Polycythemia

Introduction

• The three pathophysiologic categories of polycythemia are:

Relative polycythemia (red blood cell mass normal; plasma volume decreased)

Secondary polycythemia (red blood cell mass increased)

Polycythemia vera (red blood cell mass increased)

POLYCYTHEMIA VERA

• 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.

• 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.

• 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.

• The mutation that causes polycythemia vera is thought to affect a protein switch that tells the cells to grow. Specifically, it's a mutation in the protein JAK2 (the JAK2 V617F mutation). Most people with polycythemia vera have this mutation.

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.

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

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

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

• Increase in blood hemoglobin level to 18g/dl. An RBC count of 6 million/mm 3 or a hematocrit of 55 percent or greater.

EPIDEMIOLOGY

• 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. The disease is slightly more common in males than in females.

PROGNOSIS

• Generally, PV is associated with a shortened life span. Median survival for all patients is around 8 to 15 yr if especially treated, although many patients live much longer. Thrombosis is the most common cause of death, followed by complications of myelofibrosis and development of leukemia.

• PV is a malignant disease that progresses in severity over time if left untreated.

SIGNS AND SYMPTOMS3 MAJOR HALLMARK SIGNS

• Massive production of RBC• Excessive leukocyte production• Excessive production of plateletsAre related to :• Hyperviscosity• Extreme hyeprcellularity –cell excess

• Facial skin have a dark, flushed appearance and can also be purplish or cyanotic

• Most patient have intense itching caused by dilated blood vessels poor O2.

• Visisble superficial vein distention.• thromboses that can lead to poor oxygen

delivery and symptoms that include: headache, dizziness, vertigo, tinnitus, visual disturbances, angina pectoris, or intermittent claudications.

RISK FACTORS• Increasing age. The risk of polycythemia vera

increases with age. It is more common in adults older than 60, and it's rare in people younger than 20.

• Being male. Polycythemia vera affects men more often than women.

• Having a family history of polycythemia vera. Having close relatives with polycythemia vera may increase your risk of the disease

DIAGNOSIS• The health care provider will perform a physical

exam. Tests that may be done include:Bone marrow biopsyComplete blood count with differentialComprehensive metabolic panelErythropoietin levelGenetic test for the JAK2V617F mutationOxygen saturation of the bloodRed blood cell massVitamin B12 level

• This disease may also affect the results of the following tests:

ESRLactate dehydrogenaseLeukocyte alkaline phosphatasePlatelet aggregation testSerum uric acid

WHO Criteria for Diagnosis of Polycythemia Vera

Level Specifics• Major criteria1. Evidence of increased RBC volume, including ≥ 1 of the following:

– Hb > 18.5 g/dL in men or > 16.5 g/dL in women– Hb or Hct > 99th percentile of method-specific reference range

for age, sex, and altitude of residence– Hb > 17 g/dL in men or 15 g/dL in women if associated with a

documented and sustained increase of at least 2 g/dL from the patient's baseline value not accounted for by correction of iron deficiency

– Elevated RBC mass > 25% above mean normal predicted value

2. Presence of JAK2 617VF or other functionally similar mutation (eg,JAK2 exon 12 mutation).

• Minor criteria1. Bone marrow biopsy showing hypercellularity

for age with trilineage growth (panmyelosis) and prominent erythroid, granulocytic, and megakaryocytic proliferation

2. Serum erythropoietin level below the reference range for normal

3. Endogenous erythroid colony formation in vitro

• 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

• 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.

Laboratory findings

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

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

• 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).

• 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.

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

• 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.

• 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.

• 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.

• Hyperuricemia occurs in 40% of patients and reflects the high turnover rate of bone marrow cells releasing DNA metabolites.

• Imaging Studies An enlarged spleen is often palpable and does not require any imaging studies. In some patients with posteriorly enlarged spleens or in those who are obese, ultrasonography or CT scanning may be able to detect an enlargement missed during the physical examination.

COMPLICATIONS• 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.

• 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.

• 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.

• Possible infarctions, necrosis• Tissue hypoxia and anoxia• Gout and hyperkalemia

• 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.

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

• extramedullary hematopoiesis: Hepatomegaly and 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.

• 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.

TREATMENTS• Treatment The objective of treatment is to

reduce the high blood viscosity (thickness of the blood) due to the increased red blood cell mass and to prevent hemorrhage and thrombosis. No single treatment is available for PV. The major goal of treatment is to prevent thrombotic events.

