Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex.

  title={Selective factor VIII activation by the tissue factor-factor VIIa-factor Xa complex.},
  author={Yu-ichi Kamikubo and Grazia Loredana Mendolicchio and Antonella Zampolli and Patrizia Marchese and Andrea S. Rothmeier and Jennifer Nagrampa Orje and Andrew J. Gale and Sriram Krishnaswamy and Andr{\'a}s Gruber and Henrik {\O}stergaard and Lars Christian Petersen and Wolfram Ruf and Zaverio M. Ruggeri},
  volume={130 14},
Safe and effective antithrombotic therapy requires understanding of mechanisms that contribute to pathological thrombosis but have a lesser impact on hemostasis. We found that the extrinsic tissue factor (TF) coagulation initiation complex can selectively activate the antihemophilic cofactor, FVIII, triggering the hemostatic intrinsic coagulation pathway independently of thrombin feedback loops. In a mouse model with a relatively mild thrombogenic lesion, TF-dependent FVIII activation sets the… 

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Regulation of coagulation by tissue factor pathway inhibitor: Implications for hemophilia therapy

  • A. MastW. Ruf
  • Biology
    Journal of thrombosis and haemostasis : JTH
  • 2022
This regulation of thrombin generation in the context of vessel injury is effectively blocked by antibodies to Kunitz 2 domain of TFPI and exploited as a therapy to restore efficient hemostasis in hemophilia.

Potential role of activated factor VIII (FVIIIa) in FVIIa/tissue factor-dependent FXa generation in initiation phase of blood coagulation

FVIII-associated intrinsic-Xa, governed by both FVIIa/TF-induced and FXa-induced FVIII activation mediated by FV III-TF interactions, together with F VIIa-dependent extrinsic-XA mechanisms, may be central to the initiation phase of coagulation.

Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis

The roles of TF in protective hemostasis and pathological thrombosis are focused on and coagulation proteases, such as FVIIa, FXa, and thrombin are described.

Biochemical, molecular and clinical aspects of coagulation factor VII and its role in hemostasis and thrombosis

The biological and clinical information that distinguishes FVII deficiency from the other clotting disorders and the impact exerted by genetically predicted FVII level variation on bleeding as well as on the thrombotic states are highlighted.

Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis.

It is shown that lipid-reactive aPL activate a common species-conserved TF signaling pathway and primes monocytes for rapid aPL pathogenic signaling and thrombosis amplification in an unexpected crosstalk between complement activation and coagulation signaling.

Factor (F)VIII/VIIa enhances global haemostatic function in the co‐presence of bypassing agents and FVIII among patients with haemophilia A with inhibitor

FVIII/FVIIa‐related coagulation mechanism enhanced global haemostatic function by the co‐presence of bypassing agents and FVIII in PWHA‐inh.

Post-transcriptional, post-translational and pharmacological regulation of tissue factor pathway inhibitor.

This review focuses on posttranscription and translational modification of TFPI and its function in thrombosis and how pharmacological inhibitors and endogenous proteases interfere with TFPi and alter haemostasis.

Tissue factor at the crossroad of coagulation and cell signaling

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 is reviewed.



Tissue factor pathway inhibitor-alpha inhibits prothrombinase during the initiation of blood coagulation

This is the first description of an endogenous human protein that inhibits prothrombinase under physiological conditions and may prevent a full thrombotic response to subthreshold coagulant stimuli that otherwise could occlude blood vessels.

Protein S enhances the tissue factor pathway inhibitor inhibition of factor Xa but not its inhibition of factor VIIa–tissue factor

The effect of protein S on TFPI inhibition of FXa was re-examined using methods designed to minimize the confounding inhibitory effect of TFPi on FXa activity and findings are consistent with those reported by Hackeng et al.

Mechanisms of factor VIIa‐catalyzed activation of factor VIII

The results demonstrated that this activation mechanism was distinct from those mediated by thrombin, and indicated that FVIIa/TF functions through a ‘priming’ mechanism for the activation of FVIII in the initiation phase of coagulation.

The tissue factor/factor VIIa/factor Xa complex: A model built by docking and site‐directed mutagenesis

The docking results identify potential interface residues, allowing rational selection of target residues for site‐directed mutagenesis, and confirms that residues Glu51 and Asn57 in the EGF1 domain, Asp92 and Asp95 in theEGF2 domain, and Lys 186 and Lys134 in the protease domain of factor Xa are involved in the interaction with TF/fVIIa.

Factor Xa Activation of Factor V Is of Paramount Importance in Initiating the Coagulation System: Lessons From a Tick Salivary Protein

The data elucidate a unique molecular mechanism by which ticks inhibit the host’s coagulation system and propose a revised blood coagulated scheme in which direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated fibrinogen and inhibitors are restrained.

Formation of Factors IXa and Xa by the Extrinsic Pathway

The findings raise the possibility that IXaβ produced by the extrinsic pathway, and its ability to function within the intrinsic Xase complex to activate X may play a significant role in producing Xa necessary for both the initiation and sustained phases of the procoagulant response following vascular damage.

Engineering of Substrate Selectivity for Tissue Factor·Factor VIIa Complex Signaling through Protease-activated Receptor 2*

Contrary to the paradigm of exosite-assisted cleavage of PAR1 by thrombin, the cofactor-associated protease FVIIa recognizes PAR2 predominantly by catalytic cleft interactions and enabled protein engineering of protease-selective PAR2 receptors that will aid further studies to dissect the roles of TF signaling complexes in vivo.

A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo.

In baboons, 14E11 reduced platelet-rich thrombus growth in collagen-coated grafts inserted into an arteriovenous shunt and supported the hypothesis that fXIIa-mediated fXI activation contributes toThrombus formation in rodents and primates.

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of T FPI released at the injury site mitigates bleeding.

Defective thrombus formation in mice lacking coagulation factor XII

These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo and identify FXII as a novel target for antithrombotic therapy.