Polycythemia Vera

An increase in red cell mass is the primary feature of polycythemia vera (PV) [4] [8] [10]. Bone marrow analysis, however, shows a proliferation of all three myeloid lines: erythrocytes, granulocytes and platelets. The onset of polycythemia vera is often insidious. Early symptoms are related to blood hyperviscosity due to polycythemia. Decreased blood flow and thrombosis result in hypoxia [8] [10] [11]. Patients often present with either arterial or venous vascular occlusive events [10].

Presenting non-specific symptoms of polycythemia vera are related to hypoxia and include [10]:

• Headache
• Dizziness
• Visual impairment
• Tinnitus
• Angina pectoris

The signs and symptoms found in individuals diagnosed with polycythemia vera include [9] [10]:

• Elevated red blood cell mass >25%
• Erythrocytosis, hematocrit >60 males, >56 females
• Leukocytosis >10.9/ml
• Thrombocytosis, platelet count >400,000/ml
• Splenomegaly and splenic infract
• Thrombotic and hemorrhagic complications
• Vasomotor disturbances
• Pruritus
• Elevated Vitamin B12 level
• Plethora, a ruddy complexion of face, palms, nail beds, mucosa, and conjunctiva, due to the increased total red blood cell count.

Thrombosis and bleeding are frequent in persons with polycythemia vera. These complications are the result of the increased red blood cell count and elevated platelet count [9] [10] [19]. Bleeding is seen in approximately 1% of patients, epistaxis, gum bleeding, ecchymoses, and gastrointestinal (GI) bleeding [8] [10]. Peptic ulcer disease occurs with polycythemia vera due to increased histamine levels and resulting gastric acidity. This causes abdominal pain, abnormal feeling of fullness, and anorexia. Weight loss may result [9].

Erythromelalgia is a syndrome specific to polycythemia vera. It increases the risk of thrombosis. The symptoms are burning pain in the feet, hands, toes and fingers, sometimes associated with pallor, erythema, or cyanosis. Occasionally, it progresses to gangrene. This can be treated with aspirin (50-300 mg/d) and dipyridamole (75 mg orally 3 times a day) [11] [15].

Pruritus also results from increased histamine levels due to increased basophils and mast cells. This occurs in up to 40% of patients with polycythemia vera [9]. Splenomegaly is present in 75% of patients at the time of diagnosis, hepatomegaly in approximately 30% of patients [10] [16].

The presence of the Janus kinase-2 (JAK2 V617F) mutation is diagnostic for polycythemia vera [4] [5] [12]. However, 2-3% of patients are negative for this genetic marker [12] [13]. The absence of the Janus kinase-2 mutation combined with a normal or increased serum erythropoietin level, excludes the diagnosis [9]. These patients have secondary erythrocytosis rather than polycythemia vera [5] [12].

Diagnostic criteria for polycythemia vera according to the World Health Organization guidelines require the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria [12] [14].

Major criteria [10] [12] [13]:

• Elevated red cell mass >25% or Hemoglobin > 18.5 g/dL (Hematocrit >60) in men and > 16.5 g/dL (Hematocrit >56) in women
• Presence of Janus kinase-2 mutation

Minor criteria [10] [12] [13]:

• Palpable splenomegaly
• Decreased serum erythropoietin level 
• Bone marrow biopsy showing erythroid, granulocytic, and megakaryocytic proliferation 
• Endogenous erythroid colony formation in vitro

Laboratory studies suggested for evaluation of polycythemia vera [2] [4] [12] [13]:

• Janus kinase-2 mutation analysis
• Direct measurement of the red blood cell mass is often not possible
• Complete blood count: Red blood cell counts with hematocrit and hemoglobin levels, Red blood cells are generally normochromic and normocytic, White blood cell count (>12,000/µL) primarily neutrophils with a left shift, Platelet count is elevated to 400,000-800,000/µL

• Serum erythropoietin level 
• Erythroid progenitor cell assay
• Leukocyte alkaline phosphatase (LAP) is elevated (>100 U/L)
• Routine coagulation tests are usually normal, 
• Vitamin B-12 levels elevated to > 900 /mL
• Oxygen saturation (SaO2) and carboxyhemoglobin (COHb) levels
• Iron studies

Imaging 

An enlarged spleen is often palpable and in such cases, imaging studies are not required [12] [13]. Ultrasonography or computed tomography scans may be able to detect splenic enlargement that was not evident on physical examination [12].

