home Consultations Polycythemia - stages and symptoms of the disease, hardware diagnostics and methods of therapy. True polycythemia: what is it, treatment, prognosis, symptoms, stages, signs Causes of hemorrhagic syndrome with true polycythemia

Polycythemia - stages and symptoms of the disease, hardware diagnostics and methods of therapy. True polycythemia: what is it, treatment, prognosis, symptoms, stages, signs Causes of hemorrhagic syndrome with true polycythemia

Polycythemia is a disease that can be determined by looking only at a person's face. And if you still conduct a diagnostic examination, then there will be no doubt at all. In the medical literature, you can find other names for this pathology: erythremia, Wakez's disease. Regardless of the term chosen, the disease carries a serious threat to human life. In this article, we will talk in more detail about the mechanism of its occurrence, primary symptoms, stages, and proposed treatments.

general information

Polycythemia vera is a myeloproliferative blood cancer in which it produces red blood cells in excess quantities. To a lesser extent, there is an increase in other enzymatic elements, namely leukocytes and platelets.

Red blood cells (otherwise erythrocytes) saturate all the cells of the human body with oxygen, delivering it from the lungs to the systems of internal organs. They are also responsible for removing carbon dioxide from the tissues and transporting it to the lungs for later exhalation.

Red blood cells are continuously produced in the bone marrow. It is a collection of spongy tissues, localized inside the bones and is responsible for the process of hematopoiesis.

Leukocytes are white blood cells that help fight various infections. Platelets are fragments that are activated when the integrity of blood vessels is violated. They have the ability to stick together with each other and clog the hole, thereby stopping the bleeding.

Polycythemia vera is characterized by excessive production of red blood cells.

Disease prevalence

This pathology is usually diagnosed in adult patients, but can occur in adolescents and children. For a long time, the disease may not make itself felt, that is, it may be asymptomatic. According to studies, the average age of patients varies from 60 to approximately 79 years. Young people get sick much less often, but the disease is much more severe for them. The representatives of the stronger sex, according to statistics, are several times more likely to be diagnosed with polycythemia.

Pathogenesis

Most of the health problems associated with this disease are due to the continuous increase in the number of red blood cells. As a result, the blood becomes excessively thick.

On the other hand, its increased viscosity provokes the formation of clots (thrombi). They can interfere with normal blood flow through the arteries and veins. This situation often causes strokes and heart attacks. The thing is that thick blood flows several times slower through the vessels. The heart has to work harder to literally push it through.

The slowdown in blood flow does not allow the internal organs to receive the necessary amount of oxygen. This entails the development of heart failure, headaches, angina pectoris, weakness and other health problems that are not recommended to be ignored.

Disease classification

I. Initial stage.

Lasts 5 years or more.
The spleen is of normal size.
Blood tests show a moderate increase in the number of red blood cells.
Complications are extremely rare.

II A. Polycythemic stage.

Duration from 5 to approximately 15 years.
There is an increase in some organs (spleen, liver), bleeding and thrombosis.
There are no sites in the spleen itself.
Bleeding can cause iron deficiency in the body.
In the blood test, there is a persistent increase in erythrocytes, leukocytes and platelets.

II B. Polycythemic stage with myeloid metaplasia of the spleen.

Analyzes show an increased content of all blood cells, except for lymphocytes.
There is a tumor process in the spleen.
In the clinical picture appears exhaustion, thrombosis, bleeding.
In the bone marrow there is a gradual formation of scars.

III. anemic stage.

In the blood, there is a sharp decrease in erythrocytes, platelets and leukocytes.
There is a pronounced increase in the size of the spleen and liver.
This stage usually develops 20 years after the diagnosis is confirmed.
The disease can transform into acute or chronic leukemia.

Causes of the disease

Unfortunately, at present, experts cannot say which factors lead to the development of such a disease as polycythemia vera.

Most tend to the virus-genetic theory. According to her, special viruses (there are about 15 of them in total) are introduced into the human body and, under the influence of certain factors that negatively affect immune defense, penetrate into the cells of the bone marrow and lymph nodes. Then, instead of maturation, these cells begin to rapidly divide and multiply, forming more and more new fragments.

On the other hand, the cause of polycythemia may be hidden in hereditary predisposition. Scientists have proven that close relatives of a sick person, as well as people with violations of the structure of chromosomes, are more susceptible to this disease.

Factors predisposing to the onset of the disease

X-ray exposure, ionizing radiation.
Intestinal infections.
Viruses.
Tuberculosis.
Surgical interventions.
Frequent stress.
Long-term use of certain groups of drugs.

Clinical picture

Starting from the second stage of the development of the disease, literally all systems of internal organs are involved in the pathological process. Below we list the subjective sensations of the patient.

Weakness and haunting tiredness.
Increased sweating.
Noticeable decrease in performance.
Severe headaches.
Memory deterioration.

Polycythemia vera may also be accompanied by the following symptoms. In each case, their severity varies.

Diagnostics

First of all, the doctor collects a complete anamnesis. He can ask a number of clarifying questions: when exactly did the malaise / shortness of breath / painful discomfort, etc. appear. It is equally important to determine the presence of chronic ailments, bad habits, and possible contact with toxic substances.

Then a physical examination is performed. The specialist determines the color of the skin. By palpation and percussion reveals an enlarged spleen or liver.

Blood tests are required to confirm the disease. If the patient has this pathology, the test results may be as follows:

An increase in the number of red blood cells.
Elevated hematocrit (percentage of red blood cells).
High levels of hemoglobin.
Low level of erythropoietin. This hormone is responsible for stimulating the bone marrow to produce new red blood cells.

