ray radiation;
• insufficient supply of oxygen to the kidneys;
• infections that cause intoxication of the body;
• smoking;
• bad ecology;
• features of genetics - Europeans are more likely to get sick.

The secondary form of Wakez's disease is caused by congenital causes - autonomous production of erythropoietin, high affinity of hemoglobin for oxygen. There are also acquired factors for the development of the disease:

• arterial hypoxemia;
• kidney pathology - cystic lesions, tumors, hydronephrosis, stenosis of the renal arteries;
• bronchial carcinoma;
• adrenal tumors;
• hemangioblastoma of the cerebellum;
• hepatitis;
• cirrhosis of the liver;
• tuberculosis.

Symptoms of Wakez disease

The disease caused by an increase in the number of red blood cells and blood volume is distinguished by characteristic signs. They have their own characteristics depending on the stage of Wakez's disease. Common symptoms of pathology are observed:

• dizziness;
• visual impairment;
• Cooperman's symptom - a bluish hue of the mucous membranes and skin;
• angina attacks;
• redness of the fingers of the lower and upper extremities, accompanied by pain, burning;
• thrombosis of various localization;
• severe itching of the skin, aggravated by contact with water.

As the pathology progresses, the patient develops pain syndromes of various localization. There are disorders of the nervous system. For the disease are characteristic:

• weakness;
• fatigue;
• temperature rise;
• enlargement of the spleen;
• noise in ears;
• dyspnea;
• feeling of loss of consciousness;
• plethoric syndrome - burgundy-red color of the skin;
• headache;
• vomit;
• increase in blood pressure;
• pain in the hands from touch;
• chilliness of the limbs;
• eye redness;
• insomnia;
• pain in the hypochondrium, bones;
• pulmonary embolism.

initial stage

The disease is difficult to diagnose at the very beginning of development. The symptoms are mild, similar to a cold or a condition of the elderly, corresponding to advanced age. Pathology is detected by chance during tests. The symptoms of the initial stage of erythrocytosis are:

• dizziness;
• decrease in visual acuity;
• headache attacks;
• insomnia;
• noise in ears;
• sore fingers from touch;
• cold extremities;
• ischemic pain;
• redness of mucous surfaces, skin.

Expanded (erythremic)

The development of the disease is characterized by the appearance of pronounced signs of high blood viscosity. Pancytosis is noted - an increase in the number of components in the analyzes - erythrocytes, leukocytes, platelets. The advanced stage is characterized by the presence of:

• reddening of the skin to purple shades;
• telangiectasia - pinpoint hemorrhages;
• acute attacks of pain;
• itching, aggravated by contact with water.

At this stage of the disease, signs of iron deficiency are observed - stratification of the nails, dry skin. A characteristic symptom is a strong increase in the size of the liver, spleen. Patients have:

• indigestion;
• breathing disorder;
• arterial hypertension;
• pain in the joints;
• hemorrhagic syndrome;
• microthrombosis;
• stomach ulcers, duodenal ulcers;
• bleeding;
• cardialgia - pain in the left chest;
• migraine.

With an advanced stage of erythrocytosis, patients complain of a lack of appetite. Investigations reveal stones in the gallbladder. The disease is different

• increased bleeding from small cuts;
• violation of the rhythm, conduction of the heart;
• puffiness;
• signs of gout;
• pain in the heart;
• microcytoses;
• symptoms of urolithiasis;
• changes in taste, smell;
• bruising on the skin;
• trophic ulcers;
• renal colic.

anemic stage

At this stage of development, the disease passes into the terminal stage. The body does not have enough hemoglobin to function properly. The patient has:

• a significant increase in the liver;
• progression of splenomegaly;
• compaction of the tissues of the spleen;
• with hardware research - cicatricial changes in the bone marrow;
• vascular thrombosis of deep veins, coronary, cerebral arteries.

At the anemic stage, the development of leukemia is a danger to the patient's life. This stage of Wakez's disease is characterized by the occurrence of aplastic iron deficiency anemia, the cause of which is the displacement of hematopoietic cells from the bone marrow by connective tissue. In this case, symptoms are observed:

• general weakness;
• fainting;
• feeling of lack of air.

At this stage, if left untreated, the patient quickly dies. Thrombotic, hemorrhagic complications lead to it:

• ischemic form of stroke;
• thromboembolism of the pulmonary arteries;
• myocardial infarction;
• spontaneous bleeding - gastrointestinal, veins of the esophagus;
• cardiosclerosis;
• arterial hypertension;
• heart failure.

Symptoms of the disease in newborns

If the fetus has suffered hypoxia during fetal development, its body, in response, begins to increase the production of red blood cells. A provoking factor in the appearance of erythrocytosis in infants is congenital heart disease, pulmonary pathologies. The disease leads to the following consequences:

• the formation of bone marrow sclerosis;
• violation of the production of leukocytes responsible for the immune system of the newborn;
• development of infections leading to death.

At the initial stage, the disease is detected by the results of tests - the level of hemoglobin, hematocrit, red blood cells. With the progression of the pathology, pronounced symptoms are observed already in the second week after birth:

• the baby cries from touch;
• the skin turns red;
• the size of the liver, spleen increases;
• thrombosis appears;
• body weight decreases;
• the analyzes revealed an increased number of erythrocytes, leukocytes, platelets.

Diagnosis of polycythemia

The patient's communication with the hematologist begins with a conversation, an external examination, and anamnesis. The doctor finds out heredity, features of the course of the disease, the presence of pain, frequent bleeding, signs of thrombosis. During the reception, the patient is diagnosed with polycythemic syndrome:

• purple-red blush;
• intense coloring of the mucous membranes of the mouth, nose;
• cyanotic (cyanotic) color of the palate;
• change in the shape of the fingers;
• red eyes;
• palpation is determined by an increase in the size of the spleen, liver.

The next stage of diagnosis is laboratory research. Indicators that indicate the development of the disease:

• an increase in the total mass of erythrocytes in the blood;
• increase in the number of platelets, leukocytes;
• a significant level of alkaline phosphatase;
• a large amount of vitamin B 12 in the blood serum;
• increased erythropoietin in the secondary form of polycythemia;
• decrease in situation (blood oxygen saturation) - less than 92%;
• decrease in ESR;
• increase in hemoglobin to 240 g / l.

For the differential diagnosis of pathology, special types of studies and analyzes are used. Urologist, cardiologist, gastroenterologist are consulted. The doctor prescribes:

• biochemical blood test - determines the level of uric acid, alkaline phosphatase;
• radiological examination - reveals an increase in circulating red blood cells;
• sternal puncture - sampling for cytological analysis of the bone marrow from the sternum;
• trepanobiopsy - histology of tissues from the ilium, revealing three-growth hyperplasia;
• molecular genetic analysis.

Laboratory research

The disease of polycythemia is confirmed by hematological changes in blood parameters. There are parameters that characterize the development of pathology. Laboratory data indicating the presence of polycythemia:

Index	Units	Meaning
Hemoglobin
Mass of circulating red blood cells
Erythrocytosis	cells/ liter
Leukocytosis		over 12x109
thrombocytosis		over 400x109
Hematocrit
Serum vitamin B level 12
Alkaline phosphatase		over 100
Color indicator

Hardware diagnostics

After conducting laboratory tests, hematologists prescribe additional tests. To assess the risk of developing metabolic, thrombohemorrhagic disorders, hardware diagnostics are used. The patient undergoes research depending on the characteristics of the course of the disease. A patient with polycythemia is given:

• Ultrasound of the spleen, kidneys;
• heart examination - echocardiography.

Methods of hardware diagnostics help to assess the condition of the vessels, to identify the presence of bleeding, ulcers. Appointed:

• fibrogastroduodenoscopy (FGDS) - an instrumental study of the mucous membranes of the stomach, duodenum;
• ultrasound dopplerography (USDG) of the vessels of the neck, head, veins of the extremities;
• computed tomography of internal organs.

Treatment of polycythemia

Before proceeding with therapeutic measures, it is necessary to find out the type of disease and its causes - the treatment regimen depends on this. The challenge for haematologists is to:

• in primary polycythemia, prevent tumor activity by influencing the neoplasm in the bone marrow;
• in the secondary form - to identify the disease that provoked the pathology and eliminate it.

Treatment of polycythemia includes drawing up a rehabilitation and prevention plan for a particular patient. Therapy includes:

• bloodletting, which reduces the number of red blood cells to normal - 500 ml of blood is taken from the patient every two days;
• maintaining physical activity;
• erythocytophoresis - blood sampling from a vein, followed by filtration and return to the patient;
• dieting;
• transfusion of blood and its components;
• chemotherapy to prevent leukemia.

In difficult situations that threaten the life of the patient, a bone marrow transplant is performed, a splenectomy is the removal of the spleen. In the treatment of polycythemia, much attention is paid to the use of medications. The treatment regimen includes the use of:

• corticosteroid hormones - with a severe course of the disease;
• cytostatic agents - Hydroxyurea, Imiphos, which reduce the growth of malignant cells;
• antiplatelet agents that thin the blood - Dipyridamole, Aspirin;
• Interferon, which increases defenses, enhances the effectiveness of cytostatics.

Symptomatic treatment involves the use of drugs that reduce blood viscosity, prevent thrombosis, and the development of bleeding. Hematologists prescribe:

• to exclude vascular thrombosis - Heparin;
• with severe bleeding - Aminocaproic acid;
• in the case of erythromelalgia - pain in the fingertips - non-steroidal anti-inflammatory drugs - Voltaren, Indomethacin;
• with skin itching - antihistamines - Suprastin, Loratadin;
• with an infectious genesis of the disease - antibiotics;
• for hypoxic causes - oxygen therapy.

Bloodletting or erythrocytopheresis

An effective way to treat polycythemia is phlebotomy. When bloodletting is performed, the volume of circulating blood decreases, the number of red blood cells (hematocrit) decreases, and skin itching is eliminated. Features of the process:

• before phlebotomy, the patient is administered Heparin or Reopoliglyukin to improve microcirculation, blood flow;
• excess is removed with leeches or an incision is made, a puncture of a vein;
• up to 500 ml of blood is removed at a time;
• the procedure is carried out with an interval of 2 to 4 days;
• hemoglobin is reduced to 150 g/l;
• the hematocrit is adjusted to 45%.

Another method of treating polycythemia, erythrocytopheresis, is effective. With extracorporeal hemocorrection, excess red blood cells are removed from the patient's blood. This improves the processes of hematopoiesis, increases the consumption of iron by the bone marrow. Scheme for performing cytopheresis:

1. They create a vicious circle - the patient's veins of both hands are connected through a special apparatus.
2. Blood is taken from one.P
3. It is passed through an apparatus with a centrifuge, a separator, filters, where some of the red blood cells are eliminated.
4. The purified plasma is returned to the patient - injected into a vein in the other arm.

Myelosuppressive therapy with cytostatics

In severe cases of polycythemia, when bloodletting does not give positive results, doctors prescribe drugs that suppress the formation and reproduction of brain cells. Treatment with cytostatics requires ongoing blood tests to monitor the effectiveness of therapy. Indications are factors associated with polycythemic syndrome:

• visceral, vascular complications;
• skin itching;
• splenomegaly;
• thrombocytosis;
• leukocytosis.

Hematologists prescribe drugs based on the results of tests, the clinical picture of the disease. Contraindications for cytostatic therapy is children's age. Drugs used to treat polycythemia:

• Myelobramol;
• Imiphos;
• Cyclophosphamide;
• Alkeran;
• Mielosan;
• Hydroxyurea;
• Cyclophosphamide;
• Mitobronitol;
• Busulfan.

Preparations for the normalization of the aggregate state of the blood

The objectives of treatment for polycythemia: normalization of hematopoiesis, which includes ensuring the liquid state of the blood, its coagulation during bleeding, restoration of the walls of blood vessels. Doctors have a serious choice of drugs so as not to harm the patient. Prescribe medications that help stop bleeding - hemostatics:

• coagulants - Thrombin, Vikasol;
• fibrinolysis inhibitors - Kontrykal, Amben;
• vascular aggregation stimulants - calcium chloride;
• drugs that reduce permeability - Rutin, Adroxon.

Of great importance in the treatment of polycythemia to restore the aggregate state of the blood is the use of antithrombotic agents:

• anticoagulants - Heparin, Hirudin, Phenylin;
• fibrolytics - Streptoliasis, Fibrinolysin;
• antiplatelet agents: platelet - Aspirin (Acetylsalicylic acid), Dipyridamole, Indobrufen; erythrocyte - Reogluman, Reopoliglyukin, Pentoxifylline.

recovery prognosis

What awaits a patient diagnosed with polycythemia? Forecasts depend on the type of disease, timely diagnosis and treatment, causes, and complications. Wakez's disease in its primary form has an unfavorable development scenario. Life expectancy is up to two years, which is associated with the complexity of therapy, high risks of strokes, heart attacks, and thromboembolic consequences. Survival can be increased by using the following treatments:

• local irradiation of the spleen with radioactive phosphorus;
• lifelong bloodletting procedures;
• chemotherapy.

A more favorable prognosis for the secondary form of polycythemia, although the disease may result in nephrosclerosis, myelofibrosis, erythrocyanosis. Although a complete cure is impossible, the patient's life is extended for a significant period - over fifteen years - provided:

• constant monitoring by a hematologist;
• cytostatic treatment;
• regular hemocorrection;
• undergoing chemotherapy;
• elimination of factors provoking the development of the disease;
• treatment of pathologies that caused the disease.

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- chronic hemoblastosis, which is based on unlimited proliferation of all sprouts of myelopoiesis, mainly erythrocyte. Clinically, polycythemia is manifested by cerebral symptoms (heaviness in the head, dizziness, tinnitus), thrombohemorrhagic syndrome (arterial and venous thrombosis, bleeding), microcirculatory disorders (chillness of the extremities, erythromelalgia, hyperemia of the skin and mucous membranes). The main diagnostic information is obtained from the study of peripheral blood and bone marrow. Bloodletting, erythrocytapheresis, and chemotherapy are used to treat polycythemia.

General information

Causes of polycythemia

The development of polycythemia is preceded by mutational changes in the pluripotent stem hematopoietic cell, which gives rise to all three cell lines of the bone marrow. The most frequently detected mutation of the JAK2 tyrosine kinase gene with the replacement of valine by phenylalanine at position 617. Sometimes there is a family incidence of erythremia, for example, among Jews, which may indicate in favor of a genetic correlation.

With polycythemia in the bone marrow, there are 2 types of precursor cells of erythroid hematopoiesis: some of them behave autonomously, their proliferation is not regulated by erythropoietin; others, as expected, are erythropoietin-dependent. It is believed that an autonomous cell population is nothing more than a mutant clone - the main substrate of polycythemia.

Pathogenesis

In the pathogenesis of erythremia, the leading role belongs to enhanced erythropoiesis, which results in absolute erythrocytosis, impaired rheological and blood clotting properties, and myeloid metaplasia of the spleen and liver. High blood viscosity causes a tendency to vascular thrombosis and hypoxic tissue damage, and hypervolemia causes increased blood filling of internal organs. At the end of polycythemia, depletion of hematopoiesis and myelofibrosis are noted.

Classification

In hematology, there are 2 forms of polycythemia - true and relative. Relative polycythemia develops with a normal level of erythrocytes and a decrease in plasma volume. This condition is called stress or false polycythemia and is not considered within the scope of this article.

True polycythemia (erythremia) by origin can be primary and secondary. The primary form is an independent myeloproliferative disease, which is based on the defeat of the myeloid germ of hematopoiesis.

Secondary polycythemia usually develops with an increase in erythropoietin activity; this condition is a compensatory reaction to general hypoxia and can occur with chronic pulmonary pathology, "blue" heart defects, adrenal tumors, hemoglobinopathies, when climbing to a height or smoking, etc. True polycythemia in its development goes through 3 stages: initial, advanced and terminal.

I stage(initial, oligosymptomatic) - lasts about 5 years; asymptomatic or with minimal clinical manifestations. It is characterized by moderate hypervolemia, slight erythrocytosis; the size of the spleen is normal.

II stage(erythremic, expanded) is divided into two substages:

• IA - without myeloid transformation of the spleen. There is erythrocytosis, thrombocytosis, sometimes pancytosis; according to the myelogram - hyperplasia of all hematopoietic sprouts, pronounced megakaryocytosis. The duration of the advanced stage of erythremia is 10-20 years.
• IIB - with the presence of myeloid metaplasia of the spleen. Hypervolemia, hepato- and splenomegaly are expressed; in peripheral blood - pancytosis.

III stage(anemic, posterythremic, terminal). Characterized by anemia, thrombocytopenia, leukopenia, myeloid transformation of the liver and spleen, secondary myelofibrosis. Possible outcomes of polycythemia in other hemoblastoses.

