Hydrogen‐deuterium exchange mass spectrometry highlights conformational changes induced by factor XI activation and binding of factor IX to factor XIa

Barroeta, Awital Bar; Galen, Josse van; Stroo, Ingrid; Marquart, J. Arnoud; Meijer, Alexander B.; Meijers, Joost C. M.

doi:10.1111/jth.14632

Cited by 16 publications

(27 citation statements)

References 24 publications

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“…Subsequently, FIXa feeds into the coagulation cascade to promote thrombin production, aiding fibrin assembly and preventing excess blood loss. 1,7 Owing to the importance of FXI in coagulation, genetic variants that disrupt the native FXI structure and function lead to bleeding diatheses. Such disorders are most commonly referred to as FXI deficiency, but have been termed Haemophilia C, Rosenthal syndrome or Plasma Thromboplastin Antecedent deficiency in the past.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Analysis of 272 Genetic Variants in the Upgraded Interactive FXI Web Database Reveals New Insights into FXI Deficiency

Harris

Lin

Perkins

2021

TH Open

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Coagulation Factor XI (FXI) is a plasma glycoprotein composed of four apple (Ap) domains and a serine protease (SP) domain. FXI circulates as a dimer and activates Factor IX (FIX), promoting thrombin production and preventing excess blood loss. Genetic variants that degrade FXI structure and function often lead to bleeding diatheses, commonly termed FXI deficiency. The first interactive FXI variant database underwent initial development in 2003 at https://www.factorxi.org. Here, based on a much improved FXI crystal structure, the upgraded FXI database contains information regarding 272 FXI variants (including 154 missense variants) found in 657 patients, this being a significant increase from the 183 variants identified in the 2009 update. Type I variants involve the simultaneous reduction of FXI coagulant activity (FXI:C) and FXI antigen levels (FXI:Ag), whereas Type II variants result in decreased FXI:C yet normal FXI:Ag. The database updates now highlight the predominance of Type I variants in FXI. Analysis in terms of a consensus Ap domain revealed the near-uniform distribution of 81 missense variants across the Ap domains. A further 66 missense variants were identified in the SP domain, showing that all regions of the FXI protein were important for function. The variants clarified the critical importance of changes in surface solvent accessibility, as well as those of cysteine residues and the dimer interface. Guidelines are provided below for clinicians who wish to use the database for diagnostic purposes. In conclusion, the updated database provides an easy-to-use web resource on FXI deficiency for clinicians.

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Section: Accepted Manuscriptmentioning

confidence: 99%

“…Subsequently, FIXa feeds into the coagulation cascade to promote thrombin production, aiding fibrin assembly and preventing excess blood loss. 1 7 …”

Section: Introductionmentioning

confidence: 99%

Analysis of 272 Genetic Variants in the Upgraded Interactive FXI Web Database Reveals New Insights into FXI Deficiency

Harris

Lin

Perkins

2021

TH Open

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“…Medicinal design of this compound resulted in a peptidomimetic, which had a 3000‐fold increase in potency in inhibiting platelet aggregation over its parental compound echistatin 22,23 . In addition, elucidation of structural changes that occur during activation of coagulation zymogens, factor XI, and prekallikrein, has provided a structural basis for the design of new and potentially safer anticoagulants, which can specifically target zymogen activation to prevent downstream thrombin generation 24,25 …”

Section: Opportunity Areas For Thrombosis and Hemostasis Fundamental ...mentioning

confidence: 99%

Basic science research opportunities in thrombosis and hemostasis: Communication from the SSC of the ISTH

Mutch

Walters

Gardiner

et al. 2022

Journal of Thrombosis and Haemostasis

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Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co-chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure-function protein analyses, and visualization of hemostasis.This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions.

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“…The initial slope of the time vs optical density curve reflects the amidolytic activity of thrombin. Similarly, the activity of recombinant factor XIa (purified as described, 33 10 nM), factor XIIa (Enzyme Research Laboratories, South Bend, IN, 19,5 µM), kallikrein (Stago, 2 nM), and activated protein C (a generous gift from the late Dr. Walter Kisiel, University of Albuquerque, New Mexico, 10 nM) were measured toward S2302 (kallikrein and FXIIa) or S2366 (XIa and activated protein C) at a final concentration of 0.5 mM (Chromogenix, Molndal, Sweden). The initial slope of the reactions without inhibitory compounds present was set at 100.…”

Section: Chromogenic Assaysmentioning

confidence: 99%

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

Lisman

Adelmeijer

Huskens

et al. 2021

TH Open

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Background Aprotinin is a broad-acting serine protease inhibitor that has been clinically used to prevent blood loss during major surgical procedures including cardiac surgery and liver transplantation. The prohemostatic properties of aprotinin likely are related to its antifibrinolytic effects, but other mechanisms including preservation of platelet function have been proposed. Aim Here we assessed effects of aprotinin on various hemostatic pathways in vitro, and compared effects to tranexamic acid(TXA), which is an antifibrinolytic but not a serine protease inhibitor. Methods We used plasma-based clot lysis assays, clotting assays in whole blood, plasma, and using purified proteins, and platelet activation assays to which aprotinin or TXA were added in pharmacological concentrations. Results Aprotinin and TXA dose-dependently inhibited fibrinolysis in plasma. Aprotinin inhibited clot formation and thrombin generation initiated via the intrinsic pathway, but had no effect on reactions initiated by tissue factor. However, in the presence of thrombomodulin, aprotinin enhanced thrombin generation in reactions started by tissue factor. TXA had no effect on coagulation. Aprotinin did not inhibit thrombin, only weakly inhibited the TF-VIIa complex and had no effect on platelet activation and aggregation by various agonists including thrombin. Aprotinin and TXA inhibited plasmin-induced platelet activation. Conclusion Pharmacologically relevant concentrations of aprotinin inhibit coagulation initiated via the intrinsic pathway. The antifibrinolytic activity of aprotinin likely explains the prohemostatic effects of aprotinin during surgical procedures. The anticoagulant properties may be beneficial during surgical procedures in which pathological activation of the intrinsic pathway, for example by extracorporeal circuits, occurs.

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Hydrogen‐deuterium exchange mass spectrometry highlights conformational changes induced by factor XI activation and binding of factor IX to factor XIa

Cited by 16 publications

References 24 publications

Analysis of 272 Genetic Variants in the Upgraded Interactive FXI Web Database Reveals New Insights into FXI Deficiency

Analysis of 272 Genetic Variants in the Upgraded Interactive FXI Web Database Reveals New Insights into FXI Deficiency

Basic science research opportunities in thrombosis and hemostasis: Communication from the SSC of the ISTH

Aprotinin Inhibits Thrombin Generation by Inhibition of the Intrinsic Pathway, but is not a Direct Thrombin Inhibitor

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