Aspirin therapy• (81 to 100 mg po once/day) reduces the

incidence of thrombotic complications. Thus, patients undergoing phlebotomy alone or phlebotomy and myelosuppression should be given aspirin unless contraindicated. Higher doses of aspirin are associated with an unacceptably increased risk of bleeding.

PHLEBOTOMY • Is a simple procedure without many risks,

except for the eventual development of iron deficiency.

• The mainstay of treatment for PV is phlebotomy, which is aimed at reducing hyperviscosity by decreasing the venous hematocrit level.

• Common thresholds for phlebotomy are Hct > 45% in men and > 42% in women.

• Initially, 300 to 500 mL of blood are removed every other day

• Because phlebotomy is the most efficient method of lowering the hemoglobin and hematocrit levels to the reference range, all new patients are initially phlebotomized to decrease the risk of complications. The presence of elevated platelet counts that may be exacerbated by the phlebotomy is an indication to use myelosuppressive agents to avoid thrombotic or hemorrhagic complications.

Myelosuppressive Therapy• The use of myelosuppressive agents such as

radioactive phosphorus (32P), chlorambucil (Leukeran), busulfan (Myleran), pipobroman (Vercyte), and hydroxyurea (Hydrea) in conjunction with phlebotomy has been studied.

• Hydroxyurea has been the mainstay therapy for PV after the PVSG results indicated it is an effective agent for myelosuppression; however, concerns have been raised regarding long-term risks for leukemic transformation. In the PVSG trial, HU therapy reduced the risk of thrombosis compared with phlebotomy alone.

• Recombinant interferon alfa-2b reduces myeloproliferation and splenomegaly, and alleviates the symptom of pruritus. It has no established mutagenic potential, and thus may prove a valuable option for younger patients and those with significant splenomegaly. However, many patients discontinue interferon because of side effects, and high cost of treatment.

• Occasionally, chemotherapy may be given to suppress the bone marrow. The use of anti-platelet therapy (such as aspirin) is controversial because it may cause gastric bleeding. Allopurinol is given for hyperuricemia (gout).

SECONDARY POLYCYTHEMIA

Introduction• Secondary erythrocytosis is erythrocytosis

that develops secondary to circulating erythropoiesis-stimulating substances.

• In secondary erythrocytosis, only the RBC line is increased.

• Spurious erythrocytosis may occur with hemoconcentration (eg, from burns, diarrhea, diuretics).

CAUSES

• Smoking• Chronic arterial hypoxemia• Tumors (tumor-associated erythrocytosis)• Secondary causes of increased red blood cell

mass (e.g., heavy smoking, chronic pulmonary disease, renal disease) are more common than polycythemia vera.

Less common causes include certain congenital disorders such as:

• High O2-affinity hemoglobinopathies• Erythropoietin receptor mutations• Chuvash polycythemia (in which a mutation in

the VHL gene affects the hypoxia-sensing pathway)

• Proline hydroxylase 2 and hypoxia-inducible factor 2 (HIF-2) α mutations

SIGNS AND SYMPTOMS

• 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.

DIAGNOSISTests done when erythrocytosis is present

include:• Arterial O2 saturation• Serum erythropoietin levels• P50

• A low or low-normal serum erythropoietin level suggests PV. Patients with hypoxia-induced erythrocytosis have an elevated level or inappropriately normal level for their elevated Hct. Patients with tumor-associated erythrocytosis typically have elevated erythropoietin levels. Patients with elevated erythropoietin levels or microscopic hematuria should undergo abdominal imaging, CNS imaging, or both to seek a renal lesion or other tumor sources of erythropoietin.

• P50 measures the affinity of Hb for O2; a normal result excludes a high-affinity Hb (a familial abnormality) as the cause of erythrocytosis.

Comparison of Polycythemia Vera and Secondary Polycythemia

Polycythemia Vera Secondary Polycythemia

Pathophysiology Neoplastic hematopoietic stem cell disorder

Due to tissue hypoxia causing an appropriate increase in Epo production, or to renal or hepatic disease causing an inappropriate increase in Epo production

CBC Hct and often WBC and platelets are increased

Only Hct is increased

Epo level Decreased or low normal Normal or increased

Treatment Phlebotomy and/or hydroxyurea to keep Hct below 45%; most patients should also take aspirin 81 mg daily to decrease the risk of thrombosis

Treatment is usually not required.

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