Diagnosis also includes brain aspiration and biopsy. The first version of the study involves the collection of the liquid part of the brain, and a biopsy of the solid component.

Polycythemia disease is confirmed by gene mutation tests.

What should be the treatment?

It is not possible to completely overcome a disease such as polycythemia vera. That is why therapy focuses solely on reducing clinical manifestations and reducing thrombotic complications.

Patients are given bloodletting first. This procedure involves the removal of a small amount of blood (from 200 to approximately 400 ml) for therapeutic purposes. It is necessary to normalize the quantitative parameters of blood and reduce its viscosity.

Patients are usually prescribed "Aspirin" to reduce the risk of developing various kinds of thrombotic complications.

Chemotherapy is used to maintain a normal hematocrit when there is severe itching or increased thrombocytosis.

Bone marrow transplantation in this disease is extremely rare, since this pathology, in the case of adequate therapy, is not deadly.

It should be noted that the specific treatment regimen in each case is selected individually. The above therapy is for informational purposes only. It is not recommended to try to cope with this disease on your own.

Possible Complications

This disease is quite serious, so do not neglect its treatment. Otherwise, the likelihood of unpleasant complications increases. These include the following:

Forecast

Wakez disease is a rare disease. Symptoms that appear in the early stages of its development should be the reason for immediate examination and subsequent therapy. In the absence of adequate treatment, if the disease was not diagnosed in a timely manner, death occurs. The main cause of death is most often vascular complications or the transformation of the disease into chronic leukemia. However, competent therapy and strict adherence to all the recommendations of the doctor can significantly extend the life of the patient (by 15-20 years).

We hope that all the information presented in the article will be really useful for you. Be healthy!

Polycythemia (synonymous with Wakez's disease) is a chronic disease of the hematopoietic system, characterized by a persistent increase in the amount of total blood volume, and increased production in the bone marrow of not only erythrocytes, but also leukocytes and.

Polycythemia belongs to the group of leukemias. Pathological anatomy reveals a sharp plethora of internal organs, often vascular thrombi, heart attacks, hemorrhages. In the bone marrow, the phenomena of hyperplasia (an increase in cellular elements) of an erythroblastic germ, in the diaphysis of long bones - the transformation of fatty bone marrow into red.

Polycythemia develops gradually and has a progressive course. Clinically manifested by dark red skin with a cyanotic tint, plethora of mucous membranes with possible bleeding from the gums, stomach, intestines, uterus, enlarged spleen and liver, hypertension. In the blood, the content of erythrocytes (6,000,000-10,000,000), hemoglobin (20-23 g%) is increased, it is slowed down to 1 mm in 1 or even 2 hours.

The course of the process is long, the prognosis worsens if the vessels of vital organs develop.

Treatment - in a hospital with repeated bloodletting, cytostatic drugs (myelosan, imifos, myelobromol).

Polycythemia red, true (polycythaemia, rubra, vera; from Greek poly - many, kytos - cell and haima - blood; synonym: erythremia, Wakez's disease) - a chronic disease of the hematopoietic apparatus of unknown etiology, characterized by a persistent increase in the number of red blood cells and total blood volume with the expansion of the bloodstream, an increase in the spleen and increased activity of the bone marrow, and the hyperplastic process concerns not only erythropoiesis, but also leuko- and thrombocytopoiesis.

Recently, the neoplastic theory of pathogenesis has been established. Polycythemia is considered an independent disease and belongs to the group of myeloproliferative leukemias, considering it as chronic erythromyelosis (see) with a predominant increase in the function of erythropoiesis.

Pathological anatomy reveals a sharp plethora of internal organs, often vascular thrombi, heart attacks, hemorrhages. The spleen is enlarged, hard, dark blue-red. The liver is often enlarged and may be cirrhotic. In the diaphysis of tubular bones - the transformation of fatty bone marrow into red. Hyperplasia of an erythroblastic germ in the bone marrow and in extramedullary foci of hematopoiesis retains the usual type of regeneration, hyperplasia of myeloid tissue sometimes becomes similar to leukemic. Significant hyperplasia of the megakaryocytic apparatus. These changes are also detected in the clinic with sternal puncture and more clearly with trepanobiopsy of the ilium.

Clinical course and symptoms. Polycythemia develops most often in old age (40-60 years), however, cases of the disease in young and even childhood have been described. The disease usually develops gradually. The life expectancy of patients from the moment of detection of the disease now reaches an average of 13.3 years [Lawrence (J. N. Lawrence)], and in some cases even up to 30 years or more (E. D. Oak and M. A. Yasinovsky).

A special color of the integument (erythrosis) is typical: intense dark red with a cherry tint, skin color, especially pronounced on the face and distal parts of the limbs; mucous membranes are bright red, often cyanotic; the injection of scleral vessels is noticeable, the gums are loosened, often bleed, periodontal disease is detected. Plethora with an increase in the mass of circulating blood by 2-4 times, with an increase in its viscosity significantly affects the state of the cardiovascular system and blood circulation, the blood flow rate decreases by 2-3 times or more. Hypertension is one of the most important and frequent symptoms of polycythemia. It is impossible to exclude the combination of polycythemia with hypertension. Of great importance are lesions of peripheral vessels with the development of obliterating thromboangiitis, and sometimes blockage of arteries with gangrene, thrombosis of cerebral vessels, coronary arteries, splenic and renal arteries with the formation of heart attacks, thrombosis of the portal vein and its branches. There are bleeding from the nose, gums, stomach, intestines, uterus, etc., hemorrhages in the brain, abdominal cavity, spleen.

Violations of the nervous system occur from the very beginning of the disease. According to the totality of neurological symptoms, separate syndromes can be distinguished: cerebrovascular insufficiency, neurasthenic, diencephalic, vegetative-vascular, polyneuritic and erythromelalgia.