The diagnosis of Budd-Chiari syndrome is made using ultrasonography, computed tomography scan and magnetic resonance imaging [18].

Other tests

Bone marrow studies are not necessary to establish the diagnosis of polycythemia vera [2] [4]. They are important in identifying transformation to acute leukemia [4] [5]. Patients should be followed monthly until normalization of blood cell counts and splenomegaly, then every 2 months for complete blood count and blood smear evaluation [5].

The goal of treatment for polycythemia vera is to control myeloproliferation [10] [15] and decrease the risk of arterial and venous thrombotic events, which occur in approximately 20% of patients [2] [9]. The optimum management plan is unclear. Significant differences exist among physicians about the appropriate management of the disease [2]. Consultation with and management by a hematologist is recommended [5].

General guidelines for the management of polycythemia vera include [2] [5] [9] [15]:

• Maintain a hematocrit of 44% or less is the target
• Minimize the risk of transformation to acute leukemia and myelofibrosis
• Manage complications such as thrombosis and hemorrhage

Medical management:

• Phlebotomy alone is the first choice
• A combination of phlebotomy and hydroxyurea
• Hydroxyurea alone, (interferon, 32P or busulfan are used infrequently)
• Low-dose aspirin
• Treatment of thrombocytosis recommended for platelet counts above 400,000

All patients with polycythemia vera require phlebotomy to keep their hematocrit levels below 44% [5] [15]. This treatment removes excess red blood cells and lowers blood viscosity [10]. Patients can be phlebotomized once or twice a week [5] [10]. Elderly patients with cardiovascular or cerebral vascular conditions should have volume replaced with saline solution after each procedure to avoid postural hypotension [10]. Chemotherapy and phlebotomy can decrease the risk for thrombotic events [11].

Patients with this disorder should routinely take low-dose aspirin, 81 mg daily [5]. Low-dose aspirin suppresses thromboxane biosynthesis resulting from increased platelets and essential thrombocythemia [5] [11]. Treatment with aspirin may also reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes, pulmonary embolism, or major venous thrombosis [10] [11]. The incidence of major bleeding episodes was not significantly increased with aspirin [11].

Patient at high risk for thrombosis should have drug therapy to decrease blood cell production. Hydroxyurea at a starting dose of 500 mg twice daily is the most commonly used agent. It is an effective agent for myelosuppression [5]. It reduced the risk of thrombosis when compared with phlebotomy [5]. It should be the drug of choice for patients older than 40 years [6]. However, there are concerns that it may increase the long-term risks of leukemic transformation [6]. 

Interferon-alpha can be used as an alternative [9] [10]. Studies have shown that treatment with this drug was not as effective when compared with hydroxyurea. However, interferon alfa 2b had a lower transformation rate and no severe hematological adverse effects [8].

Busulfan is also an option for patients older than 65 years of age who do not respond to hydroxyurea [10].

Ruxolitinib (Jakafi), a Janus-associated kinase inhibitor, is the first US Food and Drug Administration drug approved specifically for polycythemia vera [1]. It is approved for use in patients with polycythemia vera who cannot tolerate or had an inadequate response to hydroxyurea [1]. Patients who received ruxolitinib had a significant reduction in splenomegaly [12] [13].

Once the patient's red blood cell values are reduced periodic phlebotomies or a myelosuppressive agent should be continued to maintain disease control [5] [10].

Splenectomy should be only considered in patients with painful splenomegaly or splenic infarction [10] [11]. Treatment of Budd-Chiari syndrome includes portal or mesenteric-systemic shunting, catheter-directed thrombolysis, and liver transplantation [18].

Untreated polycythemia has a very poor prognosis. The median survival in untreated patients is 1.5-3 years. Treated this may be extended to at least 10-20 years [1]. Thrombosis is the leading cause of death [10]. Thrombotic complications including stroke and other arterial thromboses occur in ~1% of patients. The risk of thrombosis depends on age of the patient and their past history of thrombosis. Patients older than 60 years or with a previous history of thrombosis are considered at high risk [1] [10].

Bleeding complications occur in ~ 1% of patients with polycythemia vera and include epistaxis, gum bleeding, ecchymoses, and gastrointestinal bleeding [8].

