Epidemiology

The incidence of PV is 0.8 to 2.6 cases per 100,000 persons per year, with most studies giving figures at the upper end of that range, and this incidence appears to be relatively stable over time.^150–152 As is the case with the other CMPD, the incidence of PV increases with age. The median age at diagnosis is approximately 60 years, but the disease can also be seen in young people.^153,154 There may be a slight male preponderance (on the order of a 1.2:1 male-to-female case ratio) and the disease is more common in Jews, especially Ashkenazi Jews.^{19,152,153,155} In a few cases, true PV may be familial, but apparently familial erythrocytosis is more often a result of a shared high-oxygen-affinity hemoglobin or a common exposure (eg, a residence at high altitude or cobalt intoxication).^156,157

Pathogenesis

X-linked (G6PD) enzyme analysis first demonstrated the clonal nature of hematopoietic cells in PV in 1976.¹⁵⁸ More than 25 years later the precise etiology of the disease remains obscure. Neoangiogenesis is seen in the marrow in PV (like other CMPD) but is not a reaction to low marrow oxygen levels, which have been measured and are normal.¹⁵⁹ The erythroid colony-forming progenitor cells (BFU-E and CFU-E) in PV appear to be very sensitive to or independent of normal growth and differentiation signals, including EPO, GM-CSF, stem cell factor, and IL-3.^160–162 Serum EPO levels in PV patients are generally very low or inappropriately normal in the setting of erythrocytosis, and excessive EPO-independent BFU-E and CFU-E proliferation leads to an increased red cell mass (RCM).^163–165 As is the case with the TPO receptor in ET, some families with recurrent PV have been found to harbor EPO receptor mutations, but structural changes in the EPO receptor have been diligently sought in nonfamilial PV but not found.^166–168 EPO receptor expression patterns may be abnormal in PV (eg, loss of the normal high-affinity EPO receptor).¹⁶⁹ Abnormalities in signaling molecules downstream of the EPO receptor in effector tyrosine kinases (eg, JAK2) or molecules such as the GATA-1 and STAT5 transcription factors have not been reported.

The genetic basis for PV is uncertain. Karyotypic abnormalities are found in about 10% to 20% of patients.¹⁷⁰ The lesions seen are those nonspecific abnormalities typical of chronic myeloid disorders, such as trisomy 8, trisomy 9, del(20q), del(13q), loss of the Y chromosome in men, and abnormalities of chromosomes 5 and 7.^170,171 Recently, a novel gene with homology to the uPAR/Ly6/CD59/snake toxin receptor superfamily was cloned and found to be overexpressed in PV neutrophils but not in normal neutrophils, and was subsequently named PRV-1.⁴⁰ The pathophysiologic significance of this gene is a subject of active investigation.

Clinical Features

Signs and symptoms associated with PV are listed in Table 137-4. Many of the clinical features of PV are a direct consequence of the increased RCM and are common to all causes of erythrocytosis. A ruddy, plethoric complexion was a classic finding seen often in the fin de siecle world of great clinicians like Osler and Vaquez, but dramatic skin rubor is less common in the present era of routine hemograms when erythrocytosis may be detected much earlier. Increased RCM can lead to blood hyperviscosity, which leads to a plethora of symptoms and signs. Headaches are frequent, but blurry vision, altered hearing, mucous membrane bleeding, shortness of breath, and malaise are also observed. Hypertension may be a consequence of increased RCM.

Table 137-4

Polycythemia Vera-Related Clinical and Laboratory Features.

