Polycythemia vera

Polycythemia vera

What every physician needs to know:

Polycythemia vera is a clonal hematopoietic stem cell disorder, characterized by the unregulated production of red cells, white cells and platelets, thrombotic and hemorrhagic events, ocular migraine, pruritus, erythromelalgia, splenomegaly due to extramedullary hematopoiesis, myelofibrosis, and, rarely, acute leukemia.

Are you sure your patient has polycythemia vera? What should you expect to find?

The symptoms associated with polycythemia vera are entirely nonspecific and due to increased blood viscosity, hypercoagulability, inappropriate release of leukocyte cytokines, and organomegaly.

The most common symptoms are:

• headache,

• scintillating scotoma,

• impaired cognition,

• weakness,

• dizziness,

• itching, particularly after a bath or shower,

• paresthesias,

• extremity pain,

• heat intolerance,

• abdominal pain,

• easy bruising.

Beware of other conditions that can mimic polycythemia vera:

Erythrocytosis

Any cause of absolute erythrocytosis can mimic polycythemia. Possible causes are:

• Hypoxia such as caused by chronic carbon monoxide exposure, high altitude, chronic pulmonary disease, high oxygen affinity hemoglobins, and right to left pulmonary artery shunts,

• Renal disease, including renal artery stenosis, focal sclerosing glomerulonephritis, and post renal transplantation,

• Tumors, including hypernephroma, hepatoma, and cerebellar hemangioblastoma,

• Drugs, such as androgenic steroids and recombinant erythropoietin, and genetic mutations in the erythropoietin receptor or rarely, in the proteins that control erythropoietin production.

Importantly, conditions that promote plasma volume contraction (pseudoerythrocytosis) such as hypertension, diuretics, tobacco use, and androgenic steroids can mimic absolute erythrocytosis.

Phenotypic mimicry involving the other chronic myeloproliferative disorders

Because polycythemia vera and its companion myeloproliferative disorders share in common the same mutations, their clinical features overlap, and because the clinical manifestations of these disorders evolve over time, it is often not possible to distinguish between them on clinical grounds. For example, isolated thrombocytosis, whether associated with a JAK2 mutation or not, can be the presenting manifestation of essential thrombocytosis, primary myelofibrosis, or polycythemia vera, while both essential thrombocytosis and primary myelofibrosis can evolve into polycythemia vera. This type of evolution can take up to a decade.

Furthermore, in addition to presenting with isolated thrombocytosis, polycythemia vera can present with just erythrocytosis alone, erythrocytosis and splenomegaly, erythrocytosis and leukocytosis or thrombocytosis, or all three together.

Finally, in polycythemia vera, in contrast to the other forms of erythrocytosis listed above, there is often expansion of the plasma volume as red cell production increases. While this prevents a rapid increase in blood viscosity, the expanded plasma volume can also mask the presence of an elevated red cell mass. Thus, a normal hematocrit or hemoglobin level does not exclude the presence of absolute erythrocytosis when polycythemia vera is a diagnostic consideration. In fact, 64% of patients considered to have JAK2 V617F-positive essential thrombocytosis were actually found to have polycythemia vera when a direct determination of the red cell mass and plasma volume was performed, and this was also true for approximately 10% of patients thought to have primary myelofibrosis.

It is also important to note in this regard, that it is often not possible on the basis of a bone marrow aspirate or biopsy to distinguish between these three chronic myeloproliferative disorders. Thus, polycythemia vera must be considered as a great imitator, and since it is the most common of the three chronic myeloproliferative disorders, it should be the first disease considered when a chronic myeloproliferative disorder is a diagnostic consideration.

Which individuals are most at risk for developing polycythemia vera:

Polycythemia vera is most common in women, the elderly, individuals of Ashkenazi extraction, and in the family members of patients with polycythemia vera, essential thrombocytosis, or primary myelofibrosis, although the overall incidence of familial polycythemia vera is very low.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Polycythemia vera is a disorder of protean manifestations, making it often difficult to diagnose solely on clinical grounds. If there is elevation of the red cell, white cell, and platelet counts, together with or without splenomegaly, the diagnosis is assured.

