POLYCYTHEMIA VERA

BY RUMANA HAMEED

170310820021PHAMR D INTERN

POLYCYTHEMIA• Polycythemia is a blood disorder in which the body produces too

many blood cells as a result of a problem with the bone marrow or an increased production of the hormone erythropoietin(EPO).

• Polycythemia is defined as an increase in the hemoglobin above normal.

• Often patients with polycythemia are detected through an incidental finding of elevated hemoglobin or hematocrit levels.

• Concern that the hemoglobin level may be abnormally high is usually triggered at 170 g/L (17 g/dL) for men and 150 g/L (15 g/dL)for women. Hematocrit levels >50% in men or >45% in women may be abnormal.

CLASSIFICATIONPOLYCYTHEMIA

RELATIVE ABSOLUTE

SECONDARY

APPROPRIATE INAPPROPRIATE

PRIMARY

RELATIVE POLYCYTHEMIALow Volume states:• Dehydration• Burns• Prolonged vomitings• Diarrhea• Excessive diuretics• Stress or Gaisbock syndrome

ABSOLUTE POLYCYTHEMIAPrimary Polycythemia:• Polycythemia Vera

Secondary Polycythemia:• Appropriate: Hypoxia,Lung disease,high altitude,cyanotic

heart disease,cabonmonoxide poisoning.• Inappropriate: EPO secreting tumors

POLYCYTHEMIA VERA• Polycythemia vera (PV) is a slow-growing type of

blood cancer in which your bone marrow makes too many red blood cells. Polycythemia vera may also result in production of too many of the other types of blood cells — white blood cells and platelets.

• PV is a clonal stem cell disorder in which there is an alteration in the pluripotent progenitor cell leading to excessive proliferation of erythroid, myeloid and megakaryocytic progenitor cells. Over 95% of patients with PV have acquired mutations of the gene Janus Kinase 2 (JAK2) (kumar and clark’s clinical medicine).

• The JAK2 gene provides instructions for making a protein that promotes the growth and division (proliferation) of cells. This protein is part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. The JAK2 protein is especially important for controlling the production of blood cells from hematopoietic stem cells. These stem cells are located within the bone marrow and have the potential to develop into red blood cells, white blood cells, and platelets.

ETIOLOGYMutation causes the disorder• The problem with blood cell production associated with polycythemia

vera is caused by a change, or mutation, to DNA in a single cell in your bone marrow. In polycythemia vera, researchers have found this mutation to be a change in a protein switch that tells the cells to grow. Specifically it's a mutation in the protein JAK2 (the JAK2 V617F mutation). More than 90 percent of patients with polycythemia vera, and about half of patients with other myeloproliferative disorders, have this mutation. Doctors and researchers don't understand the full role of this mutation and its implications for treating the disease.

• The DNA mutation that causes polycythemia vera occurs after conception — meaning that your mother and father don't have it — so it's acquired, rather than inherited from a parent. Researchers and doctors don't know what causes the mutation.

RISK FACTORS

• Some factors may increase your risk of developing polycythemia vera :

• Age. Polycythemia vera is more common in adults and older than 60. It's rare in people younger than 20.

• Sex. Polycythemia vera affects men more often than it does women.

• Family history. In some cases, polycythemia vera appears to run in families, indicating that genetic factors other than JAK2 may contribute to the disease.

CLINICAL FEATURES

• In its early stages, polycythemia vera usually doesn't cause any signs or symptoms. As the disease progresses, the following Symptoms may be experienced:

• Headache• Dizziness• Itchiness, especially following a warm bath or shower• Redness of your skin and plethoric facial appearance• Shortness of breath• Breathing difficulty when you lie down• Numbness, tingling, burning or weakness in your hands, feet,

arms or legs• Chest pain• A feeling of fullness or bloating in your left upper abdomen

due to an enlarged spleen• Fatigue

• Bleeding complications, seen in approximately 1% of patients with PV, include epistaxis, gum bleeding, ecchymoses, and gastrointestinal (GI) bleeding. Thrombotic complications (1%) include venous thrombosis or thromboembolism and an increased prevalence of stroke and other arterial thromboses.