At least two-thirds of PV patients have splenomegaly, so the combination of splenomegaly and erythrocytosis should strongly suggest PV.¹⁷² Thrombosis occurs in about 40% of patients, most commonly arterial thrombosis.¹⁵³ Clots occur at a rate of about 3.9% of patients per year.¹⁵³ Arterial thromboses are more likely to be fatal than venous thromboses. Venous thrombosis can occur in unusual sites, such as mesenteric or hepatic vessels. Bleeding, especially gastrointestinal, is seen in PV but less often than thrombosis.¹⁵³

Pruritus is a common and classic complaint, may be provoked by warm water (“aquagenic”), and may be related to serotonin release by platelets as well as elevated histamine levels.^173,174 Erythromelalgia (described above under ET) also troubles patients with PV, as do other vasomotor symptoms; paresthesias and headaches may be in part a result of vasomotor imbalance. Bone pain and neutrophilic dermatosis do occur in PV but are uncommon.

Leukocytosis and thrombocytosis are present in less than half of PV patients. The unsaturated vitamin B₁₂-binding level is high in PV due to excess transcobalamin I and III released by granulocytes.¹⁷⁵ Vitamin B₁₂ levels may be elevated in PV, and this can be useful diagnostically.

Diagnosis

The major diagnostic difficulty with respect to PV is distinguishing PV from other nonclonal causes of erythrocytosis, since clonal myeloid disorders other than PV are only very rarely associated with an elevated RCM. To make the diagnosis of PV, erythrocytosis must first be determined to be due to a true increase in RCM (ie, exclusion of relative erythrocytosis that is due to a decrease in plasma volume), and then the genuine elevation in RCM must be shown to be a primary EPO-independent erythrocytosis (ie, exclusion of secondary EPO-driven erythrocytosis, such as that caused by hypoxia, high-oxygen-affinity hemoglobin, EPO-producing tumors, and cobalt intoxication).

For many years, an international collaborative effort called the PV Study Group (PVSG) led the way in defining diagnostic criteria and treatment approaches for PV. In 1975, the PVSG published a set of diagnostic criteria to ensure accrual of a uniform group of patients to PV treatment protocols (Table 137-5).¹⁷² These criteria included direct measurement of the RCM, which is a cumbersome procedure that is no longer strictly necessary. The availability of new diagnostic tools, as well as better appreciation of the tight relationship between hematocrit and RCM, have undermined the use of RCM measurement in the diagnosis of PV.⁴² Progress in clinical laboratory science and further understanding of the biology of PV and related disorders (eg, the wide availability of assays for measurement of EPO and the recent discovery of PRV-1) should make diagnosis easier and liberate clinicians from strict adherence to PVSG guidelines.^{43,164,176–180}

Table 137-5

The Polycythemia Vera Study Group (PVSG) Diagnostic Criteria for Polycythemia Vera.

The first steps in solving the erythrocytosis riddle include taking a careful history to rule out the possibility of dehydration or dramatic fluid volume shifts that might be consistent with relative erythrocytosis, measuring oxygen saturation to exclude hypoxia, and ensuring that erythrocytosis is not familial. The next test should be a measurement of the serum EPO level. Serum EPO is generally low in true PV but may be in the normal range, even in untreated cases.¹⁶⁴ The presence of other PV-related features (see Table 137-4) should nudge the clinician toward a tentative diagnosis of PV in polycythemic patients with inappropriately normal serum EPO levels. A high serum EPO level is not consistent with PV and should prompt a careful search for the usual instigators of secondary erythrocytosis with tests such as hemoglobin electrophoresis, measurement of the hemoglobin oxygen dissociation curve (ie, a “P50” determination), cobalt measurement, and appropriate imaging for EPO-producing tumors (eg, cerebellar and liver vascular tumors and renal cell carcinoma).^164,181

Bone marrow sampling is not often helpful in the diagnosis of PV (the PVSG did not use any marrow parameters as diagnostic criteria) but some groups have incorporated marrow findings into their diagnostic algorithms (eg, the European Working Group on CMPD).¹⁸² The marrow in PV may show hypercellularity, relative erythroid excess, increased megakaryocyte numbers with some cluster formation, giant megakaryocytes, and decreased iron stores. Some fibrosis may be seen in 10% to 15% of patients.¹⁸³ The demonstration of markedly decreased megakaryocyte c-Mpl expression supports the histological diagnosis of PV and may be helpful when there is diagnostic ambiguity.¹⁸⁰ Measurement of spontaneous (“EPO-independent”) marrow erythroid colony growth may also be useful for the diagnosis of PV, but limited availability of the test and the need for special expertise in setting up and interpreting the assay restrict its use.^176,184,185