Splenomegaly is observed in 2/3-3/4 of all cases. Enlargement and thickening of the liver is noted in 1/3-1/2 patients.

There are no marked changes in the condition of the kidneys.

The number of erythrocytes in 1 ml3 of blood is usually 6-10 million, in some cases - 12 million. The percentage of reticulocytes is relatively low. The content of hemoglobin reaches 120-140% (20-23 g%), rarely higher. The color index is below one. The number of leukocytes is increased (in more than 1/2 of patients) and sometimes reaches 20,000-25,000 or more per 1 mm 3, mainly due to neutrophils with a shift to the left to metamyelocytes and myelocytes. The greatest number of leukocytes and the appearance of younger forms is observed with the development of myeloid leukemia. The number of platelets also increases for the most part - up to 600,000 and even sometimes up to 1 million or more in 1 mm 3. ROE is slowed down to 1 mm for 1 and even 2 hours. The ratio between the mass volume of erythrocytes and plasma, determined using hematocrit, increases to 85:15. Quite frequent are pains in the bones with a change in the structure of their tissue, especially in the epimetaphyses of long tubular bones.

In the early stages, the appearance of neurovascular disorders acquires diagnostic value. With a pronounced picture of polycythemia, recognition is primarily based on the classic triad: erythrosis, polyglobulia, splenomegaly. Polycythemia should be distinguished from a number of conditions that are also characterized by an increase in the number of red blood cells per unit volume of blood - the so-called polyglobulia, or erythrocytosis. False polyglobulia is not associated with a real increase in the number of red blood cells in the peripheral blood, but occurs due to thickening of the blood, for example, with significant diarrhea and vomiting (for example, with cholera), increased sweating, and profuse diuresis. Symptomatic polyglobulia can be relative when the number of erythrocytes in the peripheral blood increases, mainly due to their redistribution (when deposited blood is released), for example, during rapid ascent to altitude, acute heart and lung failure.

True absolute polyglobulia with a reactive increase in bone marrow erythropoiesis is of particular importance in differential diagnosis. Most often, it is associated with a prolonged anoxic state: in residents of highlands, with congenital heart defects, acquired defects with severe circulatory failure, sclerosis of the branches of the pulmonary artery, pneumosclerosis, pronounced emphysema and other lung diseases. This includes polyglobulia when exposed to toxic substances on hematopoiesis. They become important in the occurrence of polyglobulia and damage to the central nervous system (for example, the subthalamic region) by an inflammatory or neoplastic process, some endocrine disorders (Itsenko-Cushing's syndrome), etc. In the differential diagnosis between polycythemia and polyglobulia, an increase in the spleen, leukocytosis with a neutrophilic shift to the left indicate in favor of polycythemia , thrombocytosis, a significant increase in the total mass of blood and especially erythrocytes with a high hematocrit, trephine biopsy data, a significant increase in the activity of neutrophil alkaline phosphatase, a high rate of Fe69 absorption from plasma, etc.

The prognosis, given the progressive nature of the course of the disease, the absence of spontaneous remissions and spontaneous cure, is generally unfavorable, although with modern therapy, life and working capacity are preserved longer. The cause of death is most often vascular complications - thrombosis, hemorrhage, bleeding, circulatory failure or transition to the picture of myelosis or, more rarely, to hemocytoblastosis, to aplastic anemia due to the development of myelofibrosis and osteomyelosclerosis.

Treatment is pathogenetic. Bloodletting (usually 400-500 ml repeatedly at intervals of 2-3-5 days until a clear decrease in red blood values) is especially indicated for high blood pressure, the threat of cerebral complications and high hematocrit. This method gives relief only for the next few months, and is often used in combination with radiophosphorus therapy.

Radiation therapy is the most effective. It is more expedient to irradiate the entire body with X-rays.

In recent years, widely used radioactive phosphorus (P 32), which is administered on an empty stomach through the mouth in the form of NaHP 32 O 4 in 20-40 ml of 40% glucose solution, can also be used intravenously. Contraindications to the use of P 32 - liver disease with significant dysfunction, kidney disease, leukopenia (below 4000 in 1 mm 3), thrombocytopenia (below 150,000 in 1 mm 3).

Fractional administration of P 32 is more widespread (to receive 1.5 - 2 microcuries once every 4-7-10 days, in total for a course of 6-8 microcuries in accordance with the indicators of red blood and the weight of the patient). Prior to treatment with P 32, it is recommended to carry out 2-3 phlebotomies of 400-500 ml at intervals of 2-3 days, especially in patients with severe symptoms of cerebrovascular accident, the number of red blood cells above 7.5-8 million in 1 mm 3 and high indicators of hematocrit (65-70).

The clinical effect is felt already after 2-4 weeks, and hematological remission occurs after 2-4 months. after the start of treatment and usually lasts 2-3 years or more.

In the treatment of P 32, complications in the form of leukopenia, thrombocytopenia, and less often anemia, which are transient, can be observed.

Repeated courses of treatment with P 32 are prescribed for relapses of the disease.

Polycythemia vera (primary polycythemia, Wakez's disease, erythremia) is the most common disease in the group of chronic myeloproliferative diseases. The pathological process mainly affects the erythroblastic bone marrow, which causes an increase in the number of erythrocytes in the peripheral blood, as well as an increase in the viscosity and mass of the circulating blood (hypervolemia).

The disease occurs predominantly in the elderly (average age of onset is approximately 60 years), but is also diagnosed in young people and children. For younger patients, a more severe course of the disease is characteristic. Men are slightly more prone to polycythemia vera than women, but young patients are characterized by an inverse proportion.

