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Thrombosis and Haemostasis, Dec 12, 2020

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Journal of Thrombosis and Haemostasis, Nov 1, 2017

This article may be used for non-commercial purposes in accordance with Wiley Terms and Condition... more This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Uploaded in accordance with the publisher's self-archiving policy.

Seminars in Thrombosis and Hemostasis, Apr 18, 2023

For decades, it was considered that plasma kallikrein's (PKa) sole function within the coagul... more For decades, it was considered that plasma kallikrein's (PKa) sole function within the coagulation cascade is the activation of factor (F)XII. Until recently, the two key known activators of FIX within the coagulation cascade were activated FXI(a) and the tissue factor–FVII(a) complex. Simultaneously, and using independent experimental approaches, three groups identified a new branch of the coagulation cascade, whereby PKa can directly activate FIX. These key studies identified that (1) FIX or FIXa can bind with high affinity to either prekallikrein (PK) or PKa; (2) in human plasma, PKa can dose dependently trigger thrombin generation and clot formation independent of FXI; (3) in FXI knockout murine models treated with intrinsic pathway agonists, PKa activity results in increased formation of FIXa:AT complexes, indicating direct activation of FIX by PKa in vivo. These findings suggest that there is both a canonical (FXIa-dependent) and non-canonical (PKa-dependent) pathway of FIX activation. These three recent studies are described within this review, alongside historical data that hinted at the existence of this novel role of PKa as a coagulation clotting factor. The implications of direct PKa cleavage of FIX remain to be determined physiologically, pathophysiologically, and in the context of next-generation anticoagulants in development.

presence of thechain modulates throm- bin and FXIII activity, influences clot archi- tecture, and... more presence of thechain modulates throm- bin and FXIII activity, influences clot archi- tecture, and eliminates a platelet-binding site. Associations of A/ fibrinogen lev- els with arterial and venous thrombosis have been reported, indicating that the functional effects of A/ fibrinogen may contribute to the pathology of thrombo- sis. This review summarizes the key bio- logic aspects of this interesting variant of fibrinogen and discusses inconsisten- cies in current reports. (Blood. 2009;114: 3994-4001) Replacement of the C-terminal residues of the chain has functional implications for the fibrinogen molecule. The -chain extension protrudes from the D region and, depending on folding, could span up to 30 to 40 A (Figure 2). The conformation of the chain in polymerizing fibrin is unknown, although it has been described that it is exposed or surface oriented in cross-linked fibrin.18 Before cross-linking, during initial polymerization, the chain may interact with the D-D interface. Considering a length of 30 to 40 A, it is possible that the extension stretches to the E region of a neighboring molecule in the D-E-D complex. The chain is therefore positioned at or near an interaction area that forms the cornerstone of protofibril forma- tion. Interactions of other coagulation proteins with the re- gion positions these proteins in a functionally active area of fibrin formation. So far, the chain has been shown to bind to thrombin and copurifies with coagulation factor XIII (FXIII), both involved in the formation of the fibrin clot. In this review, we describe what is currently known about the influence of the chain in hemostasis. We illustrate that the chain may contribute to the pathology of thrombosis via modulating thrombin and FXIII activity, eliminating a platelet binding site, influencing clot architecture, and modifying thrombosis risk.

Journal of Thrombosis and Haemostasis, 2018

Access microbiology, Jul 1, 2020

Background: Fibrin formation is an essential part of innate immunity, sealing off infections to l... more Background: Fibrin formation is an essential part of innate immunity, sealing off infections to limit bacterial spreading.The surface-anchored M1 protein is a major virulence determinant of Group A streptococcus (GAS). During early infection M1 is cleaved from the cell surface by SpeB, a streptococcal protease regulated by CovR/S. M1 forms a supramolecular complex with fibrinogen however the impact on fibrin formation is not known. Methods: The effects of recombinant M1 (rM1) were assessed in fibrin clots made from plasma or purified fibrinogen incubated with thrombin, by confocal microscopy and scanning electron microscopy. Clotting and lysis profiles (with plasminogen activators and plasminogen) were investigated kinetically using thromboelastography (ROTEM). Results: rM1 (0.47-60 μg/ml) increased clotting rates to produce heterogeneous clots with irregular fibre bundles and compacted fibrin. Formation of the protective fibrin biofilm was also disrupted by rM1. Furthermore, mechanical strength of fibrin clots was reduced with increasing rM1 concentrations and was undetectable above 15.5 μg/ml. Purified and plasma clots formed with rM1 were more susceptible to lysis by plasmin, with a 1.4 – 2-fold reduction in lysis times. Conclusions: At sites of GAS infection, cleaved M1 may bind to fibrinogen generating fibrin clots which: lack the protective film at the clot surface; are mechanically weaker; and are less resistant to lysis by plasmin. GAS strains of M1-type are commonly associated with invasive infections; the impact of M1 on fibrin structure could contribute to the severity of GAS infection by compromising the fibrin barrier that limits bacterial proliferation and migration.

Hamostaseologie, Feb 1, 2019

Journal of Thrombosis and Haemostasis, Apr 1, 2023

Journal of Thrombosis and Haemostasis, Feb 1, 2014

Human Mutation, Sep 13, 2016

Proceedings of the National Academy of Sciences of the United States of America, Jan 4, 2021

Expert Review of Hematology

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than ... more Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized r...

Journal of Blood Disorders and Transfusion, Oct 20, 2014

Thrombosis and Haemostasis, 1993

Thrombosis and Haemostasis, 1995

Basic Science, 2019

BS58 Table 1 Effect of renal function on plasma clot properties in AF patients on warfarin