Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding

Schreuder, Mark; Reitsma, Pieter H.; Bos, Mettine H.A.

doi:10.1111/jth.14487

Cited by 41 publications

(46 citation statements)

References 98 publications

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“…Specifically, the negatively charged γ-carboxyglutamate (Gla) residues at the NH 2 termini of the vitamin K-dependent factors, FIX(a), FX(a), and prothrombin, interact with negatively charged PS via Ca 2+ . FVIII binds to PS via its C2 domain and FVa via its C1 and C2 domains (5,6). Tenase and prothrombinase activities are enhanced by PS-containing membranes by up to three orders of magnitude (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

Reddy

Rand

2020

Front. Cardiovasc. Med.

112

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The physiological heterogeneity of platelets leads to diverse responses and the formation of discrete subpopulations upon platelet stimulation. Procoagulant platelets are an example of such subpopulations, a key characteristic of which is exposure either of the anionic aminophospholipid phosphatidylserine (PS) or of tissue factor on the activated platelet surface. This review focuses on the former, in which PS exposure on a subpopulation of platelets facilitates assembly of the intrinsic tenase and prothrombinase complexes, thereby accelerating thrombin generation on the activated platelet surface, contributing importantly to the hemostatic process. Mechanisms involved in platelet PS exposure, and accompanying events, induced by physiologically relevant agonists are considered then contrasted with PS exposure resulting from intrinsic pathway-mediated apoptosis in platelets. Pathologies of PS exposure, both inherited and acquired, are described. A consideration of platelet PS exposure as an antithrombotic target concludes the review.

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Section: Introductionmentioning

confidence: 99%

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

Reddy

Rand

2020

Front. Cardiovasc. Med.

112

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“…This is consistent with the fact that the FVaprothrombin interaction facilitates efficient proteolytic conversion to thrombin. 32 To better understand the observed zymogen activity, we next examined the putative contribution of autoactivation or thrombin-mediated activation of zymogen FX. Prolonged incubations of zymogen FX in the presence of cofactor lipids did not effectuate enzymatic activity towards the peptidyl substrate SpecXa (<0.04% mol/mol FXa) (►Supplementary Table S1, available in the online version), suggestive of incomplete maturation of the active site.…”

Section: Thrombosis and Haemostasismentioning

confidence: 99%

Evolutionary Adaptations in Pseudonaja Textilis Venom Factor X Induce Zymogen Activity and Resistance to the Intrinsic Tenase Complex

et al. 2020

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The venom of the Australian snake Pseudonaja textilis comprises powerful prothrombin activators consisting of factor X (v-ptFX)- and factor V-like proteins. While all vertebrate liver-expressed factor X (FX) homologs, including that of P. textilis, comprise an activation peptide of approximately 45 to 65 residues, the activation peptide of v-ptFX is significantly shortened to 27 residues. In this study, we demonstrate that exchanging the human FX activation peptide for the snake venom ortholog impedes proteolytic cleavage by the intrinsic factor VIIIa–factor IXa tenase complex. Furthermore, our findings indicate that the human FX activation peptide comprises an essential binding site for the intrinsic tenase complex. Conversely, incorporation of FX into the extrinsic tissue factor–factor VIIa tenase complex is completely dependent on exosite-mediated interactions. Remarkably, the shortened activation peptide allows for factor V-dependent prothrombin conversion while in the zymogen state. This indicates that the active site of FX molecules comprising the v-ptFX activation peptide partially matures upon assembly into a premature prothrombinase complex. Taken together, the shortened activation peptide is one of the remarkable characteristics of v-ptFX that has been modified from its original form, thereby transforming FX into a powerful procoagulant protein. Moreover, these results shed new light on the structural requirements for serine protease activation and indicate that catalytic activity can be obtained without formation of the characteristic Ile16–Asp194 salt bridge via modification of the activation peptide.

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“…As FXa is capable of directly activating FV, 64 a positive feedback loop is generated through the assembly of the prothrombinase complex and the conversion of prothrombin to thrombin. 65 Additionally, the thrombin formed will initiate the intrinsic pathway by the activation of factors VIII and XI, thereby further propagating FXa and TG. While the latter mechanism describes the mode of action of aPCC, PCC is considered to mainly function by elevating the circulating levels of several coagulation factor substrates.…”

Section: Mechanistic Principles Of the Nonspecific Reversal Agentsmentioning

confidence: 99%

Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies

Schreuder

Reitsma

Bos

2020

Semin Thromb Hemost

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The direct oral anticoagulants targeting coagulation factor Xa or thrombin are widely used as alternatives to vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation. In case of bleeding or emergency surgery, reversal agents are helpful to counteract the anticoagulant therapy and restore hemostasis. While idarucizumab has been established as an antidote for the direct thrombin inhibitor dabigatran, reversal strategies for the direct factor Xa inhibitors have been a focal point in clinical care over the past years. In the absence of specific reversal agents, the off-label use of (activated) prothrombin complex concentrate and recombinant factor VIIa have been suggested as effective treatment options during inhibitor-induced bleeding complications. Meanwhile, several specific reversal agents have been developed. In this review, an overview of the current state of nonspecific and specific reversal agents for the direct factor Xa inhibitors is provided, focusing on the biochemistry and mechanism of action and the preclinical assessment of newly emerging therapies.

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Blood coagulation factor Va's key interactive residues and regions for prothrombinase assembly and prothrombin binding

Cited by 41 publications

References 98 publications

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

Procoagulant Phosphatidylserine-Exposing Platelets in vitro and in vivo

Evolutionary Adaptations in Pseudonaja Textilis Venom Factor X Induce Zymogen Activity and Resistance to the Intrinsic Tenase Complex

Reversal Agents for the Direct Factor Xa Inhibitors: Biochemical Mechanisms of Current and Newly Emerging Therapies

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