Polycythemia vera and its neurologic manifestations …

Douglas J Lanska MD MS MSPH

General Neurology

Updated 05.14.2024
Released 04.03.2006
Expires For CME 05.14.2027

Polycythemia vera and its neurologic manifestations

Author: Douglas J Lanska MD MS MSPH

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Polycythemia vera and its neurologic manifestations

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Introduction

Overview

Polycythemia vera is the commonest of chronic myeloproliferative disorders, which are a group of bone marrow stem cell neoplasms characterized by an autonomous expansion of the cellular elements of the marrow and the peripheral blood. In polycythemia vera, the increase in red cell mass predominates the clinical picture, with other cell lines showing lesser increases. The presenting symptoms are frequently vague and consist of fatigue, headaches, dizziness, bleeding, pruritus, dyspepsia, and thrombosis. Many patients have neurologic symptoms, such as headaches, dizziness or vertigo, visual problems, and paresthesias, at the time of diagnosis. Neurologic complications are seen in 50% to 80% of the cases during the course of the disease and include headaches, dizziness, visual changes, transient ischemic attack, cerebral thrombosis and hemorrhage, and cerebral venous sinus thrombosis. The causes of neurologic (and other) complications are increased blood viscosity and associated coagulopathy. An elevated white blood cell count is associated with a higher risk of complications. Virtually all patients with polycythemia vera are treated with phlebotomy to keep hematocrit under 45% in men and 40% in women. This simple therapy improves patient survival to near normal. Aspirin therapy is useful in the prevention of arterial thrombosis. Some patients, such as those with elevated white cell and platelet counts or symptomatic splenomegaly, require treatment with hydroxyurea. In over 90% of patients with polycythemia vera, JAK2 (Janus kinase 2) mutations can be demonstrated, and these mutations constitute a major diagnostic criterion of this disorder.

Key points

	• Polycythemia vera is the commonest of myeloproliferative neoplasms and is associated with elevated hemoglobin, white cell, and platelet counts.
	• Virtually all patients with polycythemia vera harbor JAK2 mutations.
	• The neurologic complications of polycythemia vera result primarily from increased viscosity of the blood.
	• Therapeutic phlebotomy is the mainstay of treatment, but newer agents such as JAK2 inhibitors appear promising.

Historical note and terminology

At the turn of the 20th century, French internist Louis Henri Vaquez (1860-1938) and Canadian-born internist Sir William Osler (1849-1919) described polycythemia vera as a distinct disease entity and made it a formal diagnosis (113; 72).

Louis Henri Vaquez (1860–1938)

French internist Louis Henri Vaquez (1860–1938). (Courtesy of the U.S. National Library of Medicine. Public domain.)
Sir William Osler (1849–1919)

Canadian-born internist Sir William Osler (1849–1919), c1912. (Source: Wrong O. Osler and my father. J R Soc Med 2003;96(9):462-4. Wellcome Library. Creative Commons Attribution Only License CC BY 4.0.)

In 1938, Rosenthal and Bassen described polycythemia as part of the spectrum of myeloproliferative disorders (87). Because of the widely varying opinions regarding diagnosis and treatment options proposed for primary polycythemia, an international Polycythemia Vera Study Group was formed in 1967 with the goal of providing a unifying diagnostic algorithm and treatment regimen for polycythemia vera, or primary polycythemia (117).

Polycythemia vera is also known as polycythemia rubra vera, primary polycythemia, erythremia, Vaquez disease, and Osler-Vaquez disease.

Clinical manifestations

Presentation and course

	• At the time of diagnosis of polycythemia vera, many patients have neurologic symptoms such as headaches, dizziness or vertigo, visual problems, and paresthesias.
	• About half of the patients have fatigue at time of diagnosis, and 40% to 50% complain of headaches.
	• Unusual sensory symptoms associated with polycythemia vera include pruritus and erythromelalgia; pruritus is present in approximately 40% to 65%, particularly after exposure to warm water (so-called “aquagenic pruritus”), such as when taking a bath.
	• Specific neurologic complications of polycythemia include motor or sensory deficits related to ischemic or hemorrhagic strokes, headaches or visual changes associated with cavernous sinus thrombosis, retinal ischemia that may cause monocular vision loss, papilledema or pseudotumor cerebri, and other conditions related to extramedullary hematopoiesis, such as spinal cord compression.