The long-term risks of polycythemia vera include leukemic and fibrotic transformation occurring in 5-10% of patients [8] [9] [15]. Studies have suggested an increased risk for all neoplasms with the use of chemotherapic agents in polycythemia vera.

Vaquez is credited with the initial description of polycythemia vera in 1892. The clinical features were first described by Osler in 1903 [2]. In 1967, the Polycythemia Vera Study Group identified criteria for diagnosis and treatment of the disease [2] [5].

The etiology of all the myeloproliferative disorders is unknown [3]. The cause of the symptoms of polycythemia vera is an uncontrolled blood cell proliferation [4] [12] [13]. The abnormal cell production is a mutation in the Janus kinase-2 gene [13]. The cause if this mutation is unknown. Virtually all patients with polycythemia vera have the mutation. The discovery of the Janus kinase-2 gene mutation has improved the diagnosis of polycythemia vera [13].

The mean age of incidence of polycythemia vera is 50-70 years [8], but it can occur in all age groups, although rarely in childhood [7] [14]. Familial cases are very rare usually in elderly family members [7].

The severity of polycythemia vera and the rate of progression vary from patient to patient [8]. All myeloproliferative disorders, including polycythemia vera, are pre-leukemic as they can transform to acute leukemia over time. The rate of leukemic transformation in polycythemia vera is 5-10% of patients [8] [15].

Polycythemia vera is relatively rare, affecting in 0.6-1.6/million population [10]. The disorder can occur at any age, but it has a median age at onset of 60 years [10]. Studies have shown that this condition concerns all ethnic groups [1]. Polycythemia vera occurs almost equally in both sexes [12], though a few studies have found that slightly more males than females are affected [2].

Myeloproliferative disorders like polycythemia vera are hematopoietic stem cell malignancies [3] [8]. Abnormal stem cells present in the bone marrow of patients with polycythemia vera suppress normal stem cell maturation [12].

These abnormal blood stem cells respond aberrantly to growth factors [4]. A mutation on the Janus kinase-2 gene (JAK2) is the most likely gene involved in polycythemia vera [4] [6] [12]. It is thought that the defect alters the signal from growth enzymes to the stem cells [12]. Polycythemia vera stem cells are hypersensitive to erythropoietin and hematopoietic growth factors [8]. This mutation occurs in most (> 80%) polycythemia vera patients [6]. The mutation leads to tyrosine phosphorylation activation that causes cytokine hypersensitivity that induces erythrocytosis [6] [8].

Serum levels of erythropoietin are normal or subnormal in polycythemia vera patients, therefore the hyperproliferation is not stimulated extrinsically and the disease is classified as a primary polycythemia [8].

In polycythemia vera excessive red blood cells are produced in the bone marrow [1]. Patients may also experience an increase in white blood cells and platelets [1]. These blood cells show no cytogenetic abnormality, all blood cells produced are normal [8]. The overabundance of blood cells causes splenomegaly, bleeding problems, and thrombosis [1] [14]. Studies have shown that hematocrits above 44 are associated with an increased number of thromboembolic events [2].

Thrombotic events in polycythemia vera are the result of the increased viscosity of the blood due to the excessive numbers of blood cells. Increased thromboxane synthesis occurs as well due to thromboxane-dependent platelet activation [11]. This is a major cause of the increased risk of thrombosis. Low-dose aspirin suppresses the production of thromboxane by platelets in patients with high platelet counts and [11].

A paradoxical bleeding or hemorrhagic tendency occurs with high platelet counts that resembles acquired Von Willebrand disease in patients with polycythemia vera[16].

As in all the myleoproliferative disorders, polycythemia vera may progress to blood malignancies such as acute leukemia and myleofibrosis [9]. Transformation rates are estimated to be 10-20% [9] [10]. Leukemic transformation of polycythemia vera can be influenced by pharmacotherapy such as alkylating agents [10]. Acute leukemia is thought to be a part of the natural course of polycythemia vera [11].

Budd–Chiari syndrome, obstruction and occlusion of the suprahepatic veins, is a rare life-threatening complication in polycythemia vera [7]. It is the result of thrombosis within the vasculature of the liver[18].

