Management of PNH with Thrombosis
Patients with PNH who develop thrombosis require immediate initiation of C5 complement inhibitor therapy (eculizumab or ravulizumab) combined with indefinite anticoagulation, as thrombosis risk persists even with complement inhibition alone. 1, 2
Immediate Management
Acute Thrombosis Treatment
- Start C5 inhibitor therapy immediately with eculizumab 900 mg IV weekly for 4 weeks, followed by 1200 mg at week 5, then 1200 mg every 2 weeks thereafter 3
- Initiate anticoagulation concurrently using warfarin, low-molecular-weight heparin (LMWH), or direct oral anticoagulants (DOACs) 2, 4
- Meningococcal vaccination is mandatory at least 2 weeks before starting C5 inhibitor, but do not delay treatment in acute thrombosis—give prophylactic antibiotics (penicillin or macrolides) immediately and vaccinate as soon as feasible 3
Site-Specific Considerations
For Budd-Chiari syndrome (hepatic vein thrombosis):
- Obtain urgent hepatology consultation for consideration of transjugular intrahepatic portosystemic shunt (TIPS) 5, 2
- Indefinite anticoagulation is required due to severity of this complication 2
- PNH is found in 9-19% of Budd-Chiari patients, making this association particularly important 2
For acute portal/mesenteric/splenic vein thrombosis:
- Assess immediately for bowel infarction with surgical consultation if peritoneal signs present (rebound tenderness, guarding, fever) 5
- Consider catheter-directed pharmacomechanical thrombectomy if diagnosed within 8 weeks of symptom onset 5
- Emergency surgery is required if bowel infarction is present 5
For cerebral venous or arterial thrombosis:
- Initiate immediate anticoagulation alongside C5 inhibitor therapy 2
- Obtain urgent neurological evaluation with appropriate imaging 2
Duration of Anticoagulation
- Indefinite anticoagulation is recommended for all patients with PNH and thrombosis, particularly when thrombosis occurs in unusual sites (hepatic, portal, mesenteric, splenic, or cerebral veins) 1, 2
- The thrombosis risk persists even on eculizumab therapy, and patients with prior thrombotic events remain at higher risk 1
- For triggered events (e.g., post-surgical), minimum duration is 6 months, but indefinite therapy should be strongly considered given the underlying PNH pathophysiology 5
Monitoring and Follow-up
Laboratory surveillance should include:
- Hemoglobin and reticulocyte count to assess hemolysis control 1, 3
- LDH, haptoglobin, and indirect bilirubin as markers of breakthrough hemolysis 3
- Signs of breakthrough hemolysis: dark urine, fatigue, abdominal pain 1, 3
Clinical monitoring:
- Assess for extravascular hemolysis, which may develop despite C5 inhibition—26.7% of treated patients still require transfusions 6
- Monitor for meningococcal infection risk (0.35 events per 100 patient-years on therapy) 6
Critical Pitfalls to Avoid
- Never delay C5 inhibitor initiation while arranging vaccination—start prophylactic antibiotics and treat immediately in acute thrombosis 3
- Do not rely on C5 inhibitor monotherapy for thrombosis prevention—anticoagulation must be continued indefinitely as thrombosis can still occur on eculizumab (3 of 26 patients in one series) 7, 8
- Screen patients of Chinese or Japanese descent before initiating C5 inhibitors, as genetic polymorphisms in the C5 gene may confer resistance to anti-C5 monoclonal antibodies 3
- Maintain antimicrobial prophylaxis (penicillin or macrolides for penicillin-allergic patients) throughout the entire duration of C5 inhibitor treatment 3
Prognosis
- With modern C5 inhibitor therapy, thrombosis-related mortality has decreased substantially—only 4 deaths from thrombosis occurred in a UK cohort of 509 treated patients 6
- Historical data showed thrombosis was responsible for death in 28 of 48 patients (58%) before C5 inhibitors were available 9
- Overall survival on C5 inhibitors approaches that of age-matched controls when bone marrow failure complications are excluded 6