Among the most prevalent symptoms associated with polycythemia vera are fatigue (92%), insomnia (68%), numbness (66%), mood disorder (65%), pruritus (65%), early satiety (62%), difficulty concentrating (61%), sexual difficulties (57%), night sweats (57%), and headache (52%), with fatigue and pruritus among the most troublesome symptoms (92). Headache is particularly common in younger patients with polycythemia vera as well as with other myeloproliferative neoplasms (eg, essential thrombocythemia) (97).

The presenting symptoms are frequently vague and consist of fatigue, headaches, dizziness, bleeding, pruritus, dyspepsia, and thrombosis (92; 30). At the time of diagnosis of polycythemia vera, many patients have neurologic symptoms such as headaches, dizziness or vertigo, visual problems, and paresthesias (92; 30). Even though polycythemia vera may be diagnosed after an accidental discovery of an elevated hemoglobin level, many patients are symptomatic at the time of diagnosis. About half of the patients have fatigue at the time of diagnosis, and 40% to 50% complain of headaches. Other symptoms include a ruddy and flushed complexion (plethora), dizziness, and weakness. Patients may also present with complications of polycythemia vera. With elevation of the red cell volume, the blood viscosity increases, resulting in many of the complications associated with polycythemia vera. Vascular complications are seen in 50% to 80% of the cases (71); these include strokes, acute coronary syndromes, pulmonary emboli, and other thrombotic phenomena (85; 08; 48; 115).

Clinical manifestations of polycythemia vera may include unusual sensory symptoms, including pruritus and erythromelalgia. Pruritus is present in approximately 40% to 65% of patients with polycythemia vera, particularly after exposure to warm water (so-called “aquagenic pruritus”), such as when taking a bath; the mechanism is still obscure, and conflicting reports have suggested it is due to abnormal histamine release or prostaglandin production, or to other mechanisms (40; 90; 55; 101; 16; 15; 01; 02; 21; 34; 52; 44; 50; 89; 92; 76; 98; 57). Large changes in ambient temperature, alcohol consumption, or exercise may induce comparable pruritic symptoms. Pruritus may persist up to 40 minutes after the inciting factor and may be associated with aggression, irritability, depression, and suicidal ideation (92). Erythromelalgia, originally described in injured Civil War veterans by American neurologist Silas Weir Mitchell (1829-1914), is a severe burning pain in the hands or feet, usually accompanied by a reddish or bluish coloration of the skin. Erythromelalgia may be caused by an increased platelet count or increased platelet aggregation, resulting in the formation of microscopic blood clots in the vessels of the extremity; it generally responds rapidly to treatment with aspirin.

Erythromelalgia in a 77-year-old woman

A 77-year-old woman with longstanding polycythemia vera had a 6-month history of increasingly prolonged episodes of redness, swelling, and burning pain in her extremities. The severity and sites of involvement varied with each epi...
Silas Weir Mitchell (1829–1914)

American neurologist Silas Weir Mitchell (1829–1914) examining a Civil War veteran at the Infirmary for Nervous Diseases of the Philadelphia Orthopedic Hospital. (Courtesy of the U.S. National Library of Medicine. Public domain.)

On physical examination, some patients exhibit plethoric facies (reddish or purplish congestion of face), and the spleen is palpable in about 60% of the patients.

Specific neurologic complications of polycythemia include motor or sensory deficits related to ischemic or hemorrhagic strokes, headaches or visual changes associated with cavernous sinus thrombosis or cerebral venous thrombosis, retinal ischemia that may cause monocular vision loss, papilledema or pseudotumor cerebri, and other conditions related to extramedullary hematopoiesis, such as spinal cord compression (04; 28; 33; 103; 85; 08; 27; 36; 10; 63). Less common findings include oculomotor nerve palsy, chorea, and peripheral neuropathy, which are likely related to ischemia resulting from increased blood viscosity and platelet dysfunction (79; 30; 43; 13; 46).