Symptoms of polycythemia

Erythremia develops for a long time, gradually and can be detected by chance during a blood test. Early symptoms, such as heaviness in the head, tinnitus, dizziness, blurred vision, chilliness of the extremities, sleep disturbance, etc., are often "written off" to advanced age or concomitant diseases.

The most characteristic feature of polycythemia is the development of a plethoric syndrome caused by pancytosis and an increase in BCC. Telangiectasia, cherry-red coloration of the skin (especially the face, neck, hands and other open areas) and mucous membranes (lips, tongue), hyperemia of the sclera serve as evidence of plethora. A typical diagnostic sign is Cooperman's symptom - the color of the hard palate remains normal, and the soft palate acquires a stagnant cyanotic hue.

Another distinguishing symptom of polycythemia is pruritus, aggravated after water procedures and sometimes unbearable. Among the specific manifestations of polycythemia is also erythromelalgia - a painful burning sensation in the fingertips, which is accompanied by their hyperemia.

In the advanced stage of erythremia, excruciating migraines, bone pain, cardialgia, arterial hypertension can occur. 80% of patients have moderate or severe splenomegaly; the liver increases a little less often. Many patients with polycythemia notice increased bleeding of the gums, bruising of the skin, prolonged bleeding after tooth extraction.

The consequence of ineffective erythropoiesis in polycythemia is an increase in the synthesis of uric acid and a violation of purine metabolism. This finds clinical expression in the development of the so-called urate diathesis - gout, urolithiasis, renal colic.

Complications

The result of microthrombosis and violation of the trophism of the skin and mucous membranes are trophic ulcers of the lower leg, gastric and duodenal ulcers. The most frequent complications in the clinic of polycythemia are vascular thrombosis of deep veins, mesenteric vessels, portal veins, cerebral and coronary arteries. Thrombotic complications (PE, ischemic stroke, myocardial infarction) are the leading causes of death in patients with polycythemia. At the same time, along with thrombosis, patients with polycythemia are prone to hemorrhagic syndrome with the development of spontaneous bleeding of various localizations (gingival, nasal, from the veins of the esophagus, gastrointestinal, etc.).

Diagnostics

Hematological changes that characterize polycythemia are decisive in the diagnosis. A blood test reveals erythrocytosis (up to 6.5-7.5x10 12 / l), an increase in hemoglobin (up to 180-240 g / l), leukocytosis (over 12x10 9 / l), thrombocytosis (over 400x10 9 / l). The morphology of erythrocytes, as a rule, is not changed; with increased bleeding, microcytosis may be detected. A reliable confirmation of erythremia is an increase in the mass of circulating erythrocytes more than 32-36 ml / kg.

For the study of the bone marrow in polycythemia, it is more informative to carry out not a sternal puncture, but a trepanobiopsy. Histological examination of the biopsy revealed panmyelosis (hyperplasia of all hematopoietic sprouts), in the later stages of polycythemia - secondary myelofibrosis.

To assess the risk of developing complications of erythremia, additional laboratory tests (functional liver tests, general urinalysis) and instrumental studies (ultrasound of the kidneys, ultrasound of the veins of the extremities, echocardiography, ultrasound of the vessels of the head and neck, FGDS, etc.) are carried out. With the threat of thrombohemorrhagic and metabolic disorders, consultations of relevant narrow specialists are necessary: ​​a neurologist, a cardiologist, a gastroenterologist, and a urologist.

Treatment of polycythemia

In order to normalize the volume of BCC and reduce the risk of thrombotic complications, bloodletting is the first measure. Blood exfusions are carried out in a volume of 200-500 ml 2-3 times a week, followed by replenishment of the removed blood volume with saline or rheopolyglucin. The consequence of frequent bloodletting may be the development of iron deficiency anemia. Bloodletting in polycythemia can be successfully replaced by erythrocytepheresis, which allows you to remove only the red blood cell mass from the bloodstream, returning the plasma.

In the case of pronounced clinical and hematological changes, the development of vascular and visceral complications, they resort to myelosuppressive therapy with cytostatics (busulfan, mitobronitol, cyclophosphamide, etc.). Sometimes radioactive phosphorus therapy is performed. To normalize the aggregate state of the blood, heparin, acetylsalicylic acid, dipyridamole are prescribed under the control of a coagulogram; at hemorrhages transfusions of thrombocytes are shown; with urate diathesis - allopurinol.

Forecast

The course of erythremia is progressive; the disease is not prone to spontaneous remissions and spontaneous cure. Patients are forced to be under the supervision of a hematologist for life, undergo courses of hemoexfusion therapy. With polycythemia, the risk of thromboembolic and hemorrhagic complications is high. The incidence of transformation of polycythemia into leukemia is 1% in patients who have not received chemotherapy, and 11-15% in those receiving cytostatic therapy.

Abdulkadyrov K. M., Shuvaev V. A., Martynkevich I. S., Shikhbabaeva D. I.

Federal State Budgetary Institution "Russian Research Institute of Hematology and Transfusiology of the Federal Medical and Biological Agency", St. Petersburg

MODERN CONCEPTS ON THE DIAGNOSIS AND TREATMENT OF POLYCYTHEMIA VERA

Abdulkadyrov K. M., Shuvaev V. A., Martynkevich I. S., Shikhbabaeva D. I.

Russian Research Institution of Hematology and Transfusiology, St-Petersburg, Russian Federation

MODERN CONCEPTS OF DIAGNOSIS AND TREATMENT OF POLYCYTHEMIA VERA

Polycythemia vera (PV) is a rare disease, the number of newly diagnosed cases of which per year is about 1 per 100,000 population. Synonyms previously used to describe this disease: true erythremia, red erythremia, Wakez's disease, etc.

The pathogenesis of PV is based on a defect in the hematopoietic stem cell, followed by a somatic mutation in the Janus kinase cytokine receptor gene, leading to the proliferation of myeloid hematopoietic lineages, more erythrocyte with the risk of developing vascular thrombosis and thromboembolism. Prolonged proliferation of hematopoietic cells leads to fibrosis and replacement of the active bone marrow with collagen fibers - the development of secondary postpolycythemic myelofibrosis. In some patients, further progression of the disease into the phase of blast transformation may occur.

Thanks to the successes achieved in recent years in deciphering the molecular genetic mechanisms of PV, diagnostics has been significantly improved and a new class of drugs with pathogenetic effects has been created.

The article presents a systematized algorithm for the management of patients with polycythemia vera, taking into account the most up-to-date information on advances in diagnosis and treatment, with a description of all stages of diagnosis and therapy.

KEY WORDS: polycythemia vera, algorithm, thrombosis risk prediction scale, ruxolitinib.

Polycythemia vera (PV) - rare disease with incidence about 1 per 100000 inhabitints yearly. Synonyms that had been used for PV previously are Erythremia vera, Red erythremia, Vaquez disease etc.

The PV pathogenesis based on stem cell defect with subsequent somatic mutation in Janus kinase gene of cytokine receptor that led to myeloid cell line proliferation, especially erythroid, with vascular thrombotic and thromboembolic complications risk. Long-term stem cells ptoliferation result to fibrosis and bone marrow substitution with collagen fibers - postpolycythemic myelofibrosis. Some patients can get disease progression with blastic transformation.

Through to recent successes in molecular-genetic PV mechanisms decryption, PV diagnostic had been significantly improved; also new class of drugs with pathogenic action had been developed.

The article contains a thorough PV management algorithm that had been systemized with information of the latest advances in PV diagnostic and treatment.

KEY WORDS: polycythemia vera, algorithm, thrombosis risk scale, ruxolitinib.

INTRODUCTION

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by stem cell damage. The disease is accompanied by a somatic mutation in the Janus kinase (JAK2) gene of cytokine receptors and is manifested by the proliferation of myeloid hematopoietic germ with the possible development of extramedullary hematopoiesis, thrombotic complications and outcome in postpolycythemic myelofibrosis or blast transformation.

Synonyms previously used to describe this disease: true erythremia, red erythremia, Wakez's disease, etc. The most common name is polycythemia vera (PV), which indicates the need for differential diagnosis with secondary erythrocytosis.

For the first time, as an independent disease, PV was described by Louis Henri Vaquez in 1892, who, while studying heart diseases, described a form of cyanosis with constant erythrocytosis. In 1903, William Osler suggested that the cause of the disease in the group of patients described by him is an increase in the activity of the bone marrow. In 1951, William Dameshek singled out a group of myeloproliferative diseases with a similar pathogenesis, including PV, and characterized the classic course of PV with an outcome in myelofibrosis. Since 1967, the Polycythemia Vera Research Group (PVSG) has been organized, which is an international methodological center for the development of diagnostic criteria and systematization of treatment results. The accumulation of data led to the refinement of the criteria for the diagnosis of PV by the expert group of the World Health Organization (WHO) in 2000 and 2008. The discovery in 2005 of the role of the JAK2V617F mutation in the pathogenesis of myeloproliferative neoplasms has led to significant progress in understanding the mechanisms of the development of the disease and the creation of targeted drugs that have already proven their effectiveness and safety in clinical trials.

PV is a rare (orphan) disease. Domestic population epidemiological data on incidence and prevalence are not available. Literature data about

morbidity according to foreign registries is approximately 1-1.9: 100,000 population. Classical ideas about the median age at the onset of the disease of 60-70 years are currently being revised. The discovery of the involvement of molecular genetic damage (mutations in the JAK2 genes) in the pathogenesis of the disease has significantly improved the quality of diagnosis and makes it possible to detect the disease in young patients.

Traditionally, the idea of ​​a more frequent incidence of PV among men compared with women (1.5-2.0: 1) .

When analyzing the ten-year dynamics of incidence, the annual primary incidence of PV in St. Petersburg ranged from 0.5 to 1.15 and averaged 0.83 per 100,000 population per year; median age at diagnosis was 59 years (20 to 86 years); the sex ratio was 145 women and 107 men (1.4:1).

Pathogenetically, PV is a clonal myeloproliferative process that develops as a result of malignant transformation in early hematopoietic progenitors followed by a somatic mutation in the cytokine receptor janus kinase gene. Increased proliferation of myeloid sprouts of hematopoiesis, mostly erythrocyte, gradually leads to the development of foci of extramedullary hematopoiesis (splenomegaly), the risk of vascular thrombosis and thromboembolism. Prolonged proliferation of pathological hematopoietic cells is accompanied by fibrosis and replacement of the active bone marrow with collagen fibers - the development of secondary post-polycythemic myelofibrosis. In some patients, the accumulation of damage in the genome and further progression of the disease ends with a phase of blast transformation.

The determining factor in PV is the detection of a point mutation in the Januskinase gene of the erythropoietin receptor JAK2V617F or other genetic disorders in the 1AK-8TAT signaling pathway (exon 12 of the JAK2 gene, the LIK gene, the BOS genes, etc.).

The overall survival rate for PV is on average about 20 years, thus not leading to a significant limitation in life expectancy in most patients. In young patients (with the onset of the disease

aged less than 50 years) with a median overall survival of 23 years, overall life expectancy is reduced due to the development of thrombosis, progression to myelofibrosis and blast transformation. The main reason leading to disability and a decrease in life expectancy of patients with PV is the tendency to thrombosis and thromboembolism. The probability of developing clinically significant thrombosis is realized in 1.8% - 10.9% of patients per year, depending on risk factors. Moreover, even in young patients, the cumulative risk of developing thrombosis is 14% with a duration of IP of ten years. With a long course of the disease, secondary postpolycythemic myelofibrosis develops in about 0.5% per year. The probability of disease progression to the blast transformation phase is 0.34% per year during the first 5 years of the disease, increasing to 1.1% per year with a disease duration of more than 10 years.

In recent years, significant progress has been made in deciphering the molecular genetic mechanisms of PV development, which has made it possible to create a new class of drugs - Janus kinase inhibitors, which have a pathogenetic effect that has shown good efficacy and safety in clinical trials.

The goal of modern PV therapy is currently the prevention of vascular accidents, containment of the progression of the disease and relief of its symptoms with an improvement in the quality of life of patients.

Accurate and timely diagnosis and regular monitoring of treatment using clinical, morphological and molecular genetic research methods is a condition for correct prediction of the course of the disease and achievement of maximum therapy efficiency.

When writing this work, the results of research by domestic and foreign authors were used. We summarized our own experience in the diagnosis and treatment of 252 patients with polycythemia vera observed at the Russian Research Institute of Hematology and Transfusiology.

This work presents an algorithm for the diagnosis and treatment of patients with PV, based on our own many years of experience in managing patients with PV, the latest recommendations of WHO and the European Organization for the Treatment of Leukemia (ELN) . It also highlights issues related to the adequate use of various methods of PV treatment in order to improve the quality of life of patients, increase life expectancy, and their social and labor rehabilitation.

ETIOLOGY AND PATHOGENESIS

The cause of PI is currently unknown. The most likely is the complex genesis of the disease, when the predisposition to the disease is realized under the influence of external factors affecting the intact genome and leading to cell malignancy. Hereditary predisposition to the disease may occur in the presence of relatives of patients with chronic myeloproliferative neoplasms (CMN). The relative risk of developing PV in relatives of patients with CKD is 5.7 (95% CI 3.5-9.1) and may be associated with the carriage of the 46/1 ha-plotype of the JAK2 gene. One of the key moments in the pathogenesis of PV is considered to be the activation of the 1AK-8TAT signaling pathway, due to the presence of a mutation in the JAK2 cytokine receptor janus kinase gene at position 617, leading to the replacement of phenylalanine by valine - JAK2V617F

Or, more rarely, in exon 12 of JAK2, even more rarely, activation of the JAKSTAT signaling pathway is observed, associated with a loss of inhibition of janus kinase phosphorylation due to a mutation in the LNK gene of the SH2B3 protein, between codons 208 and 234, or mutations in the genes of the SOC cytokine signal suppressor family, most commonly SOC3 or hypermethylation of CpG regions in the SOC1 and SOC3 genes. Subsequently, mutations in other genes can also join: EZH2 and TET2, which include epigenetic mechanisms.

At present, there is no clear explanation for the development of various nosological forms upon activation of the same JAK-STAT signaling pathway: polycythemia vera (PV), primary myelofibrosis (PMF), or essential thrombocythemia (ET). To explain this phenomenon, several pathogenetic hypotheses have been proposed:

Carriers of mutations - various stem cells in various diseases;

The different level of activity of the mutant JAK2V617F determines a special disease phenotype - the mutation load theory;

The specific genotype of the patient is a hereditary predisposition;

Molecular events preceding the occurrence of a mutation in the 1AK2 gene;

The contribution of non-mutational factors - epigenetic mechanisms, pathological miRNA expression, etc. .

Primary genomic damage leading to malignancy in PV is unknown, although the vast majority (95%) of patients with PV have a JAK2V617F point mutation in the signal transducer kinase (JAK2) gene from cytokine receptors or more rarely in exon 12 of JAK2 (4%) . These mutations, although they are specific for PV, have a secondary genesis in the chain of genetic events.

Nam-kinase is a member of the family of non-receptor tyrosine kinases. The mutation causes a substitution of 1849 nucleotide O^T, which

For the first time in evolutionary terms, kinases appear in primitive chordates. In mammals, the family of kinase kinases is represented by four proteins: 1AK1, 1AK2, 1AK3, and TYK2. At present, the JAK2V617F mutation has been described not only in PV, but also in other myeloid neoplasms. However, she never

in turn, leads to the replacement of phenylalanine in exon 14 of the JAK2 gene with valine at codon 617. The molecules contain about 1100 amino acids with a total mass of 120–140 kDa (Fig. 1). Structurally, they consist of seven homologous regions forming four domains: kinase (JH1), pseudokinase (JH2), oncoprotein Sarc homology domain (SH2), FERM domain. The first domain (JH1) from the carbohydrate end of the molecule is a typical tyrosine kinase with catalytic activity and is very similar to the catalytic domain of epidermal growth factor tyrosine kinases, the next domain (JH2) is structurally similar to the tyrosine kinase domain, but lacks catalytic activity and performs regulatory functions of activity. This feature in the form of two similar sections gave the name to the whole family, dedicated to the ancient Roman god Janus, who had two faces. The SH2 domain facilitates the binding of other proteins to JAK, the FERM domain, located at the amino acid end of the molecule, interacts with transmembrane receptor proteins for some cytokines, regulating the activity of JAK kinase.

Carboxyl terminus

was not determined in patients with tumors of the lymphatic tissue, epithelial tumors and sarcomas. Localization of genes encoding the corresponding proteins and participation in the signaling pathways of specific cytokines are shown in Table. one.

Figure 1. Structure of JAK2 and location of point mutations causing its independent gene activation.

Table 1.

