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V.R. Gordeuk et al.
chlorambucil and 32P arms if the hematocrit was >45% despite the chemotherapy regimen. In 1987, with a maxi- mal follow-up of 19 years, 37.8% of the patients had expe- rienced thrombosis as a major study outcome and 14.8% had died from thrombosis. Overall, therapeutic phleboto- my was independently and significantly associated with an increased risk of thrombosis compared to chemotherapy, but hematocrit level was not independently associated with thrombotic risk. The increased risk of thrombosis in patients undergoing phlebotomy compared to that in patients treated with myelosuppressive therapy seemed to be limited to the first 3 years of therapy.57 The increased thrombotic risk did not seem to be related to poorer disease control as reflected by hematocrit and platelet count: in a retrospective analysis that paired patients with thrombosis to those without thrombosis within the same treatment group, neither hematocrit nor platelet count was associated with thrombosis.70 As of 1987, 10.2% of the patients in the PVSG 01 study had developed acute leukemia and 11.8% had died from a hematologic malignancy. Acute leukemia was much more common in the 32P arm (9.6%) and the chlorambucil arm (13.5%) than in the phlebotomy alone arm (1.5%), and this contributed to the finding that the overall survival of patients treated with phlebotomy was comparable to that of patients treated with 32P and slightly better than that of patients treated with chlorambucil.70,71
The increased risk of thrombosis with phlebotomy com- pared to chemotherapy observed in the PVSG 01 study was followed up in the PVSG 05 study. Patients were initially phlebotomized to achieve a hematocrit ≤40% and then ran- domized to treatment with phlebotomy and the combina- tion of aspirin (300 mg) and dipyridamole (75 mg) three times daily (n = 88) versus 32P (n = 90) to maintain the hema- tocrit <45%.57 The study was stopped at a median follow- up of <2 years when seven (8.0%) patients in the phleboto- my, aspirin and dipyridamole group had experienced a major thrombosis versus two (2.2%) in the 32P group, provid- ing further evidence of a higher rate of thrombosis with therapeutic phlebotomy versus chemotherapy for PV.
The European Collaboration on Low-Dose Aspirin in the Polycythemia Vera study (ECLAP), which included 1,638 patients from 12 countries and 94 centers, found no differ- ence in thrombotic complications for patients with hemat- ocrits within the range of 40-55%; however, there were not enough subjects with hematocrits >55% for evaluation.72 Evaluation of a cohort of 1,042 patients with PV in the ECLAP trial demonstrated an advantage of hydroxyurea therapy over phlebotomy with respect to the proportion of fatal/nonfatal cardiovascular events: 13.2% in the phleboto- my group versus 7.9% in the hydroxyurea group (P=0.006).73 An important attempt to clarify this issue was a prospective study by the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) Collaborative Group of the effect of hematocrit on thrombosis in PV patients. This study showed that patients treated with phlebotomy and hydroxyurea to a hematocrit <45% (n = 182) had a lower rate of thrombosis compared to that of patients treated to a target hematocrit of 45-50% (n = 183).74 Hydroxyurea is the most common myelosuppressive agent used in the treatment of PV;75,76 it is effective at controlling erythrocyte, leukocyte, and platelet counts without inducing acute leukemia, and it decreased the risk of thrombosis during the first few years of therapy compared to that in a historical cohort treated with phle- botomy alone.57 By 6 months into the CYTO-PV study,74 fewer patients in the high-hematocrit group were receiving
hydroxyurea (47% versus 59%) and among those receiving hydroxyurea the mean daily dose was 12% lower in the high-hematocrit group. This eventuated in a higher white blood cell count in the high-hematocrit group throughout the study (P<0.001). Although absence of hydroxyurea therapy77 and high leukocyte counts78 are independent cor- relates of thrombotic risk in PV, the rate of thrombosis was greater in the higher hematocrit group whether or not the patient was treated with chemotherapy and whether or not the white blood cell count was elevated.74 Thus, we cannot rule out the possibility that hematocrit may contribute to increased risk of thrombosis in PV along with other PV- associated prothrombotic factors. However, some of the authors of the CYTO-PV and ECLAP studies re-analyzed the study population73 and concluded that there is a “greater antithrombotic protection of hydroxyurea over phlebotomy against arterial thrombosis while the two treatments produce similar results in the protection from venous thrombosis.”79
In the PVSG 01 study, a history of previous thrombosis and older age were independent risk factors for thrombosis after controlling for therapeutic phlebotomy versus chemotherapy.57,70 Currently, the age of the patient (>60 years) and previous thrombotic events are universally acknowledged risk factors for major vascular complications in PV.60 The proportion of activated neutrophils is increased in PV,80 and it is possible that neutrophils may be an impor- tant factor in PV-associated thrombosis.81 In a multivariate analysis of the relationship of peripheral blood cell counts with thrombosis in PV subjects, an increased number of leukocytes was the most significant correlate of increased thrombotic risk.78 A study of 1,545 patients by the International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) found that survival of PV patients correlated negatively with leukocytosis, older age, venous thrombosis, and atypical karyotype.82 It was also reported that PV may be associated with tissue factor expression in polymorphonuclear leuko- cytes in the absence of any in vitro challenge, and that expression is decreased after treatment with hydroxyurea.83 An additional risk for thrombotic events in PV may be envi- ronmental hypoxia. We found that PV patients residing in Salt Lake City at approximately 1,400 meters have a higher rate of arterial and venous thromboses than that of patients residing at sea level in Baltimore,84 even though they are only exposed to modest hypoxia.85 In a multivariate analy- sis, living in Salt Lake City was an independent thrombotic risk factor in PV.84 This may be explained by the recent observation that hypoxia decreases protein S levels in nor- mal subjects by an HIF-1-mediated mechanism.86
Conclusion
Certain disorders with elevated hematocrit, such as PV, CE, primary familial and congenital polycythemia or ery- throcytosis (EPOR mutation), and EPAS1 gain-of-func- tion mutations, are associated with thrombotic compli- cations. These conditions are characterized by diverse cellular and metabolic changes that could be directly associated with thrombotic risk, irrespective of hemat- ocrit level. The challenge in these conditions is to eluci- date factors for the thrombotic risk other than the elevat- ed hematocrit, and to define what, if any, role that vis- cosity plays in thrombotic risk. Defining these thrombo- sis-predisposing factors would provide the basis for iden-
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haematologica | 2019; 104(4)