Stroke and polycythemia vera. Polycythemia vera can cause arterial and venous cerebral thrombosis and transient ischemic attacks (30; 28; 33; 85; 08; 27; 36; 115; 10; 22; 42; 12; 63; 102). In fact, the most common neurologic manifestations of polycythemia vera are cerebral infarction and transient ischemic attacks (28). Polycythemia vera was implicated as the cause of a pontine stroke in a 51-year-old man with a right horizontal gaze palsy and an ipsilateral-lower-motor-neuron facial palsy (88). The most likely mechanisms are hyperviscosity and impaired cerebral blood flow. Hyperviscosity results from an increased packed red cell volume, and cerebral blood flow has been found to decrease when red cell volume rises (49). In the Framingham study, men with hemoglobin values of 15 gm or greater and women with 14 gm or more had twice as many cerebral infarctions, as did their cohorts with lower values (58). Moreover, an increased hematocrit has been associated with decreased reperfusion and increased infarct size following an acute ischemic stroke (05). Provided there are no contraindications, patients should receive proper antithrombotic (eg, anticoagulation in cerebral venous thrombosis cases) and vascular risk factor modification management. The use of venesection to reduce hyperviscosity (and increase cerebral blood flow) is of paramount importance in the management of patients with polycythemia vera who suffer an ischemic stroke.

Polycythemia as a probable cause of stroke in children is rare (25; 64). In a systematic review of 35 children and adolescents with polycythemia vera, there was one case of stroke (24). However, secondary polycythemia associated with other manifestations (eg, neurocutaneous syndromes) could be a clinical clue to the underlying etiology (eg, von Hippel-Lindau disease) (14).

Extramedullary hematopoiesis and neurologic manifestations of polycythemia vera. Although the most common sites of extramedullary hematopoiesis are the liver and the spleen, it can rarely occur in the nervous system (19). Extramedullary hematopoiesis in polycythemia vera has been reported to cause brain, cranial nerve, spinal cord, and nerve root compression. Extramedullary hematopoiesis may impact the nervous system by expansion of bone around cranial marrow or accumulation of hematopoietic tissue along the dura matter.

Spinal cord compression caused by extramedullary hematopoiesis in polycythemia vera was first described in 1958 (29). Latency from onset of symptoms to diagnosis ranged from 1 to 9 months with a mean of 6.7 months. Rarely, patients may present with acute myelopathy caused by hemorrhage from spinal extramedullary hematopoietic tissue, possibly related to spinal venous thrombosis (26). The most common area involved is the thoracic cord. Nevertheless, in most cases, there is extensive involvement of the spinal cord rather than localized disease. Available treatment approaches include radiotherapy, decompressive neurosurgery, and chemotherapy. Spinal irradiation in combination with decompressive neurosurgery seems to be the best available therapeutic approach (94). Regardless of the type of therapy, most patients do not achieve complete neurologic recovery.

Optic nerve compression at the orbital apex (orbital apex syndrome) may occur due to extramedullary hematopoiesis from polycythemia vera. Symptoms may include unilateral vision loss, proptosis, and ophthalmoplegia. Diagnosis is typically established with neuroimaging and biopsy of the surrounding bone (78).

Chorea and polycythemia vera. Although chorea is rare in polycythemia vera (0.5% to 5%), it is the most common of the extrapyramidal syndromes to occur in this disorder. It is important to recognize because it can be the initial manifestation of disease and requires specific treatment. The onset of chorea in a patient with polycythemia vera probably indicates a progression of the underlying myeloproliferative disorder (70). Chorea in polycythemia vera has been attributed to different pathogenetic mechanisms: (1) neostriatal hyperviscosity syndrome (leading to venous stasis, decreased cerebral blood flow, and impaired brain glucose metabolism), (2) dopaminergic hyperactivity (presumably due to excess of dopamine-laden platelets), (3) ischemic stroke of the caudate nucleus, and (4) iron imbalance (20). In cases of so-called “senile chorea,” polycythemia vera should be considered in the differential diagnosis because both disorders tend to occur in the same age group. Polycythemic chorea is usually generalized, predominantly affects orofaciolingual and brachial muscles, and is associated with hypotonia. However, polycythemic chorea can also occur as hemichorea-ballism (66). Phlebotomy and haloperidol are the usual therapies. The chorea typically resolves after repeated phlebotomies, and symptomatic treatments such as haloperidol can then be withdrawn.

Neurologic complications of treatment for polycythemia vera. Although not the focus of this article, neurologic complications can occur from treatment for polycythemia vera (41). For example, an 80-year-old outpatient woman with polycythemia vera that had progressed to myelofibrosis experienced episodes of hypoesthesia and weakness of the right arm and leg during ruxolitinib treatment. Ruxolitinib is a highly potent JAK2 inhibitor approved for the treatment of myelofibrosis post-polycythemia vera and for the treatment of polycythemia vera with an inadequate response to or intolerant of hydroxyurea (41).

