Identification of a congenital dysthrombin, thrombin Quick.

Henriksen, Ruth Ann; Owen, Whyte G.; Nesheim, Michael E.; Mann, Kenneth G.

doi:10.1172/jci109961

Cited by 32 publications

(12 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent progress has been made delineating the interactions responsible for binding of FV to thrombin and the mechanism that regulates the specificity of the interaction. Using proteolytic derivatives of thrombin [85–87], thrombin mutants [32,88,89] and exosite I and II specific ligands [32,86,87,90–92], the findings indicate that both thrombin exosites contribute to FV activation to varying degrees. Bock and coworkers [91,93] made use of equilibrium binding studies to show that thrombin binds FV in an exosite I‐dependent fashion through a site within the FV heavy chain region.…”

Section: Fv Procofactor Activation: Transition To the Active Cofactormentioning

confidence: 99%

The molecular basis of factor V and VIII procofactor activation

Camire

Bos

2009

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

To cite this article: Camire RM, Bos MHA. The molecular basis of factor V and VIII procofactor activation. J Thromb Haemost 2009; 7: 1951-61. Summary. Activation of precursor proteins by specific and limited proteolysis is a hallmark of the hemostatic process. The homologous coagulation factors (F)V and FVIII circulate in an inactive, quiescent state in blood. In this so-called procofactor state, these proteins have little, if any procoagulant activity and do not participate to any significant degree in their respective macromolecular enzymatic complexes. Thrombin is considered a key physiological activator, cleaving select peptide bonds in FV and FVIII which ultimately leads to appropriate structural changes that impart cofactor function. As the active cofactors (FVa and FVIIIa) have an enormous impact on thrombin and FXa generation, maintaining FV and FVIII as inactive procofactors undoubtedly plays an important regulatory role that has likely evolved to maintain normal hemostasis. Over the past three decades there has been widespread interest in studying the proteolytic events that lead to the activation of these proteins. While a great deal has been learned, mechanistic explanations as to how bond cleavage facilitates conversion to the active cofactor species remain incompletely understood. However, recent advances have been made detailing how thrombin recognizes FV and FVIII and also how the FV Bdomain plays a dominant role in maintaining the procofactor state. Here we review our current understanding of the molecular process of procofactor activation with a particular emphasis on FV.

show abstract

Section: Fv Procofactor Activation: Transition To the Active Cofactormentioning

confidence: 99%

The molecular basis of factor V and VIII procofactor activation

Camire

Bos

2009

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…The observation that Arg382His zymogen also exhibited a similar defect for interaction with FVa (as evidenced by the lack of a competitive effect for the hirudin fragment on the mutant zymogen activation) suggests that His at this position of (pro)exosite-1 is as disruptive as Glu for interaction of the zymogen with the cofactor in the activation complex. We speculate that the Arg382 to Cys substitution, which causes a very mild bleeding phenotype in both Quick I and Corpus Christi patients (24,25), is tolerated better than His, explaining the pathogenic basis for the severe bleeding and paradoxical clotting defects observed with the proband in this study. It is worth noting that analysis of data in the context of zymogen activation should be interpreted with some caution since we expressed the mutant in the prethrombin-1 form.…”

Section: Par1-dependent Signalling Activitymentioning

confidence: 60%

“…The bleeding diathesis of patient with hypoprothrombinaemia (type I deficiency with low coagulant activity and antigen level) usually correlates well with their plasma prothrombin level; however, the bleeding tendency of those with dysprothrombinaemia (type II deficiency with low coagulant activity) varies, showing a strong discrepancy with thrombin coagulant activity levels. Some dysprothrombinaemia (prothrombin Himi I, II, Quick I/Corpus Christi and Perija) shows significant loss of thrombin coagulant activity (FII:C <10 %) but is asymptomatic or only causes mild bleeding (22)(23)(24)(25)(26)(27)(28). Counter-intuitively, patients with an F2 mutation involving residue Arg553 (residue 553 is numbered 596 in the cDNA numbering system) including Arg553Leu (27,28), Arg553Gln (29) and Arg553Trp (30) all have been reported to suffer thrombosis instead of bleeding complications, pointing toward the complex nature of regulatory mechanisms that can influence coagulation reactions.…”

Section: Introductionmentioning

confidence: 99%

Paradoxical bleeding and thrombotic episodes of dysprothrombinaemia due to a homozygous Arg382His mutation

Ding¹,

Yang²,

Zhao³

et al. 2017

Thromb Haemost

View full text Add to dashboard Cite

Summary We have characterized the pathogenic basis of dysprothrombinemia in a patient exhibiting paradoxical bleeding and thrombotic defects during pregnancy and postpartum. Genetic analysis revealed that the proband is homozygous for the prothrombin Arg382His mutation, possessing only ~1% clotting activity. The proband experienced severe bleeding episodes during her pregnancy, which required treatment with prothrombin complex concentrates, and then pulmonary embolism and deep vein thrombosis at 28 days postpartum, which required treatment with LMWH and fresh frozen plasma. Analysis of hemostatic parameters revealed that the subject had elevated FDP and DD and decreased fibrinogen levels, indicating the presence of hyperfibrinolysis. Thrombin generation and clotting assays with the proband’s plasma in the presence of soluble thrombomodulin and tissue-type plasminogen activator indicated a defect in activation of both protein C and thrombin activatable fibrinolysis inhibitor (TAFI). Unlike normal plasma, no TAFI activation could be detected in the patient’s plasma. The expression and characterization of recombinant prothrombin Arg382His indicated that zymogen activation by prothrombinase was markedly impaired and the activation of protein C and TAFI by thrombin-Arg382His was impaired 600-fold and 2500-fold, respectively. The recombinant thrombin mutant exhibited impaired catalytic activity toward both fibrinogen and PAR1 as determined by clotting and signaling assays. However, the mutant activated factor XI normally in both the absence and presence of polyphosphates. Arg382 is a key residue on (pro)exosite-1 of prothrombin and kinetic analysis of substrate activation suggested that the poor zymogenic activity of the mutant is due to its inability to bind factor Va in the prothrombinase complex.

show abstract

“…Several dysprothrombinemias with mutations in sites of the protein upstream on downstream of the Arg596 site have been described but no association with thrombosis has ever been reported (Table 3). These dysprothrombinemias are prothrombin Salakta (Gln509Ala), prothrombin Greenville (Arg517Gln), prothrombin Perija (Gly548Ala), prothrombin Scranton (Lys599Thr) and others show mutation close to the Arg596 amino acid but apparently no venous thrombosis has ever been reported [12][13][14][15][16][17][24][25][26]. As far as we can tell the critical area seems to reside around Arg596, site of the mutation of the cases associated with a demonstrated occurrence of venous thrombosis.…”

Section: Discussionmentioning

confidence: 99%

“…This interesting observation remained silent for several years and the prothrombin defects were always considered to be responsible of a bleeding tendency. Several dysprothrombinemias were reported but no thrombosis event was ever mentioned [2,3,[12][13][14][15][16][17].…”

Section: Dysprothrombinemias With Thrombosismentioning

confidence: 99%