Gene localization and cytokine signaling pathways involving Janus kinases

Janus kinase name Gene localization (chromosome/arm/site) Cytokines interacting with Janus kinase

JAK1 1p31.3 IL-1, IL-4, IL-6, IL-7, IL-9, IL-11, IL-15, IL-21, oncostatin M, leukemia inhibitory factor (LIF), ciliary neutrotrophic factor ( CNF), G-CSF, interferons

JAK2 9p24 IL-3, IL-6, IL-11, oncostatin M, leukemia inhibitory factor (LIF), ciliary neutrotrophic factor (CNF), interferon-gamma hormone-like cytokines (erythropoietin, growth hormone, prolactin, thrombopoietin)

JAK3 19p13.1 IL-1, IL-4, IL-7, IL-9, IL-15, IL-21

TYK2 19p13.2 IL-12, bacterial lipopolysaccharides

At the cellular level, kinase kinases are located in the cytosol and are localized near endosomes and the cell membrane near cytokine receptors. Proteins of the linn-kinase family are involved in the regulation of many processes. One of the most significant is the transmission of a cytokine signal to the nucleus to stimulate proliferation through the 1AK-8TAT signaling pathway, schematically shown in Fig. 2. When a cytokine receptor is activated, its conformational structure changes, which causes auto- and/or transphosphorylation of two 1AK kinases. In turn, kinase kinases phosphorylate the intracellular part of the cytokine receptor. 8TAT proteins bind to phosphorylated portions of cytokine receptors, and are also phosphorylated by kinase kinases. The binding of 8TAT proteins to phosphorus allows them to form active dimers, which, penetrating into the nucleus, regulate gene expression. It is assumed that it is this pathway that underlies the signal transduction from cytokine receptors via 1AK2-kinase in myelopoiesis precursor cells and determines the general pathogenesis of chronic myeloproliferative neoplasms. One of the key moments of pathogenesis is often the occurrence of a point mutation in the 1849 position of the JAK2 gene in the form of a replacement of guanine for thymine, resulting in the transformation of phenylalanine to valine in codon 617 of the regulatory domain III2 of the pseudokinase of the IAK2 protein. This leads to independent activation of Janus kinase and second messenger phosphorylation in the absence of receptor stimulation. These changes lead to the activation

1AK-8TAT signaling pathway and increased myeloid proliferation.

The JAK2V617F mutation is found in pluripotent stem cells, which are common precursors of myelo- and lymphopoiesis; however, activation of proliferation via the 1AK-8TAT signaling pathway requires co-expression with type I cytokine receptors: erythropoietin, granulocyte colony-stimulating factor, and thrombopoietin. This fact is an explanation for the fact that in the presence of JAK2V617F, isolated myeloid hyperplasia occurs in the absence of changes in lymphopoiesis, despite the presence of the same JAK2 gene mutation in lymphoid cells.

When comparing the characteristics of JAK2V617F-mutant clones in patients with polycythemia vera (PV), primary myelofibrosis (PMF) and ET, it was found that the frequency of homozygous carriage of JAK2V617F mutations was 30% in PV and PMF compared with 2-4% in ET. At the same time, the frequency of heterozygotes for JAK2V617F, according to another study, is 67.8% in IP and 57.6% in ET. When studying the allelic load of JAK2V617F by real-time quantitative PCR in the group of patients with chronic myeloproliferative neoplasms (CMN), it turned out that the highest load in patients with PV (48±26%), intermediate in PMF (72±24%), the lowest in ET (26 ±15%) . The results obtained formed the basis of the theory of "mutation load" in the development of CKD: the different phenotype of the nosological variant of CKD: PI, PMF or ET is caused by a different degree of allelic

loading JAK2V617F and, as a result, different activation of the 1AK-8TAT signaling pathway.

Mutations in the genes EZH2 (the gene for the catalytic unit of histone methyltransferase) and TET2 (the TET enzyme is involved in the conversion of 5-methylcytosine to 5-hydroxymethylcytosine), accompanying JAK2 mutations in PV in 3% and 16% of cases, respectively, introduce epigenetic disturbances in the regulation of transcription . The addition of these and other mutations (ASXL1, CBL, GON1/2, IKZF1, etc.) that transform the course of the disease can lead to blast transformation (Fig. 5). The morphological substrate of the disease (blasts) in different variants of blast crisis after transformation may or may not contain JAK2 gene mutations. Hyperplasia of hematopoiesis in PV may be accompanied by abnormal production of cytokines, leading to secondary inflammation and changes in the bone stroma.

leg brain. The cytokines involved in this mechanism are transforming growth factor myeloid progenitor beta (TGF-P), platelet-derived growth factor (PDGFR), and endothelial vascular growth factor (VEGF), which can lead to the development of secondary myelofibrosis, osteosclerosis, and angiogenesis. Pathological production of cytokines, chemokines, and metalloproteinases may be involved in the perverse intercellular interaction of neutrophils, monocytes, and megakaryocytes, leading to the release of CD34+ myeloid precursors and endothelial cells into the peripheral blood with the development of foci of extramedullary hematopoiesis, primarily myeloid metaplasia of the spleen. The result of the long-term influence of these changes may be the transition of the disease to the phase of post-polycythemic myelofibrosis.

Figure 2. Schematic of the JAK-STAT signaling pathway.

Figure 3. Molecular genetic pathogenesis of CKD (adapted to PI).

Molecular genetic events in IP lead to activation of the JAK-STAT signaling pathway, independent of the influence of external stimuli, manifested by the proliferation of myeloid lineages (erythrocyte, granulocytic, megakaryocytic). The result of this is an increase in the number of erythrocytes, granulocytes, platelets, hemoglobin levels in peripheral blood, which leads to thickening of the blood and increases the risk of thrombosis and bleeding. The most significant factors in the pathogenesis of thrombosis in PV are the following: erythrocytosis, thrombocytosis, violations of the structure and function of platelets, activation of leukocytes.

The relationship between erythrocytosis and an increase in hematocrit with the risk of thrombosis is not so clear. Under in vitro conditions, hematocrit has been shown to be the main determinant of blood viscosity. However, in vivo, blood flow velocity and arterial oxygen saturation are essential. With increased hematocrit, as expected, the blood flow velocity in the vessels of the brain is reduced; with IP, this is associated not only with increased blood viscosity, but also with a reduced blood flow velocity of the cerebral vessels, in accordance with increased oxygen tension. For example, in pulmonary diseases and hypoxia, the vessels are dilated due to hypercapnia and, as a result, cerebral blood flow is less reduced than with PI. moving

erythrocytes in the vessel occurs along the axis of blood flow with platelet displacement into the plasma parietal zone with the maximum effect of lateral hemodynamic pressure. With an increase in hematocrit, the plasma zone of blood flow narrows, which leads to more platelet interactions with both the endothelium and other blood cells. The greatest lateral hemodynamic pressure, comparable to the axial one, is observed in arterioles and capillaries, while in the venous system it is much lower. At high lateral pressure, platelet receptors change, which leads to increased binding of glycoprotein Ib receptors to von Willebrand factor and, after platelet activation, to the glycoprotein IIb / IIIA receptor. With a high hematocrit and a small size of the plasma zone, an increased interaction of activated platelets with each other leads to thrombosis against the background of previous vascular pathology.

The platelet count itself does not have a direct statistically significant correlation with the incidence of thrombosis.

However, in patients at high risk, reducing platelet levels below 400 x 109/L with drug therapy may lead to a decrease in the incidence of thrombosis. However, it remains unclear whether this is due only to a decrease in platelet levels or to myelosuppression.

To assess the qualitative and structural changes in platelets in PV, studies of platelet aggregation are most often performed in routine clinical practice. Unfortunately, despite the frequent deviations of the results of these studies (decrease or increase in aggregation), the clinical correlation of these results with the risk of thrombosis or bleeding is insignificant. Most often, there is a decrease in primary or secondary aggregation with adrenaline and / or ADP, a reduced response to collagen, although aggregation with arachidonic acid remains intact. Spontaneous platelet aggregation may also be observed. Deficiency of accumulation granules is a characteristic feature of platelets in all CKD. The difference in hereditary deficiency is that the cause of the deficiency is not due to a decrease in production, but due to increased consumption - degranulation as a result of constant activation of platelets. Signs of platelet activation in CKD are an increase in the concentration of arachidonic acid metabolites in plasma and urine, alpha-granule proteins and activation markers on the platelet membrane (p-selectin, thrombospondin, fibrinogen receptors, glycoprotein IIb / IIIa). Disruption of the metabolism of arachidonic acid in CKD leads to a constant increase in the concentration of thromboxane A2, which is a powerful vasoconstrictor and stimulator of platelet aggregation. This is confirmed by the effectiveness of the use of small doses of acetylsalicylic acid, which reduce the clinical manifestations of microcirculation disorders and the risk of thrombosis in PV. With chronic MPN, multiple disorders in the expression of proteins and receptors on the platelet membrane are also observed: a decrease in the number of adrenergic receptors, glycoproteins Ib and IIb / IIIa, while the expression of glycoprotein IV is increased, especially in patients who have undergone thrombosis.

The role of abnormal leukocyte clone activation in the pathogenesis of thrombosis in PV has been empirically proven to reduce the risk of thrombosis.

when using myelosuppressive agents. Studies have shown frequent neutrophil activation in PV, evidenced by high levels of markers of endothelial injury and clotting activation. Also, with IP, a greater number of circulating aggregates of leukocytes and platelets were found compared with the control. The number of these aggregates correlated with the level of platelets, the percentage of platelets positive for p-selectin and thrombospondin, and the expression of glycoprotein IV. The presence of microcirculation disorders or thrombosis is also associated with a higher number of leukocyte-platelet aggregates.

In the pathogenesis of bleeding in PV, there is a combination of causes: violations of the structure and function of platelets and acquired secondary von Willebrand syndrome. Disturbances in the structure and function of platelets, caused by the proliferation of a pathological clone of transformed cells in PV, most often manifest themselves in a change in the absolute amount and relative ratio of the expression of proteins and receptors on the membrane, as well as a deficiency of accumulation granules associated with their depletion against the background of permanent platelet activation. The causes of secondary von Willebrand syndrome are a decrease in the concentration of von Willebrand factor, due to its binding to an excess number of platelets. A relationship has been established between platelet levels and a decrease in large von Willebrand factor multimers, which is a more accurate indicator than the measurement of its antigen or the level of the eighth factor

Despite the different causes, the clinical manifestations of the secondary syndrome are similar to those of von Willebrand disease. Secondary von Willebrand syndrome is also seen in reactive hyperthrombocytosis.

The leading role of hyperthrombocytosis in the pathogenesis of secondary von Willebrand syndrome, both in CKD and in reactive states, is confirmed by the relief of its manifestations during cytoreductive therapy.

CLINICAL MANIFESTATIONS

Some patients, especially in the initial stages of the disease, may not have any complaints. The main symptoms of PV are associated with manifestations of plethora (plethora) and disorders

blood circulation (disorders of microcirculation and thrombosis). The most common complaints of 252 patients observed in RosNI-IGT are given in Table. 2.

table 2

Clinical manifestations of polycythemia vera at the time of diagnosis of the disease

Symptom Frequency, % of the total number of patients (n) (n=252)

Plethora 85% (215)

Headaches 60% (151)

Weakness 27%(68)

Skin itching 21% (55)

Joint pain 7% (18)

Erythromelalgia 5% (13)

Thrombosis 11%(28)

Asymptomatic 3% (8)

The most common symptoms of the disease:

Expansion of the saphenous veins and changes in skin color. The characteristic shade of the skin and mucous membranes occurs due to the overflow of superficial vessels with blood and a slowdown in the rate of its flow. As a result, most of the hemoglobin has time to go into the reduced form. On the skin of the patient, especially in the neck, protruding, dilated swollen veins are clearly visible. With polycythemia, the skin has a red-cherry color, especially pronounced on open parts of the body - on the face, neck, hands. The tongue and lips are bluish-red in color, the eyes are as if bloodshot (the conjunctiva of the eyes is hyperemic). Changed the color of the soft palate while maintaining the normal color of the hard palate (Kuperman's symptom).

Headache, impaired concentration, dizziness, weakness are manifestations of microcirculation disorders in cerebrovascular vessels. Deterioration of blood circulation in the organs leads to complaints of patients about fatigue, headache, dizziness, tinnitus, flushing of blood to the head, fatigue, shortness of breath, flies before the eyes, blurred vision. Patients may notice their increase in hot weather, during physical exertion - conditions leading to dehydration. A positive effect is noted when drinking water (for which patients often carry it with them), acetylsalicylic acid.

An increase in blood pressure is a compensatory reaction of the vascular bed

to increase blood viscosity. There is a manifestation or worsening of the course of a previous cardiac pathology (hypertension, coronary heart disease). The rate of progression of heart failure and cardiosclerosis increase.

Skin itching. Itching of the skin is observed in a significant proportion of patients and is a characteristic feature of PV. Itching is worse after bathing in warm water, which is thought to be related to the release of histamine, serotonin, and prostaglandins.

Erythromelalgia - unbearable burning pain in the tips of the fingers and toes, accompanied by reddening of the skin and the appearance of purple cyanotic spots. The occurrence of erythromelagia is explained by a violation of microcirculation against the background of increased hematocrit and platelet count and, as a result, the appearance of microthrombi in the capillaries. This assumption is confirmed by the good effect of the use of acetylsalicylic acid.

Arthralgia - up to 20% of patients complain of persistent pain in the joints. Joint pain may be due to impaired microcirculation due to an increase in blood viscosity, but can also be a symptom of secondary gout. An increase in the level of uric acid in IP occurs as a result of the destruction of an excess amount of cell mass, and as a result, an increase in the exchange of purine bases - DNA degradation products.

The resulting hyperuricemia can manifest a typical clinical picture of gout - joint pain with arthritis, urolithiasis, extra-articular deposition of uric acid (tophi).

Pain in the lower limbs. Patients with PV may complain of persistent pain in the legs, the cause of which is vascular insufficiency against the background of an increase in blood viscosity and a decrease in blood flow velocity, worsening of the course of concomitant vascular diseases of the lower extremities (varicose veins, obliterating endarteritis, etc.) against the background of PV.

Splenomegaly and hepatomegaly, manifested by heaviness in the hypochondrium, rapid satiety after eating, are a common symptom of PV. In contrast to liver disease, the spleen in PV is significantly more enlarged than the liver. In the initial phase of the disease, an increase in the liver and spleen is due to excessive blood supply. Subsequently, with the development of foci of extramedullary hematopoiesis (myeloid metaplasia), the severity of splenomegaly progressively increases.

Development of ulcers in the duodenum and stomach. In 10-15% of patients, ulcers of the duodenum, less often of the stomach, may be observed, which is associated with thrombosis of small vessels and trophic disorders in the mucous membrane, leading to a decrease in the strength of the mucous barrier and the penetration of Helicobacter pylori.

The occurrence of blood clots in the vessels. During the first years of the disease, the main risks in PV are thrombosis and thromboembolism against the background of existing cardiovascular pathology and atherosclerosis. Previously, vascular thrombosis and embolism were the main causes of death in PV. Patients have a tendency to form blood clots due to increased

blood viscosity, thrombocytosis and changes in the vascular wall. This leads to circulatory disorders in the veins of the lower extremities, cerebral, coronary and splenic vessels. Leukocytosis and thrombocytosis can lead to microcirculation disorders and the development of thrombosis. The occurrence of thrombosis in PV is always the result of the interaction of disease manifestations and multiple risk factors for thrombosis (Fig. 4). Factors contributing to the development of thrombosis can be divided into two groups:

Factors caused by the disease: thrombocytosis, leukocytosis, activation of leukocytes and platelets, interaction between leukocytes and platelets, biochemical and functional abnormalities in platelets, activation of blood coagulation factors, the presence of JAK2V617F mutations and high allelic load;

Individual patient factors: age, history of thrombosis, risk of developing cardiovascular complications, hereditary genetic factors (thrombophilia).

Despite the decrease in the activity of stimulated platelet aggregation in IP, there is a significant increase in their number, which causes their multiple interaction with each other and leukocytes, which leads to spontaneous aggregation. When the diagnosis is established, the presence of thrombosis is noted in 12-39% of patients with PV. Subsequently, against the background of the course of PV, thrombosis develops in another 10.3% -25% of patients. The probability of developing clinically significant thrombosis ranges from 1.8% to 10.9% of patients per year, depending on risk factors. Moreover, even in young patients, the cumulative risk of thrombosis is 14% with a duration of IP of ten years. At the same time, the proportion of deaths in patients with PV with thrombosis ranges from 11% to 70%.

Figure 4. Risk factors for thrombosis in PV.

In PV, arterial thrombosis occurs more frequently than venous thrombosis. Compared with essential thrombocythemia (ET), thrombosis in PV occurs more often in the cerebrovascular system, coronary or abdominal vessels, while microcirculatory disorders occur more often in ET. Thrombosis of large vessels, which are the leading causes of disability and death, is distributed according to a decrease in the frequency of occurrence as follows: the most common disorders occur in the cerebrovascular system (strokes and transient ischemic attacks), then myocardial infarction and occlusion of peripheral arteries. Most venous thrombosis in PV occurs in the venous systems of the lower extremities or lungs. Also, compared with the population with PV, in the structure of venous thrombosis, thrombosis of the abdominal vessels (portal and hepatic veins) occurs much more often (up to 10%), the symptoms of which are difficult to diagnose, especially when this thrombosis is the first clinical manifestation of undiagnosed PV.