Causes and risk factors

The causes contributing to the occurrence of true polycythemia have not been finally established. Pathology can be both hereditary and acquired. Found family predisposition to the disease. In patients with true polycythemia, gene mutations are detected that are inherited in an autosomal recessive manner.

Risk factors include:

impact on the body of toxic substances;
ionizing radiation;
x-ray exposure;
extensive burns;
long-term use of a number of drugs (gold salts, etc.);
advanced forms of tuberculosis;
distress;
viral diseases;
tumor neoplasms;
smoking;
endocrine disorders caused by tumors of the adrenal glands;
heart defects;
diseases of the liver and / or kidneys;
extensive surgical interventions.

Forms of the disease

Polycythemia vera is of two types:

primary (not a consequence of other pathologies);
secondary (develops against the background of other diseases).

Without adequate therapy for polycythemia vera, 50% of patients die within 1-1.5 years from the time of diagnosis.

Stages of the disease

There are three stages in the clinical picture of polycythemia vera:

Initial (malosymptomatic) - clinical manifestations are insignificant, duration is about 5 years.
The erythremic (extended) stage lasting 10–20 years, in turn, is divided into substages: IIA - myeloid metaplasia of the spleen is absent; IIB - the presence of myeloid metaplasia of the spleen;
Stage of posterythremic myeloid metaplasia (anemic) with or without myelofibrosis; capable of developing into chronic or acute leukemia.

Symptoms

Polycythemia vera is characterized by a long asymptomatic course. The clinical picture is associated with an increased production of red blood cells in the bone marrow, which is often accompanied by an increase in the number of other cellular elements in the blood. An increase in platelet count leads to vascular thrombosis, which can cause strokes, myocardial infarction, transient ischemic attacks, etc.

In the later stages of the disease, there may be:

skin itching, aggravated by exposure to water;
bouts of pressing pain behind the sternum during physical exertion;
weakness, increased fatigue;
memory disorder;
headaches, dizziness;
erythrocyanosis;
eye redness;
visual impairment;
increased blood pressure;
spontaneous bleeding, ecchymosis, gastrointestinal bleeding;
varicose veins (especially neck veins);
short-term intense pain in the fingertips;
stomach ulcer and / or duodenal ulcer;
joint pain;
heart failure.

Diagnostics

The diagnosis of polycythemia vera is established on the basis of data obtained during the examination:

collection of anamnesis;
objective examination;
general and biochemical blood test;
general urine analysis;
trepanobiopsy followed by histological analysis of the biopsy;
ultrasound examination;
computed or magnetic resonance imaging;
molecular genetic analysis.

A blood test for polycythemia vera shows an increase in the number of red blood cells

Diagnostic criteria for polycythemia vera:

increased mass of circulating erythrocytes: in men - more than 36 ml / kg, in women - more than 32 ml / kg;
leukocytes - 12 × 10 9 / l and more;
platelets - 400 × 10 9 / l and more;
increase in hemoglobin up to 180–240 g/l;
an increase in oxygen saturation in arterial blood - 92% or more;
an increase in the serum content of vitamin B 12 - 900 pg / ml or more;
increased activity of alkaline phosphatase of leukocytes up to 100;
splenomegaly.

The disease occurs predominantly in the elderly (average age of onset is approximately 60 years), but is also diagnosed in young people and children.

Differential diagnosis is required with absolute and relative (false) erythrocytosis, neoplasms, hepatic vein thrombosis.

Treatment

Treatment of polycythemia vera is aimed primarily at preventing the development of leukemia, as well as the prevention and / or therapy of thrombohemorrhagic complications. Symptomatic therapy is carried out in order to improve the patient's quality of life.

To reduce blood viscosity in hyperviscosity syndrome, a course of phlebotomy (exfusion, bloodletting) is performed. However, with initially high thrombocytosis, phlebotomy can contribute to the occurrence of thrombotic complications. Myelosuppressive therapy is indicated for patients who do not tolerate bloodletting, as well as in childhood and adolescence.

Interferon preparations are prescribed for a long course (2-3 months) to reduce myeloproliferation, thrombocythemia, and also to prevent the development of vascular complications.

With the help of hardware methods of therapy (erythrocytapheresis, etc.), excess blood cells are removed. In order to prevent thrombosis, anticoagulants are prescribed. To reduce the manifestations of itching, antihistamines are used. In addition, patients are advised to adhere to a dairy-vegetarian diet and limit physical activity.

With a pronounced increase in the size of the spleen (hypersplenism), splenectomy is indicated for patients.

Possible complications and consequences

Polycythemia vera can be complicated by:

Forecast

With timely diagnosis and treatment, survival exceeds 10 years. Without adequate therapy, 50% of patients die within 1-1.5 years from the moment of diagnosis.

Prevention

Due to the fact that the exact causes of the disease are unclear, effective methods for the prevention of polycythemia vera have not yet been developed.

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Erythremia (polycythemia vera, Wakez's disease) is a hereditary disease of the blood system, occurring mainly in elderly women.

An increase in the number of red blood cells in polycythemia vera

This pathology is characterized by malignant hypertrophy of the bone marrow. Most often, this pathology is known to patients as blood cancer (although such a judgment is erroneous) and leads to a progressive increase in the number of blood cells, primarily red blood cells (the number of other elements also increases). As a result of an increase in their number, an increase in hematocrit is observed, which leads to a decrease in the rheological properties of blood, a decrease in the rate of blood flow through the vessels, and as a result, an increase in thrombus formation and deterioration in tissue supply.

These reasons lead to the fact that most tissues experience oxygen starvation, which reduces their functional activity (ischemic syndrome). Polycythemia vera occurs mainly in women. Men get sick a little less often, the frequency of occurrence of this pathology is approximately 3:2.