Unfortunately, however, this type of presentation is uncommon and the approach to diagnosis more often depends on the specific clinical setting. For example, when a patient has new onset erythrocytosis with a hematocrit greater than 60%, or a hemoglobin greater than 20gm%, absolute erythrocytosis is present, and if the high hematocrit or hemoglobin is associated with splenomegaly, leukocytosis, thrombocytosis or all three, the diagnosis of polycythemia vera is confirmed.

However, if there is only isolated erythrocytosis, another cause of erythrocytosis is more likely and even when there is isolated erythrocytosis together with a JAK2 mutation, a diagnosis of polycythemia vera cannot be made with certainty, since there may be no further disease evolution. Furthermore, if the hematocrit is less than 60% or the hemoglobin less than 20gm%, the presence of an absolute erythrocytosis is not assured and a red cell mass and plasma volume determination must be performed to avoid confusion with pseudoerythrocytosis due to plasma volume contraction.

As a corollary, even if the hematocrit or hemoglobin level is normal, in a patient with unexplained splenomegaly or hepatic vein thrombosis, because of the possibility of plasma volume expansion, polycythemia vera cannot be excluded without red cell mass and plasma volume measurements. In this regard, it is important to remember that the presence of a JAK2 mutation only suggests that a chronic myeloproliferative disorder is present, but not its type, while the absence of such a mutation does not exclude the presence of a chronic myeloproliferative disorder.

Since only in polycythemia vera is there elevation of the red cell mass, a red cell mass measurement serves to distinguish this disorder from its companion myeloproliferative disorders, essential thrombocytosis, and primary myelofibrosis, and also establishes the basis for specific therapy. It should also be noted that while cytogenetic abnormalities occur in polycythemia vera, they are not common, not specific for the disorder, and usually have no prognostic significance. It is also worth emphasizing that marrow fibrosis is part of the natural history of the disease and per se has no prognostic significance.

Proposed diagnostic studies for polycythemia vera

The World Health Organization (WHO) has published diagnostic criteria for polycythemia vera which include suggested hemoglobin levels that are, unfortunately and inexplicably, not inclusive of those that characterize the disease, while increasing the possibility of confusing plasma volume contraction with true erythrocytosis, leading to false positive and negative diagnoses.

The WHO also recommends a bone marrow examination as part of the diagnostic evaluation, together with an assay for a JAK2 mutation, a serum erythropoietin assay, and an in vitro assay for endogenous erythropoietin colonies (EEC). However, the latter two tests are essentially surrogates for the JAK2 V617F mutation, and the EEC assay is neither specific for polycythemia vera nor commercially available. The serum erythropoietin level is also nonspecific unless it is elevated, in which case it excludes polycythemia vera. Moreover, bone marrow histology cannot be used to distinguish one chronic myeloproliferative disorder from another. Finally, inexplicably omitted from the WHO diagnostic criteria are splenomegaly, leukocytosis, and thrombocytosis.

Since polycythemia vera is one of the least common causes of erythrocytosis, all correctable disorders causing erythrocytosis need to be excluded first, as suggested in diagnostic algorithm (Table I).

Table I.n

What imaging studies (if any) will be helpful in making or excluding the diagnosis of polycythemia vera?

Ultrasonography is often used to determine if splenomegaly is present when the spleen is not palpable, or if there is morbid obesity or difficulty in obtaining abdominal muscle relaxation. However, there are no established norms for spleen size relative to body habitus or gender. Such a measurement can also be imprecise and, of course, splenomegaly is not specific for a particular myeloproliferative disorder. Imaging studies are, however, useful in establishing the present of hepatic vein thrombosis, which can be a presenting manifestation of polycythemia vera, particularly in young women.

If you decide the patient has polycythemia vera, what therapies should you initiate immediately?

Thrombosis is the greatest immediate risk to the polycythemia vera patient, due to the hyperviscosity and nitric oxide scavenging associated with an elevated red cell mass. Therefore, once the diagnosis is established, therapeutic phlebotomy should be initiated, to reduce the red cell mass, decrease blood viscosity and keep it reduced, by inducing and maintaining an iron deficient state. Not only is phlebotomy the fastest and most direct method for reducing the red cell mass, it also provokes a rapid increase in the plasma volume, and an improvement in platelet function, reducing the risk of hemorrhage as well as thrombosis.