The old supposition of “stress erythrocytosis” (Gaisböck syndrome), a chronic mild erythrocytosis purportedly due to a chronically contracted plasma volume, still finds its way unchallenged into many textbooks, but there is no clear evidence that this syndrome actually exists. Clinicians need not be concerned with it.^42,186

Prognosis

The median life expectancy for patients diagnosed with PV exceeds 10 years but is worse than a gender-and age-matched control population.⁷¹ Thrombohemorrhagic complications and transformation into AML account for much of the inferior survival.¹⁸⁷ Older age (> 60 years) appears to be a risk factor for thrombosis.¹⁸⁸ Other clearly prognostic factors in PV beyond old age and thrombosis have not been determined. Cytogenetic abnormalities are among the other specific markers that don't predict very much.^171,189 In about 15% to 20% of cases, PV terminates in a “spent phase,” an MMM-like state to which use of ³²P might contribute.¹⁹⁰ This transition is usually characterized by worsening anemia and increasing white count and spleen size.

Treatment

As is the case with ET, PV-associated vasomotor symptoms are usually alleviated by low doses of ASA, which inhibit the synthesis of vasoactive thromboxane A2 by platelets.¹⁹¹ (The use of ASA for thrombosis prevention in PV is discussed below.) PV-associated pruritus is more difficult to treat; antihistamines such as hydroxyzine and diphenhydramine may be effective.¹⁹² There are no data about the efficacy of less sedating H1-selective antihistamines, such as loratadine and fexofenadine, for this indication. Selective serotonin reuptake inhibitors, such as paroxetine, appear to be very effective in refractory cases and are also appropriate first-line treatment for pruritus.¹⁷³ IFNα also can offer some relief but has an unfavorable toxicity profile.

The primary goal of treatment in PV is to prevent disastrous thrombotic events without increasing the risk of other life-threatening problems, such as bleeding or altering the potential for transformation to a fibrotic marrow or acute leukemia. The main tool used to accomplish this goal is therapeutic phlebotomy. The importance of regular phlebotomy as part of a successful treatment program for PV cannot be overemphasized; marrow-suppressing drugs play only a supplementary role. In the first few decades after the disease's description, before aggressive phlebotomy became de rigueur, the median survival for patients with PV was on the order of 2 years, and most deaths were due to thrombotic events.^193–195 Today, most PV-related deaths are still due to thrombosis, but patients treated initially with phlebotomy alone have a median survival of more than 15 years.¹⁵³

Based on studies that have shown an improved cerebral blood flow and normalization of blood viscosity with a hematocrit below 45%, as well as less thrombosis in patients with hematocrits in this range, dropping the hematocrit to below this level and keeping it there should be the goal of phlebotomy-based treatment in PV.^196–199 It has also been widely recommended that females be reduced to a hematocrit of less than 42%, but this has not been rigorously tested and whole blood viscosity should not depend significantly on gender.

Some patients need extremely frequent phlebotomy to keep the hematocrit below goal levels, which is an inconvenience, and phlebotomy can also lead to iron deficiency, which can exacerbate thrombocytosis. In addition, patients treated with phlebotomy alone still suffer from thrombosis. Therefore, there has been a long-standing interest in the addition of other therapies to try to further decrease that risk. Just when these other agents should be added to phlebotomy is controversial. Known risk factors for clotting include an advanced age (> 60 years), a history of thrombosis, and a need for frequent phlebotomy (ie, maintenance phlebotomy more often than once every 3 months).²⁰⁰ In contrast, an elevated platelet count does not appear to be a major thrombotic risk factor in PV, and a very elevated platelet count (eg, > 1 million / μL), as in ET, is a risk factor for bleeding in PV. Therefore, young PV patients without a history of thrombosis and with a near-normal platelet count are probably safe with phlebotomy alone.