In the group of patients with thrombosis of the portal and hepatic veins without an obvious previous cause, CKD as the cause of thrombosis is detected in 31-53% of patients, while this occurs more often in young patients. In the absence of an obvious cause (carcinoma or cirrhosis of the liver) of abdominal vein thrombosis, a screening test for the JAK2V617F mutation is necessary.

Age is a proven risk factor for thrombosis. Time frequency

of thrombosis in patients with PV younger than 40 years old is 1.8% per year, at the age of over 70 years it rises to 5.1% per year. .6 times higher than in patients younger than 60 years. The presence of a history of thrombosis is an independent prognostic factor for the development of thrombosis recurrence and, together with age, determines the indications for starting cytoreductive therapy. In patients with PV who had a history of thrombosis, their recurrence developed in 26.5% of cases, while for the first time thrombosis occurred only in 17.3% of patients. The combination of a history of thrombosis and age over 60 increases the risk of developing thrombosis to 17.3.

The presence of risk factors for cardiovascular disease (smoking, diabetes, signs of heart failure) also has a statistically significant effect on the likelihood of thrombosis in PV. Hereditary and acquired thrombophilic conditions as risk factors for thrombosis in PV have been extensively studied in recent years. The influence of natural anticoagulants (antithrombin, protein C, protein 8) was studied; polymorphism in the genes of factor V, prothrombin, methylenetetrahydrofolate reductase; acquired conditions (anti-cardiolipin antibodies (lupus anticoagulant), homocysteine, etc.). It was shown that in patients with venous thrombosis, factor V Leiden mutation was detected significantly more often (in 16%) than in patients without thrombosis (in 3%). The frequency of carrying this mutation also correlated with the number of thromboses: 3.6% in patients without thrombosis, 6.9% in patients with one episode of thrombosis, and 18.1% in patients with recurrent thrombosis. Several studies have shown that patients with CKD have elevated levels of homocysteine. However, an association between arterial thrombosis and elevated homocysteine ​​has only been shown in one study.

Bleeding. Along with increased blood clotting and thrombosis in PV, 1.7-20% of patients may experience bleeding from the gums and dilated veins of the esophagus. Hemorrhagic syndrome can be the cause of death from 3.1 to 11% of deaths in PV. At the same time, if over the past years, due to the expansion of therapeutic options, mortality in PV from thrombosis has been gradually

but decreases, then the mortality associated with bleeding remains stable. The probability of massive bleeding and death is 0.8% and 0.15% per year, respectively. Hemorrhagic syndrome in IP affects primarily the skin and mucous membranes and can manifest itself in the form of ecchymosis, nasal and gingival bleeding, menorrhagia. Gastrointestinal bleeding is often associated with the intake of acetylsalicylic acid, occurs less frequently, but is massive and requires hospitalization and transfusion of blood components. This type of bleeding is associated with quantitative or qualitative defects in platelets as a result of the proliferation of a defective clone and / or secondary von Willebrand syndrome. Although hemorrhagic syndrome in PV is observed with significant hyperthrombocytosis, a direct correlation

between the number of platelets and the risk of bleeding is absent. In some cases, bleeding in PV is associated with thrombotic complications, varicose veins in portal hypertension. Also, hemorrhagic syndrome can also be caused by the use of antiplatelet agents and anticoagulants.

The most common clinical manifestations in 252 patients with PV diagnosed at RosNIIGT were: plethora (85%), headache and dizziness (60%), weakness (27%), pruritus (21%), joint pain (7%), erythromelalgia (5%) (Table 2). Thrombotic complications in the study group of patients were registered in 11.1% of patients (16 arterial and 13 venous thromboses). Myocardial infarctions were observed in 3.6% of patients and acute cerebrovascular accidents in 5.2% of patients. Bleeding of varying intensity was observed in 2.4% of patients.

MORPHOLOGICAL AND LABORATORY MANIFESTATIONS

At the onset of the disease in the clinical analysis of blood, the number of erythrocytes and the level of hemoglobin are moderately increased with normal levels of leukocytes and platelets. When analyzing our own experience, isolated erythrocytosis was observed in 19.0% of patients with PV. The level of hemoglobin at the onset of PI, more often in women, may remain within the normal range, being masked by concomitant iron deficiency. We observed this situation in 3.2% of patients with PV.

In the future, the mass of circulating erythrocytes progressively increases (the number of erythrocytes, the level of hemoglobin and hematocrit increase). In the blood, due to an increase in the number of leukocytes, the concentration of transcobalamin-1 contained in them, associated with vitamin B12, increases. In the bone marrow, there is a change in the ratio of active and fatty bone marrow towards the expansion of all the sprouts of myeloid hematopoiesis. When studying the colony-forming ability of myelokaryocytes, spontaneous growth of cell colonies in the medium without the addition of growth factors is observed - the implementation of independent activation of the JAK-STAT signaling pathway of cell proliferation. On cytochemical examination, the level of activity of alkaline phosphatase of neutrophils is normal. Acute phase parameters (fibrinogen,

C-reactive protein, etc.) and LDH, as a rule, remain within normal values. Coagulogram indicators can often indicate plasma hypocoagulation - a decrease in fibrinogen, the level of von Willebrand factor, which can be both compensatory in nature and be due to the sorption of plasma coagulation factors on platelets in the vascular bed. Instrumental research methods (doppler ultrasound, computed and magnetic resonance imaging, scintigraphy) may indicate the consequences of past thrombosis and thromboembolism, some of which may occur subclinically. With the subsequent development of the disease in the peripheral blood, the number of leukocytes increases due to neutrophils with a gradually increasing shift to the left, thrombocytosis increases, ESR slows down. In the bone marrow, total three-growth hyperplasia is panmyelosis. The size of the spleen and liver increases, initially due to the accumulation of excess cell mass, and then due to their myeloid metaplasia.

With the development of foci of extramedullary hematopoiesis, immature cells of the granulocytic series, erythroblasts appear in the peripheral blood; CD34-positive cells are detected during immunophenotyping.

The development of reticulin and collagen fibrosis of the bone marrow leads to the transition of the disease to the stage of postpolycythemic myelofibrosis. In the blood test, the hemoglobin level drops to normal, and then anemia develops. The level of leukocytes can increase or, conversely, decrease, while in the leukocyte formula, a shift to the left increases until blast forms appear. The number of platelets can also increase, but subsequently they decrease with the development of thrombocytopenia and the risk of hemorrhagic complications. The level of LDH increases as a marker of tumor progression. A change in the secretion profile of cytokines leads to an increase in their pro-inflammatory fraction (tumor necrosis factor alpha, interleukin-6, etc.) with the appearance of symptoms of tumor intoxication. The severity of hepatosplenomegaly increases with the formation of portal hypertension with its clinical and laboratory manifestations - hepatorenal insufficiency.

In PV, no specific cytogenetic markers were found, chromosomal abnormalities are detected in a small proportion of patients. The most frequently detected deletion of the long arm of chromosome 20, trisomy 9 chromosomes. With the transition of IP to the stage of postpolycythemic myelofibrosis, the frequency of karyotype aberrations increases - partial or complete trisomy of the long arm of chromosome 1 is detected in 70% of patients, while genetic material can form it 1, 6, 7, 9, 13, 14 , 15, 16, 19 and Y chromosomes. It is assumed that these changes are related to the leukemic effect of long-term exposure to cytostatics.

Molecular genetic markers are highly specific for PV: the JAK2V617F mutation is detected in 95% of patients with PV, more rarely (4%) there are mutations in exon 12

the JAK2 gene. In rare cases, mutations in the LNK gene of the 8H2B3 protein, between codons 208 and 234, or mutations in the genes of the BOS cytokine signal suppressor family, most often BOS3 or hypermethylation of CpG regions in the BOS1 and BOS3 genes, are observed. With the progression of the disease and the formation of postpolycythemic myelofibrosis, mutations in other genes may appear: EZH2 in 3% and TET2 in 16% of patients, including epigenetic mechanisms.

A typical histological picture of the bone marrow in PV is the proliferation of all three myeloid lines with a significant increase in the number of megakaryocytes. Immunohistochemical staining reveals acidophilic-stained neutropoiesis cells, basophilic nucleated erythropoiesis precursors, and scattered clusters of megakaryocytes of various sizes. With the development of postpolycythemic myelofibrosis, there is a decrease in cellularity with a few scattered islets of erythropoiesis, pathological megakaryocytes, and a significant expansion of the structures of the bone marrow stroma. Specific staining shows the formation of bundles of collagen and reticulin with the formation of osteosclerosis and single scattered megakaryocytes (Fig. 5).

One of the main methods for diagnosing CKD is histological assessment of the degree of fibrosis in the bone marrow according to the standard scale of the European Consensus of Pathologists for assessing bone marrow cellularity and fibrosis. Micrographs of the bone marrow corresponding to different degrees of the scale are shown in Fig. 6. In the chronic phase of PV, in contrast to postpolycythemic myelofibrosis and PMF, the degree of fibrosis should not exceed MB-1.

Figure 5 Bone marrow micrographs in polycythemia vera (A, B—chronic phase PV; C, D—postpolycythemic myelofibrosis).

MF-0 sparse reticulin fibers without intersections, corresponding to normal bone marrow;

MF-1 loose reticulin network with many intersections, especially in the perivascular zones;

MF-2 diffuse increase in reticulin density with redundant intersections

Figure 6. Micrographs of bone marrow, European consensus (A - N¥-0; B

occasionally with focal collagen formations and / or focal osteosclerosis;

MF-3 Diffuse increase in reticulin density with redundant intersections with collagen bundles, often associated with significant osteosclerosis.

corresponding to various degrees of the scale > - W-1; B - Sh-2; G - W-3).

CLASSIFICATION OF POLYCYTHEMIA VERIS

In domestic hematology, there are four clinical stages of PV development associated with the pathogenesis of the disease.

I stage - initial. At this stage, bone marrow hyperplasia occurs without the presence of any signs of fibrosis, in the peripheral blood there is mainly an increase in the mass of circulating erythrocytes. Clinical manifestations - plethora, acrocyanosis, erythromelalgia, itching of the skin after water procedures (washing hands, shower, bath). An increase in blood viscosity leads to an increase in blood pressure - a worsening of the course of hypertension with a decrease in the effectiveness of antihypertensive drugs or the occurrence of symptomatic arterial hypertension. The course of coronary heart disease, cerebrovascular disease and other pathological conditions associated with impaired microcirculation is also aggravated. The reason for examination by a hematologist at this stage is often an increase in the level of hemoglobin and the number of red blood cells in a clinical blood test performed for other diseases, or a preventive examination.

Stage 11A - erythremic (deployed) without myeloid metaplasia of the spleen. In the peripheral blood, in addition to erythrocytosis, significant neutrophilia is observed, sometimes with a shift in the leukoformula to single myelocytes, basophilia, and thrombocytosis. In the bone marrow, there is total hyperplasia of all three myeloid sprouts with pronounced megakaryocytosis; there may be initial reticulin fibrosis. At this stage, there are no foci of extramedullary hematopoiesis, and hepatosplenomegaly is due to the sequestration of excess cell mass. Due to more pronounced deviations of blood parameters, the frequency of thrombosis is greater, and their nature is more severe compared to the previous stage. Often, the diagnosis of PV at this stage is established after thrombotic complications have occurred.

Stage II B - erythremic (deployed) with myeloid metaplasia of the spleen. At this stage, foci of extramedullary hematopoiesis appear in the liver and spleen, their progressive increase occurs against the background of stable peripheral blood parameters or even a slight decrease in the amount

erythrocytes and platelets as a result of secondary hypersplenism. In the leukocyte formula, the shift to the left gradually increases and the proportion of immature cells of the granulocytic series increases. In the bone marrow, fibrosis grows to pronounced reticulin and foci of collagen fibrosis. A gradual decrease in blood counts, regardless of the influence of drugs, indicates a transition to stage III of PV.

Stage III - postpolycythemic myelofibrosis (anemic). In the bone marrow, collagen fibrosis increases with the development of osteosclerosis. Depression of myelopoiesis leads to a progressive decrease in hemoglobin, leukopenia, and thrombocytopenia. The clinical picture is dominated by anemic, hemorrhagic syndromes, infectious complications, symptoms of tumor intoxication are added.

Another option for the outcome of PV is blast transformation of the disease and the development of a blast crisis. The use of chemotherapy drugs as a restraining therapy, according to some authors, may increase the risk of this transformation. A blast crisis in PV can either develop de novo or after the development of secondary myelodysplastic syndrome.

With a long course of the disease, an outcome may occur in secondary post-polycythemic myelofibrosis. The probability of disease progression to the blast transformation phase is 0.34% per year during the first 5 years of the disease, increasing to 1.1% per year with a disease duration of more than 10 years. In patients with PV observed at RosNIIGT, the incidence of postpolycythemic myelofibrosis was 5.7% over 10 years.

DIAGNOSTICS OF POLYCYTHEMIA VERA

The diagnosis of PV is based on the presence of:

Complaints about discoloration of the skin and mucous membranes, dilatation of the saphenous veins, burning sensation, paresthesia in the fingers and toes, skin itching after taking water procedures, headaches, increased blood pressure, pain in the joints and lower extremities, feelings of heaviness in the left and right hypochondria , bleeding with minimal trauma, extraction of teeth;

Anamnestic data: a gradual increase in the level of erythrocytes and hemoglobin, leukocytes, platelets in blood tests for several years, past thrombosis, especially unusual localizations in young people, recurrent peptic ulcer, hemorrhagic syndrome with minimal surgical intervention or extraction of teeth;

The results of clinical and laboratory studies: persistent erythrocytosis, leukocytosis, thrombocytosis, expansion of the myeloid germ with hyperplasia of megakaryocytes in the myelogram and histological examination of the bone marrow, detection of the JAK2V617F point mutation or

ethin, the absence of causes of secondary erythrocytosis.

A reliable diagnosis of the disease can only be established with a full examination, the parameters of which are presented below. Of particular difficulty is the differential diagnosis between true polycythemia and the prefibrotic stage of primary myelofibrosis, secondary erythrocytosis in other diseases and hereditary (family) conditions.

Required research:

Primary appointment-examination of a hematologist with the collection of complaints, anamnesis (symptoms of tumor intoxication), examination of the objective status of the patient with the obligatory determination of the size of the liver and spleen;

General (clinical) blood test, expanded with a visual examination of a smear for the morphological characteristics of a myeloid germ (impaired maturation of neutrophils with a shift in the formula to the left, pathology of the size and shape of platelets, erythrocytes, the presence of intracellular inclusions, normoblasts);

Biochemical blood markers: total bilirubin, AST, ALT, LDH, uric acid

lota, urea, creatinine, total protein, albumin, LDH, alkaline phosphatase, electrolytes (potassium, sodium, calcium, phosphorus), serum iron, ferritin, trans-ferrin, vitamin B12, erythropoietin;

Oxygen saturation of arterial blood (on a pulse oximeter or by measuring the partial tension of oxygen on a gas analyzer);

Sternal puncture with myelogram count, determination of the ratio of myeloid and erythroid germ, quantitative and qualitative characteristics of myelokaryocytes;

Cytogenetic study of bone marrow cells;

Molecular genetic study of peripheral blood: qualitative PCR for the presence of the JAK2V617F mutation; with a positive result, the determination of the allelic load of the mutant JAK2V617F and "wild" types of the JAK2 gene by realtime PCR;

Trepanobiopsy of the bone marrow with determination of cellularity, three-color staining (van Gieson, silver impregnation, Perls), assessment of the degree of fibrosis according to a standard scale;

Ultrasound of the abdominal organs (size and density of the liver and spleen, diameter of the portal vein);

Indication research:

Determination of mutations in exon 12 of the JAK2 gene, LNK, CALR, MPL genes (W515L; W515K) in JAK2V617F negative patients;

Determination of mutations in the genes CBL, TET2, ASXL1, IDH, IKZF1, EZH2 - with PV in the stage of postpolycythemic myelofibrosis;

Coagulogram (activated partial thromboplastin time (APTT), thrombin time (TV), international normalized ratio (INR), fibrinogen) at risk of thrombotic or hemorrhagic complications;

Molecular genetic screening of markers of hereditary thrombophilia, homocysteine, consultation of a vascular surgeon in the presence of previous thrombosis and thromboembolism to determine the indications and volume of anticoagulant therapy;

Determination of the activity of alkaline phosphatase of neutrophils;

Cytochemical (myeloperoxidase, lipids, PA8 reaction, alpha-naphthylesterase) and immunophenotypic study of blast cells (in the phase of blast crisis);

Determination of blood group (AB0, Rh factor) if necessary, hemocomponent therapy (in the phases of postpolycythemic myelofibrosis and blast crisis);

Blood test for HBsAg, antibodies to NSU ^b, HIV 1 and 2 types Wasserman reaction;

Rehberg's test with signs of kidney pathology;

Fibrogastroduodenoscopy to exclude secondary thrombocytosis against the background of pathology of the gastrointestinal tract and with signs of portal hypertension to exclude varicose veins of the esophagus and stomach in the post-thrombocythemic myelofibrosis phase;

ECG standard in 12 leads in the presence of cardiac pathology;

X-ray of tubular bones for indirect assessment of osteosclerosis when the patient refuses a trepanobiopsy (in phase-post-polycythemic myelofibrosis);

X-ray of the chest organs to exclude secondary thrombocytosis against the background of chronic diseases and lung neoplasms;

Consultations of specialist doctors (neurologist, cardiologist, ophthalmologist, endocrinologist, gynecologist, gastroenterologist, etc.) in the presence of complications and comorbidities to optimize therapy.

