The role of anti-complement factor H antibodies in the development of atypical haemolytic uremic syndrome: a possible contribution to abnormality of platelet function.

Published on Apr 1, 2020in British Journal of Haematology6.998
· DOI :10.1111/BJH.16297
Madoka Fujisawa3
Estimated H-index: 3
(UTokyo: University of Tokyo),
Atsushi Yasumoto14
Estimated H-index: 14
(UTokyo: University of Tokyo)
+ 4 AuthorsMasaomi Nangaku84
Estimated H-index: 84
(UTokyo: University of Tokyo)
Sources
Abstract
Atypical haemolytic uremic syndrome (aHUS) is associated with complement system abnormality, such as production of complement factor H (CFH) autoantibodies. The growing evidence indicates complement overactivation on platelets is intimately involved in aHUS pathogenesis, besides endothelial injury. We here showed plasma from patients with anti-CFH antibodies induced aggregation of washed platelets, while purified anti-CFH antibodies suppressed aggregation. This suggested anti-CFH antibody itself suppressed thrombosis, while other plasma factor including complement factors could overactivate the platelets, leading to aggregation, which augmented the notion the state of complement activation influenced by anti-CFH antibodies is important in the aggregation of platelets in aHUS.
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2016
4 Authors (Marina Noris, ..., Giuseppe Remuzzi)
References15
Newest
#1Madoka Fujisawa (UTokyo: University of Tokyo)H-Index: 3
#2Hideki Kato (UTokyo: University of Tokyo)H-Index: 24
Last. Masaomi Nangaku (UTokyo: University of Tokyo)H-Index: 84
view all 13 authors...
Background Atypical hemolytic uremic syndrome (aHUS) is caused by complement overactivation, and its presentation and prognosis differ according to the underlying molecular defects. The aim of this study was to characterize the genetic backgrounds of aHUS patients in Japan and to elucidate the associations between their genetic backgrounds, clinical findings, and outcomes.
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#1Atsushi Yasumoto (UTokyo: University of Tokyo)H-Index: 14
#2Suzumi M. Tokuoka (UTokyo: University of Tokyo)H-Index: 10
Last. Yutaka Yatomi (UTokyo: University of Tokyo)H-Index: 73
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Abstract Eicosanoid mediators play important roles in maintaining the physiological and pathophysiological homeostasis in the body. Their measurements, however, are rarely performed in clinical practice. In the present study, we analyzed 30 varieties of eicosanoid mediators that were detectable in human plasma and serum collected from healthy donors, using liquid chromatography-tandem mass spectrometry from the viewpoint of the clinical application of the multiplex quantitation of eicosanoid med...
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#1Satu Hyvärinen (UH: University of Helsinki)H-Index: 10
#2Seppo Meri (UH: University of Helsinki)H-Index: 89
Last. T. Sakari Jokiranta (UH: University of Helsinki)H-Index: 41
view all 3 authors...
Uncontrolled activation of the complement system against endothelial and blood cells is central to the pathogenesis of atypical hemolytic uremic syndrome (aHUS). aHUS patients frequently carry mutations in the inhibitory complement regulator factor H (FH). Mutations cluster in domains 19 and 20 (FH19-20), which are critical for recognizing self surfaces. On endothelial cells, binding of FH is generally attributed to heparan sulfate. This theory, however, is questioned by the puzzling observation...
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#1Cornelia Speth (Innsbruck Medical University)H-Index: 33
#2Günter Rambach (Innsbruck Medical University)H-Index: 17
Last. Kristina Nilsson Ekdahl (Uppsala University)H-Index: 48
view all 8 authors...
Abstract In recent years, the view of platelets has changed from mere elements of hemostasis to immunological multitaskers. They are connected in manifold ways to other cellular and humoral components of the immune network, one of which is the complement system, a potent player in soluble innate immunity. Our article reviews the crucial and complex interplay between platelets and complement, focusing on mutual regulation of these two interaction partners by their respective molecular mechanisms....
