Polycythemia

1. Polycythemia Victor Politi, M.D., FACP Medical Director, SVCMC, School of Allied Health Professions, Physician Assistant Program

2. Introduction • Polycythemia vera is a chronic myeloproliferative disorder characterized by increased red blood cell mass (RCM), or erythrocytosis • The resultant hyperviscosity of the blood predisposes such patients to thrombosis

3. Introduction • Increased RCM is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation.

4. Introduction • Its etiology is not fully established, but hypersensitivity to interleukin-3 may play a role in the sustained erythrocytosis observed in this disease.

5. Introduction • Polycythemia vera should be suspected in patients with elevated hemoglobin or hematocrit levels, splenomegaly, or portal venous thrombosis.

6. Introduction • Secondary causes of increased red blood cell mass (e.g., heavy smoking, chronic pulmonary disease, renal disease) are more common than polycythemia vera and must be excluded

7. Introduction • Patients may present with complaints of pruritus after bathing, burning pains in the distal extremities (erythromelalgia), gastrointestinal disturbances, or nonspecific complaints such as weakness, headaches, or dizziness. • Other patients are diagnosed after an incidental finding of an elevated hemoglobin and/or hematocrit level on a complete blood count.

8. Introduction • Diagnosis is made using criteria developed by the Polycythemia Vera Study Group; major criteria include elevated red blood cell mass, normal oxygen saturation, and palpable splenomegaly.

9. Introduction • Untreated patients may survive for six to 18 months, whereas adequate treatment may extend life expectancy to more than 10 years.

10. Introduction • Treatment includes phlebotomy with the possible addition of myelosuppressive agents based on a risk-stratified approach. • Agents under investigation include interferon alfa-2b, anagrelide, and aspirin. Consultation with a hematologist is recommended.

11. Introduction • Alternative Names: • Primary polycythemia • Polycythemia rubra vera • Myeloproliferative disorder • Erythremia • Splenomegalic polycythemia • Vaquez's disease • Osler's disease • Polycythemia with chronic cyanosis • Myelopathic polycythemia • Erythrocytosis megalosplenica • Cryptogenic polycythemia

12. Pathophysiology • Normal stem cells are present in the bone marrow of patients with PV. • Also present are abnormal clonal stem cells that interfere with or suppress normal stem cell growth and maturation.

13. Pathophysiology • Evidence indicates that the etiology of panmyelosis is unregulated neoplastic proliferation. • The origin of the stem cell transformation remains unknown

14. Polycythemia vera • Bone marrow film at 100X magnification demonstrating hypercellularity and increased number of megakaryocytes

15. Pathophysiology • Thromboses and bleeding are frequent in persons with PV and myeloproliferative disease (MPD), and they result from the disruption of hemostatic mechanisms because of • an increased level of red blood cells • an elevation of the platelet count

16. Pathophysiology • Tissue factor is also synthesized by blood leukocytes, the level of which is increased in persons with MPD, which can contribute to thrombosis.

17. Pathophysiology • Hyperhomocysteinemia is a risk factor for thrombosis and is also widely prevalent in patients with MPD (35% in controls, 56% in persons with PV).

18. Statistics • Polycythemia vera is a rare disease • The peak incidence of PV is age 50-70 years • However, it occurs in persons of all age groups, including those in early adulthood and childhood, albeit rarely. • The disease is slightly more common in males than in females.

19. History • The disease usually develops slowly • Symptoms are often insidious in onset • They are often related to blood hyperviscosity secondary to a marked increase in the cellular elements of blood, which impairs microcirculation.

20. History • Symptoms are related to hyperviscosity, sludging of blood flow, and thromboses, which lead to poor oxygen delivery and symptoms that include: • headache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittent claudications

21. History • Bleeding complications ,, include epistaxis, gum bleeding, ecchymoses, and GI bleeding. • Thrombotic complications ,, include venous thrombosis or thromboembolism and an increased prevalence of stroke and other arterial thromboses.

22. History • Abdominal pain due to peptic ulcer disease is present because PV is associated with increased histamine levels and gastric acidity or possible Budd-Chiari syndrome (hepatic portal vein thrombosis) or mesenteric vein thrombosis.