If a red cell mass measurement has been performed, this will indicate how much excess blood is present and needs to be removed. If not, the therapeutic goal is still a hematocrit of 45% or less in a man and 42% or less in a woman, which, if maintained will protect against thrombosis. Marrow suppressive therapy with an agent such as pegylated interferon can also be started if clinically indicated as discussed below, but given the long red cell life span, the risk of thrombosis will not be promptly alleviated by this drug, and phlebotomy therapy will still be necessary initially.

If there is marked elevation of the leukocyte count or the uric acid is 10mg% or greater, allopurinol should be given. If there is ocular migraine or erythromelalgia not relieved by phlebotomy, low dose aspirin should be given unless the platelet count is greater than 1.5 million per microliter, because a very high platelet count can be associated with an acquired form of von Willebrand disease.

Usually, the leukocyte count is not markedly elevated or a source of symptoms and does not require reduction routinely. Extreme thrombocytosis causes acquired von Willebrand disease, due to the destruction by the platelets of high molecular weight von Willebrand multimers. Bleeding due to this will require cytoreduction for its alleviation, as well for its correction before surgery, or if there is a need to use aspirin therapeutically.

Thrombocytosis causing ocular migraine, transient ischemic attacks, or erythromelalgia that are unresponsive to aspirin will also require platelet count reduction, but only to the extent that symptoms are relieved. Hydroxyurea is the drug of choice for preventing transient ischemic attacks, because it is a nitric oxide donor but, because it has leukemic potential in the chronic myeloproliferative disorders, its use chronically should be avoided in favor of definitive therapy for the disease with pegylated interferon alpha. Otherwise, anagrelide, if tolerated, is as effective as hydroxyurea for reducing the platelet count.

It is important to emphasize that there is no correlation between the platelet count and thrombosis in polycythemia vera and thus, platelet count reduction is only necessary to the extent that symptoms or a hemorrhagic diathesis are alleviated. Asymptomatic thrombocytosis requires no therapy.

More definitive therapies?

General management

In general, the management of polycythemia vera is dictated by the clinical features of the individual patient. Many patients are asymptomatic or their symptoms are a consequence only of hyperviscosity or thrombocytosis. In these instances, phlebotomy therapy for the former and aspirin, taken as needed, for the latter may be all that is necessary.

Bone marrow transplantation

To date, only bone marrow transplantation is potentially curative in polycythemia vera but all other current therapies must be considered supportive. However, given the morbidity and mortality associated with allogeneic bone marrow transplantation, relative to the longevity experienced by most polycythemia vera patients, this procedure cannot be recommended routinely and is, of course, unsuitable for many patients because of their age, or unavailable because of lack of a suitable donor.

Irradiation and chemotherapy

It is also important to note that neither irradiation nor chemotherapy has been effective in controlling the complications of polycythemia vera and both modalities are leukemogenic in this disorder. Pegylated interferon alpha is the only therapy to date that has produced complete and durable hematologic and molecular remissions in polycythemia vera. Unmodified interferon alpha has also been used successfully to control leukocytosis, thrombocytosis, pruritus, and splenomegaly, but has not produced complete molecular remissions.

Nonspecific JAK2 inhibitors

Nonspecific JAK2 inhibitors are currently in clinical trial and while this type of therapy appears successful in alleviating constitutional symptoms, suppressing hematopoiesis and reducing splenomegaly in a durable fashion, none of these inhibitors appears to affect the involved pluripotent stem cell or significantly reduce the JAK2 V617F allelic burden. They can therefore only be considered as supportive therapy (but still important), since, unlike hydroxyurea, they do not have the potential to cause long term marrow damage.

Pruritus

Pruritus, however, can be a significant symptom in some patients. Therapy for this should be layered, starting with a long-acting antihistamine or an ataractic such as doxepin and, if alleviation is not achieved, proceeding to hydroxyurea if symptoms are acute or to PUVA light therapy or pegylated interferon alpha, or unmodified interferon alpha for long term control according to patient preference. Acid reflux is not uncommon and there is a high incidence of Helicobacter pyloriinfection in polycythemia vera.