Prognosis and complications

Without any therapy, patients with polycythemia vera have a median survival of about 18 months. With treatment, it is close to 14 years and may approach normal survival.

The most important complications of primary polycythemia are arterial or venous thrombotic events (33%), including stroke, myocardial infarction, and pulmonary embolism. In addition, a significant proportion of patients with polycythemia vera develop myelofibrosis (spent phase of polycythemia vera).

Clinical vignette

Vignette 1. A 67-year-old man presented to his physician for intermittent difficulty with his speech during the previous 2 weeks. According to his wife, he had trouble with word-finding. In addition, he also has had trouble keeping his balance for the last three months because of a vague dizziness. His history was remarkable for hypertension for 10 years and angina for nine months. A review of systems was remarkable for itching after taking hot showers for about two years. Physical examination was normal except for a palpable spleen tip.

Lab studies. Complete blood count (CBC) showed a white blood cell count of 18,100/uL with a normal differential, hemoglobin 21 g/dL, hematocrit 63%, MCV 72, and platelet count 675,000/uL. EKG showed old T wave changes. Echocardiogram and CT scan of the head were unremarkable. JAK2 mutation was present. Serum erythropoietin level was 2 ng/uL. Pulse oximetry showed an oxygen saturation of 98%.

A diagnosis of polycythemia vera was made, and he was started on serial phlebotomies to bring his hematocrit below 45%. With this treatment, his symptoms fully resolved. He was started on aspirin 81 mg/d and had his CBC checked monthly. Therapeutic phlebotomy was performed for hematocrits of 45% or higher. After 6 months, his requirement for phlebotomy decreased significantly. He remained asymptomatic over an ensuing 10-year period.

Vignette 2. An obese, 48-year-old, right-handed man was in good general health until three months before his first clinical visit. After a recent presentation to a large audience, he was told he was mixing words, slurring his speech, and acting confused. Complete blood count showed a white cell count 11,900/uL, hemoglobin 18.9 g/dL, hematocrit 57%, and platelet count 453,000/uL. JAK2 mutation was present. Neurologic work-up was normal. He underwent therapeutic phlebotomy, and his symptoms improved. He was already on a combination of antiplatelet therapy for coronary artery disease and was continued on the same therapy. On follow-up visits, he complained of increasing sleepiness and confusion while driving back and forth to work. His family members noted forgetfulness, glassy eyes, fatigue, and increasing sleepiness. His complete blood count showed his hematocrit to be 43%. Sleep studies showed that he had significant sleep apnea. His symptoms improved with weight loss and appropriate therapy.

Biological basis

	• The etiology of polycythemia vera is unknown, but exposure to benzene, petroleum products, and radiation has been associated with a higher risk of polycythemia vera.
	• Polycythemia vera is a clonal myeloproliferative disorder originating from a hematopoietic stem cell in the bone marrow.
	• Genomic studies of polycythemia and related myeloproliferative disorders have identified a mutation in the genetic sequence of a specific tyrosine kinase called Janus kinase 2 (JAK2) that induces a growth factor-independent proliferation of cell lines and leads to unregulated hematopoiesis.
	• The neurologic complications of polycythemia result primarily from the hyperviscosity of blood due to increased red blood cell mass, and the main consequence of hyperviscosity is thromboembolism; hyperviscosity-induced thromboembolism may be venous or arterial and is seen in about a third of the patients.

Etiology and pathogenesis

The etiology of polycythemia vera is unknown, but exposure to benzene, petroleum products, and radiation has been associated with a higher risk of polycythemia vera. Survivors of Hiroshima and Nagasaki atomic bomb explosions, as well as the observers of nuclear blasts in the United States, were found to have a higher-than-expected incidence of polycythemia vera (54; 23). Less convincing is the reported increased risk of polycythemia vera to embalmers. Viruses have also been invoked as a possible etiology of polycythemia vera (91), but these findings have not been confirmed.