On average, Wakez disease occurs around the age of 40, and the peak of symptoms occurs in the 60s and 70s. There is a hereditary predisposition to the disease. In the population, erythremia is quite rare - about 30 cases per million population.

The main symptoms of the disease

Erythremia is an excessive saturation of the blood with red blood cells, which leads to various tissue and vascular disorders. Among the most common symptoms are:

Among the general symptoms, if erythremia occurs, headache, dizziness, a feeling of heaviness in the head, tinnitus, general weakness syndrome (all symptoms are due to a decrease in tissue oxygenation, impaired blood circulation in certain parts of the body) come first. When diagnosing, they are not used as mandatory criteria, since they can correspond to any systemic disease.

Stages and degrees of polycythemia

True polycythemia occurs in three stages (stages):

stage of initial manifestations. At this stage, the patient does not present specific complaints. He is concerned about general weakness, increased fatigue, a feeling of discomfort in the head. All these symptoms are most often attributed to overwork, social and life problems, which is why the disease itself is diagnosed quite late;
extended stage (clinical stage). At this stage, the appearance of a headache, discoloration of the skin and mucous membranes is characteristic. The pain syndrome develops quite late and indicates the neglect of the disease;
terminal stage. At this stage, damage to internal organs due to their ischemia, dysfunction of all body systems are most pronounced. There may be a lethal outcome due to secondary pathology.

All stages proceed sequentially, and the diagnosis of the disease (blood test) becomes informative from the stage of clinical signs.

Diagnosis of Wakez disease

To make a diagnosis, a complete blood count plays a decisive role. It shows pronounced erythrocytosis, an increase in hemoglobin and hematocrit. The most reliable is the analysis of bone marrow punctate, which reveals signs of hyperplasia of the erythroid germ, and also calculates how many cells are present in it and what is their morphological distribution.

To clarify the nature of concomitant pathology, it is recommended to conduct a biochemical analysis, which provides information about the state of the liver and kidneys. With massive thrombosis, the state of blood coagulation factors is assessed by analyzing it for coagulability - a coagulogram.

Other studies (ultrasound, CT, MRI) give only an indirect idea of the state of the body and are not used in making a diagnosis.

Treatment of erythremia

Despite the variety and severity of the manifestations of Wakez disease, there are relatively few treatments for it. It depends on what the analysis of the hemogram showed, whether a cytological syndrome has developed and what symptoms the patient has.

As mentioned above, the cause of the disease is an increased concentration of blood cells (especially red blood cells), which develops due to bone marrow hyperplasia. In this regard, the correct analysis of the paths of the development of the disease allows us to determine the basic principles of pathogenetic treatment, which include a decrease in the number of blood cells and an impact directly on the places of their formation. This is achieved through the following treatments:

Such treatment should be accompanied by the appointment of antiplatelet drugs such as aspirin, chimes, clopidogrel or anticoagulants (heparin). The use of these drugs with one of the procedures significantly increases the effectiveness of therapy than using them separately.

It is also recommended to add some cytostatic drugs (if the cause of bone marrow hyperplasia is cancer), interferons (with the development of secondary viral complications) or hormones (mainly dexamethasone and prednisolone are used) to the treatment regimens, which improves the prognosis of the disease.

Complications, consequences and prognosis

All complications of the disease are due to the development of vascular thrombosis. As a result of their blockage, infarcts of internal organs (heart, liver, spleen, brain), obliterating atherosclerosis (with thrombosis of vessels of the lower extremities affected by atherosclerotic plaques) can develop. An excess of hemoglobin in the blood provokes the development of hemochromatosis, urolithiasis or gout.

All of them develop secondarily and require the elimination of the main cause - erythrocytosis, for the most effective cure.

As for the prognosis of the disease, much depends on the age at which treatment was started, what methods were used, and whether they were effective.

As mentioned at the beginning, polycythemia vera tends to develop later. If the appearance of the main symptoms in young people (aged 25 to 40 years) is observed, then the disease proceeds malignantly, that is, the prognosis is unfavorable, and secondary complications develop much faster. Accordingly, the later the development of the disease is observed, the more benignly it proceeds. In the case when adequately prescribed drugs are used, the period and life of patients is significantly improved. Such patients can live normally with their disease for quite a long time (up to several decades).

Answering the question, what could be the outcome of erythremia, it should be noted that it all depends on:

what secondary processes have developed
what are their reasons
how long have they existed
whether polycythemia vera was diagnosed in a timely manner and the necessary treatment was started.

Most often, due to damage to the liver and spleen, there is a transition from polycythemia to the chronic form of myeloid leukemia. The life expectancy with it remains almost the same, and with the right selection of drugs it can reach tens of years (forecast regarding

Polycythemia vera (erythremia, Wakez's disease or primary polycythemia) is a progressive malignant disease belonging to the group of leukemias, which is associated with hyperplasia of the cellular elements of the bone marrow (myeloproliferation). The pathological process affects mainly the erythroblastic germ, therefore, an excess number of red blood cells is detected in the blood. There is also an increase in the number of neutrophilic leukocytes and platelets.

ICD-10	D45
ICD-9	238.4
ICD-O	M9950/3
Medline Plus	000589
MeSH	D011087

An increased number of red blood cells increases the viscosity of the blood, increases its mass, causes a slowdown in blood flow in the vessels and the formation of blood clots. As a result, patients develop impaired blood supply and hypoxia.

General information

True polycythemia was first described in 1892 by French and Vaquez. Vakez suggested that hepatosplenomegaly and erythrocytosis revealed in his patient arose as a result of increased proliferation of hematopoietic cells, and singled out erythremia as a separate nosological form.

