Selective factor VIII activation by the tissue factor–factor VIIa–factor Xa complex

Kamikubo, Yu-ichi; Mendolicchio, Grazia Loredana; Zampolli, Antonella; Marchese, Patrizia; Rothmeier, Andrea S.; Orje, Jennifer N.; Gale, Andrew J.; Krishnaswamy, Sriram; Gruber, András; Østergaard, Henrik; Petersen, Lars C.; Ruf, Wolfram; Ruggeri, Zaverio M.

doi:10.1182/blood-2017-02-767079

Cited by 64 publications

(46 citation statements)

References 56 publications

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“…TFPIα inhibits FV activation in simulated reactions of TF‐initiated coagulation, but, surprisingly, under the same conditions TFPIα did not interfere with FXa activation of the anti‐hemophilic cofactor VIII . The nascent product FXa can be trapped with a nematode inhibitor, NAPc2 ; in this complex FXa still activates FVIII, but not FV.…”

Section: Cell Type‐specific Roles Of Tf In Thrombosis and Hemostasismentioning

confidence: 91%

Tissue factor at the crossroad of coagulation and cell signaling

Zelaya

Rothmeier

Ruf

2018

Journal of Thrombosis and Haemostasis

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125

123

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The tissue factor (TF) pathway plays a central role in hemostasis and thrombo-inflammatory diseases. Although structure-function relationships of the TF initiation complex are elucidated, new facets of the dynamic regulation of TF's activities in cells continue to emerge. Cellular pathways that render TF non-coagulant participate in signaling of distinct TF complexes with associated proteases through the protease-activated receptor (PAR) family of G protein-coupled receptors. Additional co-receptors, including the endothelial protein C receptor (EPCR) and integrins, confer signaling specificity by directing subcellular localization and trafficking. We here review how TF is switched between its role in coagulation and cell signaling through thiol-disulfide exchange reactions in the context of physiologically relevant lipid microdomains. Inflammatory mediators, including reactive oxygen species, activators of the inflammasome, and the complement cascade play pivotal roles in TF procoagulant activation on monocytes, macrophages and endothelial cells. We furthermore discuss how TF, intracellular ligands, co-receptors and associated proteases are integrated in PAR-dependent cell signaling pathways controlling innate immunity, cancer and metabolic inflammation. Knowledge of the precise interactions of TF in coagulation and cell signaling is important for understanding effects of new anticoagulants beyond thrombosis and identification of new applications of these drugs for potential additional therapeutic benefits.

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Section: Cell Type‐specific Roles Of Tf In Thrombosis and Hemostasismentioning

confidence: 91%

Tissue factor at the crossroad of coagulation and cell signaling

Zelaya

Rothmeier

Ruf

2018

Journal of Thrombosis and Haemostasis

Self Cite

125

123

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“… 12 FXa when associated with phospholipids or the TF/FVIIa complex is also a potent activator of FVIII. 13 14 Although not causally involved in the activation process of coagulation, FVIII helps to further maintain and strengthen the production of FXa, ultimately resulting in the generation of thrombin and formation of a stable fibrin clot. In patients with hemophilia A, lack or dysfunction of FVIII impedes physiologic coagulation function and increases the risk of bleeding.…”

Section: Role Of Factor VIII In the Coagulation Cascadementioning

confidence: 99%

Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

et al. 2020

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Hemophilia A, characterized by absent or ineffective coagulation factor VIII (FVIII), is a serious bleeding disorder that entails severe and potentially life-threatening bleeding events. Current standard therapy still involves replacement of FVIII, but is often complicated by the occurrence of neutralizing alloantibodies (inhibitors). Management of patients with inhibitors is challenging and necessitates immune tolerance induction for inhibitor eradication and the use of bypassing agents (activated prothrombin complex concentrates or recombinant activated factor VII), which are expensive and not always effective. Emicizumab is the first humanized bispecific monoclonal therapeutic antibody designed to replace the hemostatic function of activated FVIII by bridging activated factor IX and factor X (FX) to activate FX and allow the coagulation cascade to continue. In the majority of hemophilic patients with and without inhibitors, emicizumab reduced the annualized bleeding rate to almost zero in several clinical trials and demonstrated a good safety profile. However, the concurrent use of emicizumab and activated prothrombin complex concentrate imposes a high risk of thrombotic microangiopathy and thromboembolic events on patients and should be avoided. Yet, the management of breakthrough bleeds and surgery remains challenging with only limited evidence-based recommendations being available. This review summarizes published clinical trials and preliminary reports of emicizumab and discusses the clinical implications of emicizumab in treatment of hemophilia A.

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“…platelet polyphoshate [1] and reaction pathways (eg. direct conversion of FVIIIa by TF/FVIIa/Xa [2]) are still being discovered. In some cases, the significance of a particular reaction studied in a purified system may be difficult to resolve since pM-levels of factors formed transiently in whole blood are challenging to measure directly.…”

Section: Introductionmentioning

confidence: 99%

Reduced model to predict thrombin and fibrin during thrombosis on collagen/tissue factor under venous flow: Roles of γ’-fibrin and factor XIa

Chen

Diamond

2019

PLoS Comput Biol

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During thrombosis, thrombin generates fibrin, however fibrin reversibly binds thrombin with low affinity E-domain sites (K D = 2.8 μM) and high affinity γ’-fibrin sites (K D = 0.1 μM). For blood clotting on collagen/tissue factor (1 TF-molecule/μm 2 ) at 200 s -1 wall shear rate, high μM-levels of intraclot thrombin suggest robust prothrombin penetration into clots. Setting intraclot zymogen concentrations to plasma levels (and neglecting cofactor rate limitations) allowed the linearization of 7 Michaelis-Menton reactions between 6 species to simulate intraclot generation of: Factors FXa (via TF/VIIa or FIXa), FIXa (via TF/FVIIa or FXIa), thrombin, fibrin, and FXIa. This reduced model [7 rates, 2 K D ’s, enzyme half-lives~1 min] predicted the measured clot elution rate of thrombin-antithrombin (TAT) and fragment F1.2 in the presence and absence of the fibrin inhibitor Gly-Pro-Arg-Pro. To predict intraclot fibrin reaching 30 mg/mL by 15 min, the model required fibrinogen penetration into the clot to be strongly diffusion-limited (actual rate/ideal rate = 0.05). The model required free thrombin in the clot (~100 nM) to have an elution half-life of ~2 sec, consistent with measured albumin elution, with most thrombin (>99%) being fibrin-bound. Thrombin-feedback activation of FXIa became prominent and reached 5 pM FXIa at >500 sec in the simulation, consistent with anti-FXIa experiments. In predicting intrathrombus thrombin and fibrin during 15-min microfluidic experiments, the model revealed “cascade amplification” from 30 pM levels of intrinsic tenase to 15 nM prothrombinase to 15 μM thrombin to 90 μM fibrin. Especially useful for multiscale simulation, this reduced model predicts thrombin and fibrin co-regulation during thrombosis under flow.

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Selective factor VIII activation by the tissue factor–factor VIIa–factor Xa complex

Cited by 64 publications

References 56 publications

Tissue factor at the crossroad of coagulation and cell signaling

Tissue factor at the crossroad of coagulation and cell signaling

Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

Reduced model to predict thrombin and fibrin during thrombosis on collagen/tissue factor under venous flow: Roles of γ’-fibrin and factor XIa

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