The role of aspirin in augmenting the role of phlebotomy in thrombosis prevention in PV is currently unclear. In an early PVSG randomized study, an aggressive regimen using high doses of aspirin (900 mg/day) in combination with dipyridamole increased the risk of bleeding in PV, particularly gastrointestinal bleeding, but had little effect on thrombosis.²⁰¹ The bleeding risk in this study was highest in those with very elevated platelet counts, perhaps due to the acquired vWF deficiency with extreme thrombocytosis that has been described in both PV and ET.²⁰² Several small studies have shown that lower doses of ASA (eg, 40–81 mg/day) appear to be safer from a bleeding standpoint, but the efficacy of this approach on thrombosis is uncertain.¹⁹¹ Low doses of ASA do have significant biologic effects. Thromboxane A2 biosynthesis has been shown to be elevated in PV patients, and thromboxane activity is suppressible with low-dose aspirin (50 mg/day).^203,204 A randomized pilot study demonstrated no bleeding complications associated with the use of low-dose aspirin (40 mg/day) in PV patients despite laboratory evidence of effective platelet cyclooxygenase inhibition.²⁰⁵ A currently ongoing large randomized European study of low-dose ASA in PV should help answer the question more definitively.²⁰⁶

There has been interest in myelosuppressive agents in PV for several decades, and the optimal regimen continues to evolve. In a landmark three-arm randomized study that originated in the 1960s, two specific agents, oral chlorambucil and intravenous radioactive phosphorus (³²P) were each found to decrease the risk of thrombosis when added to phlebotomy.²⁰⁰ However, overall survival was inferior with either of the additional treatments because of an increased incidence of acute leukemia. The incidence of acute leukemia over 13 to 19 years was 1.5, 9.6, and 13.2% for phlebotomy alone, ³²P, and chlorambucil, respectively, and the corresponding median survivals were 12.6, 9.1, and 10.9 years.¹⁸⁷ Several cases of lymphoma were seen in patients treated with chlorambucil, and the incidence of gastrointestinal and skin cancer was also increased in those patients treated with more than phlebotomy. It is not clear whether these agents affect the rate of transformation to MMM. Another alkylating agent, busulfan, improves overall survival above that achievable with ³²P.²⁰⁷

Other agents have the potential to decrease thrombosis without the same degree of leukemia risk as ³²P or alkylators. One of these agents is hydroxyurea, which decreases thrombotic risk when used as a supplement to phlebotomy but appears less leukemogenic than chlorambucil and ³²P. In one PVSG study, hydroxyurea was associated with lower risk of thrombosis in the first 2 years after diagnosis (6.6% vs 14%) when compared to a historical cohort of patients treated with phlebotomy alone, and only 5.9% of patients had transformed to acute leukemia after a median follow-up of 8.6 years.²⁰⁸ Because the true leukemogenic risk of hydroxyurea is unknown, it is used most often as a supplement to phlebotomy for groups at especially high risk for thrombosis, such as the elderly and those with prior thrombosis (Table 137-6).^187,209 Occasionally, oscillatory thrombopoiesis may develop in PV patients treated with hydroxyurea, and this can make dose adjustment very difficult.²¹⁰ Alternatives to hydroxyurea include pipobroman, which is not available in the US but which may be associated with a slight reduction in the risk of progression of PV to the “spent phase.”²¹¹

Table 137-6

Risk Stratification in Polycythemia Vera.

