The polycythemia vera is an idiopathic chronic myeloproliferative disease, which is characterized by an increase in red cell mass. This leads to an increase in hematocrit and blood viscosity. As a result, thrombosis may occur. This leads to an increased risk of thrombosis and rarely acute leukemia and myelofibrotischer transformation. The disease may also be associated with hepatosplenomegaly. The diagnosis is made by a blood count, a test for JAK2 mutations and clinical criteria. Treatment is with phlebotomy, acetylsalicylic acid in low doses and in high risk patients in addition with myelosuppressive drugs; in rare cases, a stem cell transplant is applied.
The polycythemia vera is the most common myeloproliferative diseases; the incidence in the US is estimated at 1.9 / 100,000, and it increases with age. Men are affected slightly more often. The mean age at diagnosis is about 60 years. It is very rare in children.
The polycythemia vera is an idiopathic chronic myeloproliferative disease, which is characterized by an increase in red cell mass. This leads to an increase in hematocrit and blood viscosity. As a result, thrombosis may occur. This leads to an increased risk of thrombosis and rarely acute leukemia and myelofibrotischer transformation. The disease may also be associated with hepatosplenomegaly. The diagnosis is made by a blood count, a test for JAK2 mutations and clinical criteria. Treatment is with phlebotomy, acetylsalicylic acid in low doses and in high risk patients in addition with myelosuppressive drugs; in rare cases, a stem cell transplant is applied. The polycythemia vera is the most common myeloproliferative diseases; the incidence in the US is estimated at 1.9 / 100,000, and it increases with age. Men are affected slightly more often. The mean age at diagnosis is about 60 years. It is very rare in children. Pathophysiology of polycythemia vera all cell lines (red cells, white cells and platelets) are affected. Since all three components in the peripheral blood increases, it is sometimes referred to as Panmyelosis. If only the red cell number involved, it is called erythrocytosis. Erythrocytosis may occur if one polycythemia vera, but is more often attributed to other causes (secondary erythrocytosis; Secondary Erythrocytosis). The production of red blood cells occurs in polycythemia vera regardless of Erythropoetinspiegeln. An extramedullary hematopoiesis can be observed in the spleen, liver and other organs. The peripheral erythrocytes sales increases. Possibly. The disease can go into the progressive late phase, wherein the phenotype of the primary myelofibrosis is indistinguishable. The degeneration to acute leukemia is rare; However, the risk is increased in contact with alkylating agents such as chlorambucil, and radioactive phosphorus (especially of historical significance). Complications There is an increase in blood volume with hyperviscosity. Patients are prone to thrombosis. By thrombosis in various blood vessels can lead to stroke, transient ischemic attacks (TIAs), deep vein thrombosis, myocardial infarction, Retinalarterien- or Retinalvenenverschlüssen, splenic infarction (often with auscultatory rubbing noises) or Budd-Chiari syndrome come (Budd-Chiari syndrome). Previously it was assumed that the hyperviscosity is a predisposition to thrombosis. Recent studies indicate that the risk of thrombosis due largely to the Leukozytosegrad. However, this assumption has yet to be confirmed in particular, prospective studies. Through disruption platelet function results in an increased risk of bleeding. Increased cell renewal rate can lead to hyperuricemia, reducing the risk of developing gout and uric acid stones zunimmt.Genetische basics Clonal hematopoiesis is a characteristic sign of polycythemia vera, suggesting that proliferation is based on a change in the hematopoietic stem cells. The JAK2 V617F mutation (or rare by several other JAK2 mutations) is found in almost all patients. But give it a high probability of further mutations that cause the disease. CALR- and MPL mutations do not occur. These mutations result in permanent activation of the JAK2 protein, resulting in excessive cell formation, regardless of erythropoietin, the consequence. Symptoms and complaints The polycythemia vera itself runs often asymptomatic. Occasionally, by increasing the red blood cell volume and viscosity performance weakness, headache, dizziness, blurred vision, fatigue and dyspnea. Especially after hot baths often itching occurs. The face is sometimes red, the vessels of the choroid are congested, and the palms and feet can be flushed, overheated and painful, sometimes with digital ischemia (erythromelalgia). Hepatomegaly is common, and> 75% of patients show some very significant splenomegaly. Thromboses can cause symptoms in the affected area (eg. As neurological deficits with stroke or transient ischemic attack, pain and / or swelling in the leg thrombosis of the lower extremity, unilateral visual loss with retinal vein occlusion). Bleeding occur in about 10% of patients (mostly in the gastrointestinal tract) on. A hypermetabolism may have low-grade fever and weight loss result and gives an indication of the progression in the progressive late phase of polycythemia vera, which is clinically indistinguishable from primary myelofibrosis. Diagnostic blood test for JAK2 mutations Sometimes bone