DIAGNOSTIC CRITERIA AND DIFFERENTIAL DIAGNOSTICS OF POLYCYTHEMIA VERA

To verify the diagnosis, an international working group on the diagnosis and treatment of PV developed diagnostic criteria, subsequently adopted by WHO in 2001. Due to the accumulation of data on the molecular genetic basis of the pathogenesis of PV, primarily information on the role of the JAK2V617F mutation, the diagnostic criteria were revised in 2007. They were significantly simplified with improved sensitivity and specificity, which made it possible in 2008 to recommend them to WHO. use in clinical practice.

The criteria are divided into two groups: large and small.

Big Criteria:

Hemoglobin level more than 185 g/l in men and 165 g/l in women or other signs of an increase in the mass of circulating erythrocytes1;

Determination of the JAK2V617F mutation or other functionally similar mutations, for example, in the 12th exon of the JAK2 gene.

Small Criteria:

Trilinear (erythroid, granulocytic, megakaryocytic sprouts) bone marrow hyperplasia according to trepanobiopsy data;

The level of erythropoietin is below the upper limit of normal;

Spontaneous growth of erythroid colonies of hemopoietic cells in the medium without the addition of growth factors.

The diagnosis of PV is reliable if two major criteria and one minor criterion are present, or the first major criterion and two minor ones.

A new version of the criteria, developed in 2014, has now been sent to WHO for consideration. Also, as in the previous version, the criteria are divided into large and small.

Big Criteria:

Hemoglobin level more than 165 g/l in men and 160 g/l in women or hematocrit more than 49% in men and more than 48% in women;

Detection of the JAK2V617F mutation or other functionally similar mutations, for example, in the 12th exon of the JAK2^ gene;

Trilinear (erythroid, granulocytic, megakaryocytic sprouts) bone marrow hyperplasia with pleomorphic megakaryocytes according to trephine biopsy.

Small Criteria:

The level of erythropoietin is below the upper limit of normal.

Differences from the previous edition are: the transfer of histological features to the group of large criteria and the exclusion from the list of spontaneous colony growth. The diagnosis of PV in this variant is verified in the presence of three major criteria or the first two major and minor criteria.

In the diagnosis of PV, it is often necessary to make a differential diagnosis with many conditions characterized by erythrocytosis, both hereditary and acquired. Some help in this can be provided by the use of the diagnostic algorithm shown in Fig. 7. The most common causes of secondary erythrocytosis are listed in Table. 3 .

Hemoglobin or hematocrit greater than the 99th percentile or greater than normal for age, sex, altitude or more than 25% increase in red blood cell count or hemoglobin greater than 170 g/l in men and 150 g/l in women if accompanied by an increase in hemoglobin levels by more than 20 g/l compared with anamnestic data and is not associated with the correction of iron deficiency.

Figure 7. Algorithm for differential diagnosis with an increase in the number of erythrocytes and / or hemoglobin levels.

Causes of secondary erythrocytosis

Table 3

Decreased plasma volume (relative erythrocytosis) Acute - Prolonged vomiting or diarrhea - Severe burns - Prolonged fever - Diabetic ketoacidosis Chronic - Prolonged inadequate use of diuretics - Geisbeck syndrome (moderately elevated hematocrit without erythrocytosis in middle-aged obese male smokers with hypertension)

DETERMINATION OF PREDICTION OF THROMBOTIC COMPLICATIONS (THROMBOSIS RISK GROUP)

Mechanism of occurrence State

Reactive increase in erythropoietin levels Chronic obstructive pulmonary disease Cardiovascular disease with circulatory failure Smoking Living in high altitude conditions Sleep apnea Obesity combined with sleep apnea Side effect of drugs (androgens and corticosteroids) Doping (administration of erythropoietin drugs) Professional activity or sports activity in hypoxic conditions (flight personnel, divers, scuba divers, divers, climbers, skiers, stokers, cryobank personnel, etc.)

Pathological increase in erythropoietin levels Renal carcinoma Non-neoplastic diseases of the kidneys (cysts, hydronephrosis, severe renal artery stenosis) Hepatocellular carcinoma Uterine fibromyoma Meningioma Hemangioblastoma of the cerebellum Other tumors (Wilms tumor, ovarian cancer, carcinoid, pituitary adenoma)

Traditionally, age and a history of thrombosis are identified as risk factors for the development of thrombosis in PV. Also, information has now been accumulated on the impact on the incidence of thrombosis in patients with PV of the allelic load JAK2V617F, leukocytosis more than 15 x 109/l, female sex, risk factors for cardiovascular diseases (diabetes mellitus, arterial hypertension, smoking), and an increase in acute phase markers inflammation, activation of leukocytes and platelets,

resistance to protein C, circulating microparticles.

In clinical practice, the thrombosis risk prediction scale developed by Marchioli R. et al. is simple and easy to use. in an international multicentre prospective study of cardiovascular events in 1638 patients with PV. The scale includes two statistically significant factors: age over 65 years and a history of thrombosis, which determine the risk of thrombosis from 2.5% to 10.9% per year (Table 4).

Table 4

Thrombosis Risk Predictive Scale in PV

Factors Risk of thrombosis development Frequency of thrombosis development, % per year

Age younger than 65 No history of thrombosis Low 2.S %

Age 65 years and older No history of thrombosis intermediate 4.9%

Age under 65 Thrombosis history S,0 %

Age 65 years and older Thrombosis history high 10.9%

The use of this scale makes it possible to choose an adequate strategy for the prevention of thrombotic complications, which are the main risks of disability and death in PV.

According to the results of a survey of 252 patients with PV during the initial examination, all patients had a simultaneous increase in hematocrit and erythrocytosis, the level of leukocytes over 9.0 x 109/l was registered in 66% (166) patients, thrombocytosis above 400 x 109/l was detected in 61.1% (154) patients. Histological examination of the bone marrow showed no signs of fibrosis (MF-0) in 91.4% of patients, the first degree of reticulin fibrosis (MF-1) was determined at the time of diagnosis in 2.9% of patients and the second degree of reticulin fibrosis (MF-2 ) in 5.7% of patients.

Cytogenetic study of bone marrow cells was performed in 18 patients. Chromosomal aberrations were not detected in any of the patients.

JAK2V617F mutation was detected in 97.7% of patients, JAK2 mutations in exon 12 were found in 2.3% of patients.

The proportion of patients who underwent thrombosis was 11.1%, including myocardial infarction 3.6%, acute cerebrovascular accident 5.2%. The frequency of thrombosis statistically significantly (p=0.0004) differed in risk groups according to the thrombosis prognosis scale in PV: in the low risk group 2.6% (2/78), intermediate risk 7.8% (6/77) and 20, 6% (20/97) with a high risk of thrombosis (Table 5).

Table 5

The incidence of thrombosis in polycythemia vera

The frequency of thrombosis Risk groups (p = 0.0004)

low intermediate high

Thrombosis, overall incidence 2.6% 7.8% 20.6%

The overall ten-year survival rate for patients with PV was 77.7%, the estimated median overall survival was 20.2 years (Fig. 8). In the analyzed group, 56 patients had registered

we have lethal outcomes. Progression to the phase of secondary myelofibrosis occurred in 12 (5.0%) patients.

Overall survival - 77.7% Estimated median overall survival - 20.2 years

% Progression to the phase of secondary myelofibrosis 5.0%

ALIVE died

1 - - - - - - - - 1 - - . . > .

duration of observation, pet

Figure 8. Overall survival of patients with PV.

THERAPY OF POLYCYTHEMIA TRUE

The goal of PI therapy is currently the prevention of thrombotic complications of the disease and the relief of its symptoms in order to improve the quality of life. The possibility of curbing the progression of the disease with standard therapy has not yet been proven. The results of the use of targeted drugs for this purpose - inhibitors of Janus kinases will be clear after the completion of clinical trials.

IP therapy primarily aims to reduce the risks of microcirculation disorders, for which angioplatelet agents and vascular drugs are used. Another important component of thrombosis prevention is the control of risk factors: the course of concomitant diseases (hypertension, diabetes), normalization of body weight, smoking cessation.

Cytoreductive therapy is prescribed for clinically significant deviations of indicators

blood, causing the risk of thrombotic complications. There are no exact levels to be corrected. Usually, it is advisable to correct blood counts with an increase in hematocrit of more than 50% (a decrease in the risk of cardiovascular complications with a hematocrit level of less than 45% has been proven), leukocytes more than 15 x 109 / l, platelets more than 1000 x 109 / l. Drug cytoreduction in PV is carried out in the form of monochemotherapy, interferon therapy, or their combined use. In some patients, most often of a young age with a low risk of vascular complications, correction of blood parameters can be carried out with the help of physical removal of excess cell mass (hemoexfusion, erythrocytepheresis). In the phase of blast transformation (BC), treatment can be carried out according to the programs for the treatment of acute leukemia, taking into account the age and comorbidity of patients.

DEFINITION OF THE THERAPEUTIC TACTICS

To determine the therapeutic tactics, it is advisable to collect the following information about the various factors that determine the ri-

ski and allowing to individualize the tactics of therapy, which are presented in Table. 6.

Table 6

Individual factors determining treatment tactics

Symptoms of the disease Symptoms of tumor intoxication (constitutional) Profuse night sweats Weight loss of more than 10% Unexplained febrile fever Skin itching (location, duration of occurrence, result of treatment) Vasomotor symptoms (headache, dizziness, ringing in the ears, integument and mucous membranes, attention problems) Myalgia, arthralgia, bone pain Abdominal discomfort, early satiety Fatigue, weakness, their impact on daily activities

History of life Concomitant pathology (hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, hyperuricemia / gout) Previous diseases Surgical interventions Past cardiovascular episodes and bleeding Presence and features of the menstrual cycle in women Altitude of residence above sea level

Life history Smoking Dietary habits Sleep apnea Physical activity Occupational hazards Willingness to make lifestyle changes as recommended

Medications Antihypertensive drugs, including diuretics Androgens Glucocorticoid hormones Antiplatelet agents or anticoagulants Contraceptives Adherence to the prescribed therapy

Pregnancy Previous pregnancies, abortions and/or miscarriages Planned future pregnancies

Family history Relatives with a diagnosis of myeloproliferative neoplasms, with other diseases of the blood system Relatives with erythrocytosis of unknown etiology Relatives with thrombosis of unusual locations and / or at a young age

During the examination, until the final diagnosis is established, the patient undergoes symptomatic therapy aimed at controlling the most pronounced symptoms, preventing thrombosis with the help of angioaggregants and stopping the manifestations of concomitant diseases (normalization of blood pressure, blood glucose levels, etc.). If there are clinical signs of microcirculation disorders (encephalopathy, decreased vision, renal failure, circulatory failure of the extremities), for symptomatic purposes, mechanical removal of excess erythrocyte mass (hemoexfusion, erythrocytapheresis) can be carried out until the hematocrit level normalizes.

To correct high erythrocytosis, leukocytosis and thrombocytosis during the examination period until the final confirmation of the diagnosis of PV, Hydroxyurea (Hydroxycarbamide) may be prescribed.

drea®, Hydroxyurea medak®, Hydroxyurea®) at an initial dose of 15 mg/kg/day with subsequent adjustment depending on the dynamics of hemoglobin, leukocyte and platelet levels.

After confirming the diagnosis, the tactics of further therapy should be determined and the question of the need and type of cytoreductive therapy should be resolved. The use of risk-adapted therapeutic tactics seems reasonable.

The main factors influencing the choice of treatment option are the following:

The presence and severity of symptoms of the disease;

The age of the patient;

The risk of developing thrombosis;

Concomitant diseases and the need for their ongoing therapy;

Lifestyle etc.

CHARACTERISTICS AND PRINCIPLES OF CHOOSING THE METHOD OF TREATMENT

PI Therapy Methods

Despite the variety of methods currently used for the treatment of PV, all of them can be divided into several groups:

Prevention of thrombotic complications;

Mechanical removal of excess cell mass (hemoexfusion, erythrocyte-pheresis);

cytoreductive drug therapy;

Targeted therapy;

Treatment of complications of the disease (thrombosis, thromboembolism);

Prevention of thrombotic complications

Efforts to prevent thrombosis and thromboembolism in PV should be aimed primarily at reducing the significance of cardiovascular risks: arterial hypertension, diabetes mellitus, smoking, hypercho-

lesterolemia, obesity, normalization of lifestyle, physical activity, etc. The use of highly effective hypocholesterolemic drugs can significantly reduce the manifestations of atherosclerosis, which is one of the main factors in thrombosis.

A decrease in the activity of platelet aggregation in most patients is traditionally carried out with the help of continuous intake of inhibitors of the arachidonic acid cascade - non-steroidal anti-inflammatory drugs. The most common drug used for this purpose is acetylsalicylic acid in small doses. Currently, there are many drugs on the pharmaceutical market with various trade names and in various forms, including enteric, to minimize the side effects of long-term use. Dosages of the drug that are optimal for achieving an antiplatelet effect are in the range of 75-100 mg / day. Lower doses are not effective enough, and higher doses are accompanied by significant side effects (development of gastric and duodenal ulcers, inhibition of prostacyclin synthesis, etc.). The use of acetylsalicylic acid in PV has been shown to be effective in multicenter, placebo-controlled, randomized clinical trials (ECLAP), both in significantly reducing the incidence of thrombosis (hazard ratio 0.4 compared with placebo) and reducing overall mortality (by 46% ) and mortality from cardiovascular diseases (59%), also the use of acetylsalicylic acid led to the relief of erythromelalgia and vasomotor symptoms. In the presence of contraindications or intolerance to acetylsalicylic acid, antiplatelet therapy can be carried out using its substitutes - clopidogrel (75 mg / day) and ticlopidine (500-750 mg / day). A certain problem, especially with hyperthrombocytosis of more than 1000 x 109 / l, may be the risk of bleeding due to acquired von Willebrand syndrome. In practice, the risk of hemorrhages can be assessed by studying the activity of ristocetin, with a value of more than 30%, the use of acetylsalicylic acid is safe.

Mechanical removal of excess cell mass

Reduction and maintenance of hematocrit within the normal range is easily achieved through the use of hemoexfusions and erythrocytepheresis. These procedures can be used as the main method of treatment in patients with low-risk PV, predominantly young, or in combination with cytoreductive therapy in all patients with PV. A decrease in hematocrit from 60% to normal reduces the incidence of cardiovascular complications by 38 times. In the Cy1;o-RU study, it was proved that in patients with PV, whose hematocrit was maintained within the normal range, the frequency of thrombosis was significantly lower. The main advantage of hemoexfusion and erythrocytepheresis is a rapid decrease in hematocrit and relief of microcirculation disorders. The disadvantages are the stimulation of the coagulation system during the procedure, which increases the risk of vascular complications and loss along with the erythrocyte mass of blood plasma with protein and other components. Much less these negative sides are expressed during manual, and even more hardware erythrocytepheresis, which allows it to be widely used on an outpatient basis.

The most common technique for hemoexfusion is the following: against the background of taking antiplatelet drugs (acetylsalicylic acid, clopidogrel), immediately before bloodletting, 400 ml of a solution of rheopolyglucin or saline is injected, as well as 5000 U of heparin intravenously, after which up to 500 ml is removed (250 ml during the first procedures) blood. The volume of bloodletting and their frequency are selected individually depending on the age of the patient, comorbidity and tolerability of the procedures. In the case of erythrocytapheresis, the same rules are followed. Most often, 2-3 sessions per week are performed. After one procedure, the hematocrit is reduced by 3-5%. The target level of hematocrit reduction is its normal (below 45% for men and 42% for women) level. As a rule, one course of hemoexfusion or erythrocytapheresis is enough to normalize hematocrit for 2-3 months. Frequent hemoexfusions and erythrocytapheresis lead to reflex hyperthrombocytosis, in order to correct it, it may be useful to prescribe

anagrelide or hydroxyurea. Another side effect is an iron deficiency state, the correction of which with the help of iron preparations is necessary only in the presence of sideropenic syndrome - tissue iron deficiency, manifested in the form of muscle weakness, trophism of the skin, hair, mucous membranes, taste perversion, swallowing disorders.