Polycythemia vera is a clonal myeloproliferative disorder originating from a hematopoietic stem cell in the bone marrow (03). The origin from a pluripotent cell explains the leukocytosis and thrombocytosis that usually accompany the elevated hemoglobin level in this disease. The marrow expansion and elevated blood counts are autonomous and are independent of hematopoietic growth factors. Polycythemia is a part of the spectrum of myeloproliferative disorders that also include chronic myeloid leukemia, idiopathic myelofibrosis, and essential thrombocytosis (thrombocythemia).

Genomic studies of polycythemia and related myeloproliferative disorders have identified a mutation in the genetic sequence of a specific tyrosine kinase called Janus kinase 2 (JAK2) that induces a growth factor-independent proliferation of cell lines and leads to unregulated hematopoiesis (56).

Janus Kinase 2 (JAK2) protein structure

(Source: Emw (2009), based on Lucet IS, Fantino E, Styles M, et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor. Blood 2006;107(1):176-83. (Courtesy of Wikimedia Commons. C...

The acquired JAK2 mutation (V617F) is seen in more than 95% to 96% of patients with polycythemia vera, and JAK2 exon 12 mutations occur in about 3% (60; 61; 95; 104). In fact, all patients with polycythemia vera may have some form of JAK2 mutation (116). A large prospective study of 338 patients with polycythemia vera and JAK2 mutations showed that there is a direct relationship between the allele burden and hemoglobin level, white cell count, spleen size, bone marrow cellularity, and the risk of developing myelofibrosis (74). However, there appears to be no relationship between allele burden and the risk of leukemic transformation.

JAK2 mutations are secondary events in the pathogenesis of polycythemia vera and other myeloproliferative disorders. In some of these patients, the initial event is a mutation of the TET2 gene (31; 69). An increasing number of recognized mutations, some common (JAK2, TET, MPL) and others uncommon (LNK, CBL, ASXL1, IDH, EZH2), may contribute to the pathogenesis of polycythemia vera (104). Polycythemia vera also carries a risk of transformation into acute myeloid leukemia or myelodysplastic syndrome (5% to 15% after 10 years of disease), with risk factors including advanced age; female sex; and the use of alkylating drugs, radiation, or a combination of cytoreductive drugs (38).

The neurologic complications of polycythemia result primarily from the hyperviscosity of the whole blood due to increased red blood cell mass. The main consequence of hyperviscosity is thromboembolism, which may be venous or arterial and is seen in about a third of the patients. The most frequent types of major thrombosis include stroke; transient ischemic attack; myocardial infarction; peripheral arterial thrombosis; deep venous thrombosis; and thromboembolism, portal vein thrombosis, and thrombosis of the hepatic veins (ie, Budd-Chiari syndrome) (106; 09). Paradoxically, hemorrhage is also commonly seen. Gastrointestinal bleeding is particularly common, perhaps due to local causes such as hyperacidity. Platelets in patients with polycythemia vera may be dysfunctional and may contribute to the bleeding risk.

Hyperviscosity also causes microvascular sludging, which can cause or contribute to various symptoms, including headaches, dizziness, visual disturbances, distal paresthesias, acrocyanosis, and erythromelalgia (09).

The mechanism for pruritus in polycythemia vera, and particularly for water-induced or aquagenic pruritis, is still obscure, and conflicting reports have suggested it is due to abnormal histamine release or prostaglandin production, or to other mechanisms (40; 90; 55; 101; 16; 15; 01; 02; 21; 34; 52; 44; 50; 89; 76; 98; 57).

Fatigue in polycythemia vera has been attributed to circulating cytokines (ie, tumor necrosis factor alpha, interleukin-1, and interleukin-6) (51).

Splenomegaly may produce secondary symptoms (eg, abdominal pain, early satiety, weight loss, and nausea) and can cause abdominal organ compression and portal hypertension (51).

Differential diagnosis

Confusing conditions

Erythrocytosis and other myeloproliferative disorders need to be ruled out when considering the diagnosis of polycythemia vera. Erythrocytosis is a condition in which only the red cells are increased. It may occur due to increased production of erythropoietin or erythropoietin-like substances, increased affinity of hemoglobin for oxygen, mutations of the erythropoietin receptor that render it more sensitive to the effect of erythropoietin, or uncommon familial conditions. Many clinical situations that induce hypoxia result in increased erythropoietin production and a corresponding rise in the red cell mass. Examples of such disorders include sleep apnea, chronic obstructive pulmonary disease, and cyanotic heart disease. High-affinity hemoglobins do not release oxygen in a normal fashion (81), thus, creating relative hypoxia. Both benign and malignant tumors of the kidneys and liver can produce erythropoietin or erythropoietin-like substances that can increase the red cell production in the marrow. Unique mutations resulting in truncated erythropoietin receptors have been identified that make the receptor hypersensitive to erythropoietin. In a rare familial condition called Chuvashian erythrocytosis, the condition is inherited in an autosomal recessive fashion and usually results in hemoglobin levels of over 20 g/dL (96).