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#1Yoko Yoshida (Nara Medical University)H-Index: 16
#2Toshiyuki MiyataH-Index: 78
Last. Yoshihiro Fujimura (Nara Medical University)H-Index: 64
view all 8 authors...
For thrombotic microangiopathies (TMAs), the diagnosis of atypical hemolytic uremic syndrome (aHUS) is made by ruling out Shiga toxin-producing Escherichia coli (STEC)-associated HUS and ADAMTS13 activity-deficient thrombotic thrombocytopenic purpura (TTP), often using the exclusion criteria for secondary TMAs. Nowadays, assays for ADAMTS13 activity and evaluation for STEC infection can be performed within a few hours. However, a confident diagnosis of aHUS often requires comprehensive gene anal...
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#1David J. Kavanagh (Newcastle University)H-Index: 96
#2Timothy H.J. Goodship (Newcastle University)H-Index: 66
Last. Anna Richards (Edin.: University of Edinburgh)H-Index: 27
view all 3 authors...
Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulato...
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#1Katerina Oikonomopoulou (UPenn: University of Pennsylvania)H-Index: 22
#2Daniel Ricklin (UPenn: University of Pennsylvania)H-Index: 52
Last. John D. Lambris (UPenn: University of Pennsylvania)H-Index: 131
view all 4 authors...
The parallel expression of activation products of the coagulation, fibrinolysis, and complement systems has long been observed in both clinical and experimental settings. Several interconnections between the individual components of these cascades have also been described, and the list of shared regulators is expanding. The co-existence and interplay of hemostatic and inflammatory mediators in the same microenvironment typically ensures a successful host immune defense in compromised barrier set...
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#1Christoph Licht (U of T: University of Toronto)H-Index: 45
#2Fred G. PlutheroH-Index: 24
Last. Walter H. A. Kahr (U of T: University of Toronto)H-Index: 31
view all 9 authors...
Atypical hemolytic uremic syndrome (aHUS) is associated with complement system dysregulation, and more than 25% of pediatric aHUS cases are linked to mutations in complement factor H (CFH) or CFH autoantibodies. The observation of thrombocytopenia and platelet-rich thrombi in the glomerular microvasculature indicates that platelets are intimately involved in aHUS pathogenesis. It has been reported that a releasable pool of platelet CFH originates from α-granules. We observed that platelet CFH ca...
Source
Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations in the C-terminal of factor H (FH). FH binds to platelets via the C-terminal as previously shown using a construct consisting of short consensus repeats (SCRs) 15 to 20. A total of 4 FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, and E1198Stop) in patients with aHUS, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding t...
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#1Vahid Afshar-Kharghan (University of Texas MD Anderson Cancer Center)H-Index: 28
Lack of regulation of the complement system is associated with thrombosis. In this issue of Blood , Stahl and colleagues report that deficiency of factor H in patients with atypical hemolytic uremic syndrome activates platelets and generates platelet microparticles. Several membrane and plasma
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Cited By2
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#1Saravanan Subramaniam (BU: Boston University)H-Index: 14
#4Paige Montanaro (BU: Boston University)H-Index: 2
Last. Andrew Emili (BU: Boston University)H-Index: 83
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Coronavirus disease-2019 (COVID-19) provokes a hypercoagulable state with increased incidence of thromboembolism and mortality. Platelets are major effectors of thrombosis and hemostasis. Suitable animal models are needed to better understand COVID-19-associated coagulopathy (CAC) and underlying platelet phenotypes. Here, we assessed K18-hACE2 mice undergoing a standardized SARS-CoV-2 infection protocol to study dynamic platelet responses via mass spectrometry-based proteomics. In total, we foun...
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#3Anastasiya V. Moskatlinova (MSMU: I.M. Sechenov First Moscow State Medical University)
view all 8 authors...
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