What is polycythemia vera, its definition, relevant anatomy and physiology, etiology, pathophysiology, signs and symptoms, diagnosis, treatment, and management in a Cardiovascular Intensive Care Unit (CVICU) setting?

Polycythemia Vera: Comprehensive CVICU Overview

Definition

Polycythemia vera (PV) is a clonal myeloproliferative stem cell disorder characterized by true increase in red blood cell mass, frequently accompanied by leukocytosis (49% of cases) and thrombocytosis (53% of cases), driven by JAK2 mutations present in >95% of patients. 1, 2

• PV represents a true polycythemia (real increase in red blood cell mass) as opposed to apparent polycythemia from plasma volume contraction or spurious elevation 1
• The disease is classified as a chronic myeloproliferative disorder alongside essential thrombocythemia and myelofibrosis with myeloid metaplasia 1, 3
• Incidence is approximately 2.3-2.6 per 100,000 population with median age at diagnosis of 60 years and slight male predominance (1.2:1) 3

Relevant Anatomy and Physiology

The bone marrow demonstrates panmyeloid hyperplasia with clonal proliferation affecting erythroid, megakaryocytic, and granulocytic cell lines, driven by constitutive activation of the JAK2 tyrosine kinase pathway. 1, 4

• JAK2 V617F mutation (exon 14) causes autonomous erythropoietin receptor signaling, leading to EPO-independent red cell production 2, 5
• Serum erythropoietin levels are characteristically suppressed (below normal) in PV, distinguishing it from secondary polycythemia where EPO is elevated or high-normal 2
• The clonal disorder involves both myeloid and lymphoid lineages at the stem cell level 1
• Increased blood viscosity occurs when hematocrit exceeds 46-52%, causing suboptimal cerebral blood flow and microvascular complications 3

Etiology and Pathophysiology

JAK2 V617F mutation drives constitutive activation of JAK-STAT signaling, causing uncontrolled myeloproliferation independent of normal erythropoietin regulation. 2, 5

Thrombotic Mechanisms:

• Baseline prothrombotic state exists from multiple qualitative platelet defects including diminished response to prostaglandin D2, increased thromboxane A2 production, and abnormal activation of leukocytes, endothelial cells, and platelets 1
• Widespread coagulation protein activation with reduced physiologic anticoagulants (antithrombin III, proteins C and S) and decreased fibrinolytic activity from elevated plasminogen activator inhibitor 1
• PIA2 allele of platelet glycoprotein IIIa associates with increased arterial thrombosis risk 1
• Thrombosis risk correlates poorly with platelet or white blood cell counts alone, suggesting qualitative cellular defects drive complications 1

Hemorrhagic Mechanisms:

• Acquired von Willebrand disease occurs in more than one-third of PV patients, associated with bleeding diathesis 1, 3
• Decreased large von Willebrand factor multimers result from abnormal adsorption to clonal platelets, exposing cleavage sites and enhancing proteolysis 1
• Multiple pro-hemorrhagic platelet defects include poor aggregation response to agonists, abnormally low adenine nucleotides and serotonin, and decreased GP IIb/IIIa expression 1

Signs & Symptoms

Patients present with plethora, engorged veins, constitutional symptoms (fatigue, pruritus, bone pain), and complications from hyperviscosity or thrombosis. 1, 6, 4

Constitutional Symptoms:

• Pruritus (itching), particularly after warm baths, from histamine release 6, 4
• Erythromelalgia: burning pain in hands or feet with erythema from platelet-mediated arteriolar inflammation 1, 6, 4
• Fatigue and bone pain 6
• Splenomegaly from extramedullary hematopoiesis 6
• Headaches from hyperviscosity 1

Laboratory Findings:

• Hemoglobin >16.5 g/dL (men) or >16 g/dL (women); hematocrit >49% (men) or >48% (women) 3
• Leukocytosis in 49% and thrombocytosis in 53% of cases 2
• Suppressed serum erythropoietin levels 2
• JAK2 V617F mutation positive in >95% 2, 5

Typical CVICU Presentation

PV patients present to CVICU primarily with acute thrombotic complications: myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, or atypical site thrombosis (portal vein, hepatic vein, mesenteric vessels). 3, 6, 7

High-Risk Thrombotic Events:

• Myocardial infarction and stroke represent the most common arterial complications 3, 6
• Portal vein thrombosis can occur, even in younger patients (<55 years) without chronic liver disease, presenting as porta hepatis mass or esophageal varices 7
• Pulmonary embolism and deep vein thrombosis 6
• Peripheral arterial ischemic events 3