In 1903, W. Osler used the term "Wakez's disease" to describe patients with splenomegaly (enlarged spleen) and severe erythrocytosis and gave a detailed description of the disease.

Turk (W. Turk) in 1902-1904 suggested that in this disease, the violation of hematopoiesis is hyperplastic in nature, and called the disease erythremia by analogy with leukemia.

The clonal neoplastic nature of myeloproliferation, which is observed in polycythemia, was proved in 1980 by P. J. Fialkov. He found in erythrocytes, granulocytes and platelets one type of enzyme glucose-6-phosphate dehydrogenase. In addition, both types of this enzyme were detected in lymphocytes of two patients heterozygous for this enzyme. Thanks to Fialkov's research, it became clear that the target of the neoplastic process is the precursor cell of myelopoiesis.

In 1980, a number of researchers managed to separate a neoplastic clone from normal cells. It has been experimentally proven that in polycythemia, a population of erythroid committed precursors is formed, which have a pathologically high sensitivity to even a small amount of erythropoietin (kidney hormone). According to scientists, this contributes to the increased production of red blood cells in polycythemia vera.

In 1981, L. D. Sidorova and co-authors conducted studies that made it possible to detect qualitative and quantitative changes in the platelet link of hemostasis, which play a major role in the development of hemorrhagic and thrombotic complications in polycythemia.

Polycythemia vera occurs predominantly in the elderly, but can also occur in young people and children. In young people, the disease is more severe. The average age of patients varies from 50 to 70 years. The average age of those who fell ill for the first time is gradually increasing (in 1912 it was 44 years, and in 1964 - 60 years). The number of patients under 40 years of age is about 5%, and erythremia in children and patients under 20 years of age is detected in 0.1% of all cases of the disease.

Erythremia is somewhat less common in women than in men (1: 1.2-1.5).

It is the most common disease in the group of chronic myeloproliferative diseases. It is quite rare - according to various sources, from 5 to 29 cases per 100,000 population.

There are sporadic data on the influence of racial factors (above average among Jews and below average among representatives of the Negroid race), but at the moment this assumption has not been confirmed.

Forms

True polycythemia is divided into:

Primary (not a consequence of other diseases).
Secondary. It can be triggered by chronic lung disease, hydronephrosis, the presence of tumors (uterine fibroids, etc.), the presence of abnormal hemoglobins, and other factors associated with tissue hypoxia.

An absolute increase in the mass of erythrocytes is observed in all patients, but only in 2/3 the number of leukocytes and platelets also increases.

Reasons for development

The causes of polycythemia vera have not been definitively established. Currently, there is no single theory that would explain the occurrence of hemoblastoses (blood tumors), which include this disease.

Based on epidemiological observations, a theory was put forward about the relationship of erythremia with the transformation of stem cells, which occurs under the influence of gene mutations.

It has been established that most patients have a mutation of the Janus kinase tyrosine kinase enzyme synthesized in the liver, which is involved in the transcription of certain genes by phosphorylation of many tyrosines in the cytoplasmic part of the receptors.

The most common mutation discovered in 2005 is in exon 14 JAK2V617F (detected in 96% of all cases of the disease). In 2% of cases, the mutation affects exon 12 of the JAK2 gene.

Patients with polycythemia vera also have:

In some cases, mutations in the thrombopoietin receptor gene MPL. These mutations are of secondary origin and are not strictly specific for this disease. They are detected in elderly people (mainly in women) with low levels of hemoglobin and platelets.
Loss of function of the LNK gene of the SH2B3 protein, which reduces the activity of the JAK2 gene.

Elderly patients with a high JAK2V617F allelic load are characterized by elevated hemoglobin levels, leukocytosis, and thrombocytopenia.

When the JAK2 gene is mutated in exon 12, erythremia is accompanied by a subnormal serum level of the hormone erythropoietin. Patients with this mutation are younger.
In polycythemia vera, mutations in TET2, IDH, ASXL1, DNMT3A, and others are often also detected, but their pathogenetic significance has not yet been studied.

There were no differences in the survival of patients with different types of mutations.

As a result of molecular genetic disorders, the JAK-STAT signaling pathway is activated, which is manifested by the proliferation (production of cells) of the myeloid germ. At the same time, proliferation and an increase in the number of erythrocytes in the peripheral blood increase (an increase in the number of leukocytes and platelets is also possible).

The identified mutations are inherited in an autosomal recessive manner.

There is also a hypothesis according to which viruses can be the cause of erythremia (15 types of such viruses have been identified), which, in the presence of predisposing factors and weakened immunity, penetrate immature bone marrow cells or lymph nodes. Instead of maturation, cells affected by the virus begin to actively divide, thus starting the pathological process.

Disease-causing factors include:

x-ray exposure, ionizing radiation;
paints, varnishes and other toxic substances that penetrate the human body;
long-term use for medicinal purposes of certain drugs (gold salts for rheumatoid arthritis, etc.);
viral and intestinal infection, tuberculosis;
surgical interventions;
stressful situations.

Secondary erythremia develops under the influence of favorable factors with:

high innate affinity of hemoglobin for oxygen;
low levels of 2,3-diphosphoglycerate;
autonomous production of erythropoietin;
arterial hypoxemia of a physiological and pathological nature (“blue” heart defects, smoking, adaptation to high altitude conditions and chronic lung diseases);
kidney diseases (cystic lesions, hydronephrosis, renal artery stenosis and diffuse diseases of the renal parenchyma);
the presence of tumors (possibly influenced by bronchial carcinoma, cerebellar hemangioblastoma, uterine fibroids);
endocrine diseases associated with tumors of the adrenal glands;
liver diseases (cirrhosis, hepatitis, hepatoma, Budd-Chiari syndrome);
tuberculosis.

