Polycythemia vera is an idiopathic chronic myeloproliferative disorder characterized by an increase in RBC mass (erythrocytosis), which increases Hct and

blood viscosity and may lead to thrombosis. Hepatosplenomegaly may also occur. Diagnosis may require measurement of RBC mass and exclusion of other causes of erythrocytosis. Treatment involves serial phlebotomies and sometimes myelosuppressive drugs. Polycythemia vera (PV) is the most common of the myeloproliferative disorders; it occurs in about 5/1,000,000 people, more often in males (about 1.4:1). The mean age at diagnosis is 60 yr (range, 15 to 90 yr; rarely in childhood); 5% of patients are < 40 yr at onset.

Pathophysiology
PV involves increased production of all cell lines, including RBCs, WBCs, and platelets. Increased production confined to the RBC line is termed primary erythrocytosis. In PV, RBC production proceeds independently of erythropoietin (EPO). Extramedullary hematopoiesis occurs in the spleen, liver, and other sites with the potential for blood cell formation. Peripheral blood cell turnover increases. Eventually, about 25% of patients have reduced RBC survival and inadequate erythropoiesis. Anemia, thrombocytopenia, and myelofibrosis may develop, and RBC and WBC precursors are released into the circulation. Depending on treatment received, the incidence of transformation to acute leukemia varies between 1.5% and 10%. In PV, blood volume expands and hyperviscosity develops, predisposing to thrombosis. Platelets function abnormally, predisposing to increased bleeding. Patients may become hypermetabolic. Increased cell turnover produces hyperuricemia.

Symptoms and Signs

PV itself is often asymptomatic. Occasionally, increased blood volume and viscosity produce weakness, headache, light-headedness, visual disturbances, fatigue, and dyspnea. Pruritus often occurs, particularly after a hot bath. The face may be red and the retinal veins engorged. The lower extremities may be red, warm, and painful, sometimes with digital ischemia (erythromelalgia). Hepatomegaly is common, and > 75% of patients have splenomegaly (which may be massive). Thrombosis can occur in most vessels, resulting in stroke, transient ischemic attack, deep venous thrombosis, MI, retinal artery or vein occlusion, splenic infarction (often with a friction rub), or Budd-Chiari syndrome. Bleeding (typically GI) occurs in 10 to 20% of patients. Complications of hyperuricemia (eg, gout, renal calculi) tend to occur later in PV. Hypermetabolism can cause lowgrade fevers and weight loss.

Diagnosis
PV must be considered in patients with suggestive symptoms, particularly Budd-Chiari syndrome, but is often first suspected because of an abnormal CBC (eg, Hct > 54% in men or > 49% in women). Neutrophils and platelets may be increased and morphologically abnormal. Because PV is a panmyelosis, its diagnosis is clear in patients with elevations of all 3 peripheral blood components, splenomegaly, and no cause for a secondary erythrocytosis. However, these findings are not uniformly present. With myelofibrosis, anemia and thrombocytopenia may develop, with massive splenomegaly. Additional findings include peripheral WBC and RBC precursors, marked anisocytosis and poikilocytosis, and microcytes, elliptocytes, and teardrop-shaped cells. Bone marrow examination is generally performed, showing panmyelosis, large and clumped megakaryocytes, and sometimes reticulin fibers. Cytogenetic analysis of bone marrow occasionally demonstrates an abnormal clone specific for a

myeloproliferative syndrome. Because the Hct is the ratio of RBCs per unit volume of whole blood, an elevated Hct may be caused by decreased plasma volume (relative or spurious erythrocytosis, also called stress polycythemia or Gaisbck's syndrome). Measurement of RBC mass has been suggested to be an early test and helps differentiate PV from an elevated Hct due to hypovolemia. Also, in PV, plasma volume may increase, particularly if splenomegaly is present, making the Hct falsely normal despite erythrocytosis. Thus, a diagnosis of true erythrocytosis requires demonstration of an increased RBC mass. When measured with radioactive chromium 51 ( Cr)-labeled RBCs, RBC mass > 36 mL/kg in men (normal, 28.3 2.8 mL/kg) and > 32 mL/kg in women (normal, 25.4 2.6 mL/kg) is considered abnormal. Unfortunately, many laboratories do not perform blood volume studies.

Polycythemia vera
Polycythemia vera (PV) is a chronic myeloproliferative disorder in which the red cells are the predominating lineage. Here are some typical student questions along with my answers. Q. Are the erythrocytes in PV normal? A. No, they arent considered normal because they come from a malignant clone of erythroblasts. But they do carry oxygen, and they do act and look like benign RBCs. Theyre just the end stage of a malignant erythroblasts development. Q. How come the oxygen saturation is normal in PV? A. You use the oxygen saturation to tell apart primary polycythemia (polycythemia vera) from secondary polycythemia. In secondary polycythemia, the oxygen saturation is usually low (thats why the patient is making so many red cells he or she needs to create more oxygen carrying capacity! Maybe the patient lives way up in the mountains or something.). In contrast, the oxygen saturation is normal in polycythemia vera, because the malignant RBCs are simply carrying the oxygen that happens to be around (and they carry it the same way benign RBCs do), and unless the person with polycythemia vera happens to live way up in the mountains and smoke (pretty unlikely), the oxygen saturation in that person should be normal. Q. Does the test for RBC mass necessarily tell you whether the red cells are benign? A. The test for RBC mass and the plain old red blood cell count (RBC) that you get in a CBC do not differentiate between benign mature red cells and the malignant mature red cells you see in polycythemia vera. So patients with any kind of polycythemia (whether its primary or secondary) will have an increased RBC mass/increased RBC.