Critical CVICU Considerations:

• Hematocrit values between 46-52% cause suboptimal cerebral blood flow, increasing stroke risk 3
• Paradoxical bleeding can occur despite thrombotic presentation due to acquired von Willebrand disease, particularly with extreme thrombocytosis 1, 3
• Hyperviscosity syndrome manifests as altered mental status, visual disturbances, or neurologic deficits 3

Diagnosis & Evaluation

Diagnosis requires JAK2 V617F mutation positivity combined with hemoglobin/hematocrit elevation (>16.5 g/dL/49% in men or >16 g/dL/48% in women), with suppressed serum erythropoietin confirming primary polycythemia. 2, 3

Diagnostic Algorithm:

1. Initial screening: Hemoglobin/hematocrit exceeding 95th percentile for sex-adjusted normal values 1, 2
2. Exclude apparent polycythemia: Rule out plasma volume depletion (dehydration, diuretics, burns) and spurious elevation from normal variation 1
3. JAK2 V617F mutation testing: Present in >95% of PV cases; absence suggests secondary polycythemia 2, 5
4. Serum erythropoietin level: Suppressed in PV versus elevated/high-normal in secondary causes 2
5. Bone marrow biopsy: Shows panmyelosis with prominent erythroid and megakaryocytic proliferation 8

Key Discriminators:

• Mild hemoglobin elevations (<18.5 g/dL in men) more typical of secondary causes than PV 2, 8
• Secondary polycythemia causes to exclude: obstructive sleep apnea, COPD, smoking (carbon monoxide), post-renal transplant erythrocytosis, post-splenectomy 2
• Red blood cell mass measurement rarely needed if clinical context clear 1

Interventions/Treatments: Medical and Nursing Management

Therapeutic phlebotomy maintaining hematocrit <45% combined with low-dose aspirin (81 mg once or twice daily) forms the cornerstone treatment for all PV patients, with cytoreductive therapy reserved for high-risk disease. 3, 4, 5

Universal Treatment (All Patients):

• Phlebotomy: Target hematocrit <45% through repeated phlebotomy sessions 3, 7, 4
• Aspirin: 81-100 mg daily (or twice daily) unless contraindicated for bleeding risk 3, 4
• Vascular risk factor control: Aggressive management of hypertension, diabetes, hyperlipidemia 5

High-Risk Patients (Age >60 years OR prior thrombosis):

• First-line cytoreductive agents: Hydroxyurea or pegylated interferon-alpha 3, 5
• Second-line agent: Ruxolitinib (JAK1/JAK2 inhibitor) for hydroxyurea-resistant or intolerant patients 5

Symptom-Directed Therapy:

• Pruritus: Selective serotonin receptor antagonists 1
• Erythromelalgia/headaches: Low-dose aspirin effective 1
• Acquired von Willebrand disease with bleeding: Normalize platelet count with cytoreduction, as correction occurs with platelet normalization 1

Critical Pitfall:

• Excessive aspirin use is contraindicated due to bleeding risk from acquired von Willebrand disease and platelet dysfunction 1

Immediate Nursing Priorities in CVICU

Immediate priorities focus on preventing thrombotic progression while monitoring for paradoxical bleeding, maintaining target hematocrit through urgent phlebotomy, and recognizing hyperviscosity syndrome. 3, 6, 7

Acute Thrombosis Management:

• Initiate anticoagulation per protocol for acute thrombotic event (MI, stroke, PE, DVT) 6, 7
• Coordinate urgent phlebotomy to reduce hematocrit to <45% within 24-48 hours 3, 7
• Monitor for extension of thrombosis, particularly in atypical sites (portal, hepatic, mesenteric vessels) 7

Bleeding Risk Assessment:

• Assess for acquired von Willebrand disease, especially if platelet count >1000 × 10⁹/L 1
• Hold aspirin if active bleeding or extreme thrombocytosis present 1
• Monitor for hemorrhagic transformation of ischemic stroke 1

Hyperviscosity Monitoring:

• Neurologic checks every 2-4 hours for altered mental status, visual changes, focal deficits 3
• Continuous cardiac monitoring for ischemic changes 3, 6
• Oxygen saturation monitoring 3

Phlebotomy Protocol:

• Remove 250-500 mL blood per session (adjust for patient tolerance and cardiovascular status) 7
• Replace volume with normal saline to prevent hypotension 7
• Repeat sessions every 2-3 days until target hematocrit achieved 7

