Eculizumab in paroxysmal nocturnal hemoglobinuria with Budd-Chiari syndrome progressing despite anticoagulation
© Brodsky et al.; licensee BioMed Central Ltd. 2012
Received: 17 July 2012
Accepted: 23 August 2012
Published: 6 September 2012
Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive, life-threatening disorder characterized by chronic intravascular hemolysis caused by uncontrolled complement activation. Hepatic vein thrombosis (Budd-Chiari syndrome) is common in PNH patients. This case report describes the response to eculizumab (a humanized monoclonal antibody that inhibits terminal complement activation) in a 25-year-old male with progressive liver function deterioration despite standard anticoagulation therapy and transjugular intrahepatic porto-systemic shunt. The patient presented with anemia, severe thrombocytopenia, headache, abdominal pain, and distention. He was diagnosed with PNH, cerebral vein thrombosis, and Budd-Chiari syndrome. Despite adequate anticoagulation, diuretic administration, and placement of a transjugular shunt, additional thrombotic events and progressive liver damage were observed. Eculizumab therapy was initiated, resulting in rapid blockade of intravascular hemolysis, increased platelet counts, ascites resolution, and liver function recovery, all of which are presently sustained. Since starting eculizumab the patient has had no further thrombotic events and his quality of life has dramatically improved. This is the first report to confirm the role of complement-mediated injury in the progression of Budd-Chiari syndrome in a patient with PNH. This case shows that terminal complement blockade with eculizumab can reverse progressive thromboses and hepatic failure that is unresponsive to anticoagulation therapy and suggests that early initiation of eculizumab should be included in the therapeutic regimen of patients with PNH-related Budd-Chiari syndrome.
KeywordsBudd-Chiari syndrome Complement inhibition Eculizumab Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening, progressive, acquired genetic disease characterized by the clonal, nonmalignant expansion of hematopoietic stem cells deficient in glycosylphosphatidylinositol (GPI) synthesis. This deficiency results in fewer GPI-anchored complement inhibitors (CD55 and CD59) on the cell surface, causing increased chronic complement-mediated intravascular hemolysis and platelet hyperactivation and aggregation . Both processes lead to an increased risk of thrombosis, renal dysfunction and damage, pulmonary hypertension, and anemia, which, despite historical treatment regimens, have resulted in up to 35% mortality within 5 years of diagnosis . Thromboembolism is the most common cause of PNH-related death, accounting for two-thirds of all mortalities in patients with this disease . Between 29% and 44% of PNH patients experience a clinically evident thromboembolism, affecting the liver, brain, gut, and kidney [3, 4]. Recent registry analyses support an 8.4- to 15.4-fold increased risk of death in patients with PNH with thromboembolism [4, 5].
Budd-Chiari syndrome (BCS) is common in PNH patients and anticoagulation therapy is traditionally the first treatment choice for the management of this disorder. However, PNH patients frequently experience new thrombotic episodes despite adequate anticoagulation, which limits the usefulness of subsequent hepatic vein angioplasty and/or stenting and transjugular intrahepatic porto-systemic shunt (TIPS) placement [3, 6, 7]. Further complicating anticoagulation management, thrombocytopenia occurs in 25% to 52% of PNH patients, creating a high risk of severe bleeding [5, 8]. Additional therapeutic options for BCS in patients with PNH are limited to high-risk allogeneic hematopoietic stem-cell transplantation or liver transplantation. In one retrospective study in patients with PNH, there was a 22% reduction in 5-year survival in patients who had received stem-cell transplantation compared with those who had not  while liver transplantation in patients with ongoing intravascular hemolysis due to PNH has been associated with high rates of thrombotic and hemorrhagic complications .
Eculizumab is a humanized monoclonal antibody that specifically targets the terminal complement protein C5, blocking complement-mediated hemolysis. Two multinational, phase 3 studies and a related extension study demonstrated that eculizumab significantly reduces hemolysis and thrombotic events in patients with PNH [3, 11, 12]. These studies also showed that eculizumab was effective in reducing renal impairment, pulmonary hypertension, and transfusion requirements, while improving fatigue and quality of life. Furthermore, long-term treatment with eculizumab has been shown to normalize survival of patients with PNH compared with age- and sex-matched controls . Long-term treatment with eculizumab has demonstrated a favorable safety profile [3, 11–13].