marrow examination and determination of erythropoietin serum level application of the WHO criteria Often there is already a first suspected polycythemia vera due to abnormal blood levels of image (eg., Hemoglobin> 18.5 g / dL in men or > 16.5 g / dL in women), but has considered especially when an Budd-Chiari syndrome or other occurring in disease symptoms are (although some patients develop a Budd-Chiari syndrome before the increase in hematocrit ). Neutrophils and platelets are often, but not always increased; only the hemoglobin value is increased, a polycythemia vera can indeed be present, but first must be a secondary erythrocytosis be considered as a frequent cause of increased hemoglobin into consideration (secondary erythrocytosis). The secondary erythrocytosis never found JAK2 mutations. A polycythemia vera should also be taken in the rare case into consideration when the hemoglobin level is normal, but there are a microcytosis and evidence of iron deficiency; this combination of findings occurs in eisenlimitierender hematopoiesis, which are a characteristic sign of some polycythemia vera cases. Revised WHO diagnostic criteria have been developed (see table: Revised diagnostic criteria of WHO in polycythemia vera *). Thus should be tested with suspected polycythemia vera usually on JAK2 mutations patient; a bone marrow examination is not always necessary. When a bone marrow examination is made, typically shows a Panmyelose, large megakaryocytes that are in clusters, and sometimes reticulin fibers. With the bone marrow examination, the polycythemia vera can not be sure are different from other diseases with excessive erythrocytosis how the congenital familial polycythemia. Patients with polycythemia vera have a low or low-normal serum levels of erythropoietin in general. Elevated values ??indicate a secondary erythrocytosis. The determination of red cell mass with chrome labeled erythrocytes can help to distinguish between genuine and spurious polycythemia vera and between polycythemia and other myeloproliferative diseases. However, this test is technically difficult and is rarely used because of its limited availability. Among the non-specific laboratory findings in polycythemia vera include increased vitamin B12 value and enhanced vitamin B12-binding capacity, hyperuricemia and hyperuricosuria (in ? 30% of patients), increased expression of the PRV-1 gene in leukocytes and decreased expression of C mpl (the receptor for thrombopoietin) in megakaryocytes and platelets. These tests are not required for diagnosis. Revised diagnostic criteria of WHO in polycythemia vera * Criteria group Main options detection of an increased erythrocyte volume, including ? 1 of the following criteria: hemoglobin> 18.5 g / dL in men or> 16.5 g / dl in women hemoglobin or hematocrit> 99th percentile the method-specific reference range for age, gender and height of residence hemoglobin> 17 g / dl in men or 15 g / dl in women, if sustainable increase of at least 2 g / dl from the basic value of the patient has been documented that can not by correcting explain iron deficiency can Erythrozytenmen ge> 25% above the predicted average normal value increases detection of JAK2 617VF- or other functionally similar mutation (eg. B. JAK2 exon 12 mutation) In addition to Criteria Bone marrow biopsy showing a hypercellularity based on the age of proliferation of 3 cell lines (Panmyelose) and prominent erythrocytic, granulocytic and megakaryocytic proliferation erythropoietin serum levels below the reference normal range Endogenous erythroid colony formation in vitro * For the diagnosis must be met two main criteria and a Nebenkriterum or the first major criterion and two minor criteria. This work was originally published in Blood. After Tefferi A, Thiele J, Orazi A, et al: Proposals and rational for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from to ad hoc international expert panel. Blood 110: 1092, 2007 © American Society of Hematology. Prognosis In general, shortened lifespan in polycythemia vera. The median survival time is about 8-15 years, but many patients live significantly longer. The most common cause of death thrombosis, followed by complications of myelofibrosis and the transition to a leukemia. Treatment may receive aspirin bloodletting possible way myelosuppressive therapy Since the polycythemia vera is the only form of erythrocytosis in which myelosuppressive therapy may be indicated, a clear diagnosis is crucial. The therapy must – according to age, sex, general condition, clinical signs and hematological findings of the patient – be determined individually. The classification is based on high-risk and low-risk patients. High-risk patients> 60 years old and had thrombosis and / or transient ischemic attack (TIA) in the past. Acetylsalicylic acid by the administration of acetylsalicylic acid (81 to 100 mg p.o. once daily) reduces the occurrence of thrombotic complications. Therefore, should also receive aspirin patients treated with phlebotomy alone or in combination with Myelosuppressiva, as long as no contraindications. A higher Acetylsalicylsäuredosierung can with an increased risk of bleeding einhergehen.Aderlass Bloodletting is an important treatment for patients with both high and low risk. Conventional thresholds for bloodletting are a hematocrit of> 45% in men and> 42% in women. A randomized controlled