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Hematocrit and thrombotic risk in erythrocytosis
and subjects with high oxygen-affinity hemoglobins. Several lines of evidence suggest that an isolated elevation in hematocrit does not, per se, lead to thrombosis. For exam- ple, cerebral infarction in young children with cyanotic heart disease is attributed to iron deficiency and relative anemia rather than to erythrocytosis.34,35 In the Framingham study hematocrit was associated with risk of stroke but this association disappeared in multivariate analysis when smoking, a well-established risk factor for stroke,36 was removed.37 In a UK study of 7,346 men, an increased risk of stroke was not seen at higher hematocrit levels (≥51%) in normotensive men but was apparent in hypertensive indi- viduals.38 Coronary blood flow is decreased in secondary erythrocytosis,22 but there is equivocal evidence as to whether the risk of coronary thrombosis is increased in patients with a high hematocrit.23,39,40 Secondary erythrocy- tosis reportedly does not pose a thrombotic risk in surgical patients.41
Studies of the influence of elevated hematocrit on the risk of thrombosis in animal models of PV and erythrocytosis secondary to elevated erythropoietin have failed to find a consistent positive relationship.42-45 A study of a murine model in which erythrocytosis was induced by transfusing packed red blood cells, with evaluation of thrombotic risk 24 hours later, found that an elevated hematocrit promoted arterial thrombus formation.46 However, acute erythrocyto- sis induced by transfusion may not reflect the physiology of the chronic elevation of hematocrit seen in PV and second- ary erythrocytosis.47 Furthermore, it is not certain how well the ferric chloride-induced thrombosis model in mice reflects thrombosis formation in humans. Thus, in this review, we focus on thrombosis in human conditions of chronic elevation in hematocrit.
Chuvash erythrocytosis and polycythemia vera share thrombosis as the principal cause of morbidity and mortality
Chuvash erythrocytosis
The propensity to thrombosis is even higher in CE than in PV.48 Although endemic in Chuvashia and Ischia, CE is distributed worldwide.8,9,49 This form of erythrocytosis is characterized by a high risk of both arterial and venous thrombosis in subjects living near sea level. It protects from anemia in heterozygotes50 but causes augmented hypoxia sensing with elevated hematocrit in homozygotes.12,51 The VHLR200W variant is not associated with tumors characteristic of the VHL tumor predisposition syndrome. Thrombosis largely accounts for the morbidity and mortality of CE although affected individuals have lower body mass index, systolic blood pressure, glucose and HbA1c levels, and white blood cell and platelet counts compared to con- trols.48,52,53 The high rate of thrombosis in CE begins in child- hood51 and increases with age.48 However, higher hemat- ocrit is not an independent predictor of thrombotic risk in either children or adults.48,51 Furthermore, a history of thera- peutic phlebotomy in CE is associated with an increased risk of thrombosis.48 Thus, the thrombotic risk in CE appears to be independent of viscosity, but rather to be related to changes in the upregulated hypoxic responses associated with the homozygous VHL598C>T mutation. We found many HIF-regulated transcripts to be differentially upregulated in CE peripheral blood mononuclear cells, including IL1B, encoding interleukin 1β (2.1-fold), TSP1,
encoding thrombospondin-1 (1.5-fold), NLRP3, encoding NLR family pyrin domain containing 3 (1.4-fold), SER- PINE1, encoding plasminogen activator inhibitor-1 (PAI-1) (1.2-fold), and F3 encoding tissue factor (1.1-fold).11 We also found differential gene expression in granulocytes and retic- ulocytes, and increased TSP-1 concentrations in plasma.48 Thus, increased HIF may cause a pro-thrombotic milieu in CE.54-56 The positive association of phlebotomy with throm- bosis in CE parallels observations in the Polycythemia Vera Study Group (PVSG) 01 and 05 studies.57 We postulate that the heightened thrombotic risk is likely due to upregulation of HIF-controlled prothrombotic genes such as tissue fac- tor54-56,58 and thrombospondin.48 It is likely that other HIF- regulated plasma or vascular factors also play contributory roles.59 In aggregate, these data demonstrate that the throm- botic risk in CE is independent of hematocrit.
Polycythemia vera
Thrombosis is the most common complication of PV.60-62 One-half to three-quarters of these events are arterial.63 Ischemic strokes and transient ischemic attacks account for the majority of thrombotic complications, followed in fre- quency by myocardial infarction, deep vein thrombosis, and pulmonary embolism. Cerebral venous thrombosis and splanchnic thrombosis, including Budd-Chiari syndrome, occur with increased frequency in PV. While it is not unusu- al for Budd-Chiari syndrome to present as the first indicator of PV, we have been unable to find the exact prevalence of this complication in any large published study of PV. Endogenous erythroid colony formation and the JAK2V617F mutation may be found in patients with splanchnic throm- bosis years before an increase in hematocrit.64,65 In fact, the majority of “idiopathic” Budd-Chiari syndrome patients have the JAK2V617F mutation despite a normal hematocrit.64 The association of Budd-Chiari syndrome and PV is so strong that many experts advocate screening for PV with JAK2V617F mutation analysis in all patients who present with hepatic vein or portal/mesenteric thrombosis, regardless of hematocrit.66,67 It should be noted that in PV the hematocrit may be normal despite a marked elevation in red cell mass and total blood volume and that the hematocrit in the splanchnic veins may not be the same as that in the periph- eral veins from where the blood sample is drawn. Furthermore, the peripheral hematocrit may be deceptively normal due to an increase in plasma volume in the presence of splenomegaly.15,68
The rationale for phlebotomy in PV was provided by a retrospective analysis of 69 patients in whom elevated hematocrit was controlled by phlebotomy and thrombocy- tosis by busulfan or other forms of chemotherapy.69 Over 15 years of observation, the incidence of thrombosis was pro- portional to the elevation in hematocrit,69 but it is not clear how much of the control of the hematocrit was related to phlebotomy versus chemotherapy-related suppression of hematopoiesis.
The prospective, randomized PVSG 01 and 05 studies demonstrated that phlebotomy to control hematocrit was associated with a higher thrombotic risk compared to chemotherapy.57 The PVSG 01 study was the first random- ized trial of PV patients.57 Enrollment in the study occurred between 1967 and 1974. All patients (n = 431) were initially treated with phlebotomy to reduce the hematocrit to <45% and then randomized to treatment with phlebotomy alone (n = 134), chlorambucil (n = 141) or 32P (n = 156) to maintain the hematocrit <45%. Phlebotomy was administered in the
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