Cytoreductive therapy

Medications are currently the primary means of reducing excess cell mass in PV. This therapy does not lead to a cure, but, with the right approach, it can stop the symptoms and maintain the quality of life of patients. The traditional drugs used for the purpose of cytoreduction are the following:

Cytostatics: Hydroxyurea (Hy-drea®, Hydroxyurea medak®, Hydroxyurea®); Cytarabine (Alexan®, Cytarabine-LENS, Cytosar®, Cytostadin®); Mercaptopurine (Mercaptopurine, Puri-Netol®) used, as a rule, as monochemotherapy in low doses (Hydroxyurea 10-30 mg / kg / day; Mercaptopurine 1-2 mg / kg / day; Cytarabine 10-20 mg / m2 / day 10-14 days every month). The purpose of the use of cytostatics is to contain tumor proliferation and control blood parameters in order to prevent complications. There are no generally accepted standard schemes of application. Preferred is a constant daily or intermittent (in the case of cytarabine) administration in doses selected taking into account individual tolerance, which allow monitoring blood counts. The most commonly used treatment for PV is hydroxycarbamide (hydroxyurea, hydrea). Hydroxyurea is a highly effective drug for the prevention of thrombosis in all patients with PV, especially in the high-risk group. The antithrombotic effect of hydrea is associated with the normalization of not only hematocrit, but also the level of leukocytes and platelets. When comparing hydroxyurea monotherapy with hemoexfusion treatment for 15 years (study RU8v-01), the effectiveness of preventing thrombosis was approximately the same. Differences were observed in a higher frequency of blast transformation (9.8% for hydrea and 3.7% for hemoexfusions), a lower frequency

those of post-polycythemic myelofibrosis (7.8% for hydrea treatment and 12.7% for hemoexfusions) and better overall survival (60.8% for hydrea and 44.8% for hemoexfusions). A randomized comparative study of pipobroman and hydroxyurea over a period of 17 years also showed that hydrea was highly effective in preventing thrombosis and maintaining a survival rate that was not inferior to pipobroman. The initial dose of hydroxyurea is 15-20 mg / kg / day (1000-1500 mg / day) with a gradual increase to a dose that allows you to achieve a normal hematocrit level and a leukocyte level of more than 3.0 x 109 / l or the maximum tolerated. The control of the number of leukocytes and other indicators of the hemogram (hemoglobin + platelets + blood count) while taking hydroxycarbamide should be carried out weekly during the first 1-2 months of treatment, then monthly. To prevent complications associated with tumor lysis syndrome during cytoreduction, it is mandatory to prescribe an adequate volume of fluid (up to 2-2.5 l / m2 per day in the absence of heart failure), allopurinol at a dose of 300-600 mg / day due to sufficient often developing at the beginning of therapy with hyperuricemia, it is also advisable to periodically monitor the level of uric acid in the blood. The most common side effects of hydroxyurea are leukopenia and thrombocytopenia, their control is achieved by individual dose selection under the control of blood parameters. Less frequent, but more difficult to correct adverse events - ulcers of the legs and mouth, skin changes, pulmonitis.

Interferon-alpha (IFN-a) (Altevir®, Alfarona®, Interferal®, Intron A®, Re-aldiron®, Roferon-A®, Reaferon-EC®) inhibits the proliferation of myeloid progenitor cells in IP, also has a direct inhibitory effect on bone marrow fibroblasts and is an antagonist of cytokines (growth factor produced by platelets; transforming growth factor B, etc.) involved in the formation of myelofibrosis. The use of IFN-a in PV has more than twenty years of history and has been well studied in several clinical studies. IFN-a allows to achieve control of blood parameters without the use of hemoexfusion in 50% of patients, in 77% of patients there is a decrease in the size of the spleen

and 75% had a reduction in the severity of pruritus. In some patients with PV, the use of IFN-a leads to a decrease in the allelic load of JAK2V617F. The use of IFN-a is most justified in patients younger than 40-50 years, in which the possible leukemogenic effect of long-term use of hydroxyurea should be taken into account. Also, the use of IFN-a is relevant, especially in women of childbearing age who are planning a pregnancy or who do not want to use adequate methods of contraception. Interferon is contraindicated in diseases of the thyroid gland and in mental illness. The initial dose is 1 million IU 3 times a week with an increase with satisfactory tolerance to 3 million IU 3 times a week or daily. When hematocrit control is achieved within normal limits, the dose can be gradually reduced to the lowest dose that allows you to maintain control over hematocrit. PEGylated interferons are much better tolerated than plain IFN-a and have not yet received official approval for use in PV. However, their action has been studied in clinical trials. The initial dose of peg-IFN is 0.5 mcg/kg per week, increased if necessary to 0.5 mcg/kg per week. A complete hematological response using pegIFN was observed in 76% of patients, and 13% also achieved a complete molecular response (no JAK2Y617F mutation). The advantages of IFN-a are the absence of leukemogenic and teratogenic effects and the likelihood of obtaining molecular responses. The biggest disadvantages are the side effects of its use: flu-like syndrome, weakness, muscle pain, weight loss, hair loss, depression, gastrointestinal and cardiovascular disorders, the appearance of which is forced to cancel therapy in a third of patients. With insufficient efficacy or poor tolerability, a combined appointment of IFN-a with hydroxyurea is possible. This combination may increase efficacy and allow dose reduction of each drug with improved tolerability.

Anagrelide is a specific drug that causes a dose-dependent and reversible decrease in the number of platelets in the peripheral blood. The mechanism of action is not fully understood. These studies suggest that anagrelide inhibits megakaryocyte hypermaturation in a dose-dependent manner. Application

anagrelide does not lead to a significant change in such parameters as blood clotting time and platelet life expectancy, while bone marrow morphology does not change. The drug does not significantly affect the level of hemoglobin and leukocytes, but significantly reduces platelets. In PV, anagrelide is a good option for combined treatment with hemoexfusions or hydroxyurea when thrombocytosis control cannot be achieved with monotherapy. The recommended starting dose of anagrelide is 0.5 mg 4 times a day or 1.0 mg 2 times a day. The maximum single dose is 2.5 mg, the daily dose is 10 mg. At the optimal dose, the platelet count begins to decrease after 7-14 days. The lowest effective dose should be used that is sufficient to maintain platelet counts below 600,000/mcL and ideally to normal levels. In most patients, an adequate response is achieved with the use of anagrelide at a dose of 1.5-5.0 mg / day. Most side effects are dose-dependent, mild and transient and do not require therapeutic measures to eliminate them. The most common adverse events are vasodilating and positive inotropic effects, headache, diarrhea, fluid retention, heart failure, arrhythmias. The frequency and severity of adverse reactions decreases with continued therapy.

Januskinase inhibitors are drugs that block the activity of 1AK2-kinases, the first drugs with targeted action aimed at a key link in the pathogenesis of PV - the 1AK-8TAT signaling pathway. It should be taken into account that these drugs affect both mutant (JAK2V617F) and wild-type 1AK kinases, therefore, they can be effective in the treatment of patients negative for the presence of the JAK2Y617F mutation. The following drugs are currently being evaluated in clinical trials: VDSV018424, TG101348, CEP-701, CYT387, AZD1480, 8B1518 and LY2784544. The trade name and approval for use in PV at the moment has been received only by the drug SHCB018424 (Kyhollshsh, Lakau1® (Ruxolitinib, Jakavi®), manufacturer No-vartis pharma AG, Switzerland) . Currently, ruxolitinib is indicated in patients with PV who have failed to respond or are intolerant to hydroxyurea. Maximum tolerable

the dose of the drug is 25 mg twice a day, therapeutic doses for PV are from 10 to 25 mg twice a day. In the RESPONSE study comparing ruxolitinib with standard therapy in 222 treatment-resistant or hydroxyurea-intolerant patients, ruxolitinib showed significant superiority in both efficacy and tolerability. Hematocrit control with ruxolitinib treatment was achieved in 97% of patients at 48 weeks and in 86% at 80 weeks. Also, in most patients, a reduction in the spleen was achieved. As a result, 84% of patients in the standard therapy group were switched to ruxolitinib. The severity of PV symptoms, especially pruritus, weakness and sweating, decreased by 49%-100% with ruxolitinib treatment, while there was no change in symptoms with standard therapy (-2%-4%). The side effects of ruxolitinib in PI are well tolerated and easily controlled by dose modification. Ruxolitinib resulted in a significant reduction in JAK2V617F allele load of 8% at 48 weeks, 14% at 96 weeks, and 22% at 144 weeks of treatment. To achieve deeper molecular responses, it seems attractive to investigate the effectiveness of combination therapy with ruxolitinib and interferon.

Telomerase inhibitors are promising drugs that block the activity of enzymes that shorten the length of telomeres - the end sections of chromosomes, thus normalizing the proliferation of myeloid precursors. Currently, there is only one representative of this new class - the drug Imetelstat (GRN163L), which was undergoing phase II studies for use in PV. Due to hepatotoxicity, the study was temporarily suspended, but in November 2014, restrictions were lifted.

Most of the 252 patients with PV who were examined and treated at our institute were treated with hydroxyurea and its analogues - 205 patients (81.8%), the average dose was 0.7 g/day. Interferon preparations were used in 43 patients (17.1%), the average dose was 8.5 million/week; mercaptopurine in 25 (10.1%). Erythrocytapheresis was performed in 221 patients (88.9%) patients, with an average frequency of 1 to 8 procedures per year (average - 2.84). Surgical treatment was used

1 patient had splenectomy due to splenic infarction. As a result of therapy, 7.5% achieved a complete response; 72.6% had a partial response and 19.8% had no response to treatment.

Principles for choosing a treatment method

The basis for choosing a treatment method is the age of the patient and the presence of cardiovascular diseases, which determine the risk of developing thrombosis, life expectancy of patients and the likelihood of disability.

Patients under the age of 50 years. Most often, these patients have a low risk of thrombosis. Often such patients do not have severe clinical symptoms and are referred to a hematologist based on the results of a clinical analysis performed during a medical examination or examination for other diseases. Patients with PV in this group are most likely to maintain life expectancy, prevent the development of thrombosis and maintain quality of life. The use of cytoreductive therapy in such patients is associated with a greater risk of developing long-term side effects than the risks of disease progression. In this group, especially in patients under the age of 40, it is often justified to use only methods of mechanical removal of excess cell mass (hemoexfusion, erythrocytepheresis) and the prevention of vascular complications by taking antiplatelet agents. Cytoreductive therapy should be started if patients have a history of cardiovascular pathology or thrombosis, as well as with insufficient effect or poor tolerance of hemoexfusion / erythrocytepheresis, with the appearance of symptoms of vascular complications (transient ischemia, thrombophlebitis of the veins of the lower extremities, etc.), a significant increase in the level platelets (up to a level of more than 1,000 x 109/l or more than 300 x 109/l for three months). If it is necessary to prescribe cytoreductive therapy at the age of up to 50 years as the first line of therapy, taking into account the possible leukemic effect of cytostatics during long-term use, it is advisable to use IFN-a preparations. To correct hyperthrombocytosis in such patients, the appointment of anagrelide is indicated, which is rarely accompanied by severe side effects in young patients. In this group of patients, the question of pregnancy planning often arises, which also

makes the choice of IFN-a drugs more reasonable. In case of resistance and/or intolerance to IFN-a preparations, it is advisable to use hydroxyurea as a second line of therapy. In case of insufficient efficacy and / or poor tolerability of hydroxyurea, therapy with Januskinase inhibitors (ruxolitinib) seems to be adequate. Prospects for clinical research, taking into account the life expectancy and long course of PV, prevention of the development of blast transformation and postpolycythemic myelofibrosis, may be the use of targeted therapy drugs, primarily Januskinase inhibitors (ruxolitinib, etc.).

Patients aged 50-70 years. Patients in this group most often have an intermediate or high risk of developing thrombosis, which accordingly determines the choice in favor of prescribing permanent cytoreductive therapy, most often hydroxyurea, which is better tolerated compared to IFN-a drugs. In the absence of cardiovascular pathology and a history of thrombosis, drug therapy can be combined with hemoexfusion/erythrocyte-tapheresis. In patients with cardiac pathology and/or who have undergone thrombosis, mechanical removal of excess cell mass may be associated with a risk of thrombotic complications. With resistance and /

or intolerance to hydroxyurea, IFN-a drugs or Januskinase inhibitors (ruxolitinib) may be used.

Patients over the age of 70 years. Patients in this group most often have a high risk of developing thrombosis. The life expectancy of patients in this group can be limited both by the presence of PV and the high frequency of recurrent thromboses associated with it, and by the residual consequences of past thromboses (chronic heart failure after a heart attack, encephalopathy after strokes, etc.). It is vital, taking into account the pronounced atherosclerosis of the vessels at this age, is the control of blood parameters (hematocrit, leukocytes, platelets) within the normal range (less than 400 x 109/l) with the help of cytoreductive drugs. The most preferred treatment option is the use of hydroxyurea. With insufficient effect or poor tolerance, targeted drugs (ruxolitinib) may be prescribed. Hydroxyurea can also be combined or replaced by other cytostatics (mercaptopurine, busulfan, cytosar). In selected patients, the possibility of introducing radioactive phosphorus or the use of low doses of IFN-a preparations may be considered. In graphical form, the recommended algorithm for the treatment of patients with PV, depending on age and comorbidity, is shown in Fig. 9.

Figure 9. Algorithm of treatment tactics in PV.

MONITORING AND EVALUATION OF TREATMENT EFFECTIVENESS

For adequate and timely correction of therapy in order to achieve maximum efficiency and control toxicity, it is necessary to conduct timely monitoring of hematological and biochemical, and, if necessary, cytogenetic and molecular genetic parameters.

Timely evaluation of the effectiveness of therapy using standardized methods allows you to obtain accurate data on the results of the use of various methods of treatment and systematize the tactics of therapy in order to individualize it.

the presence of complications, etc.), the frequency of clinical and laboratory monitoring may be more intensive. The results of therapy in patients with PV are evaluated according to clinical assessment, hematological and molecular genetic studies. Currently, promising methods are being proposed to evaluate the effect of PV treatment in clinical trials, including patient symptom assessment and histological method. Depending on the methods of assessment and the degree of suppression of the tumor clone, different types of response are distinguished: clinical-hematological, cytogenetic and histological.

Table 7

The frequency of dynamic examination of patients with PV

Study Frequency of monitoring

General (clinical) blood test detailed At the time of diagnosis, then at least 1 time in three months or more often, depending on blood counts

Biochemical parameters (bilirubin, AST, ALT, LDH, uric acid) At the time of diagnosis, then at least once every three months with cytoreductive therapy

Coagulogram (APTT, TT, INR, fibrinogen) At the time of diagnosis, in the presence of thrombosis and anticoagulant therapy at least 1 time in three months

Ultrasound of the abdominal cavity with determination of the size of the liver, spleen, assessment of portal blood flow At the time of diagnosis, then at least 1 time per year

Sternal puncture with myelogram count and cytogenetic examination Bone marrow trephine biopsy with histological examination and assessment of the degree of fibrosis When making a diagnosis, then with the development of leukocytosis, a shift in the leukoformula, cytopenia

The clinical and hematological response is assessed by the level of hematocrit, the presence or absence of symptoms of circulatory failure, ischemia, splenomegaly, and blood counts. It may be complete or partial, or absent. Criteria for determining the clinical and hematological response are given in table. 8. A complete clinical and hematological response is determined with complete normalization of blood parameters (hematocrit, leukocytes, platelets), normal size of the spleen and the absence of clinical symptoms of the disease.

niya. A partial response is established when the criteria for a complete response are not fully met, but either the normalization of hematocrit without the need for hemoexfusion (erythrocytapheresis) or the presence of three or more criteria (normalization of leukocytes, platelets), the absence of splenomegaly and other symptoms of PV is necessary. Lack of response to treatment is stated when the assessment does not correspond to a complete or partial clinical and hematological response.

BULLETIN OF HEMATOLOGY, volume XI, No. 1, 2015

Table 8

Criteria for clinical and hematological response in the treatment of PV

Response Type Definition

Full answer Hematocrit<45 % без необходимости гемоэксфузий (эритроцитафереза) Тромбоциты < 400 х 109/л Лейкоциты < 10 х 109/л Нормальные размеры селезенки Нет симптомов заболевания*

Partial response Does not meet complete response criteria Hematocrit<45 % без необходимости гемоэксфузий (эритроцитафереза) ИЛИ ответ по трем или более критериям (лейкоциты, тромбоциты, размеры селезенки, симптомы заболевания)

No response Any response that does not match a partial response

*Microcirculation disorders, pruritus, headache

The molecular response is assessed during a molecular genetic study of peripheral blood in dynamics. The response rate can

be big and small. Criteria for molecular response are given in table. 9 .