In virtually all patients with erythrocytosis, erythropoietin levels are increased. Patients have higher than normal hemoglobin levels but normal white blood cell and platelet counts. The JAK2 mutation, which is characteristically present in polycythemia vera, is absent in erythrocytosis.

On the other hand, differentiation between polycythemia vera and other myeloproliferative disorders may be difficult. This is especially true for essential thrombocythemia and idiopathic myelofibrosis. Patients have been known to transform from essential thrombocythemia to polycythemia vera and vice-versa. Similarly, a significant portion of the patients with polycythemia vera have bone marrow fibrosis and progress to a state called post-polycythemic myelofibrosis. In most cases, careful history and review of old CBC results are helpful in distinguishing one disorder from the other.

Diagnostic workup

	• A hematocrit value in the 95th percentile in the absence of plasma volume-contracted states is suggestive of polycythemia.
	• Alternatively, a hematocrit of greater than 52% in men and 48% in women is considered indicative of polycythemia.
	• Measurement of the serum erythropoietin level is important in determining whether polycythemia vera is present or the rise in hemoglobin is erythropoietin-dependent: in polycythemia vera, erythropoietin levels are below normal values.
	• The JAK2 mutational analysis is an essential confirmatory test in the diagnostic work-up of polycythemia vera.

The diagnostic criteria for polycythemia vera have undergone significant change. In the 1980s and the 1990s, measurement of the red cell mass was a standard criterion (37; 77). This test has fallen into disfavor because of inaccurate and unreliable results. Most institutions now depend on the hemoglobin/hematocrit level. A hematocrit value in the 95th percentile in the absence of plasma volume-contracted states is suggestive of polycythemia. Alternatively, a hematocrit of greater than 52% in men and 48% in women is considered indicative of polycythemia. Next, measurement of the serum erythropoietin level is important in determining whether polycythemia vera is present or the rise in hemoglobin is erythropoietin dependent. In polycythemia vera, the erythropoietin levels are below the normal values (84). Arterial blood gas measurement documenting the hypoxemic state can also confirm appropriate versus inappropriate elevations in hemoglobin levels. The JAK2 mutational analysis is an essential confirmatory test in the diagnostic work-up of polycythemia vera.

Splenomegaly, a finding associated with primary polycythemia, may be found on physical examination or by using abdominal imaging, such as abdominal ultrasound or CT scanning. CT imaging can also help establish the etiology of secondary polycythemia by identifying malignant tumors, renal diseases, or cysts (80). Bone marrow biopsy is not considered essential in establishing the diagnosis of polycythemia vera. If done, it shows increased cellularity and absence of iron (110). In cases where there is suspicion of another myeloproliferative disorder, bone marrow biopsy can be extremely helpful. Cytogenetic analysis of the bone marrow can rule out chronic myeloid leukemia.

The WHO criteria for establishing the diagnosis of polycythemia vera were revised in 2008 (111). Diagnosis of polycythemia vera is based on the presence of both major and one minor criterion or the presence of the first major criterion plus two minor ones:

Major criteria

1. Hemoglobin greater than 18.5 g/dL in men, 16.5 g/dL in women
or
Hgb or Hct higher than the 99th percentile of reference range for age, sex, or altitude of residence,
or
Hgb greater than 17 g/dL (men) or 15 g/dL (women) if associated with a documented and sustained increase of more than 2 g/dL from baseline that cannot be attributed to correction of iron deficiency
or
Elevated red cell mass more than 25% above mean normal predicted value.

2. Presence of JAK2 V617F or other functionally similar mutations (eg, exon 12 mutation)

Minor criteria

1. Hypercellular bone marrow with trilineage growth
2. Low serum erythropoietin level
3. In vitro formation of endogenous erythroid colonies.