23. History • Splenomegaly, when present, can cause early satiety because of • gastric filling being impaired by the enlarged spleen or, rarely, symptoms of splenic infarction. • Weight loss may result from early satiety or from the increased myeloproliferative activity of the abnormal clone.

24. History • Pruritus results from increased histamine levels released from increased basophils and mast cells and can be exacerbated by a warm bath or shower. • This occurs in up to 40% of patients.

25. Physical • The following symptoms are due to the manifestations of myeloproliferative disorders with extramedullary hematopoiesis: • Splenomegaly - Present in 75% of patients at the time of diagnosis • Hepatomegaly - Present in approximately 30% of patients with PV

26. Physical • Hypertension is common in patients with PV. The red blood cell mass should differentiate PV from Gaisbock syndrome, which is hypertension and pseudopolycythemia (i.e., high hemoglobin levels due to low plasma volume).

27. Physical • Polycythemia is characterized by increased cell counts in all cell lines in the myeloid series (i.e., red blood cells, white blood cells [preferentially granulocytes], and platelets).

28. Physical • However, if red blood cell levels are increased, several conditions must be excluded, including: • conditions that increase red blood cells secondary to systemic hypoxic conditions or an artificial condition stimulating EPO secretion in the kidneys • granulocytosis from infections or mobilization by secondary causes, as in leukemoid reactions • thrombocytosis from bleeding and iron deficiency.

29. Secondary Causes of Increased Red Cell Mass (Erythrocytosis) • Chronic pulmonary or cardiac disease • Decreased 2,3-diphosphoglycerate • High oxygen affinity hemoglobinopathy • Increased carboxyhemoglobin (in smokers) and methemoglobin • Residence at high altitude • Adrenal cortical hypersecretion • Hydronephrosis • Tumors producing erythropoietin or anabolic steroids • Relative (stress) • Disorders associated with decreased plasma volume (e.g., diarrhea, emesis, renal diseases)

30. Diagnosis • PV should be suspected when hemoglobin and/or hematocrit levels are elevated • (> than 18 g per dL [180 g per L] in white men and > than 16 g per dL [160 g per L] in blacks and women) • hematocrit level greater than 52 percent (0.52) in white men and 47 percent (0.47) in blacks and women

31. Diagnosis • PV also should be suspected in patients with portal venous thrombosis and splenomegaly with or without thrombocytosis and leukocytosis.

32. More Common Hematocrit level >52 percent (0.52) in white men, >47 percent (0.47) in blacks and women Hemoglobin level >18 g per dL (180 g per L) in white men, >16 g per dL (160 g per L) in blacks and women) Plethora Pruritus after bathing Splenomegaly Weight loss Weakness Sweating Less Common Bruising/epistaxis Budd-Chiari syndrome Erythromelalgia Gout Hemorrhagic events Hepatomegaly Ischemic digits Thrombotic events Transient neurologic complaints (headache, tinnitus, dizziness, blurred vision, paresthesias) Atypical chest pain Diagnosis: Other Signs and Symptoms of Polycythemia Vera

34. Diagnosis • In making the diagnosis of PV, once a secondary cause is ruled out, the diagnosis of PV is made using a combination of major and minor criteria defined by the Polycythemia Vera Study Group (PVSG). • Although new diagnostic modalities have been developed, these criteria remain the standard method to diagnose PV

35. A diagnosis of polycythemia vera is made when a patent fulfills • all three of the major criteria • Or • any two major and any two minor criteria • Major Criteria • total RBC vol. • Men > or = to 36 mL/kg • Women > or = to 32 mL/kg • arterial 02 saturation > or = to 92% • Splenomegaly • Minor Criteria • Thrombocytosis with platelet count > 400,000/mL • Leukocytosis with WBC > 12,000/mL • Increased leukocyte alkaline phosphatase LAP > 100U/L (no infection) • Serum B12 > 900 pg/mL or binding capacity UB12 BC > 2200 pg/mL

36. Serum EPO assay • EPO levels in patients with PV are often below the lower limit of normal compared with patients with secondary erythrocytosis and pseudo erythrocytosis • but the levels for PV and secondary erythrocytosis or pseudo erythrocytosis overlap and are nonspecific for differentiating these conditions.