Table 9

Evaluation of the molecular response in the treatment of PV

Response Type Definition

Complete response Decreased allelic load of a molecular marker (JAK2V617F etc.) to an undetectable level

Partial response* >50% reduction from baseline in patients with allelic burden< 50 % при первоначальном исследовании ИЛИ Снижение >25% of baseline level in patients with >50% allelic burden at baseline

No response Any response that does not correspond to a full or partial response

*can be used only for patients with an allelic load level > 10% at the initial study

Trepanobiopsy with histological examination of the bone marrow makes it possible to evaluate the histological response, the achievement of which has become possible with the use of new methods of treatment with IP-targeted drugs. The presence of a histological response is stated in the absence of trilinear bone marrow hyperplasia and cellularity corresponding to the patient's age.

Hydroxyurea is the most widely used drug for the treatment of PV. At the same time, as literature data and our own experience show, hydroxyurea therapy infrequently (7-10%) allows to achieve a complete clinical and hematological outcome.

veta . An effective alternative in case of insufficient efficacy and / or intolerance to hydroxyurea are Januskinase inhibitors (ruxolitinib), which allow achieving independence from hemoexfusions in the vast majority of patients. In order to determine the indications for the need to transfer patients with PV from hydroxyurea to therapy with Januskinase inhibitors, the European Organization for the Diagnosis and Treatment of Leukemia (ELN) developed criteria for determining the ineffectiveness (resistance) and intolerance of hydroxyurea in patients with PV, presented in Table. ten .

Table 10

Criteria for ineffectiveness (resistance) and intolerance to hydroxyurea in patients with PV

No. Definition

1. The need for hemoexfusion (erythrocytepheresis) to maintain the hematocrit level< 45 % после 3 месяцев терапии гидроксимочевиной в дозе не менее 2 г/сут ИЛИ

2. Uncontrolled myeloproliferation (platelets > 400 x 109/l, leukocytes > 10 x 109/l) after 3 months of therapy with hydroxyurea at a dose of at least 2 g/day OR

3. Failure to reduce massive splenomegaly by more than 50% on palpation OR failure to completely resolve symptoms associated with splenomegaly after 3 months of therapy with hydroxyurea at a dose of at least 2 g/day OR

4. Absolute neutrophil count< 0,5 х 109/л ИЛИ тромбоцитов <100 х 109/л ИЛИ гемоглобина < 100 г/л при приеме наименьшей дозе гидроксимочевины, позволяющей достичь полного или частичного клинико-гематологического ответа ИЛИ

5. Presence of leg ulcers or other unacceptable non-haematological toxicity associated with hydroxyurea, such as skin and mucosal lesions, gastrointestinal symptoms, pneumonitis, or fever at any dose of hydroxyurea

COMPLICATIONS IN POLYCYTHEMIA VERA AND TACTICS OF THEIR THERAPY

The course of PV can be complicated by: the development of thrombosis and thromboembolism, bleeding, secondary postpolycythemic myelofibrosis,

THROMBOSES AND THROMBOEMBOLIAS

The main risks of PV are associated with the accumulation of excess blood cell mass, which leads to a significant increase in the risk of thrombosis and manifestations of cardiac pathology. Clinically significant thrombosis develops in 1.8%-10.9% of patients with PV annually. Statistically significant risk factors for thrombosis in PV are elevated hematocrit and leukocyte levels, age over 60 years, and a history of thrombosis. Prevention of thrombosis by prescribing antiplatelet agents - acetylsalicylic acid or its analogues is indicated for all patients with PV in the presence of at least one risk factor. An effective means of reducing the risk of thrombosis in PV is the use of Januskinase inhibitors, in particular ruxolitinib. In the RESPONSE study, ruxolitinib reduced the likelihood of major thrombosis and death from cardiovascular events by 45% compared with usual clinical practice. Secondary prevention after thrombosis has already occurred is reduced to the normalization of blood counts with the help of

cytoreductive therapy and prescribing, according to indications, anticoagulant therapy with direct and indirect anticoagulants with the achievement of target indicators of the coagulation system. As a rule, in the acute period of thrombotic complications, low molecular weight heparins are prescribed, which can subsequently be replaced by warfarin in combination with antiplatelet agents while maintaining the therapeutic level of INR within 2.0-3.0.

Thrombosis of the abdominal veins. The development of thrombosis in unusual places, in particular abdominal veins, can often be the first manifestation of PV, which requires a screening study to rule out CKD in such patients. These thromboses can lead to serious consequences, including the development of hepatic vein occlusion with Bud-Chiari syndrome and subhepatic jaundice. Emergency therapy may include the imposition of a transjugular portosystemic vascular shunt, angioplasty with stenting, the imposition of porto-caval vascular anastomoses, in exceptional cases transplantation

tation of the liver. In the presence of abdominal thrombosis in the acute phase, the appointment of heparin or its low molecular weight analogues is required. Subsequently, lifelong therapy is indicated

anticoagulants in combination with cytoreduction with hydroxyurea while maintaining the target hematocrit level within the normal range and platelets less than 400 x 109/l.

BLEEDING

Hemorrhagic syndrome can complicate the course of PV with severe thrombocytosis, more often with more than 1500 x 109/l, and may be due to secondary von Willebrand syndrome. This phenomenon is due to the consumption of von Willebrand factor multimers due to their sorption on an excess amount of platelets. When the level of platelets is normalized, the concentration of the free factor is restored and the hemorrhagic syndrome is relieved. Bleeding in patients with PV with hyperthrombocytosis may be more pronounced when taking antiaggregants and/or anticoagulants. If patients with PV have a history of bleeding or conditions with a risk of hemorrhagic syndrome (peptic ulcer of the stomach and duodenum, varicose veins of the esophagus) for the prevention of hemorrhagic

syndrome, it is advisable to refrain from prescribing antiplatelet agents and anticoagulants against the background of thrombocytosis and to achieve a reduction in the risks of thrombosis and bleeding by normalizing blood parameters using cytoreductive therapy. Treatment of hemorrhagic episodes in PV primarily consists of stopping antiplatelet and anticoagulant drugs and lowering platelets, most commonly with hydroxyurea. As a hemostatic, it is possible to prescribe tranexamic acid (1 g every 6-8 hours) and desmopressin (0.3 μg / kg / day). To compensate for the functional deficiency of von Willebrand factor, transfusions of hemocomponents with its content (cryoprecipitate, fresh frozen plasma) or synthetic coagulation factors (von Willebrand factor in combination with factor VII, etc.) are carried out.

SKIN ITCH

Itchy skin that worsens after skin contact with water is a typical symptom of PV. In some patients, the severity of itching is excruciating, causing serious concern, reducing the quality of life. The pathogenesis of pruritus is not entirely clear, it is believed that its occurrence is associated with the activation and release of inflammatory mediators by tissue basophils of the skin. Management of pruritus in PV is often challenging. For symptomatic purposes, antihistamines are used.

sedatives such as cyproheptadine (Peritol®) or hydroxyzine (Atarax®), antidepressants (paroxetine-Rexetin®) or psoralen with ultraviolet irradiation of the skin. IFN-a preparations, including pegylated ones, can have a pathogenetic effect on pruritus. A significant reduction in the severity of pruritus in almost all (97%) patients was observed with the use of ruk-solitinib in the RESPONSE study.

SECONDARY POSTPOLYCYTHEMIC MYELOFIBROSIS

Prolonged proliferation of hematopoietic cells in PV after total bone marrow hyperplasia leads to fibrosis and replacement of the active bone marrow with reticulin and collagen fibers, and subsequently to osteosclerosis - the development of secondary postpolycythemic myelofibrosis. The probability of outcome in post-polycythemic myelofibrosis is about 0.5% per year. With the development

secondary myelofibrosis, the addition of new syndromes can be observed: tumor intoxication, extramedullary proliferation, anemia, infectious complications, hemorrhagic syndrome.

Tumor intoxication. Symptoms of tumor intoxication (fever, heavy sweats and weight loss) cause restrictions in daily life and worsening

improving the quality of life of patients. Traditional therapy, in the form of hydroxyurea, as a rule, leads to some decrease in the severity of tumor intoxication, but does not completely stop it. The use of glucocorticoids and immunomodulators, as well as their combinations, which in a significant proportion of patients lead to a decrease in cytokine secretion disorders and an improvement in their condition, has a great effect. Currently, the most effective drugs that affect the level of pro-inflammatory cytokines are Januskinase inhibitors, which was confirmed by the COMFORT-II study, which compared the effect of treatment with ruxolitinib and standard therapies. In the ruxolitinib group, a statistically significant decrease in the severity of symptoms of intoxication and an improvement in quality of life indicators were obtained, while standard therapy did not significantly affect these indicators.

extramedullary proliferation. With myelofibrosis, foci of hematopoiesis can develop outside the organs of hematopoiesis. In addition to the liver and spleen, extramedullary foci of hematopoiesis can appear in the peritoneum with the development of ascites, lungs with the formation of pulmonary hypertension and exudative pleurisy, lymph nodes with their enlargement and compression of underlying organs and vessels, thoracic and lumbar spine with possible compression of the spinal cord, limbs with compression nerve trunks and neuropathic pain. The appearance of areas of extra-medullary hematopoiesis is accompanied by damage to the structure of the organ and a violation of vascular blood flow (portal hypertension, exudative pleurisy and ascites). The presence of asymptomatic foci of extramedullary hematopoiesis does not require the addition of systemic therapy. The most effective means of prevention and pathogenetic therapy of these complications may be immunomodulators in combination with glucocorticoids and Januskinase inhibitors. The presence of local clinical symptoms associated with extramedullary lesions is an indication for local radiation therapy at low doses (in a single dose of 1 Gy, a course dose of 10 Gy). With the accumulation of fluid in the cavities, it is possible to use pleural punctures and paracentesis with pleurodesis. Enlargement of the spleen due to extramedullary hematopoiesis

is one of the most frequent manifestations of myelofibrosis and can be a significant problem in the treatment of patients. In addition to physical symptoms in the form of an increase and bloating, early satiety, and abdominal pain, splenomegaly can lead to the development of spleen infarcts, compression of the abdominal organs, and portal hypertension. The syndrome of hypersplenism due to the sequestration of a significant amount of blood, the development of autoimmunization leads to an increase in the severity of cytopenias. Splenomegaly can be treated with drugs or surgery. The most commonly used is hydroxyurea, which can lead to a decrease in the size of the spleen, but the use of Januskinase inhibitors (ruxolitinib) is much more effective, leading to a significant and persistent decrease in splenomegaly in almost all patients. Splenectomy is an alternative to medical treatment when drug therapy is ineffective or poorly tolerated. Indications for removal of the spleen are massive splenomegaly, cachexia, portal hypertension with the presence of varicose veins of the esophagus and stomach, anemia with transfusion dependence. However, an enlarged spleen, the presence of portal hypertension, concomitant cytopenias and hemostasis disorders cause significant difficulties in performing the operation and in 3050% of patients lead to postoperative complications, and in 5-10% to death. Radiation therapy to the area of ​​the spleen can moderately reduce the clinical symptoms and size of the spleen in patients and is used when drug therapy is ineffective and splenectomy is impossible or is refused. The therapeutic effect of radiation therapy does not lead to the complete elimination of pathological symptoms, is unstable and lasts only a few months. Irradiation, as a rule, leads to increased cytopenias, which causes mortality in about 10-15% of patients. At the same time, radiation therapy leads to the development of local fibrosis and the formation of adhesions with the peritoneum and adjacent organs, which subsequently makes splenectomy extremely difficult technically.

Anemia. One of the most frequent complications of myelofibrosis is anemia, which is often observed at the onset of the disease and serves as a reason for the patient to visit a hematologist and diagnose PMF. To correct anemia

in order to replace the deficiency and prevent life-threatening conditions, it is often necessary to resort to red blood cell transfusions. Anemia in PMF can be of a polyetiological nature and be, among other things, the result of a deficiency of vitamins and microelements, as well as concomitant pathology. In order to correct anemia, it is necessary to conduct a comprehensive examination and correction of iron deficiency, vitamins, the introduction of erythropoietin preparations in case of its insufficient production. In the presence of splenomegaly and hypersplenism syndrome, a moderate increase in hemoglobin may be observed after splenectomy.

infectious complications. Leukopenia and neutropenia, which are sometimes manifestations of secondary myelofibrosis, cause an increase in the incidence of infectious complications. Infectious processes in patients with myelofibrosis are caused by secondary immunodeficiency and often proceed atypically. Diagnosis of infectious complications is based on a thorough history taking with the identification of a possible focus of infection with a thorough topical study, including visualization (methods of radiation diagnosis and endoscopy) of the structure of organs and the collection of material to identify the pathogen (washouts, examination of biological fluids, etc.). Prior to the identification of the pathogen, patients, due to the frequent presence of combined immunodeficiency, should be prescribed empirical antibiotic therapy using antibiotics that cover the entire spectrum of infectious pathogens at maximum doses. If the effect is insufficient, it is necessary to prescribe other antibiotics or their combination, taking into account clinical data and the results of microflora studies on sensitivity to antibiotics. After identifying the pathogen and determining its individual sensitivity, antibiotic therapy should be rationalized by choosing the most effective drug.

With infectious complications that have arisen against the background of neutropenia, it is possible to use

administration of G-CSF 5 mcg/kg/day, as well as human immunoglobulin at doses of 0.2-0.5 g/kg for 3-5 days, and plasmapheresis to detoxify and improve drug sensitivity.

Thrombocytopenia and hemorrhagic syndrome. Thrombocytopenia in post-thrombocytic myelofibrosis may occur in the presence of severe bone marrow fibrosis and depletion of hematopoiesis. A certain contribution to the development of hemorrhages is also made by secondary coagulopathy associated with impaired production of coagulation factors by the liver due to damage to the parenchyma by foci of extramedullary hematopoiesis and portal hypertension. Therapeutic tactics for thrombocytopenia should be aimed at eliminating the cause of thrombocytopenia and preventing hemorrhagic syndrome. The causes of thrombocytopenia may be a decrease in the production of platelets and their increased destruction. Prevention of complications should be aimed at improving the condition of the vascular wall by prescribing vitamin C, rutin, sodium etamsylate and eliminating risk factors - normalizing venous pressure (reducing portal hypertension with beta-blockers, calcium channel blockers, vascular bypass), preventing mucosal damage (moisturizing the nasal mucosa, secretolytics for the prevention of ulcer formation, local therapy of hemorrhoidal venous nodes). Transfusion of platelet concentrate has a short-term effect and is advisable only in the presence of a hemorrhagic syndrome or at a high risk of bleeding, moreover, with multiple transfusions, resistance to transfusions may develop due to autoimmunization. To correct DIC and disorders of the plasma link of hemostasis, transfusions of fresh frozen plasma in adequate doses and the introduction of recombinant coagulation factors are also used.

BLAST TRANSFORMATION

Long-term proliferation of a tumor clone of IP with genetic instability can lead to the accumulation of additional mutations and the development of the terminal stage of the disease - blast transformation. Progressive

The progression of the disease to the phase of blast transformation is observed with a probability of 0.34% of the total number of patients per year during the first 5 years of the disease, with an increase of up to 1.1% annually with a disease duration of more than 10 years.

The time from the onset of the disease to the development of transformation into a blast crisis can vary significantly from several to decades. The difference in the timing of the development of blast transformation is due to the heterogeneity of the disease, as well as the inaccuracy in establishing the timing of the onset of the disease. Proven means of preventing the blast crisis of the disease, due to insufficient knowledge of the mechanisms of its occurrence, have not yet been developed. Ruxolitinib, which has shown this effect in studies in the treatment of PMF, may be a promising means of reducing the rate of blast transformation.

With the development of blast transformation, the prognosis is unfavorable, the median survival is several months. The tactics of therapy is determined by the age of patients and concomitant

existing pathology. In patients with a preserved general somatic status, an attempt can be made to conduct course chemotherapy according to the treatment regimens for acute leukemia, which brings a temporary effect in a small part of patients. When the effect of induction chemotherapy is achieved in order to increase life expectancy, it is possible to perform allo-TCM. For elderly patients with significant comorbidity and thrombotic complications of PV, it is advisable to conduct restraining palliative monochemotherapy and prescribe low doses of glucocorticoids. These measures are aimed at inhibition of tumor growth and relief of complications (transfusion of hemocomponents, treatment of infectious complications, etc.), in order to improve the patient's quality of life.