Symptoms
Patients with polycythemia vera can be asymptomatic. A classic symptom of polycythemia vera is itching, particularly after exposure to warm water (such as when taking a bath), which may be due to abnormal histamine release or prostaglandin production. Such itching is present in approximately 40% of patients with polycythemia vera. Gouty arthritis may be present in up to 20% of patients. Peptic ulcer disease is also common in patients with polycythemia vera; the reasons for this are unclear, but may be related to an increased susceptibility to infection with the ulcer-causing bacterium H. pylori. Another possible mechanism for the development for peptic ulcer is increased histamine release and gastric hyperacidity related with polycythemia vera. A rare but classic symptom of polycythemia vera (and the related myeloproliferative disease essential thrombocythemia) is erythromelalgia.[11] This is a sudden, severe burning pain in the hands or feet, usually accompanied by a reddish or bluish coloration of the skin. Erythromelalgia is caused by an

increased platelet count or increased platelet "stickiness", resulting in the formation of tiny blood clots in the vessels of the extremity; it responds rapidly to treatment with aspirin. Patients with polycythemia vera are prone to the development of blood clots (thrombosis). A major thrombotic complication (e.g. heart attack, stroke, deep venous thrombosis, or Budd-Chiari syndrome) may sometimes be the first symptom or indication that a person has polycythemia vera. Headaches, lack of concentration and fatigue are common symptoms that occur in patients with policythemia vera as well.

Diagnosis
Patients with polycythemia vera may often be asymptomatic. Physical exam findings are nonspecific, but may include enlarged liver or spleen, plethora, or gouty nodules. The diagnosis is often suspected on the basis of laboratory tests. Common findings include an elevated hemoglobin level or hematocrit, reflecting the increased number of red blood cells; the platelet count or white blood cell count may also be increased. Because polycythemia vera results from an essential increase in erythrocyte production, patients have a low erythropoietin (EPO) level. In primary polycythemia, there may be 8 to 9 million and occasionally 11 million erythrocytes cubic millimeter of blood (a normal range for adults is 4-6), and the hematocrit may be as high as 70 to 80%. In addition, the total blood volume sometimes increases to as much as twice normal. The entire vascular system can become markedly engorged with blood, and circulation times for blood throughout the body can increase up to twice the normal value. The increased numbers of erythrocytes can cause the viscosity of the blood to increase as much as five times normal. Capillaries can become plugged by the very viscous blood, and the flow of blood through the vessels tends to be extremely sluggish. Recently, in 2005, a mutation in the JAK2 kinase (V617F) was found by multiple research groups to be strongly associated with polycythemia vera. JAK2 is a member of the Janus kinase family and makes the erythroid precursors hypersensitive to erythropoietin (EPO). This mutation may be helpful in making a diagnosis or as a target for future therapy. As a consequence of the above, people with untreated polycythemia vera are at a risk of various thrombotic events (deep venous thrombosis, pulmonary embolism), heart attack and stroke, and have a substantial risk of Budd-Chiari syndrome (hepatic vein thrombosis), or Myelofibrosis. The condition is considered chronic; no cure exists. Symptomatic treatment (see below) can normalize the blood count and most patients can live a normal life for years.

Treatment
As the condition cannot be cured, treatment focuses on treating symptoms and reducing thrombotic complications by reducing the erythrocyte levels. Bloodletting or phlebotomy is one form of treatment, which often may be combined with other therapies. The removal of blood from the body reduces the blood volume and brings down the hematocrit levels; in patients with polycythemia vera, this reduces the risk of blood clots. Phlebotomy is typically performed in people with polycythemia vera to bring their hematocrit (red blood cell percentage) down below 45 for men or 42 for women.[17]. It has been observed that phlebotomy also improves cognitive impairment. [18] Low dose aspirin is often prescribed. Research has shown that aspirin reduces the risk for various thrombotic complications. Chemotherapy for polycythemia may be used sparingly, when the rate of bloodlettings required to maintain normal hematocrit is not acceptable. This is usually with a "cytoreductive agent" (hydroxyurea, also known as hydroxycarbamide). The tendency to avoid chemotherapy if possible, especially in young patients, is due to research indicating increased risk of transformation to acute myelogenous leukemia (AML), and while hydroxyurea is considered safer in this aspect, there is still some debate about its long-term safety. In the past, injection of radioactive isotopes (principally Phosphorus-32) was used as another means to suppress the bone marrow. Such treatment is now avoided due to a high rate of AML transformation. Other therapies include interferon injections, and in cases where secondary thrombocytosis (high platelet count) is present, anagrelide may be prescribed. Bone marrow transplants are rarely undertaken in polycythemia patients; since this condition is non-fatal if treated and monitored, the benefits rarely outweigh the risks involved in such a procedure. There are indications that with certain genetic markers, Erlotinib may be an additional treatment option for this condition.