Just how leukemogenic is hydroxyurea? The answer to this question remains controversial. The mechanism of action of hydroxyurea certainly allows for the possibility of leukemogenicity. Hydroxyurea is thought to work by inhibiting ribonucleotide reductase, which in turn quenches DNA synthesis and kills cells in S phase. However, the agent also inhibits repair of DNA that has been damaged by agents such as chemicals or irradiation, and some cells that receive such damage might survive and acquire a growth advantage.²¹² Several small, nonrandomized studies have argued both for and against a significant increase in leukemic conversion associated with the long-term use of hydroxyurea in PV, but larger, long-term studies that might definitively address the question have not yet been reported. Reported rates of leukemic conversion in hydroxyurea-treated PV patients (in series with differing follow-up lengths) range from 1% to 10%, but these figures are not controlled for the more aggressive disease biology and increased patient age that necessitated the use of hydroxyurea in the first place.^{208,211,213–215} It is certainly possible that leukemia may develop more often in patients whose underlying disease biology is more aggressive and who require drug therapy. Pipobroman is widely believed to have a low leukemogenic risk, and a randomized trial incorporating similar patients with PV demonstrated similar leukemia rates with pipobroman and hydroxyurea.²¹¹

Several newer agents do not yet have a long track record of success in PV but show potential. IFNα has multiple salutary effects in PV and operates via an uncertain mechanism of action. This drug controls erythrocytosis in approximately 76% of the patients who can tolerate the necessary dose, which ranges from 4.5 to 27 million units per week (the usual starting dose is 3 million units subcutaneously three times a week), and IFN has a beneficial effect on thrombocytosis.^86,216 IFN can also reduce spleen size and offer relief from intractable pruritus. However, at least 20% of patients discontinue therapy because of drug side effects, including fatigue, malaise, fevers, and myalgias and arthralgias.²¹⁷ IFN is also more expensive than hydroxyurea. It is reasonable to choose IFNα for high-risk patients who need a supplement to phlebotomy where the potential benefit of relief from refractory pruritus is desired, or for patients who are particularly concerned about the potential leukemogenicity of hydroxyurea.

Anagrelide is a newer oral agent that lowers platelet production and at higher doses can also inhibit platelet aggregation.^218–220 The mechanism of action may interference of the drug with megakaryocyte maturation.^221,222 More than 80% of previously treated and untreated patients with thrombocytosis experience a reduction in platelet count with anagrelide.⁸⁴ Anagrelide also results in modest red cell suppression via an unclear mechanism. The toxicity and other relevant properties of anagrelide are outlined in Table 137-1.^223,224 The role of anagrelide in PV is currently undefined.

Bone marrow transplantation has been successfully performed in PV but is generally reserved for patients who have transformed to a “spent phase” or for those rare, young, treatment-refractory patients with multiple thrombohemorrhagic complications.

As is the case in ET, treatment must be individualized according to thrombotic risk and patient preferences.²²⁵ The therapeutic value of aggressive phlebotomy in all patients with PV is universally agreed upon. Pending the results of the European randomized study, the addition of low-dose aspirin seems reasonable, especially for patients with vasomotor symptoms. Most experts would agree on the addition of cytoreductive drug therapy to phlebotomy for preventing thrombotic complications in high-risk patients (ie, those with age ≥ 60 years or a history of thrombosis). Hydroxyurea or pipobroman (where available) are good first choices here. But there is considerable controversy over the appropriate management of younger, asymptomatic patients with PV, especially those with either cardiovascular risk factors or thrombocytosis. The thrombogenic potential of thrombocytosis or the presence of cardiovascular risk factors in low-risk patients with PV is uncertain, so cytoreductive therapy should be approached with caution. If extreme thrombocytosis develops, the risk of bleeding becomes an issue, and anagrelide is a reasonable choice. Interferon is appropriate for patients concerned about the potential leukemogenicity of hydroxyurea. A suggested treatment algorithm is outlined in Table 137-7. Once the optimal regimen for thrombosis control in PV is defined, trials of agents to prevent transformation to the MMM-like “spent phase” will likely move to the forefront.

Table 137-7

Suggested Treatment Algorithm for Patients with Polycythemia Vera.