SELECTED CLINICAL SITUATIONS IN IP

PREGNANCY

The introduction of the determination of molecular genetic markers (JAK2V611F) into wide practice has made it possible to identify a significant proportion of young patients with PV. Violation of blood rheology in PV leads to pathology of microcirculation of placental blood flow and complicates the course of pregnancy. Pregnancy in patients with PV is often complicated by miscarriage, early miscarriages, placental insufficiency, developmental delay, preeclampsia, and venous thrombosis can also be observed, especially in the postpartum period, more often in patients with a history of thrombosis. The risk of developing thrombosis during pregnancy is 3-5%. During pregnancy in a patient with PV, it is first necessary to determine the risk of pregnancy complications, based on the presence or absence of a history of thrombosis, miscarriage of previous pregnancies.

The use of acetylsalicylic acid in pregnant women at risk of preeclampsia was analyzed in a large multicenter study and found to be safe and recommended for its prevention. The use of heparin in unfractionated form and low molecular weight

log has a positive experience of use and is especially recommended during the last weeks of pregnancy and within 4-6 weeks after childbirth. In order to prevent increased blood loss during childbirth, it is recommended to interrupt the administration of heparin 12 hours before the expected birth and resume the next day after the birth.

Hemoexfusion (erythrocytapheresis) and cytoreductive therapy are recommended in the presence of a history of thrombosis, as well as in recurrent miscarriage and fetal growth retardation. The use of hydroxyurea during pregnancy is not recommended due to the presence of a proven teratogenic effect. Anagrelide can cross the placenta, its effect on fetal development is unknown, so its use during pregnancy cannot be recommended. The safest drug option for cytoreduction in pregnant PIs is IFN-a preparations. Its use has been reported in a small number of cases to reduce both the risk of PV complications and pregnancy complications. In general, recommendations for the management of pregnancy in patients with CKD are given in Table. eleven .

Table 11

Pregnancy management strategy in patients with CKD

Risk of pregnancy Therapy

Low risk Maintain hematocrit less than 45% or at 2nd trimester hematocrit; antiplatelet agents (low doses of acetylsalicylic acid or other drugs for intolerance); low molecular weight heparins after delivery for 6 weeks

High risk* Low risk interventions, supplemented: If there is a history of serious thrombosis or severe complications of pregnancy: low molecular weight heparins throughout pregnancy. If the platelet level is more than 1500 x 109/l, the appointment of interferon alfa. If there is a history of bleeding: use interferon, avoid prescribing acetylsalicylic acid.

*signs of a high risk of pregnancy: a history of venous or arterial thrombosis, bleeding associated with CKD, previous pregnancy complications (recurrent early miscarriage, intrauterine growth retardation, placental dysfunction, miscarriages, preterm birth, severe preeclampsia, severe birth or postpartum blood loss), hyperthrombocytosis more than 1500 x 109/l

SURGICAL INTERVENTIONS IN PATIENTS WITH PV

The presence of PV increases the risk of complications in surgical interventions: mortality due to thrombosis is 7.7%, mortality due to bleeding 7.3% and surgical mortality 1.6%. When planning surgical interventions in all patients with PV, it is advisable to pre-normalize hematocrit and platelet count using hemoexfusions (erythrocytapheresis and plateletpheresis) and/or cytoreductive therapy. 7-10 days before surgery, planned cancellation of antiplatelet agents and cytoreductive drugs. For all patients with PV over 12

hours before surgery and in the postoperative period, prophylactic administration of low molecular weight heparins is recommended. Given that PV increases the risk of both thrombotic and hemorrhagic complications, antiplatelet agents and cytoreductive therapy are resumed as soon as possible with stable hemostasis and after healing of surgical wounds. To eliminate risks and timely correction of complications in the postoperative period, it is advisable to inpatient observation of the patient with daily monitoring of blood counts.

CONCLUSION

In recent years, significant progress has been made in deciphering the molecular genetic mechanisms of PV pathogenesis, and the role of the JAK-STAT signaling pathway has been established. The quality of diagnostics has significantly improved, new diagnostic criteria for the disease, monitoring and evaluation of response to treatment have been created. Currently, molecular targets for directed pathogenetic therapy have been identified and evidence has been obtained.

Evidence of the efficacy and safety of a new class of targeted drugs for the treatment of PV.

The typical course of the disease is associated with the onset of symptoms of microcirculation disorders. Identification of the disease occurs when referring to a hematologist about deviations in the clinical analysis of blood during a preventive examination or after thrombosis and thromboembolism.

The diagnosis of PV is established on the basis of a combination of clinical data and the results of laboratory and instrumental studies. Deciphering the molecular genetic pathogenesis of the disease and introducing into practice the determination of mutations in the JAK2 gene has significantly improved the accuracy of diagnosis. To verify the diagnosis, an international working group on the diagnosis and treatment of PV has developed new diagnostic criteria for WHO approval.

With timely diagnosis and adequate treatment with the prevention of vascular complications and hematocrit, the manifestations of the disease may not bother patients for many years. The main risk factors for thrombosis are age and a history of thrombosis. With a long course of the disease, some patients may experience an outcome in secondary postpolycythemic myelofibrosis or progression to the phase of blast transformation.

The goal of PI therapy at present is to contain the progression of the disease and relieve its symptoms in order to improve the quality of life of patients. With the right approach to treatment and monitoring of its results, the life expectancy of patients with PV should not differ from the population. Treatment of patients with PV should be carried out under the supervision of a hematologist with monitoring of its results in accordance with standard criteria for evaluating responses. The choice of treatment method should be based on an assessment of the possible benefits and risks of side effects of therapy for a particular patient.

The obtained new data on the pathogenesis of PV served as the basis for the development and introduction into practice of treatment of new classes of drugs (Janus kinase inhibitors), which have shown high efficacy and safety even with resistance to previous treatment.

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Polycythemia vera (erythremia, Wakez's disease, polycythemia erythema) - PV - a chronic neoplastic myeloproliferative disease with stem cell damage, proliferation of three hematopoietic lineages, increased production of red blood cells and, to a lesser extent, white blood cells and platelets. At a certain stage of the disease, myeloid metaplasia of the spleen joins.

The incidence of polycythemia vera is approximately 1 random per 100,000 population per year and has a clear upward trend in recent years. Men get sick a little more often than women (1.2: 1). The average age of patients is 60 years old, patients under 40 years old make up only 5%.

Etiopathogenesis. Polycythemia vera is a clonal neoplastic disease, which is based on the transformation of the hematopoietic stem cell. Since malignant transformation occurs at the level of a pluripotent stem cell, all three hematopoietic lineages are involved in the process. In patients suffering from PV, there is an increased content of CFU-GEMM (colony-forming units - granulocytic, erythroid, macrophage and megakaryocytic) - precursor cells close to the pluripotent stem cell. In cell culture, these cells actively proliferate in the absence of erythropoietin. A low serum erythropoietin level is a specific feature of PV. In the bone marrow, hyperplasia is observed predominantly of erythroid cells, as well as granulocytic and megakaryocytic sprouts. A characteristic feature is the presence of clusters of polymorphic megakaryocytes (from small to giant). Myelofibrosis is rarely observed at the time of diagnosis, but manifests itself distinctly with a long course of the disease. Gradually there is an increase in the number of reticulin and collagen fibers, myelofibrosis develops and myelopoiesis is reduced. The mass of circulating erythrocytes (MCE) increases, hematocrit rises, blood viscosity increases (there is a significant increase in the content of hemoglobin in the blood (from 180 g / l and above), erythrocytes (from 6.6 x 10 12 / l) and the hematocrit index (from 55 % and above). These factors, along with thrombocytosis, lead to impaired microcirculation and thromboembolic complications. In parallel, myeloid metaplasia of the spleen joins. In PV, there is no specific cytogenetic marker; anomalies.

Clinical picture changes with the course of the disease and is determined mainly by the stage of the disease. In the domestic literature, it is customary to distinguish four stages of PV, which reflect the pathological processes occurring in the bone marrow and spleen of patients.

Stages:

I - initial, asymptomatic (5 years or more):

spleen is not palpable

moderate erythrocytosis

moderate plethora

panmyelosis in the bone marrow

vascular and thrombotic complications are possible but not common

External manifestations of the disease - plethora, acrocyanosis, erythromelalgia (burning pain, paresthesia in the fingertips) and skin itching after washing. An increase in MCE and, consequently, in the volume of circulating blood leads to arterial hypertension. If the patient has previously suffered from hypertension, then there is an increase in blood pressure, antihypertensive therapy becomes ineffective. The manifestations of coronary heart disease, cerebral atherosclerosis are aggravated. Since MCE increases gradually, plethora, an increase in the number of erythrocytes and hemoglobin, signs of a microcirculation disorder in a number of patients appear 2-4 years before the diagnosis is made.

II - erythremic, deployed (10-15 years):

A. Without myeloid metaplasia of the spleen

general condition is disturbed

severe plethora (Hb 200 g/l or more)

thrombotic complications (stroke, myocardial infarction, necrosis of the fingertips)

panmyelosis

erythromelalgia (pain in limbs and bones)

In the picture of peripheral blood, in addition to erythrocytosis, neutrophilia is often present with a shift of the leukocyte formula to the left to single myelocytes, as well as basophilia and thrombocytosis. In the bone marrow, total three-growth hyperplasia with pronounced megakaryocytosis is detected, and reticulin myelofibrosis is possible. But at this stage of the disease, myeloid metaplasia of the spleen (MMS) is still absent, and the observed splenomegaly is due to increased sequestration of erythrocytes and platelets. Vascular complications are more frequent and severe than in the first stage of the disease. In the pathogenesis of thrombosis, an important role is played by an increase in MCE, which leads to an increase in blood viscosity and a slowdown in blood flow, thrombocytosis, and endothelial dysfunction. Ischemia associated with impaired arterial blood flow occurs in 24-43% of patients. Thrombosis of the vessels of the brain, coronary and blood-supplying organs of the abdominal cavity arteries predominate. Venous thrombosis occurs in 25-30% of patients and is the cause of death in about a third of patients with PV. Frequent thrombosis of the veins of the portal system and mesenteric veins. In a number of patients, it is thrombotic complications that become a manifestation of PV. Polycythemia vera may be accompanied by hemorrhagic syndrome: frequent nosebleeds and bleeding after tooth extraction. Hypocoagulation is based on a slowdown in the conversion of fibrinogen to fibrin, which occurs in proportion to an increase in hematocrit, and a violation of blood clot retraction. Erosions and ulcers of the stomach and duodenum are considered as visceral complications of PV.

B. With myeloid metaplasia of the spleen (MMS).

hepatosplenomegaly

plethora is moderately expressed

panmyelosis

increased bleeding

thrombotic complications

Splenomegaly increases, the number of leukocytes increases, the shift of the leukocyte formula to the left becomes more pronounced. In the bone marrow - panmyelosis; gradually develops reticulin and focal collagen myelofibrosis. The number of erythrocytes and platelets is somewhat reduced due to their increased destruction in the spleen, as well as the gradual replacement of hematopoietic tissue with fibrous tissue. At this stage, stabilization of the condition of patients can be observed, the level of hemoglobin, erythrocytes and platelets approaches the norm without therapeutic measures.

III - anemic:

anemic s-m (even pancytopenia)

pronounced myelofibrosis

liver, spleen enlarged

In the bone marrow, collagen myelofibrosis increases and myelopoiesis is reduced. The hemogram shows anemia, thrombocytopenia, pancytopenia. In the clinical picture of the disease, anemic and hemorrhagic syndromes may be present, splenomegaly and cachexia are increasing. The outcome of the disease can be transformation into acute leukemia and myelodysplastic syndrome (MDS).

Diagnostics. Currently, the criteria developed by the American Polycythemia Vera Study Group (PVSG) are used to establish the diagnosis of polycythemia vera. You-

1) an increase in the mass of circulating erythrocytes (more than 36 ml / kg for men and more than 32 ml / kg for women);

2) normal saturation of arterial blood with oxygen (pO2 over 92%);

3) splenomegaly.

1) thrombocytosis (platelet count over 400 x 10 9 /l);

2) leukocytosis (the number of leukocytes is more than 12 x 10 9 / without signs of infection);

3) alkaline phosphatase activity (neutrophils above 100 units in the absence of fever or infection);

4) high content of vitamin B12 (more than 900 pg/ml).

The diagnosis of PV is considered reliable if the patient has all three signs of category A, or if the first and second signs of category A and any two signs of category B are present.

Currently, the characteristic histological picture of the bone marrow is considered the most important diagnostic sign; hyperplasia of cells of erythroid, granulocytic and megakaryocytic sprouts with a predominance of erythroid, accumulations of polymorphic megakaryocytes (from small to giant). Myelofibrosis is rarely observed at the time of diagnosis, but becomes distinct with a long course of the disease.

At stage I, true polycythemia, characterized by isolated erythrocytosis, must be differentiated from secondary erythrocytosis, which is a response to any pathological process in the body and can be both true and relative.

Relative erythrocytosis is a consequence of hemoconcentration, that is, MCE is normal, but the plasma volume is reduced, which is observed when the body is dehydrated (for example, taking diuretics, polyuria in patients with diabetes mellitus, vomiting and diarrhea), loss of a large amount of plasma during burns.

True secondary erythrocytosis (MCE is increased, hematocrit is increased) is due to increased production of erythropoietin. The latter is compensatory in nature and is caused by tissue hypoxia in people living at a considerable height above sea level, in patients with pathology of the cardiovascular and respiratory systems, and in smokers. This category also includes patients with hereditary hemoglobinopathies, characterized by an increased affinity of hemoglobin for oxygen, which is released in the tissues of the body in a smaller amount. Inadequate production of erythropoietin is observed in kidney diseases (hydronephrosis, vascular pathology, cysts, tumors, congenital anomalies), hepatocellular carcinoma, large uterine myoma. An essential differential diagnostic sign is the level of erythropoietin in blood serum.

Treatment. In the initial stages of the disease, it is recommended to use bloodletting, which greatly alleviates the manifestations of the plethoric syndrome. The method of choice for lowering hematocrit (and hemoglobin to normal values) is phlebotomy (exfusion), which is recommended if the hematocrit exceeds 0.54. The goal of treatment is a hematocrit of less than 0.42 for women and 0.45 for men. In modern conditions, bloodletting can be replaced by erythrocytapheresis. In addition, to facilitate bloodletting and prevent thrombotic complications, patients are given courses of antiplatelet therapy (aspirin, reopoliglyukin, etc.). The choice of a treatment method in advanced stage II of PV is perhaps the most difficult task. In addition to erythrocytosis, patients have leukocytosis and thrombocytosis, and the latter can reach very high numbers. Some patients have already experienced any thrombotic complications, and exfusions increase the risk of thrombosis.

When individualizing therapy, the age of patients should be taken into account. So the treatment of patients younger than 50 years, without a history of thrombotic complications and severe hyperthrombocytosis (< 1000,0 х 10 9 /л) может быть ограничено только кровопусканиями в сочетании с терапией аспирином (или без него) в дозе 100-375 мг в день.

Patients over 70 years of age with a history of thrombotic complications and severe hyperthrombocytosis are treated with myelosuppressive drugs. Patients aged 50-70 years without thrombotic complications and severe hyperthrombocytosis may be treated with myelosuppressive agents or phlebotomy, although the latter may increase the risk of thrombotic complications.

Currently, in addition to bloodletting and antiplatelet agents, hydroxyurea and interferon alpha are mainly used for the treatment of PV, less often busulfan, and anagrelide is used abroad. Hydroxyurea may be the drug of choice if patients with PV have severe leukocytosis and thrombocytosis. But for young patients, the use of hydroxyurea is limited by its mutagenic and leucosogenic effects. In addition to hydroxyurea, interferon-alpha is widely used in the treatment of PV. Firstly, IF-a suppresses pathological proliferation well and does not have a leukemogenic effect. Secondly, like hydroxyurea, it significantly reduces the production of platelets and leukocytes. The ability of IF-a to eliminate itching caused by taking water procedures deserves special attention.

Aspirin in a daily dose of 50-250 mg, as a rule, eliminates microcirculation disorders. The use of this drug or other antiplatelet agents for therapeutic or prophylactic purposes is recommended for all patients with PV.

Unfortunately, there is currently no effective treatment for stage III anemic PV. Therapy is limited to palliative care. Anemic and hemorrhagic syndrome is corrected by transfusions of blood components. The effectiveness of hematopoietic stem cell transplantation in patients with PV in the stage of myelofibrosis with splenomegaly and pancytopenia and transformation into acute leukemia or MDS has been reported. Three-year survival of patients after transplantation was 64%.

Forecast. Despite a long and in some cases favorable course, PV is a serious disease and is fraught with fatal complications that reduce the life expectancy of patients. The most common cause of death in patients is thrombosis and embolism (30-40%). In 20-50% of patients in the stage of post-polycythemic myelofibrosis (stage III PV), a transformation into acute leukemia occurs, which has an unfavorable prognosis - a three-year survival rate of only 30%.