Severe ocular migraine and erythromelalgia

In some patients, particularly those with severe ocular migraine, it may be necessary to lower the platelet count to achieve relief; it is usually not necessary to lower it to normal but only to the point that symptomatic relief is achieved. This can be done acutely with either hydroxyurea or anagrelide and in the long term with pegylated or unmodified interferon alpha. Erythromelalgia usually requires only aspirin for relief.

Leukocytosis

Ordinarily, modest leukocytosis does not require therapy. A rising leukocyte count is usually a harbinger of advancing disease and is generally accompanied by increasing splenomegaly. Unless there is hyperuricemia (serum uric acid of 10gm% or greater), which indicates the need for allopurinol, treatment should be directed at control of the disease in general and not the leukocyte count in particular. For this purpose, currently pegylated interferon alpha is the treatment of choice, because of its potential to induce complete molecular remissions; unmodified interferon alpha is also effective in reducing splenomegaly, but does not produce complete molecular remissions.

Low dose aspirin and hydroxyurea

Although low dose aspirin has been recommended routinely for polycythemia vera patients, there is insufficient evidence to support its use as prophylaxis against anything other than microvascular complications such as ocular migraine or erythromelalgia. Nor is there any evidence to support the recommended use of hydroxyurea in patients over the age of 65, or those at high risk for a thrombotic event, since hydroxyurea was not found to be effective in preventing either arterial or venous thrombosis in such potentially high risk patients.

Hemorrhage due to von Willebrand disease

In patients experiencing hemorrhage due to acquired von Willebrand disease, epsilon-aminocaproic acid (Amicar) is an effective remedy until the platelet count can be reduced. Apheresis for extreme thrombocytosis cannot be recommended except rarely in a very acute situation since it is not an efficient procedure when thrombocytosis is extreme and there is also a rapid rebound of the platelet count.

Splenomegaly

Massive splenomegaly is the most difficult complication of polycythemia vera to manage, since it is usually refractory to chemotherapy and not durably alleviated by irradiation. Splenectomy is associated with a high morbidity rate because of postoperative splanchnic vein thrombosis or intra-abdominal hemorrhage, extreme leukocytosis or thrombocytosis, hepatomegaly due to exuberant extramedullary hematopoiesis, and abdominal wall weakness or herniation. Splenectomy should be avoided when there is significant cachexia until the catabolic state can be reversed with parenteral nutrition.

Alternative therapies include pegylated interferon alpha or unmodified interferon alpha, if tolerated. Low dose thalidomide and prednisone is another alternative as will be the nonspecific JAK2 inhibitors when they become available. Splenic embolization for massive splenomegaly is not recommended because of the toxicity associated with the attendant spleen necrosis.

Leukemia

Acute leukemia, regardless of etiology, usually has a rapid clinical course, unresponsive to the treatments effective for primary acute myeloid leukemias.

What other therapies are helpful for reducing complications?

In some patients, imatinib has led to satisfactory clinical responses, but this is uncommon.

What should you tell the patient and the family about prognosis?

Polycythemia vera is not a monolithic disorder with an inexorable clinical course. Rather, the disorder in most patients has a very slow clinical course, with a progressive increase in the blood counts and an increase in spleen size, but which often requires no more than periodic phlebotomy and attention to specific issues such as pruritus or ocular migraine. This is because the stem cell burden increases very slowly, and for many years normal hematopoietic stem cells persist.

However, in a small proportion of patients, the disease has a more aggressive course, much like that of primary myelofibrosis, with massive splenomegaly due to extramedullary hematopoiesis, which may also compromise other organs, and marrow fibrosis.

Pulmonary hypertension is also a frequent complication in this setting, together with anorexia, weight loss, night sweats, and anemia. Unless treated, this form of the disease has an inexorable course and leads to a shortened life span. Although myelofibrosis is considered a complication of the disease, it is actually a reversible reactive process and the real problem is hematopoietic stem cell failure. If not recognized and treated early, bone marrow failure will result in intolerance to interferon or other forms of cytoreduction therapy. This is also a situation where the new nonspecific JAK2 inhibitors should be useful with respect to alleviation of constitutional symptoms, reduction in spleen size, and avoidance of potentially leukemogenic drugs.

