Polycythemia vera

The polycythemia vera (abbreviated PV, also polycythemia or polycythemia called; engl primary myelopathic polycythemia, .. Syn Vaquez - Osler 's disease ) is a rare myeloproliferative ( hematopoiesis in the bone marrow related) disease in which too many formed blood elements (cells) be formed without a physiological stimulus is present. In polycythemia vera, especially the erythrocytes (red blood cells ) are affected, to a lesser extent, the platelets ( platelets) and leucocytes (white blood cells). The resulting ratio falling liquid portion ( plasma ) makes the blood progresses, untreated disease always " viscous " ( hyperviskoser ) are to the effect that the risk of thrombosis increases sharply.

• 6.1 phlebotomy and apheresis
• 6.2 platelet aggregation inhibition by anticoagulants
• 6.3 Zellreduktive, interferon therapy
• 6.4 Other measures

Word Meaning

The Greco-Latin parts of the name polycythemia vera describe the main feature of the disease:

• Poly (Greek ) = much
• Cyt and cyt (Latin ) = cell
• Vera ( lat.) = true, actually

Thus, the name refers to a disease, blood cells are formed in which too many (especially red ). The addition cause indicates that the high proportion of red blood cells is due to illness.

High concentrations of hemoglobin or hematocrit values ​​, which indicate an increased proportion of red cells in healthy people can also be measured, for example, after a long stay in high mountain regions ( polycythemia ).

Epidemiology

The number of new cases (incidence) of polycythemia vera is 1-2 cases per 100,000 people per year. It is thus the most common form of myeloproliferative disorders. It can occur at any age, the peak age is 5 to 6 decades of life. The ratio between male and female patients is about 2:1. In Germany is expected 2,000 to 3,000 new cases annually. A family history (which involved an inheritance can ) does occur but is rare.

Course

Often show itself up to a decade before the onset of polycythemia vera to chronic phase single latent signs of the disease, for example in the form of a slight increase in blood - depleting organs spleen and liver. The blood -forming bone marrow, however, has no discernible changes. However, the JAK2 mutation ( see below) is already detectable.

In general, two stages of polycythemia vera can be distinguished. A first chronic phase with increased production of erythrocytes may be two decades or more, a progressive late-stage with diverse, even acute life-threatening, complications may be followed in a subset of patients in mind.

Causes and development

The causes (etiology ) of polycythemia vera are unknown. The disease is due to a not yet fully understood change ( malignant transformation ) of multipotent stem cells, which can be congenital or acquired.

A congenital polycythemia is attributed to mutations in different genes. These include changes in the hemoglobin released by the oxygen in too small quantities and lead to a compensatory increase in hemoglobin concentration in the blood. Another mutation causes the hemoglobin is not degradable in a sufficient amount.

Not until 2005 that a mutation in the JAK2 gene was ( JAK stands for " Janus kinase ", a tyrosine kinase ) described. This mutation of the genomic DNA results in an amino acid substitution ( valine for phenylalanine) at position 617 of the JAK2 protein ( " V617F mutation "). The JAK2 protein plays an important role in signal transduction in the cell. The mutation it is activated so that affected cells permanently have an increased rate of cell division. The V617F mutation is found in several hematological disorders, and particularly frequent ( more than 50%) in polycythemia vera. The affected blood-forming stem cells, regardless of the stimulation by erythropoietin (EPO), and show a hundred -fold increase in sensitivity to growth factors such as IGF -1 ( insulin -like growth factor 1) and IL -3 ( interleukin -3).

The acquired polycythemia may develop due to various triggers. It may be a physiological response compensation by long periods of oxygen deficiency (hypoxia) by excessive smoking ( Raucherpolyzythaemie ), by chronic obstructive pulmonary disease or rarely sleep apnea. Other oxygen-independent triggers may be renal dysfunction or reactions after transplantation ( Posttransplantationserythrozytose ) (eg, Wilms' tumor, polycystic kidney or renal cell carcinoma).