Here, we describe the effect of eculizumab in a patient with PNH who was being considered for liver transplantation because of multiple thrombotic events, progressive BCS, and declining liver function.
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.
Effect of eculizumab on liver function
Laboratory value (normal range)
× 10 9/L
0 (1st dose)
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.
This is the first report to confirm the role of complement-mediated injury in the progression of BCS in a patient with PNH and its improvement with eculizumab treatment.
Thromboembolism is the most common cause of PNH-related death, accounting for two-thirds of all mortalities in patients with this disease . Between 29% and 44% of PNH patients experience a clinically evident thromboembolism, which affects the liver, brain, gut and kidney [3, 4]. This patient was no exception as he developed 2 hepatic and 2 pulmonary thromboembolisms, despite 40 months of anticoagulation and TIPS therapy. Recent registry analyses support an 8.4- to 15.4-fold increased risk of death in patients with PNH with thromboembolism [4, 5]. Historically, this increased risk of thrombosis, along with other life-threatening complications such as chronic kidney disease, pulmonary hypertension and anemia, have resulted in up to 35% of patients with PNH dying within 5 years of diagnosis .
The patient is currently receiving eculizumab and since starting this therapy has not experienced any new thromboses. This is consistent with recent large cohort analyses in the United Kingdom that show that anticoagulation for primary antithrombotic prophylaxis can be safely discontinued in some patients with PNH who are concurrently receiving eculizumab .
Hepatic dysfunction and deterioration in patients with PNH may also result, in part, from increased vascular resistance and/or inflammation, as reported in renal and pulmonary systems [14, 15]. For example, chronic complement activation in PNH can lead to local damage of hepatic and/or Kupffer cells, subsequent upregulation of adhesion molecules, and release of proinflammatory cytokines, such as interleukin-1 and -6 [16, 17]. In addition, complement-mediated depletion of the smooth muscle relaxant nitric oxide has been linked to pulmonary and systemic hypertension [15, 18], as well as reduction of renal blood flow and function . These effects are ameliorated by the inhibition of terminal complement activation by eculizumab, which improves chronic kidney disease in patients with PNH as early as 12 weeks post-treatment  and reduces the risk of systemic and pulmonary hypertension . Thus, it is reasonable to suggest that terminal complement inhibition, besides blocking thrombosis in PNH, may prevent vasoconstriction and inflammation that affects both hepatic flow and liver function in PNH patients with BCS. In addition, patients with PNH who are thrombocytopenic, including the patient in this case, are at higher risk of thromboembolism than PNH patients with normal platelet levels . Eculizumab-mediated improvement of platelet count reduces the risk of thromboembolism, and may increase the safety of concomitant anticoagulation and/or subsequent treatment modalities, including allogeneic hematopoietic stem-cell transplantation or liver transplantation.
In this case, the patient responded to eculizumab with a dramatic restoration of hepatic function. The retraction of a planned liver transplant highlights the remarkable improvements that this patient experienced, and bodes well for future PNH cases with similar symptom presentations.
Eculizumab, a humanized monoclonal antibody that targets the C5 complement protein, is effective at blocking complement-mediated hemolysis in PNH patients. The ability of eculizumab to reverse the damaging effects of BCS confirms the role of complement in the progression of this disease in PNH patients. The absence of new thromboses in this patient after receiving eculizumab supports the application of eculizumab in the treatment of PNH patients with BCS.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Paroxysmal nocturnal hemoglobinuria
Transjugular intrahepatic porto-systemic shunt
Magnetic resonance imaging
Magnetic resonance angiography.
We thank Mark Hughes, PhD, and Shannon Davis of Infusion Communications for their writing and editorial assistance with this manuscript, which was funded by Alexion Pharmaceuticals, Inc.
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