"What if" scenarios.

Common pitfalls

The most common pitfalls in the management of polycythemia vera are failure to maintain the hematocrit by phlebotomy at a level that will protect against thrombosis, and the inappropriate use of drugs such as hydroxyurea, which are mutagenic but unable to control the disorder at the level of the involved hematopoietic stem cell. Aside from pegylated interferon alpha, there is currently no drug that can produce a complete molecular remission in polycythemia vera. Thus, if supportive therapy is to be used, considering that polycythemia vera is compatible with substantial longevity in most patients, the therapy should not be potentially more dangerous than the disease itself.

Thrombotic events

If a patient has a thrombotic event, it should also not necessarily be assumed that the thrombosis was due to the disease per se, and certainly not to a specific platelet count, since there is no correlation between thrombosis and the platelet count in polycythemia vera; the highest platelet counts are actually associated with hemorrhage and not thrombosis.

Assuming that the hematocrit is within the normal range for gender, a thrombosis should be treated no differently than if it had occurred in a patient with normal blood counts. In this regard, if the hematocrit is not controlled, because of the increased number of red cells in the peripheral veins, there will be an imbalance between the amount of anticoagulant in the specimen tube and the plasma, and a falsely elevated international normalized ratio (INR) will be obtained, resulting in poor anticoagulant control.

Pregnancy

Because polycythemia vera is most common in women, particularly in the reproductive age range, pregnancy is always a possibility and the principles of management include avoidance of mutagenic drugs such as hydroxyurea and other chemotherapeutic agents, and also anagrelide.

Phlebotomy is safe and important therapeutically, because in pregnancy there is normally plasma volume expansion, making it even more difficult to assess the size of the red cell mass in polycythemia vera. Since there is normally a fall in the hematocrit during pregnancy, this situation needs to be recapitulated in the pregnant polycythemia vera patient, by phlebotomy, to a hematocrit of 33% or less. This will not harm the fetus, but will ensure protection from thrombosis.

As a corollary, iron therapy should be avoided.

There is no proof that aspirin therapy has any role, and anticoagulation is not indicated in the absence of a specific clinical indication. Interferon alpha is safe to administer during pregnancy if splenic enlargement is an issue, or it can be used to shrink the spleen in anticipation of conception and discontinued when that has been achieved.

For unknown reasons, the platelet count usually falls during pregnancy, but will increase after delivery. Patients with a history of a prior thrombosis, including an intra-abdominal venous thrombosis, can safely undergo pregnancy by switching from warfarin to low molecular weight heparin with weight-based administration.

While there is an increase in miscarriages and still births with a chronic myeloproliferative disorder, these disorders are generally compatible with maternal safety and a high rate of normal deliveries.

Pathophysiology

Polycythemia vera is a disorder of a pluripotent hematopoietic stem cell that is very much influenced by host genetics. For example, the disease is more common and its onset occurs earlier in women, but male patients have a higher JAK2 V617F allele burden. In some patients, the size of the offending stem cell pool remains limited, while in others, the size of the affected stem cell pool progressively expands over time until normal hematopoietic stem cells are not found, a process called clonal dominance. This process can take decades and is more pronounced if the there is mitotic recombination of chromosome 9, with the acquisition of an additional JAK2 V617F allele (so-called uniparental disomy), a particular feature of polycythemia vera.

Clonal dominance is associated with a higher leukocyte count and extramedullary hematopoiesis, manifested primarily by splenomegaly, but liver involvement with an elevation of the alkaline phosphatase occurs as well. Splenomegaly can cause portal hypertension and variceal formation because of increased blood flow to the liver. Myelofibrosis is part of the natural history of the disease and has no impact per se on prognosis because it is a reactive process, and it is hematopoietic stem cell behavior that dictates the clinical course.

Pulmonary hypertension, whether due to extramedullary hematopoiesis, pulmonary fibrosis, or a combination of these, is an insidious but clinically significant complication in patients who have an aggressive form of polycythemia vera.