trial, published in 2013, showed that patients with a randomized hematocrit of <45% a significantly lower rate of cardiovascular deaths and thrombosis had than those with a target hematocrit of 45 to 50%. In a minority of patients with symptoms of Rubor and hyperviscosity Phlebotomy may be therapeutic. Initially, every 2 days are taken 300-500 ml of blood, in elderly patients and patients with cardiac or cerebrovascular disease less (200 to 300 ml 2 times per week). If the hematocrit once fallen below the target value, it is checked at monthly intervals and, if necessary, supported by additional bloodletting at this level. If required, the intravascular volume can be maintained with crystalline solutions. The platelet count may increase at a Hämatokritabnahme and anagrelide or hydroxyurea may be required sein.Myelosuppressive Therapy A myelosuppressive therapy is indicated for high-risk patients. Hydroxyurea inhibits the enzyme ribonucleoside diphosphate reductase, also it is used to myelosuppression. The associated with its use leukaemogenic potential is not yet fully understood; but if there is also little risk of leukemic degeneration. Hydroxyurea is initially p.o. in a dose of 500-1000 mg given once daily. To monitor weekly blood count determinations are necessary first. After a stable disease state check interval can initially be later extended to up to 4 weeks to 2. If the leukocytes 4,000 / ul or platelets below 100,000 / ul fall, the therapy is paused. is rescheduled begin with 50% of the initial dose after normalizing the values. It is advisable to titrate the Hydroxyureadosis to achieve an approximately normal hematocrit, although there is no evidence of the benefit of a titration. Presumably, the normalization of white blood cell count is important, but this was previously not used in prospective studies. There is not any evidence that the normalization of platelet count is required, and raise some doctors Hydroxyureadosis long as the platelet count is <1.5 Mio./?l. The occurrence of acute toxicity is rare; Occasionally, patients develop a rash, gastrointestinal symptoms, fever, nail changes and skin ulcers which may require discontinuation of therapy. If there is insufficient response or intolerance interferon alpha-2b can be used. Pegylated interferon alpha-2b is generally well tolerated. This drug works at the molecular level with relatively low toxicity. Various inhibitors of JAK2 signaling pathway are currently clinically tested, especially in patients with advanced myelofibrosis; and Ruxolitinib is approved at a myelofibrosis after PV. Radioactive phosphorus (32P) has long been used for the treatment of polycythemia vera, though its availability is nowadays limited. The success rate is 80-90%. The duration of remission may be 6 months to several years. Radioactive phosphorus is well tolerated, and treatment requires fewer follow-up visits when the disease is under control. However, during treatment with radioactive phosphorus, an increased occurrence of acute leukemic transformation is observed. These forms of leukemia that develop after treatment, are often resistant and not curable at an induction chemotherapy. must therefore prior to treatment with radioactive phosphorus careful patient selection are carried out (eg. as used only in patients who will die with high probability within the next five years for other reasons). It should be as little as possible employed, many doctors it does not use. Alkylating agents such as chlorambucil, are leukemogenic and should, if possible, avoided werden.Behandlung of complications A hyperuricemia should allopurinol (300 mg po once daily) to be treated if it is symptomatic or myelosuppressive therapy is used. Itching is usually difficult to control. It can be treated with antihistamines, but is most effective application myelosuppressive therapy. Cholestyramine, cyproheptadine, cimetidine or paroxetine can be successful. After bathing the skin should be carefully dried. Aspirin reduces the symptoms of erythromelalgia; higher doses may be necessary, but significantly increase the risk of bleeding. The important points polycythemia vera is an idiopathic chronic myeloproliferative disease, including an increased production of all types of cells, including red cells, white cells and platelets. The cause of the PV seems to be hematopoietic stem cells, which results in a persistent activation of the JAK2 protein, which causes an excessive cell production a mutation. Complications include thrombosis, bleeding and hyperuricemia; some patients eventually develop myelofibrosis or more rarely a transformation to acute leukemia. PV is often initially due to increased hemoglobin (> 16.5 g / dl> 18.5 g / dl in men, in women) suspected; the number of neutrophils and platelets is often increased, but not always. It is carried out a test for JAK mutations and sometimes a bone marrow examination and the determination of erythropoietin in serum; while the WHO criteria are applied (see table: Revised diagnostic criteria of WHO in polycythemia vera *). Treatment must be individualized, but most patients should take aspirin; bloodletting to achieve a desired hematocrit <45% probably helps; High-risk patients (age> 60 years, history of thrombosis and / or transient ischemic attack) can benefit from the use myelosuppressive drugs (eg, Hydroxyurea.); JAK2 inhibitors are tested.