Pathogenesis

The pathogenesis of polycythemia vera is associated with a violation of the process of hematopoiesis (hematopoiesis) at the level of the progenitor cell. Hemopoiesis acquires the unlimited proliferation of a progenitor cell characteristic of a tumor, the descendants of which form a specialized phenotype in all hematopoietic lineages.

Polycythemia vera is characterized by the formation of erythroid colonies in the absence of exogenous erythropoietin (the appearance of endogenous erythropoietin-independent colonies is a sign that distinguishes erythremia from secondary erythrocytosis).

The formation of erythroid colonies indicates a violation of the implementation of regulatory signals that the myeloid cell receives from the external environment.

The basis of the pathogenesis of true polycythemia are defects in the genes encoding proteins that are responsible for maintaining myelopoiesis within the normal range.

A decrease in the concentration of oxygen in the blood causes a reaction of the interstitial cells of the kidneys that synthesize erythropoietin. The process that takes place in interstitial cells concerns the work of many genes. The main regulation of this process is carried out by factor-1 (HIF-1), which is a heterodimeric protein consisting of two subunits (HIF-1alpha and HIF-1beta).

If the oxygen concentration in the blood is within the normal range, proline residues (a heterocyclic amino acid of the free-existing HIF-1 molecule) are hydroxylated under the influence of the regulatory enzyme PHD2 (molecular oxygen sensor). Due to hydroxylation, the HIF-1 subunit acquires the ability to bind to the VHL protein, which provides tumor prevention.

The VHL protein forms a complex with a number of E3 ubiquitin ligase proteins, which, after the formation of covalent bonds with other proteins, are directed to the proteasome and degraded there.

Under hypoxia, hydroxylation of the HIF-1 molecule does not occur, the subunits of this protein combine and form a heterodimeric HIF-1 protein, which is directed from the cytoplasm to the nucleus. The protein that has entered the nucleus binds in the promoter regions of genes with special DNA sequences (the conversion of genes into protein or RNA is induced by hypoxia). As a result of these transformations, erythropoietin is released into the bloodstream by the interstitial cells of the kidneys.

Myelopoiesis precursor cells carry out their genetic program as a result of the stimulating effect of cytokines (these small peptide control (signal) molecules bind to the corresponding receptors on the surface of precursor cells).

When erythropoietin binds to the EPO-R erythropoietin receptor, this receptor dimerizes, which activates the kinase associated with intracellular EPO-R domains Jak2.

Jak2 kinase is responsible for signal transduction from erythropoietin, thrombopoietin and G-CSF (it is a granulocyte colony stimulating factor).

The activation of Jak2 kinase results in phosphorylation of a number of cytoplasmic target proteins, which include adapter proteins of the STAT family.

Erythremia was detected in 30% of patients with constitutive activation of the STAT3 gene.

Also, with erythremia, in some cases, a reduced level of expression of the MPL thrombopoietin receptor, which is compensatory in nature, is detected. The decrease in MPL expression is secondary and is caused by a genetic defect responsible for the development of polycythemia vera.

A decrease in degradation and an increase in the level of the HIF-1 factor are caused by defects in the VHL gene (thus, representatives of the population of Chuvashia are characterized by a homozygous mutation 598C>T of this gene).

Polycythemia vera can be caused by chromosome 9 abnormalities, but the most common is a deletion of the long arm of chromosome 20.

In 2005, a point mutation of exon 14 of the Jak2 kinase gene (mutation JAK2V617F) was identified, which causes the replacement of the amino acid valine by phenylalanine in the JH2 pseudokinase domain of the JAK2 protein at position 617.

The JAK2V617F mutation in hematopoietic precursor cells in erythremia is presented in a homozygous form (the formation of the homozygous form is affected by mitotic recombination and duplication of the mutant allele).

With the activity of JAK2V617F and STAT5, the level of reactive oxygen species increases, resulting in a transition of the cell cycle from G1 to S phase. phase G1 in S. As a result, the proliferation of erythroid cells that carry the mutant form of the JAK2 gene is enhanced.

In JAK2V617F-positive patients, this mutation is detected in myeloid cells, in B- and T-lymphocytes, and natural killer cells, which proves the proliferative advantage of defective cells compared to the norm.

Polycythemia vera in most cases is characterized by a rather low ratio of the mutant and normal allele in mature myeloid cells and early precursors. In the presence of clonal dominance, patients have a more severe clinical picture compared to patients without this defect.

Symptoms

The symptoms of polycythemia vera are associated with an overproduction of red blood cells, which increase the viscosity of the blood. In most patients, the level of platelets also increases, which cause vascular thrombosis.

The disease develops very slowly and is asymptomatic at the initial stage.
In later stages, polycythemia vera manifests itself:

plethoric syndrome, which is associated with increased blood supply to organs;
myeloproliferative syndrome, which occurs when there is an increased production of red blood cells, platelets and white blood cells.

Plethoric syndrome is accompanied by:

Headaches.
Feeling of heaviness in the head;
Vertigo.
Attacks of pressing, squeezing pain behind the sternum, which occurs during physical exertion.
Erythrocyanosis (reddening of the skin to a cherry hue and a bluish tint of the tongue and lips).
Redness of the eyes, which occurs as a result of the expansion of blood vessels in them.
Feeling of heaviness in the upper abdomen (left) due to an enlarged spleen.
Skin itching, which is observed in 40% of patients (a specific sign of the disease). It intensifies after water procedures and occurs as a result of irritation by the breakdown products of erythrocytes of nerve endings.
An increase in blood pressure, which is well reduced with bloodletting and slightly reduced with standard treatment.
Erythromelalgia (sharp, burning pain in the fingertips that improves with blood-thinning drugs, or painful swelling and redness of the foot or lower third of the leg).