Differential diagnoses for polycythemia vera include [7] [9]:

• Chronic myeloid leukemia (CML)
• Agnogenic myeloid metaplasia (AMM)
• Fibrotic myelofibrosis
• Conditions causing systemic hypoxia
• Conditions stimulating erythropoietin secretion
• Infections or leukemoid reactions
• Thrombocytosis from bleeding
• Iron deficiency
• Essential thrombocytosis

A cause for the development of the Janus kinase-2 genetic mutation is unknown, therefore there is no way to prevent its occurrence.

Phlebotomy, myelosuppressive drugs, and anticoagulants can prevent thrombosis, stroke, liver and renal damage, and other cardiovascular events [10] [11]. Studies have shown that low dose aspirin (81 mg/d) is effective for preventing thrombosis without causing bleeding [11].

Polycythemia vera is a chronic myeloproliferative stem cell disorder [1] [2]. It is one of several acquired myeloproliferative diseases that are considered malignant bone marrow disorders [1] [3] [4]. Polycythemia vera and the other myeloproliferative diseases are relatively uncommon [5].

The primary characteristic of polycythemia vera is an elevated absolute red blood cell count due to uncontrolled red blood cell production [2]. Panmyelosis may also be seen as increased white blood cell and platelet production [1] [2]. Other characteristic features of polycythemia vera are splenomegaly, a predisposition to venous/arterial thrombosis, and bleeding [6]. It can eventually progress to myelofibrosis, and acute leukemia [2].

Polycythemia vera arises from acquired mutations in a hematopoietic stem cell [7] [8]. The mechanisms accounting for the development of these mutations are poorly understood [8]. The genetic mutations of polycythemia vera usually occurs sporadically, but occasional familial cases have been reported [7]. The median age at diagnosis of polycythemia vera is 60 years of age [11]. It is a progressive disease and approximately 5% of patients progress to acute leukemia [9] [10].

The rise in red blood cell load in polycythemia vera results in hyperviscosity of the blood and subsequent circulatory disturbances. The primary cause of death is acute cardiovascular or cerebrovascular events [11].

What is polycythemia vera ?

Polycythemia vera is a chronic disease of blood cell producing stem cells of the bone marrow. The overproduction of red blood cells, primarily, white blood cells and platelets occur because of a genetic mutation of these stem cells. The median age at diagnosis is 60 years of age. Although disease itself is not fatal, death will occur within 1 ½ to 3 years from cardiovascular complications of blood clot formation.

What are the symptoms?

Polycythemia vera is often asymptomatic at first. It may initially present with non-specific symptoms of decreased oxygen supply such as: headache, dizziness, vertigo, and angina. Other individuals will not be diagnosed until they experience a major blood clotting event.

The clinical signs of the disorder are:

• Elevated red blood cell count; hematocrit over 60
• Elevated white blood cell and platelet count
• Enlarged spleen
• Tendency for abnormal clotting

What causes polycythemia vera?

The cause is a mutation of the Janus Kinase-2 gene that is responsible for the regulation of blood cell production. Because of this mutation blood cell production is excessive. The extreme number of circulating blood cells causes the blood to be more viscous increasing the risk of blood clot formation.

Who gets polycythemia vera?

Polycythemia vera can occur at any age, however it is rare in individuals younger than 40 years of age. Mean age at onset is 60 years.

How is it diagnosed?

The definitive diagnosis of polycythemia vera is made when the Janus Kinase-2 gene mutation is detected. Routine blood tests will show an excessive increase in red blood cells, white blood cells, and platelets.

How is polycythemia vera treated?

Polycythemia vera is treated primarily with periodic phlebotomy, blood-letting, to remove excessive blood cells and reduce blood viscosity. Myelosupressive medications, such as Hydroxyurea, reduce blood cell production. All patients are also given low-dose aspirin to prevent clotting.

What are the complications?

The complications of polycythemia vera are due to abnormal clotting and include:

• Stroke
• Pulmonary emboli
• Myocardial infarct
• Circulatory compromise in the extremities
• Obstructive liver disease
• Obstructive renal damage

How can it be prevented?

Since a cause of the Janus kinase-2 genetic mutation is unknown, there is no way to prevent polycythemia vera. Phlebotomy, myelosuppressive drugs, and anticoagulants can prevent the complications of the disease and extend life expectancy.

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