Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy

Division of Bone Marrow Transplantion and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Blood (Impact Factor: 10.43). 06/2013; 122(12). DOI: 10.1182/blood-2013-05-501445
Source: PubMed

ABSTRACT Hematopoietic stem cell transplant (HSCT)-associated thrombotic microangiopathy (TMA) is a complication that occurs in 25-35 % of HSCT recipients and shares histomorphological similarities with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The hallmark of all thrombotic microangiopathies is vascular endothelial cell injury of various origins, resulting in microangiopathic hemolytic anemia, platelet consumption, fibrin deposition in the microcirculation and tissue damage. While significant advances have been made in the understanding of the pathogenesis of other thrombotic microangiopathies, post-HSCT TMA remains poorly understood. We report an analysis of the complement alternative pathway, which has recently been linked to the pathogenesis of both the Shiga toxin mediated and the atypical forms of HUS, with a focus on genetic variations in the complement Factor H (CFH) gene cluster and CFH autoantibodies in six children with post-HSCT TMA. We identified a high prevalence of deletions in CFH-related genes 3 and 1 (delCFHR3-CFHR1) and CFH autoantibodies in these patients with HSCT-TMA. Conversely, CFH autoantibodies were not detected in 18 children undergoing HSCT who did not develop TMA. Our observations suggest that complement alternative pathway dysregulation may be involved in the pathogenesis of post-HSCT TMA. These findings shed light on a novel mechanism of endothelial injury in transplant-associated thrombotic microangiopathy and may therefore guide the development of targeted treatment interventions.

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    ABSTRACT: Objective To review the clinical features and pathophysiologic mechanisms of the thrombotic microangiopathies (TMAs) including acquired and congenital thrombotic thrombocytopenic purpura (TTP), Shiga toxin-induced and atypical (non-Shiga toxin-induced) hemolytic uremic syndrome (HUS), and the TMAs associated with pregnancy, drugs, and organ transplantation. Methods PubMed Medline was used to identify articles published from 2000 to July 2013 using the following key words: thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, Shiga toxin, ADAMTS13, and eculizumab. Articles in languages other than English, papers available in abstract form only, and nearly all single case reports were excluded. Small series, reports from registries and study groups, reviews, guidelines, and articles concerning pathophysiology and therapy were preferentially considered. Results Impaired post-secretion processing of unusually large von Willebrand multimers due to deficiency of ADAMTS13 (IgG antibodies or congenital), dysregulation of the alternative complement pathway (mutations and/or specific antibodies), and endothelial injury are pathophysiologic mechanisms involved in the TMAs. Acquired and congenital TTP are due primarily to severe ADAMTS13 deficiency, atypical HUS is commonly associated with complement dysregulation, and Shiga toxin, drugs, immune complexes, and others likely damage endothelium. However, there is considerable mechanistic overlap, and the TMAs often have multifactorial causation. Plasma procedures, complement pathway inhibition, immunosuppression, and general supportive care are the principal therapies. Conclusions The TMAs are very important conditions because of their associated organ damage and mortality rates. Prompt recognition and categorization by both clinical presentation and pathophysiologic mechanisms should become routine as they are crucial to an optimal treatment plan. Treatment advances have substantially reduced the morbidity of these disorders. Investigational therapies are promising.
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  • Blood 09/2013; 122(12):1997-9. DOI:10.1182/blood-2013-07-512707 · 10.43 Impact Factor
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    ABSTRACT: We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated six children with severe HSCT-TMA using eculizumab and adjusted the dose to achieve a therapeutic level of >99 μg/ml. HSCT-TMA resolved over time in four of six children after achieving therapeutic eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that eculizumab may be a therapeutic option for HSCT-TMA but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ≤4 complement activity enzyme (CAE) units correlated with therapeutic eculizumab levels and clinical response, and therefore CH50 may be useful to guide eculizumab dosing in HSCT patients as drug level monitoring is not readily available.
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