How does polycythemia vera (PV) lead to acute stroke?

Pathophysiology of Polycythemia Vera Leading to Acute Stroke

Polycythemia vera causes acute stroke through a complex interplay of elevated hematocrit-induced hyperviscosity, qualitative platelet dysfunction, and a systemic prothrombotic state that affects both large and small cerebral vessels. 1

Primary Mechanism: Elevated Hematocrit and Hyperviscosity

The fundamental driver of stroke risk in PV is the elevated hematocrit, which was definitively established when aggressive phlebotomy improved median survival from less than 2 years to over 10 years in the pre-phlebotomy versus phlebotomy era. 1 However, the mechanism is more nuanced than simple viscosity:

• Decreased cerebral blood flow occurs not primarily from viscosity changes, but from alterations in arterial oxygen content associated with elevated hematocrit 1
• In vitro viscosity studies overestimate the in vivo effects due to different flow dynamics in blood vessels and the relationship between hematocrit and oxygen transport 1
• The CYTO-PV trial demonstrated that maintaining hematocrit strictly below 45% significantly reduces thrombotic events 1

Flow-Dependent Thrombogenic Mechanisms

The pathophysiology varies by vessel size and flow characteristics:

Low Shear Rate Conditions (Large Veins)

• Axial migration of red blood cells displaces platelets, leukocytes, and proteins toward the endothelium, enhancing thrombogenic interactions 1
• This mechanism explains venous thrombosis patterns in PV patients

High Shear Rate Conditions (Arterioles and Small Vessels)

• Platelet-leukocyte-red blood cell interactions generate platelet aggregates through adenosine diphosphate (ADP) release 1
• Combined with decreased flow rates from high hematocrit, this creates conditions for arterial thrombosis 1

Qualitative Platelet Abnormalities

Phlebotomy substantially reduces but does not abolish thrombosis risk, indicating that factors beyond hematocrit contribute significantly. 1 Multiple prothrombotic platelet defects exist:

• Diminished response of platelet adenylate cyclase to prostaglandin D2 (a physiological platelet aggregation inhibitor) 1
• Increased baseline production of thromboxane A2, a potent platelet aggregator 1
• Abnormal in vivo activation of platelets, leukocytes, and endothelial cells 1
• The PIA2 allele of platelet glycoprotein IIIa is associated with increased arterial thrombosis risk 1

Systemic Prothrombotic State

PV creates a baseline hypercoagulable environment through multiple mechanisms:

• Widespread activation of coagulation proteins 1
• Reduced levels of physiologic anticoagulants including antithrombin III, proteins C and S 1
• Decreased fibrinolytic activity partly due to increased plasminogen activator inhibitor levels 1
• These abnormalities persist even with hematocrit control, explaining residual stroke risk

Stroke Patterns and Clinical Manifestations

Large Vessel Thrombosis

• PV can cause thrombosis in extracranial carotid arteries and major intracranial branches, not just small distal vessels 2
• Carotid thrombus with middle cerebral artery occlusion has been documented as an initial PV manifestation 2

Embolic Mechanisms

• Micro-embolic events originating from outside the brain have been documented, suggesting cardioembolic or artery-to-artery embolism mechanisms 3
• This challenges the traditional assumption that all PV strokes are purely hyperviscosity-related

Hemorrhagic Transformation

• Hemorrhagic stroke can occur despite the prothrombotic state, likely due to paradoxical pro-hemorrhagic platelet defects including poor aggregation responses and acquired von Willebrand disease 1, 4
• Bilateral hemorrhagic infarction has been reported as an initial PV presentation 4

Epidemiologic Impact

• Ischemic stroke represents the first manifestation of PV in up to 16.2% of cases 5
• Cumulative cerebrovascular event rate reaches 5.5 per 100 persons per year 5
• Stroke accounts for 8.8% of all PV-related deaths 5
• Major symptoms relate to arterial hypertension and arterial/venous thrombosis, with strokes potentially being the first manifestation 1

Clinical Pitfalls

Clinicians must suspect PV in cryptogenic strokes, particularly in younger patients with elevated platelet counts, even when potential causes of reactive thrombocytosis exist. 2 The condition often remains underdiagnosed due to PV's low prevalence, but early recognition enables prompt treatment with phlebotomy, cytoreduction, and low-dose aspirin to prevent recurrence 5

The relationship between thrombosis and high hematocrit represents a complex scenario with multiple physical and chemical factors beyond simple viscosity, requiring aggressive hematocrit control combined with antiplatelet therapy and consideration of cytoreductive agents in high-risk patients. 1