Potential Complications

Thrombotic events represent the leading cause of morbidity and mortality, with additional risks of hemorrhage, transformation to myelofibrosis (10-15% at 15 years), and acute leukemia (blast phase). 1, 3, 6, 5

Thrombotic Complications:

• Arterial thrombosis: MI, stroke, peripheral arterial occlusion 3, 6
• Venous thrombosis: DVT, PE, portal vein thrombosis, hepatic vein thrombosis (Budd-Chiari), mesenteric thrombosis 3, 6, 7
• Microvascular disturbances: erythromelalgia, digital ischemia, transient neurologic symptoms 1, 6

Hemorrhagic Complications:

• Acquired von Willebrand disease causing mucosal bleeding, ecchymoses, or post-procedural hemorrhage 1, 3
• Gastrointestinal bleeding from esophageal varices (if portal vein thrombosis present) 7
• Intracranial hemorrhage, particularly with uncontrolled hypertension 3

Disease Transformation:

• Myelofibrosis with myeloid metaplasia (post-PV myelofibrosis) 1, 5
• Acute myeloid leukemia (blast phase) with reduced long-term survival 1, 6, 5

Other Complications:

• Splenomegaly causing abdominal discomfort, early satiety, splenic infarction 6
• Hyperuricemia and gout from increased cell turnover 6

Relevant Red Flags & CVICU Tips

Recognize that PV patients face dual competing risks of thrombosis AND bleeding; hematocrit >45% dramatically increases thrombotic risk, while extreme thrombocytosis and acquired von Willebrand disease increase bleeding risk. 1, 3

Critical Red Flags:

• Hematocrit 46-52%: Suboptimal cerebral blood flow zone—urgent phlebotomy indicated 3
• Platelet count >1000 × 10⁹/L: High risk for acquired von Willebrand disease and paradoxical bleeding 1
• Abdominal pain in PV patient: Consider atypical site thrombosis (portal, hepatic, mesenteric vessels) requiring urgent imaging 7
• New neurologic symptoms: May represent stroke, TIA, or hyperviscosity syndrome requiring immediate intervention 3

CVICU Management Pearls:

• Do not assume adequate anticoagulation prevents thrombosis if hematocrit remains elevated—phlebotomy is mandatory 3, 7
• Avoid aggressive aspirin dosing (>100 mg daily) due to bleeding risk from platelet dysfunction 1
• Portal vein thrombosis can occur in young PV patients (<55 years) without cirrhosis—maintain high index of suspicion 7
• Leukocytosis and thrombocytosis do not correlate with thrombosis risk—focus on hematocrit control 1

Common Pitfalls to Avoid:

• Delaying phlebotomy while awaiting hematology consultation—initiate immediately in acute thrombotic presentation 3, 7
• Assuming normal hemoglobin rules out PV—inapparent polycythemia can occur when increased plasma volume masks elevated RBC mass 1
• Overlooking secondary causes before diagnosing PV—always check JAK2 mutation and EPO level, especially in obese patients with fatigue who may have obstructive sleep apnea 2, 8
• Treating thrombocytosis aggressively without recognizing bleeding risk—extreme thrombocytosis paradoxically increases hemorrhage from acquired von Willebrand disease 1

Expected Course and Prognostic Clues

Median survival approximates 15 years overall but exceeds 35 years for patients diagnosed at age ≤40 years; prognosis depends primarily on thrombotic complications and disease transformation risk. 3, 5

Prognostic Factors:

• Age >60 years and prior thrombosis identify high-risk patients requiring cytoreductive therapy 3, 4, 5
• JAK2 V617F variant allele frequency links to prognosis and complication risk; reduction is being evaluated as treatment target 5
• Elevated white blood cell count, platelet count, and cytokine levels may alter prognosis beyond hematocrit alone 6

Disease Trajectory:

• Early phase: Thrombotic and hemorrhagic complications dominate clinical course 3, 6
• Spent phase: Progression to post-PV myelofibrosis with cytopenias, massive splenomegaly, and constitutional symptoms 1, 5
• Blast transformation: Evolution to acute myeloid leukemia in subset of patients, associated with poor survival 1, 6, 5

Treatment Response:

• Phlebotomy with aspirin reduces thrombotic events when hematocrit maintained <45% 3, 4
• Cytoreductive therapy in high-risk patients further decreases thrombosis incidence 3, 5
• Ruxolitinib improves symptom burden and may reduce JAK2 allele burden, with long-term benefits emerging 5
• Polycythemia from secondary causes (e.g., OSA) resolves with treatment of underlying condition (CPAP therapy for sleep apnea) 8