37. Bone marrow morphology and histology • Overall hypercellularity with expansion of all cell lines with megakaryocytic proliferation and the presence of myelofibrosis can help diagnose PV and MPD • PV patients may have normal bone marrow findings • These results are nonspecific and may be observed in the other Philadelphia chromosome–negative MPDs.

38. Bone marrow findings for Polycythemia vera include • Moderate to marked hypercellularity • trilineage hyperplasia • megakaryocytes increased; hyper lobulated • dilated sinusoids with intravascular hematopoiesis • decreased or absent iron stores • increased reticulin (only in a minority of patients)

39. Labs • Peripheral blood findings • Increased hemoglobin & hematocrit • Normal red blood cell morphology, unless iron deficient or spent phase • Normoblasts may be present • Mild to moderate leukocytosis • Mild neutrophilia and/or basophilia • Thrombocytosis

40. Labs • This disease may also alter the results of the following tests: • Lactate dehydrogenase • u/a • Serum uric acid • T- WBC • RBC count • Platelet aggregation test • Leukocyte alkaline phosphatase • Hemoglobin • ESR • Erythropoietin

41. Labs • Automated red blood cell counts and hematocrit values (including hemoglobin levels) may be deceptive with regard to the total red blood cell mass. • Direct measurement of the red blood cell mass should show an increase with a normal or slightly decreased plasma volume. • This is a nuclear medicine test that uses radiochromium-labeled red blood cells to measure actual red blood cell and plasma volume. • However, patients with hemoglobin concentrations of at least 20 g/dL or hematocrit values of at least 60% in males and 56% in females always have an elevated red blood cell mass.

42. Labs • The red blood cells in patients with PV are usually normochromic normocytic unless the patient has been bleeding from underlying peptic ulcer disease or phlebotomy treatment (wherein the cells may be hypochromic and microcytic, reflecting low iron stores).

43. Labs • An elevated white blood cell count (>12,000/µL) occurs in approximately 60% of patients. It is mainly composed of neutrophils with a left shift and a few immature cells. • Mild basophilia occurs in 60% of patients. • The leukocyte alkaline phosphatase score is elevated (>100 U/L) in 70% of patients. • This technique is only semiquantitative and is susceptible to laboratory errors unless it can be performed by flow cytometry, which is not routinely available

44. Labs • The platelet count is elevated to 400,000-800,000/mL in approximately 50% of patients.

45. Labs • The release of potassium into the serum caused by the increased number of platelets during in vitro coagulation may cause a pseudohyperkalemia in the serum, while the true plasma potassium level in vivo is actually within the reference range, as shown by measuring plasma levels and the lack of ECG changes.

46. Labs • Abnormal platelet function (as measured by platelet aggregation tests with epinephrine, adenosine diphosphate, or collagen) may be demonstrated, but bleeding time may be normal. • Some patients' platelet-rich plasma aggregates spontaneously without the addition of any of the above substances. • This indicates a propensity for thromboses

47. Labs • Bone marrow studies are not necessary to establish the diagnosis but the findings of: • hypercellularity • hyperplasia of the erythroid, granulocytic and megakaryocytic cell lines • myelofibrosis • support the diagnosis of a myeloproliferative process.

48. Labs • Iron stores are decreased or absent because of the increased red blood cell mass, and macrophages may be masked in the myeloid hyperplasia that is present.

49. Labs • Fibrosis is increased and detected early by silver stains for reticulin

50. Labs • Cytogenetics of the bone marrow cells show a clonal abnormality in • 30% of patients who are not treated and in 50% of patients who are treated with alkylating or myelosuppressive agents. • These chromosomal abnormalities include deletions of the long arm of chromosome 5 or 20 (5q-, 20q-) and trisomy 8 (+8) or 9 (+9). • Leukemic transformation is usually associated with multiple or complex abnormalities.