How is arterial and venous thrombosis managed in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)?

Management of Arterial and Venous Thrombosis in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Patients with PNH require complement inhibitor therapy as the cornerstone of thrombosis management, with appropriate anticoagulation based on thrombosis type and location. Thrombosis is a major complication of PNH, affecting up to 40% of patients and representing the primary cause of morbidity and mortality in this population 1.

Pathophysiology and Risk Assessment

• PNH is a rare acquired hematopoietic stem cell disorder characterized by hemolytic anemia, bone marrow failure, and a high risk of thrombotic events 1, 2
• Thrombosis in PNH primarily affects venous circulation (especially unusual sites like hepatic veins), but arterial thrombosis can also occur 3, 1
• Patients with PNH clone size >60% of granulocytes have significantly higher thrombosis risk 4
• The prothrombotic state in PNH results from multiple mechanisms including complement activation, endothelial dysfunction, hemolysis, impaired nitric oxide bioavailability, and activation of platelets and neutrophils 5

First-Line Management

• C5 complement inhibitors (eculizumab or ravulizumab) should be initiated immediately in all PNH patients with thrombosis 1, 2

  • Eculizumab (900 mg IV every 2 weeks) or ravulizumab (dosing based on weight, every 8 weeks) effectively reduces thrombotic events by inhibiting terminal complement activation 6, 2
  • C5 inhibitors have reduced thrombosis rates by approximately 50% (21 vs 40 thrombotic events per 1000 patient-years) 7

• Anticoagulation therapy must be administered concurrently with complement inhibitors 1, 7

  • For venous thrombosis: Therapeutic anticoagulation with either warfarin (target INR 2.0-3.0), low-molecular-weight heparin, or direct oral anticoagulants (DOACs) 7
  • For arterial thrombosis: Combination of antiplatelet therapy (aspirin 81-100 mg daily) plus anticoagulation is recommended 3

Specific Management Based on Thrombosis Location

Budd-Chiari Syndrome (Hepatic Vein Thrombosis)

• PNH is strongly associated with Budd-Chiari syndrome (BCS), found in 9-19% of BCS patients 4
• Management requires:
  • Immediate initiation of C5 inhibitor therapy 1
  • Long-term anticoagulation is warranted due to the severity of BCS 4
  • Hepatology consultation for consideration of transjugular intrahepatic portosystemic shunt (TIPS) in selected cases 4

Portal Vein Thrombosis

• PNH is less commonly associated with portal vein thrombosis (0-2% of cases) 4
• Management includes:
  • C5 inhibitor therapy 1
  • Anticoagulation for at least 6 months, with consideration for long-term treatment based on risk factors 4
  • Careful monitoring for variceal bleeding risk in patients with portal hypertension 4

Cerebral Venous and Arterial Thrombosis

• Cerebral venous thrombosis and less commonly arterial thrombosis can occur in PNH patients 4
• Management requires:
  • Immediate anticoagulation along with C5 inhibitor therapy 4, 1
  • Neurological evaluation and appropriate imaging 4

Duration of Anticoagulation

• For venous thrombosis in unusual sites (Budd-Chiari, portal vein): Indefinite anticoagulation is recommended even with complement inhibitor therapy 4
• For other venous thrombosis: Minimum of 6-12 months of anticoagulation, with consideration for indefinite treatment while monitoring bleeding risk 7
• For arterial thrombosis: Indefinite anticoagulation plus antiplatelet therapy is typically recommended 3

Anticoagulant Options and Monitoring

• Warfarin: Target INR 2.0-3.0, used in 39% of PNH patients with thrombosis 7
• Low-molecular-weight heparin: Used in 16% of PNH patients with thrombosis, especially during acute phase or when oral options are contraindicated 7
• Direct oral anticoagulants (DOACs): Used in 37% of PNH patients with thrombosis with no reported recurrences in recent studies 7
• Regular monitoring: Frequent assessment of hemolysis parameters, complement blockade, and anticoagulation efficacy is essential 3

Special Considerations

• Catheter-related thrombosis: PNH patients with central venous catheters require vigilant monitoring and may benefit from prophylactic anticoagulation 4
• Pregnancy: PNH is associated with high maternal mortality (30-50%), making pregnancy a relative contraindication; specialized management is required if pregnancy occurs 4
• Surgery: Increased thrombotic risk during perioperative period requires careful planning, with preference for epidural over general anesthesia when possible 4, 3

Newer Therapeutic Approaches

• Upstream complement inhibitors (pegcetacoplan, iptacopan, danicopan) are emerging options that may provide additional benefits for patients with extravascular hemolysis while maintaining thrombosis protection 2
• These agents may be considered in patients with inadequate response to C5 inhibitors or breakthrough hemolysis 2

Pitfalls and Caveats

• Despite standard anticoagulation, PNH patients may remain hypercoagulable and require more aggressive anticoagulation regimens 3
• Complement inhibitors increase infection risk, requiring vigilant monitoring and appropriate prophylaxis 3
• Breakthrough hemolysis can occur with complement inhibitors during strong complement triggers, potentially increasing thrombosis risk 2
• Regular monitoring of hemolysis parameters is essential to adjust therapy and prevent thrombotic complications 3, 7