Diagnosis

In most cases, the disease is discovered in that in a blood image - often an incidental finding - noticed a massive increase in hematocrit, red blood cell or hemoglobin concentration. Rare cause rather unspecific symptoms such as itching, a slight enlargement of the spleen, thrombosis, tinnitus or other clinical symptoms mean that based on these initial symptoms ( Keynotes ) targeted searches for polycythemia vera.

Diagnostic criteria of the WHO

The increase of erythrocytes can be detected by measuring the hematocrit or hemoglobin, and erythropoietin in the laboratory. Also, leukocytes and platelets are usually increased in the blood picture. The erythrocyte sedimentation rate (ESR ) is slowed, however, frequently uric acid and LDH are elevated in the serum. The World Health Organization (WHO ) has established summarized in the following table diagnostic criteria.

The diagnosis of polycythemia vera can be found if either:

• Both major criteria and one minor criterion are met,

Or:

• Was the first major criterion and two minor criteria are met.

Specific and non-specific clinical symptoms

Due to the increased number of platelets, granulocytes, and erythrocytes the blood viscous ( hyperviscosity ). Thus, it can reduce the blood flow in all regions of the body (in particular in the capillary ), the risk of thrombosis and embolism in the sequence of increasing. At the same time can also increase the risk of bleeding because the body's hemostasis no longer drains properly as a whole.

Many of the possible symptoms of polycythemia vera are not specific to the disease, while giving the history and course of disease the doctors and patients important information. Among possible ( not all patients also lockable ) clinical symptoms:

• Splenomegaly (enlargement of the spleen)
• Hepatomegaly ( enlarged liver )
• Headache
• Tinnitus ( ringing in the ears )
• Blurred vision
• Vertigo (dizziness )
• Fatigue
• Dysphoric ( misslaunische ) or depressive moods
• Paresthesia Tingling or numbness of the extremities in particular

• Especially in heat
• Aquagener pruritus ( itching stinging after contact with water )

• Skin and mucous membranes deep red with red-blue cyanosis
• Red face - patients have a " thriving " appearance
• During an eye examination often dark -red- bluish-colored vessels

• Arterial and venous thrombosis and / or embolism especially in the stomach and intestines ( gastrointestinal tract )
• Transient ischemic attacks

When the disease progresses, the number of erythrocytes and leukocytes and platelets may decrease, the spleen may increase in size, often in conjunction with myelofibrosis and extramedullary hematopoiesis ( blood formation outside the bone marrow ).

A part of the individual differences occurring symptoms, especially when associated with circulatory disorders, disappears or is diminished when the disease is detected and treated by the hematocrit is lowered into the normal range of approximately 45 percent.

Differential Diagnosis

Provided that in patients, both the number of erythrocytes and the leukocytes and platelets are increased, the diagnosis of polycythemia vera is highly probable. Are only the erythrocytes increased, an extensive differential diagnostic investigation program must be carried out. In particular, to clarify whether the cause may be a dehydration, hypoxia, a carbon monoxide intoxication, heart disease (eg, a right-left shunt), a hypersplenism, paraneoplastic syndromes, myelodysplastic syndromes, myelofibrosis, a neurological disease or medication causally come into question (eg, androgens or erythropoietin ).

Therapy

As can be delayed a final diagnosis for several weeks ( eg in the genetic determination of JAK2 ), prophylactically appropriate measures may need even during the investigation be taken to lower a live dangerously high hematocrit. Essentially, a therapy runs on three tracks:

Other disease individually accompanying complaints can only be treated symptomatically.

Phlebotomy and apheresis

Serve as the most important measure, at diagnosis, frequent ( weekly ), later ( after reaching the normal values ​​) regular (6 to 10 weeks) phlebotomy for reduction of red blood cells and to a lesser extent other cellular components of blood.

As an alternative measure to multiple phlebotomy is the therapeutic apheresis (known as hemodialysis ) application. This method filters the excess blood components out in a 20-minute operation. During Phlebotomy lowered the hematocrit to a maximum of 3 percent, he can be reduced by up to 10 percent targeted in an apheresis. In subsequent occasional blood level checks a new application in three-to six-month distance is required. Currently, the apheresis not part of the standard therapy and must be justified medically. Because of the complex technology and the associated cost apheresis is nationwide in a few hospitals, barely, performed in hematological practices.