The red blood cells in patients with polycythemia vera are typically normochromic and normocytic but may be hypochromic and microcytic if the patient has been receiving phlebotomy treatments or has been bleeding (eg, from underlying peptic ulcer disease). Red cells may vary in size and shape (anisopoikilocytosis) and red cell precursors may be present on peripheral blood smears.

Polycythemia vera (blood smear)

Blood smear from a 68-year-old woman with a 13-year history of polycythemia vera treated with phlebotomy, 32P (32-phosphorus), and hydroxyurea. There was a 6-to 7-month history of decreasing hemoglobin level and platelet count. Th...

Other findings on a complete blood count may include thrombocytosis (> 400,000 platelets/µL) in approximately 50% of patients, and leukocytosis (> 12,000/µL) in approximately 60% of patients. Morphologic abnormalities in platelets may include macrothrombocytes and granule-deficient platelets. Leukocytosis, when present, is mainly due to neutrophilia with a left shift and a few immature cells, but mild basophilia occurs in 60% of patients.

In about half of the cases, MRI of the brain may disclose asymptomatic focal changes, particularly localized in the subcortical areas of the frontal and parietal lobes, in the absence of significant corresponding vascular disease (hypertension, atherosclerotic vascular disease, heart rhythm disorders) (103). Such patients are also prone to acute strokes, often with thrombotic occlusion of the internal carotid artery.

Management

	• The earliest, easiest, and most effective treatment of polycythemia vera remains serial therapeutic phlebotomies to keep the hematocrit below 45% in men and 40% in women.
	• Low-dose aspirin has been shown to reduce thrombotic risks in patients with polycythemia vera.
	• When phlebotomies alone fail to control the rising hematocrit, or if patients develop markedly elevated leukocyte and platelet counts, additional myelosuppressive agents may be used.
	• Interferon alfa-2a is a useful, albeit toxic, agent in the treatment of polycythemia vera because it can induce complete remissions of the disease.

The earliest, easiest, and most effective treatment of polycythemia vera remains serial therapeutic phlebotomies to keep the hematocrit below 45% in men and 40% in women (88; 102). This may also result in improvement of neurologic deficits associated with polycythemia, whether primary or secondary (73).

In addition to phlebotomies, low-dose aspirin has been shown to reduce thrombotic risks in patients with polycythemia vera (59). One disadvantage is the theoretical increased risk of bleeding in patients known to have qualitative platelet dysfunction. A Cochrane review of two randomized controlled trials of 630 patients comparing the use of low-dose aspirin versus placebo concluded that aspirin reduces the risk of fatal thrombotic events (although it was a statistically nonsignificant reduction) without an increase in major bleeding (100). Low-dose aspirin is recommended for patients with polycythemia vera without a clear contraindication for its use. There are no data on the use of other antiplatelet drugs as preventive therapies in patients with polycythemia vera.

When phlebotomies alone fail to control the rising hematocrit, or if patients develop markedly elevated leukocyte and platelet counts, additional myelosuppressive agents may be used (45; 86; 47; 105). These additional agents may also be considered in patients in whom the thrombotic risks are high (45; 47). First-line choices for high-risk patients (ie, over 60 years of age, prior thrombosis) are hydroxyurea and interferon alpha, whereas second-line options include JAK2 inhibitors, busulfan, and ³²P (47). Hydroxyurea is the most commonly used agent because it is safe and effective.

Interferon alfa-2a is a useful, albeit toxic, agent in the treatment of polycythemia vera because it can induce complete remission of the disease (82; 47). However, it causes significant and often intolerable side effects that include flu-like symptoms (eg, myalgias), fatigue, anorexia and weight loss, neuropsychiatric symptoms (eg, depression), neuropathy, and autoimmune problems (eg, thyroiditis) (47). The use of interferon alfa-2b, which has stronger immunomodulatory activity, is associated with a risk of developing progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy usually manifests in immunosuppressed individuals (eg, AIDS or organ transplant patients) and is caused by the JC virus. Serotonin receptor 5HT2 in glial cells is needed for the virus to infect such cells. Down-regulation of 5HT2a receptors is thought to be the reason for the observed clinical and radiological improvement of progressive multifocal leukoencephalopathy in some patients treated with mirtazapine (114).

