Is paroxysmal nocturnal hemoglobinuria (PNH) another condition that can cause both arterial (radial artery) and venous (saphenous vein) thrombosis in a patient with negative antiphospholipid antibodies?

Is PNH a Condition Causing Both Arterial and Venous Thrombosis?

Yes, paroxysmal nocturnal hemoglobinuria (PNH) is definitively a condition that causes both arterial and venous thrombosis, making it a critical diagnosis to consider in patients with thrombotic events in unusual locations, particularly when antiphospholipid antibodies are negative. 1, 2

PNH as a Thrombophilic Disorder

PNH is classified as an acquired thrombophilia characterized by a unique predisposition to both venous and arterial thrombotic complications. 3, 4, 5

Venous Thrombosis Patterns

• PNH demonstrates a particularly strong association with venous thrombosis in unusual anatomic sites, especially splanchnic vessels. 1, 2
• Budd-Chiari syndrome (hepatic vein thrombosis) is found in 9-19% of tested BCS patients, representing one of the strongest associations between PNH and thrombosis. 1, 2, 6
• Portal vein thrombosis occurs less frequently than Budd-Chiari syndrome but remains a recognized complication. 1, 6
• Cerebral venous thrombosis can occur and requires immediate anticoagulation combined with complement inhibitor therapy. 6
• Deep vein thrombosis and pulmonary embolism are also documented complications. 3

Arterial Thrombosis

• PNH causes arterial thrombotic events, including peripheral arterial thrombosis and critical limb ischemia, though less commonly than venous events. 5, 7
• Arterial thrombosis in PNH can affect multiple vascular beds and may occur despite standard anticoagulation regimens. 7
• The mechanism involves increased platelet aggregation and thrombin generation related to complement-mediated activation. 1

Risk Stratification by Clone Size

Patients with PNH clone size >60% of granulocytes have markedly elevated thrombosis risk and represent a high-risk phenotype requiring aggressive management. 2, 6, 8

• Clone sizes of 10-60% warrant close monitoring with consideration for anticoagulation if any thrombotic event occurs. 2
• Even small clones (1-10%) should not be dismissed, as they may expand and are often associated with bone marrow failure syndromes. 2

Diagnostic Approach in Thrombosis Patients

When evaluating patients with arterial or venous thrombosis in unusual sites (such as your patient with radial artery and saphenous vein involvement) and negative antiphospholipid antibodies, PNH testing should be performed routinely. 1, 2

Specific Testing Recommendations

• Flow cytometry detecting deficiency of GPI-anchored proteins CD55 and CD59 on peripheral blood cells is the definitive diagnostic test and should be performed in every patient with suspected PNH. 2, 9
• Evaluate for hemolysis markers including elevated LDH, reduced haptoglobin, elevated indirect bilirubin, and presence of schistocytes on peripheral smear. 2, 8
• JAK2V617F mutation testing should be performed to exclude concurrent myeloproliferative neoplasms, which can also cause thrombosis. 1, 2
• Comprehensive thrombophilia screening is recommended in patients presenting with thrombosis. 2, 6

Clinical Pitfalls to Avoid

• Do not dismiss PNH as a diagnosis solely because thrombosis occurred in typical sites (radial artery, saphenous vein) rather than classic splanchnic locations—PNH can cause thrombosis anywhere. 5, 7
• Negative antiphospholipid antibodies do not exclude PNH; these are distinct thrombophilic conditions that require different diagnostic approaches. 1
• Small PNH clones may be missed if testing is not repeated when clinical suspicion remains high despite initial negative results. 2, 5
• Thrombosis in PNH can occur despite therapeutic anticoagulation, requiring more aggressive management strategies including complement inhibitor therapy. 6, 7

Management Implications

Once PNH is diagnosed in a patient with thrombosis, indefinite anticoagulation is required regardless of thrombosis location, combined with complement inhibitor therapy (eculizumab, ravulizumab, or crovalimab). 6, 4

• Anticoagulation options include warfarin, direct oral anticoagulants (DOACs), or low-molecular-weight heparin. 6
• Complement inhibitors (C5 inhibitors) serve as primary prophylaxis against future thrombotic events and reduce mortality. 6, 4
• Thrombosis represents a life-threatening complication of PNH and is the major cause of mortality in this disorder. 3, 4