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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Given its non-specific clinical presentation it is likely that this clinical entity is under diagnosed after HSCT. Data describing the incidence, risk factors, and etiology of PH in HSCT recipients is minimal. Physicians caring for HSCT recipients should be aware of this severe post-transplant complication since timely diagnosis and treatment may allow improved clinical outcomes. We summarize the pathophysiology, clinical presentation, diagnosis and management of PH in HSCT recipients.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 07/2013; 19(11). DOI:10.1016/j.bbmt.2013.07.017 · 3.35 Impact Factor
  • Blood 09/2013; 122(12):1997-9. DOI:10.1182/blood-2013-07-512707 · 10.43 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Seminars in arthritis and rheumatism 11/2013; 43. DOI:10.1016/j.semarthrit.2013.11.004 · 3.63 Impact Factor
Show more