Myeloproliferative syndrome manifests itself:

soreness in flat bones and joint pain;
a feeling of heaviness in the right upper abdomen as a result of an enlarged liver;
general weakness and increased fatigue;
an increase in body temperature.

There are also dilated veins, especially noticeable in the neck, Cooperman's symptom (discoloration of the soft palate with normal coloration of the hard palate), duodenal ulcer and in some cases of the stomach, bleeding of the gums and esophagus, increased uric acid levels. Perhaps the development of heart failure and cardiosclerosis.

Stages of the disease

Polycythemia vera is characterized by three stages of development:

Initial, stage I, which lasts about 5 years (a longer period is possible). It is characterized by moderate manifestations of plethoric syndrome, the size of the spleen does not exceed the norm. A general blood test reveals a moderate increase in the number of red blood cells, an increased formation of red blood cells is observed in the bone marrow (an increase in the number of all blood cells, with the exception of lymphocytes, is also possible). At this stage, complications practically do not arise.
The second stage, which can be polycythemic (II A) and polycythemic with myeloid metaplasia of the spleen (II B). Form II A, lasting from 5 to 15 years, is accompanied by a pronounced plethoric syndrome, an enlarged liver and spleen, the presence of thrombosis, and bleeding. Tumor growth in the spleen is not detected. Possible iron deficiency due to frequent bleeding. A general blood test reveals an increase in the number of erythrocytes, platelets and leukocytes. There are cicatricial changes in the bone marrow. Form II B is characterized by a progressive enlargement of the liver and spleen, the presence of tumor growth in the spleen, thrombosis, general exhaustion, and bleeding. A complete blood count can detect an increase in the number of all blood cells, with the exception of lymphocytes. Erythrocytes acquire different sizes and shapes, immature blood cells appear. Cicatricial changes in the bone marrow gradually increase.
Anemic, stage III, which develops 15-20 years after the onset of the disease and is accompanied by a pronounced increase in the liver and spleen, extensive cicatricial changes in the bone marrow, circulatory disorders, a decrease in the number of red blood cells, platelets and white blood cells. Transformation into acute or chronic leukemia is possible.

Diagnostics

Erythremia is diagnosed based on:

Analysis of complaints, anamnesis of the disease and family history, during which the doctor clarifies when the symptoms of the disease appeared, what chronic diseases the patient has, whether there was contact with toxic substances, etc.
Physical examination data, in which attention is drawn to the color of the skin. In the process of palpation and with the help of percussion (tapping), the size of the liver and spleen is determined, the pulse and blood pressure are also measured (may be elevated).
A blood test, which determines the number of erythrocytes (normal 4.0-5.5x109 g / l), leukocytes (may be normal, increased or decreased), platelets (at the initial stage it does not deviate from the norm, then there is an increase in the level, and then a decrease ), hemoglobin level, color indicator (usually the norm is detected - 0.86-1.05). ESR (erythrocyte sedimentation rate) in most cases is reduced.
Urinalysis, which allows you to identify concomitant diseases or the presence of renal bleeding.
A biochemical blood test, which allows to identify an elevated level of uric acid, characteristic of many cases of the disease. To detect concomitant organ damage, the level of cholesterol, glucose, etc. is also determined.
Data from a bone marrow study, which is carried out using a puncture in the sternum and reveals an increased production of red blood cells, platelets and white blood cells, as well as the formation of scar tissue in the bone marrow.
Trepanobiopsy data, which most fully reflect the state of the bone marrow. For examination, using a special trephine device, a bone marrow column is taken from the iliac wing along with the bone and periosteum.

A coagulogram, studies of iron metabolism are also carried out, and the level of erythropoietin in the blood serum is determined.

Since chronic erythremia is accompanied by an increase in the liver and spleen, ultrasound of the internal organs is performed. With the help of ultrasound, the presence of hemorrhages is also detected.

To assess the prevalence of the tumor process, CT (spiral computed tomography) and MRI (magnetic resonance imaging) are performed.

To identify genetic abnormalities, a molecular genetic study of peripheral blood is performed.

Treatment

The goal of treatment for polycythemia vera is:

prevention and therapy of thrombohemorrhagic complications;
elimination of symptoms of the disease;
reducing the risk of complications and the development of acute leukemia.

Erythremia is treated with:

Bloodletting, in which 200-400 ml of blood is removed to reduce blood viscosity in young people and 100 ml of blood in concomitant heart diseases or in the elderly. The course consists of 3 procedures, which are carried out with an interval of 2-3 days. Before the procedure, the patient takes drugs that reduce blood clotting. Bloodletting is not performed in the presence of recent thrombosis.
Hardware methods of treatment (erythrocytepheresis), with the help of which excess red blood cells and platelets are removed. The procedure is carried out at intervals of 5-7 days.
Chemotherapy, which is used at stage II B, in the presence of an increase in the number of all blood cells, poor tolerance to bloodletting, or the presence of complications from the internal organs or blood vessels. Chemotherapy is carried out according to a special scheme.
Symptomatic therapy, including antihypertensive drugs for high blood pressure (ACE inhibitors are usually prescribed), antihistamines to reduce skin itching, antiplatelet agents that reduce blood clotting, hemostatic drugs for bleeding.

For the prevention of thrombosis, anticoagulants are used (usually acetylsalicylic acid is prescribed at 40-325 mg / day).

Nutrition for erythremia should comply with the requirements of the treatment table according to Pevzner No. 6 (the amount of protein products is reduced, fruits and vegetables of red color and products containing dyes are excluded).