Eculizumab in paroxysmal nocturnal hemoglobinuria with Budd-Chiari syndrome progressing despite anticoagulation

In June 2005, a 25-year-old white male was hospitalized when he presented with progressive headache, emesis, abdominal pain, and abdominal distension. Ascites was diagnosed and 2500 mL serous liquid was drained via paracentesis. Physical examination revealed hepatomegaly, splenomegaly, and bilateral papilloedema. Blood analysis showed a hemoglobin concentration of 9 g/dL (normal range: 14–18 g/dL), white blood cell count of 3.3 × 10⁹/L (normal range: 4.3–10.8 × 10⁹/L), platelet count of 19 × 10⁹/L (normal range: 150–400 × 10⁹/L), unbound bilirubin concentration of 1.7 mg/dL (normal range: 0.2–0.8 mg/dL), and lactate dehydrogenase (LDH) levels of 1684 U/L (upper limit of normal: 480 U/L). Both Ham and sucrose tests were positive and peripheral blood flow cytometry confirmed the diagnosis of PNH with a granulocyte clone size of 95%. Magnetic resonance imaging (MRI) scans showed BCS (Figure 1) and magnetic resonance angiography (MRA) identified thromboses of the left transverse and superior sagittal cerebral sinus veins (Figure 2).

Despite severe thrombocytopenia, the patient received anticoagulation therapy in the form of subcutaneous enoxaparin (1 mg/kg every 12 hours) for 80 months. The patient also received supplemental oral iron and folic acid and was treated with a short course of corticosteroids (methylprednisone, 1 mg/kg/day) to improve thrombocytopenia. In spite of adequate parenteral anticoagulation, BCS progressed and the patient experienced two symptomatic suprahepatic thromboses, increasingly refractory ascites, and painful congestive hepatomegaly, requiring the placement of a TIPS, an immediate splenic embolization (Figure 3), and an additional course of corticosteroids to treat severe refractory thrombocytopenia. A TIPS thrombosis developed and endovascular repermeabilization was required to restore TIPS patency succesfully. A second definitive TIPS thrombosis soon ensued, which was followed by refractory ascites that required paracentesis every 2 to 3 weeks, progressive liver damage (resulting in consideration for liver transplantation), and two episodes of symptomatic pulmonary embolism (Figure 4).

Neither anticoagulation nor TIPS placement prevented further thromboembolisms—the patient experienced two hepatic thromboses and two pulmonary embolisms over more than 40 months of therapy—that increased the extent of liver damage. Therefore, alternative treatment to prevent complement-mediated thrombosis was explored.

In January 2009, eculizumab (Alexion Pharmaceuticals, Cheshire, CT) treatment was initiated at the approved dosing regimen: 600 mg weekly for the first 4 weeks, followed by 900 mg for the fifth dose 1 week later, then 900 mg every 2 weeks thereafter. Within 2 weeks of starting treatment with eculizumab, LDH levels had decreased by 73% from an average of 2.9-fold above normal 1 to 2 months before treatment to within normal levels (≤480 U/L). This reduction was maintained for more than 2.5 years (921 days; Table 1), the latest data collected for this patient. Platelet count increased from 23 × 10⁹/L on day 1 of eculizumab treatment to 53 × 10⁹/L, a 130% increase, after 1 week and was sustained at a level of between 53 and 94 × 10⁹/L (average 67 × 10⁹/L) for 921 days. Rapid improvements in hepatic function were also observed, with alanine aminotransferase and aspartate aminotransferase levels reduced by 68.3% and 76.9%, respectively, from assessments made 68 days prior to treatment initiation to after 1 week of eculizumab therapy (Table 1). The significant reductions in both of these enzymes were sustained over the 921-day treatment time frame reported in this case study. Over the same period, total bilirubin level declined by between 36.1% and 61.1%. The concentration of cholinesterase, a marker of liver function, improved to within the normal level within 56 days of treatment initiation, the earliest time at which this parameter was measured, with a progressive increase thereafter, which is a clear sign of ongoing hepatic functional recovery. Changes in albumin levels paralleled those for cholinesterase and are representative of improvements in the synthetic capacity of the liver.

The interval between paracentesis increased progressively, giving a clear indication of a decrease in portal hypertension. After 7.5 months of eculizumab treatment, no further ascitic fluid evacuation was required. Diuretics, beta blockers, and hydrosaline restriction were also stopped after 2 years of eculizumab treatment. Serial liver MRA studies showed abundant intrahepatic venous collateral circulation without recanalization of the hepatic veins (Figure 5), and development of portal cavernomatosis (evidence of portal vein thrombosis, which appeared after TIPS thrombosis; Figure 5), paralleled the progressive improvement in liver function and hemodynamics. An ultrasound study showed a partial recanalization of the suprahepatic veins, which was unnoticed in MRA studies due to the low blood flow in the recovered blood vessels (Figure 6). In parallel with the improvement in liver vein thrombosis, a near-complete recanalization of the cerebral left transverse venous sinus, as well as partial recanalization of the sagittal vein sinus, also took place (Figure 7). As a consequence of these improvements, plans for liver transplantation were rescinded.

Following initiation of eculizumab, the patient experienced no new symptomatic thrombotic episodes, had a dramatic improvement in fatigue, and did not experience any clinically significant treatment-related adverse events. Consequently, the patient was able to resume a near-normal work and social life.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.