Often increases during the treatment by bloodletting ( phlebotomy) or blood washings ( apheresis) the proportion of the platelets and white blood cells, as only the amount of red blood cells may be reduced in the medium term by these measures. The other solid blood components ( thrombocytes and leukocytes) are due to illness continues - individually different - produced in higher dimensions. After lowering the hematocrit to about 45 percent of platelet proportion should be observed in particular.

Platelet aggregation inhibition by anticoagulants

Due to the increased risk that blood cells, especially platelets ( platelet aggregation) clumping and blood vessels clog (thrombosis ), and that they be solved thrombosis and in another place the blood circulation blood flow block ( embolism), it is important to reduce the increased risk of thrombosis. Cause of this tendency to thromboembolism one hand, the increased number of blood cells (especially in greatly increased levels of erythrocytes and platelets) and the other part not yet completely understood, a failure of the whole control mechanism of blood coagulation.

If there are no contraindications (contraindications ) are, such as increased bleeding, may by long-term use of oral anticoagulants such as acetylsalicylic acid (ASA, better known under the trade name Aspirin) in relatively low doses (50 or 100 mg per day), the thrombosis risk be reduced. Doses are generally even before the start and parallel to the bloodletting therapy. In some of the literature is critical advised not to take such a drug because of side effects only if thrombosis have already taken place and that simultaneously the red cell mass is strictly controlled.

Zellreduktive, interferon therapy

As long as the necessary reduction in hematocrit can be achieved by bloodletting and no thromboembolic complications, chemotherapy is not indicated. If a too high number of leukocytes or platelets is increasingly leading to thrombosis and / or embolism if a very strong enlargement of the spleen can be detected and / or occurring after phlebotomy water-induced itching arises is to investigate whether chemotherapy as cytoreductive measure (reduction of about high formation of new cells) could be useful. The aim would be to limit the formation of the platelets in particular.

Currently are used to treat the approved in Germany hydroxyurea (eg Litalir ) and the not yet approved in Germany medication alpha interferon and used in testing anagrelide. As with any chemotherapy side effects can not be excluded. As a side effect, for example, mucous membrane irritation, fever, mental changes, skin tumors, strong fluctuations in the platelet count or diarrhea may occur. In rare cases, an acute leukemia are triggered.

Other measures

Due possibly associated with the disease, individually very different symptoms, a number of complementary measures are carried out, which should alleviate the side effects in the first place. Since this can not be acted causally, the use ultimately depends on the direct effect from the respective patients.

In addition, the administration of allopurinol because of an increased uric acid attack ( especially during cytoreductive therapy) for the prevention of gout or urate nephropathy an attached (indexed) to be. In general it is not necessary to treat an asymptomatic hyperuricemia below 10 mg / dl.

An error occurring in more than half of the patients aquagener itching, which may impair the quality of life significantly, may, in addition to phlebotomy only symptomatic by bath additives (eg bicarbonate, starch), antihistamines, serotonin reuptake inhibitors, itch -reducing creams (eg with capsaicin) or phototherapy ( will not be safe more or less alleviated because of possible carcinogenicity ).

In some patients with an extremely enlarged spleen, which can no longer be treated with medication, surgery may be necessary. In young patients in extreme cases, a bone marrow transplant is discussed.

Alternatively, in elderly patients, a radio phosphorus treatment may be considered.

Forecast

Since the disease is generally indolent ( painless ) and which can extend over decades, individuals can have a long life without functional limitations before him, provided that the number of erythrocytes is controlled permanently by venesection. The bloodletting required desirably lead to an iron deficiency, which leads to a reduction of blood production. Accompanying symptoms of iron deficiency, for example, fatigue, headache, decreased energy or dizziness.

Complications can thrombosis, enlargement of the spleen ( splenomegaly) or liver ( hepatomegaly ), bone marrow fibrosis (10-20%) and in rare cases (1-10 % ) - especially after chemotherapy or radiation - with an additional acute myeloid leukemia arising. Pregnancy is possible in spite of the disease, but must be accompanied interdisciplinary intensive because of the increased thrombotic risk, as the risk of miscarriage or damage to the placenta is greatly increased ( about 50% of live births).