Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria

Abstract

Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n ‫؍‬ 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n ‫؍‬ 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317). IntroductionIntravascular hemolysis and cell-free plasma hemoglobin have been implicated in the serious clinical sequelae of various hemolytic disorders. 1 Hemolysis is the primary clinical manifestation of the uncommon disease paroxysmal nocturnal hemoglobinuria (PNH) and has been shown to result in chronic disabling morbidities including anemia, severe fatigue, difficulty in functioning, pain, and thrombosis, all of which have a major effect on the patient's quality of life. 1-5 Paroxysmal nocturnal hemoglobinuria is defined by the acquired genetic deficiency of glycosylphosphatidylinositol (GPI)-linked proteins from the surface of blood cells. The absence of GPI-linked complement regulatory proteins on PNH erythrocytes renders them susceptible to terminal complement-mediated hemolysis.Hemolysis most likely contributes to thromboembolism (TE) in PNH, as patients with larger PNH clones have a higher incidence of TE and events have been temporally associated with increased hemolysis. 6-10 Although the mechanism is not fully understood, hemolysis has been implicated in the initiation of platelet activation and aggregation. 1 Additional in vitro studies have suggested that complement may directly activate platelets from PNH patients. 11,12 Thromboembolism is the leading cause of mortality in patients with PNH, 2,3,13-17 and an initial thrombotic event increases the relative risk of death in PNH 5-to 10-fold. 15,17 Retrospective studies suggest that, in non-Asian patients, TE accou...

Procoagulant properties of microparticles released from red blood cells in paroxysmal nocturnal haemoglobinuria

“…It should be noted that a significant population of PS-exposed RBC was also detected in PNH-RBC treated by C' activation (3AE3% in Fig 4Ae). haemolysis (Hillmen et al, 2004(Hillmen et al, , 2007 indicate the importance of C¢-mediated mechanisms, haemolysis in particular, for thrombogenesis in PNH. As has been well documented for platelets, cell membrane-derived MPs provide the catalytic surface necessary for the assembly of procoagulant enzyme complexes, prothrombinase and tenase.…”

“…Complement (C¢) sensitivity of PNH red blood cells (RBC) is due to a deficiency in the expression of glycosyl-phosphatidylinositol (GPI)-anchored membrane proteins with C¢-regulatory activity, CD55 and CD59, on PNH-affected RBC (Wilcox et al, 1991;Parker et al, 2005;Brodsky, 2008). The clinical evidence that eculizumab (Soliris, Alexion Pharmaceuticals, Chelshire, CT, USA), a humanized monoclonal anti-C5 antibody therapy, reduced the risk of clinical thromboembolism in addition to its reducing effect on intravascular haemolysis strongly suggests a major role of C¢-induced haemolysis in thrombogenesis in PNH (Hillmen et al, 2004(Hillmen et al, , 2007.…”

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

“…13 The latter process can be eliminated by treatment with eculizumab and the thrombophilia of PNH may also respond to inhibition of intravascular hemolysis by eculizumab. 30 Nonetheless, transplantation is the only curative therapy for PNH, and the availability of molecularly defined, matched unrelated donors; less toxic conditioning regimens; reductions in transplantation-related morbidity and mortality; and improvements in posttransplantation supportive care make this option a viable alternative to medical management. The decision of who should receive a transplantation and when it should be performed is complex, however, and requires an understanding of the unique pathobiology of PNH and the input of physicians experienced in transplantation and medical management of PNH.…”

“…Eculizumab appears to reduce the risk of thromboembolic complications. 30 For patients being treated with eculizumab who have no prior history of thromboembolic complications, prophylactic anticoagulation may be unnecessary. Because PNH patients with prior thrombosis are at higher risk for recurrent thrombosis, anticoagulation for eculizumab-treated patients who experienced a prior thromboembolic event should be continued.…”

Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria

“…5,6 Eculizumab significantly reduces the risk of TE by inducing a substantial and sustained decrease in the activation of both the plasma hemostatic system and the vascular endothelium, 7 likely contributing to its protective effect on the risk of thromboembolism. 8 Moreover, it has recently been suggested that eculizumab improves survival. 9 Patients with severe aplastic anemia (SAA) with or without a PNH clone are currently treated with either allogeneic stem cell transplantation (SCT) or immunosuppressive therapy depending on the patient's age and availability of a suitable human leukocyte antigen (HLA)-matched hematopoietic stem cell donor.…”