What are the complications and management of polycythemia vera?

Complications of Polycythemia Vera

Major Thrombotic Complications

Thrombotic events are the leading cause of morbidity and mortality in polycythemia vera, occurring in approximately 16% of patients with arterial thrombosis and 7% with venous thrombosis at or before diagnosis. 1

Arterial Thrombotic Events

• Myocardial infarction, stroke, and peripheral ischemic events represent the most common arterial complications 2
• The highest rates of thrombosis occur shortly before or at diagnosis, then decrease with appropriate treatment 3
• Cardiovascular risk factors and elevated hematocrit levels significantly increase arterial thrombosis risk 4

Venous Thrombotic Events

• Venous thrombosis can occur in unusual sites, particularly splanchnic veins (hepatic, portal, mesenteric) 1
• Higher absolute neutrophil count and JAK2V617F allele burden predict increased venous thrombosis risk 4
• The 20-year cumulative risk of thrombotic events reaches approximately 26% 5, 4

Hemorrhagic Complications

Despite the thrombotic tendency, PV patients paradoxically face significant bleeding risk, particularly with extreme thrombocytosis. 1

Acquired von Willebrand Disease

• Occurs in more than one-third of PV patients and is associated with bleeding diathesis 6
• Characteristically develops with extreme thrombocytosis (platelet count ≥1000 × 10⁹/L) 1
• Results from decreased large von Willebrand factor multimers due to abnormal adsorption to clonal platelets, exposing protein cleavage sites 6
• Corrects with platelet count normalization 6

Platelet Dysfunction

• Poor platelet aggregation in response to multiple agonists (thrombin, ADP, epinephrine, collagen, thromboxane A2) 6
• Abnormally low intraplatelet levels of adenine nucleotides and serotonin 6
• Impaired binding to fibrinogen due to decreased GP IIb/IIIa expression 6

Microvascular Complications

Erythromelalgia

• Affects approximately 3-5% of PV patients 7, 1
• Presents as painful burning sensation in extremities, often associated with thrombocythemia 7
• Results from platelet-mediated arteriolar inflammation and increased thromboxane production 6
• Typically responds to low-dose aspirin therapy 7

Hyperviscosity-Related Symptoms

• Suboptimal cerebral blood flow occurs with hematocrit values between 46-52% 2
• Transient visual changes affect approximately 14% of patients 1
• Pruritus occurs in approximately 33% of patients 1

Disease Transformation

Progression to Myelofibrosis (Post-PV MF)

• Approximately 10% risk of transformation in the first decade 7
• 20-year cumulative risk reaches 16% 5, 4
• Overall incidence of 12.7% across disease course 1

Leukemic Transformation

• Acute myeloid leukemia develops in approximately 6.8% of patients 1
• 20-year cumulative risk is approximately 4% 5, 4
• Risk increases progressively beyond the first decade 7
• Certain cytoreductive agents (chlorambucil, ³²P) significantly increase leukemia risk and should be avoided in younger patients 7

Prothrombotic Mechanisms

Cellular and Molecular Abnormalities

• Diminished platelet adenylate cyclase response to prostaglandin D2 (physiological inhibitor of platelet aggregation) 6
• Increased baseline platelet production of thromboxane A2 (platelet aggregator) 6
• Abnormal in vivo activation of leukocytes, endothelial cells, and platelets 6
• Widespread activation of coagulation proteins with reduced levels of physiologic anticoagulants (antithrombin III, proteins C and S) 6
• Decreased fibrinolytic activity partially due to increased plasminogen activator inhibitor levels 6

Genetic Risk Factors

• PIA2 allele of platelet glycoprotein IIIa associated with increased arterial thrombosis risk 6
• Factor II G20210A mutation correlates with microvascular disturbances 6

Impact on Survival Without Treatment

Untreated polycythemia vera historically resulted in median survival of less than 2 years in non-phlebotomized patients. 2

• With aggressive phlebotomy, median survival improved to >10 years compared to <4 years with inadequate phlebotomy 7
• Current median survival ranges from 14.1 to 27.6 years with appropriate treatment 1
• Survival exceeds 35 years in patients aged ≤40 years at diagnosis 5, 4

Critical Risk Factors for Complications

High-Risk Features

• Age ≥60 years 3, 1, 5, 4
• History of prior thrombosis 3, 1, 5, 4
• Uncontrolled hematocrit >45% 2, 3
• Leukocytosis 3, 4
• Abnormal karyotype 4
• Presence of adverse mutations (SRSF2, IDH2, RUNX1, U2AF1) 4

Common Pitfalls

• Accepting hematocrit targets of 45-50% increases thrombotic risk, as the CYTO-PV trial definitively demonstrated increased events at these levels 7
• Inadequate fluid replacement during phlebotomy can precipitate hypotension, particularly in elderly patients with cardiovascular disease 7
• Using aspirin in patients with extreme thrombocytosis (>1000 × 10⁹/L) requires caution due to bleeding risk from acquired von Willebrand disease 2