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

• 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 with PV.

DIAGNOSIS

• Blood tests If a person has polycythemia vera, blood tests may reveal :

• An increase in the number of red blood cellsand, in some cases, an increase in platelets or white blood cells.

• Elevated hematocrit measurement, the percentage of red blood cells that make up total blood volume.

• Elevated levels of hemoglobin, the iron-rich protein in red blood cells that carries oxygen.

• Lower than normal levels of oxygen in your blood.• Very low levels of erythropoietin (EPO), a hormone

that stimulates bone marrow to produce new red blood cells, because the excess red blood cells turn off the production of EPO by the kidneys.

Bone marrow aspiration or biopsy: Examination of bone marrow shows that it's producing higher than normal amounts of blood cells, it may be a sign of

polycythemia vera. If you have polycythemia vera, analysis of your bone marrow or blood also may show the DNA change (JAK2 V617F mutation) that's associated

with the disease.

Polycythaemia vera (PV) – modified fromrevised WHO criteria for diagnosis

Major criteria• Haemoglobin >185 g/L in men, 165 g/L in women or other evidence of

increased red cell volume.• Presence of JAK2 tyrosine kinase V617F or otherfunctionally similar mutation

such as JAK2 exon 12mutation.Minor criteria• Bone marrow biopsy, showing hypercellularity for age with trilineage growth

(panmyelosis) with prominent erythroid, granulocytic and megakaryocytic proliferation.

• Serum erythropoietin level below the reference range for• normal• Endogenous erythroid colony (EEC) formation in vitroa• Diagnosis requires the presence of both major criteria and one minor criterion

or the presence of the first major criterion together with two minor criteria.

TREATMENT

• polycythemia vera is a chronic condition that can't be cured. Treatment focuses on reducing the amount of blood cells in order to control signs and symptoms of the disease and decrease the risk of complications.

• Treatment may include :• Phlebotomy. This is usually the first treatment option for most people with polycythemia

vera. Phlebotomy involves drawing a certain amount of blood from one of your veins. This reduces the number of blood cells and decreases your blood volume, making it easier for your blood to function properly. How often you need phlebotomy depends on the severity of your condition.

• Medication to decrease blood cells. Phlebotomy alone may not be enough to control the signs, symptoms and complications of polycythemia vera in some people. If this is the case for you, your doctor may prescribe medications such as hydroxyurea or anagrelide to suppress your bone marrow's ability to produce blood cells. Radioactive phosphorus (32p) also can be used to reduce the number of red blood cells. Interferon-alpha may be used to stimulate your immune system to fight the overproduction of red blood cells.

• Low-dose aspirin. Your doctor may recommend you take a low dose of aspirin to reduce your risk of blood clots. Low-dose aspirin may also help reduce burning pain in your feet or hands.

• Therapy to reduce itching. If you have bothersome itching, your doctor may prescribe medication, such as antihistamines or H-2-receptor blockers, or recommend ultraviolet light treatment to relieve your discomfort.

RUXOLITINIB• Second line therapy for PV• Ruxolitinib (Jakafi), a JAK1/JAK2 inhibitor, was approved by the FDA in

December 2014 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Approval was based on data from the phase III RESPONSE trial. In this trial, patients treated with ruxolitinib demonstrated superior hematocrit control and reductions in spleen volume compared with best available therapy. A greater proportion of patients on the ruxolitinib treatment arm achieved complete hematologic remission (ie, hematocrit control and lowered platelet count and WBC). Hematologic adverse reactions are prevalent with ruxolitinib (incidence >20%) and include thrombocytopenia and anemia.[24]

• Ruxolitinib was initially approved in the United States in 2011 for patients with intermediate- or high-risk myelofibrosis including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post–essential thrombocythemia myelofibrosis.

REFRENCES

• Harrison’s Principle Of Internal Medicine• Kumar and Clark’s Internal Medicine• Netters illustrated pathology• Guyton and Hall Textbook of Medical Physiology• http://emedicine.medscape.com/article/

205114-treatment#d10• http://www.knowyourdisease.com/

treatment-of-polycythemia-vera.html