Veno-Occlusive Disease (VOD / Sinusoidal Obstruction Syndrome, SOS)
Definition
- A potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) or high-dose chemotherapy.
- Caused by toxic injury to hepatic sinusoidal endothelial cells, leading to obstruction of hepatic venules → hepatic congestion, hepatomegaly, jaundice, and multi-organ dysfunction.
Pathophysiology
- Endothelial damage (from alkylating agents, TBI, immunotherapy) → activation of coagulation cascade, fibrin deposition, sinusoidal narrowing.
- Leads to portal hypertension, hepatocellular necrosis, and fluid retention.
Risk Factors
Patient-related:
- Pre-existing liver disease (hepatitis, cirrhosis, fatty liver)
- Prior abdominal irradiation
- Iron overload
Treatment-related:
- Myeloablative conditioning regimens (esp. busulfan, cyclophosphamide, carmustine, melphalan)
- TBI-containing regimens
- Gemtuzumab ozogamicin, inotuzumab ozogamicin (anti-CD33/CD22 antibody-drug conjugates)
- Allogeneic HSCT (esp. mismatched, unrelated donor, cord blood)
Clinical Features
- Typically within 21 days post-HSCT (but can be late-onset)
- Classic triad:
- Painful hepatomegaly (RUQ pain)
- Jaundice (bilirubin ≥2 mg/dL)
- Fluid retention/ascites (weight gain >5%)
- Severe cases → multi-organ dysfunction (renal, pulmonary, encephalopathy).
Diagnostic Criteria
Modified Seattle or Baltimore Criteria:
- Seattle: ≥2 of the following within 20 days post-HSCT: hepatomegaly/RUQ pain, weight gain >2%, bilirubin ≥2 mg/dL
- Baltimore: bilirubin ≥2 mg/dL + ≥2 of (painful hepatomegaly, weight gain >5%, ascites)
Severity Grading (EBMT 2016): mild → severe → very severe (with multi-organ failure).
Prevention
- Defibrotide prophylaxis in high-risk patients (especially pediatric)
- Avoid hepatotoxic drugs when possible
- Ursodeoxycholic acid sometimes used for prophylaxis (controversial, more common in Europe)
- Careful busulfan pharmacokinetics monitoring to avoid high exposure
Treatment
- Supportive care: fluid balance, paracentesis, diuretics, pain control
- Defibrotide (only approved therapy):
- Dose: 6.25 mg/kg IV q6h (25 mg/kg/day) for ≥21 days or until resolution
- Mechanism: protects endothelial cells, anti-thrombotic/anti-inflammatory (without systemic anticoagulation)
- Discontinue hepatotoxic/veno-occlusive drugs
- Manage complications (renal failure → dialysis, pulmonary edema → oxygen/ventilation support)
Pharmacist Considerations
- Monitor for early signs in HSCT patients (daily weight, bilirubin, LFTs, fluid status)
- Know which regimens carry highest risk (BuCy, TBI, inotuzumab, gemtuzumab)
- Ensure defibrotide access in transplant centers
- Educate patients/families on reporting RUQ pain, jaundice, rapid weight gain
- Watch drug interactions (e.g., anticoagulants + defibrotide ↑ bleeding risk)