Spontaneous acute leukemia occurs in approximately 1 to 2% of polycythemia vera patients and at a much higher rate in patients exposed to alkylating agents, radiophosphorus (32P), or hydroxyurea. Exposure to both hydroxyurea and an alkylating agent in any order potentiates the risk of acute leukemia.

In some JAK2 V617F-positive polycythemia vera patients, the acute leukemia may be JAK2 V617-negative. Since JAK2 V617F is not the initiating mutation in polycythemia vera, this observation indicates that the initiating stem cell in this disorder is genetically unstable. Spontaneous transformation to acute leukemia occurs most often in patients with the aggressive form of the disease, the so-called post polycythemic myelofibrosis state, while JAK2 V617F-negative acute leukemia is usually associated with exposure to hydroxyurea.

What other clinical manifestations may help me to diagnose polycythemia vera?

Aquagenic pruritus and erythromelalgia are distinctive symptoms associated with polycythemia vera and may be among the earliest presenting manifestations but their absence does not mitigate against the diagnosis. In women particularly, there is an increased predilection for hepatic vein thrombosis and this is often the first manifestation of the disorder. Unfortunately, in this circumstance, the hematocrit and hemoglobin levels will invariably be normal or even low because of marked expansion of the plasma volume, and the diagnosis will be missed, and the appropriate therapy not administered, unless this phenomenon is understood. Furthermore, and most importantly, anticoagulation of any type will not prevent continued thrombosis, unless the red cell mass is restored to normal.

In addition to hepatic vein thrombosis, polycythemia vera needs to be considered whenever the possibility of a hypercoagulable state arises.

What other additional laboratory studies may be ordered?

The laboratory evaluation with respect to unusual clinical manifestations is not different than recommended above whenever polycythemia vera is considered a diagnostic possibility.

Figure 1

What’s the evidence?

Tefferi, A, Thiele, J, Orazi, A. “Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel”. . vol. 110. 2007. pp. 1092-1097. [The new WHO diagnostic criteria for the chronic myeloproliferative disorders.]

Spivak, JL, Silver, RT. “The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal”. . vol. 112. 2008. pp. 231-239. [This publication discusses the serious flaws in the WHO proposed criteria for the diagnosis of polycythemia vera, essential thrombocytosis and primary myelofibrosis. The algorithm used to illustrate this chapter was originally published in this publication; Copyright – The American Society of Hematology.]

Cassinat, B, Laguillier, C, Gardin, C. “Classification of myeloproliferative disorders in the JAK2 era: is there a role for red cell mass”. . vol. 22. 2008. pp. 452-453. [Direct red cell mass and plasma volume measurements unmask polycythemia vera in over 50% of patients thought to have essential thrombocytosis.]

James, C, Ugo, V, Le Couedic, JP. “A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera”. . vol. 434. 2005. pp. 1144-1148. [Seminal publication about the JAK2 V617F mutation.]

Spivak, JL. “Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation”. . vol. 152. 2010. pp. 300-306. [Review of the clinical significance of the JAK2 V617F mutation.]

Moliterno, AR, Williams, DM, Rogers, O, Isaacs, MA, Spivak, JL. “Phenotypic variability within the JAK2 V617F-positive MPD: Roles of progenitor cell and neutrophil allele burdens”. . vol. 36. 2008. pp. 1480-1486. [Role of clonal dominance in the chronic myeloproliferative disorders.]

Stein, BL, Williams, DM, Wang, NY. “Sex differences in the JAK2 V617F allele burden in chronic myeloproliferative disorders”. . vol. 95. 2010. pp. 1090-1097. [Importance of gender in the expression of JAK2 V617F in the chronic myeloproliferative disorders.]

Passamonti, F, Rumi, E, Caramella, M. “A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis”. . vol. 111. 2008. pp. 3383-3387. [The clinical course of aggressive polycythemia vera.]

Spivak, JL, Hasselbalch, H. “Hydroxycarbamide: a user's guide for chronic myeloproliferative disorders”. . vol. 11. 2011. pp. 403-414. [A review of therapies for polycythemia vera.]

Quintas-Cardama, A, Kantarjian, H, Cortes, J, Verstovsek, S. “Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond”. . vol. 10. 2011. pp. 127-140. [A review of the newest therapies for the chronic myeloproliferative disorders.]

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