Second-line agents, like the alkylating antineoplastic agent busulfan and radioactive phosphorus (³²P), have been linked to potential leukemic transformation, and consequently, they are usually reserved for elderly patients (70 years of age or older) or those with advanced disease, in whom the risk of thrombosis outweighs the risk of developing acute myeloid leukemia or a myelodysplastic syndrome (17; 18; 47). In patients who are refractory or intolerant of hydroxyurea, or have massive splenomegaly or intractable symptoms, JAK2 inhibitors (eg, ruxolitinib) are recommended (47; 112).

Other classes of agents are being investigated in the treatment of polycythemia vera, including pegylated formulations of interferon alpha-2a (which are better tolerated and allow less frequent administration) and histone deacetylase inhibitors (83; 51; 47).

Patients should avoid iron supplements and diets rich in iron, which may increase red cell volume. Regular exercise and proper hydration help decrease the risk of thromboembolism. Patients should be made aware of the risk of moving to higher altitudes, which may further increase hemoglobin levels (99).

Symptomatic treatments, especially treatment of pruritus, are often an important part of disease management. Therapeutic options include the use of antihistamines, aspirin, paroxetine (a selective serotonin reuptake inhibitor), and naltrexone (an opioid antagonist) (35; 40; 93; 118; 107; 53). Interferon-alpha has also been shown to have some effect in high-risk patients (32; 39; 68). Antidepressants, JAK2 inhibitors, and rapamycin (an m-TOR inhibitor) have also been reported to be useful in the management of pruritus associated with polycythemia vera (89).

Management of erythrocytosis or secondary polycythemia is based on treatment of the underlying etiology. For example, cessation of cigarette smoking or the treatment of an underlying lung disease may be helpful if hypoxia is thought to underlie a patient’s polycythemia. If there is a congenital heart anomaly leading to shunting, surgery to correct the defect may be helpful. Phlebotomy should be avoided in these patients.

The role of splenectomy in the management of polycythemia vera is controversial. In general, splenectomy should be avoided because medical therapy is usually very effective in this disorder. Painful splenomegaly with infarction or compression of the surrounding viscera is the most accepted indication for surgery. Other indications include dyspnea and early satiety leading to weight loss in situations in which the spleen becomes massive in size. Anemia and thrombocytopenia in polycythemia vera only respond transiently to splenectomy (62).

Outcomes

Patients with polycythemia vera treated with phlebotomy alone have a 2% lifetime risk of leukemic transformation. In patients who have been treated with alkylating chemotherapeutic agents or radioactive phosphorus, the risk increases to about 15%. This risk is considered unacceptable, and such agents are to be avoided. Hydroxyurea, which is commonly used in patients with polycythemia vera, increases the risk of leukemic transformation to slightly above 5%, but this difference is not statistically significant.

Media

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Douglas J Lanska MD MS MSPH

Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
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Former Authors

Tyler Y Kang MD
Sucha Nand MD
Athena Kostidis MD
Sarkis Morales-Vidal MD
Alan Lichtin MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: male>female, >1:1
Heredity: heredity may be a factor

autosomal dominant

autosomal recessive

sex-linked dominant

sex-linked recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively

ICD & OMIM codes

ICD-10: Polycythemia vera: D45
ICD-11: Neoplasms, polycythemia vera: 2A20.4

Chronic myeloproliferative disorders, polycythemia vera: XH0453

Pruritus due to other specified systemic disorder: EC90.1Y

Polycythaemia vera: M-9950/3
OMIM: Polycythemia vera: #263300

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Polycythemia vera and its neurologic manifestations

Associated Disorders

Chronic obstructive pulmonary disease

Differential Diagnosis

polycythemia vera
secondary polycythemia
myeloproliferative disorders
myelofibrosis
essential thrombocytosis
- acute myelocytic leukemia
- acute lymphoblastic leukemia
- Chuvash polycythemia

	• The prevalence of polycythemia vera is between 44 to 57 per 100,000 persons, and its annual incidence is estimated at between 4 to 28 cases per million.
	• The median age at diagnosis is 60 years of age.
	• The median survival is about 14 years.

	• There are no known ways to prevent the occurrence of polycythemia vera.
	• Measures can be taken to prevent complications such as thromboembolism.

Polycythemia vera and its neurologic manifestations

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Major criteria

Minor criteria

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Former Authors

Patient Profile

ICD & OMIM codes

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