Screening and functional exploration of prothrombin Arg596 related mutations in Chinese venous thromboembolism patients

Wu, Xi; Li, Lei; Ding, Qiulan; Wang, Xuefeng; Wu, Fang; Wu, Wenman

doi:10.1136/jclinpath-2017-204888

Cited by 8 publications

(12 citation statements)

References 25 publications

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“…The probands with previously reported ATR are shown in Table 2 . Most of the ATR cases had thrombotic events at a relatively young age, but some of the family members with ATR remained asymptomatic beyond 55 years old ( 5 , 6 ). Almost all patients had a strong family history and recurrence of VTE.…”

Section: Discussionmentioning

confidence: 99%

Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance

et al. 2023

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Antithrombin resistance (ATR) is a newly identified strong genetic predisposition to venous thromboembolism (VTE) caused by genetic variations in prothrombin with substitutions of Arg at position 596 with either Leu, Gln, or Trp. In the present report, we identified a missense variant p.Arg596Gln in 3 patients from 2 families with unprovoked VTE who each experienced their first VTE event at 19, 67, and 19 years old. The three patients did not show any positive markers for thrombophilia on routine testing, suggesting that patients with unprovoked VTE who have negative findings on thrombophilia tests may carry a prothrombin variant with ATR.

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Section: Discussionmentioning

confidence: 99%

Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance

et al. 2023

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“…A recent study by Wu et al has demonstrated the presence of 14 heterozygotes among 267 Chinese patients with idiopathic venous thromboembolism. 38 There is a certain parallelism between the Arg596 Prothrombin abnormalities and Arg338Lys FIX Padua. 39 The latter condition is due to a mutation in the FIX protein associated with greatly increased levels of activity (about 10 times the wild type), no bleeding, and a prothrombotic tendency that causes venous thrombosis.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Wu et al has demonstrated the presence of 14 heterozygotes among 267 Chinese patients with idiopathic venous thromboembolism. 38…”

Section: Discussionmentioning

confidence: 99%

Prothrombin: Another Clotting Factor After FV That Is Involved Both in Bleeding and Thrombosis

Girolami

Cosi

Ferrari

et al. 2018

Clin Appl Thromb Hemost

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Clotting factor defects are usually associated with bleeding. About 2 decades ago, 2 polymorphisms, one of FII (G20210A) and another of FV (Arg506Gln), have been shown to be associated with prothrombotic state and venous thrombosis. As a consequence, FII and FV could be considered both as prohemorrhagic factors and prothrombotic conditions. Recently, it has been shown that missense mutations in the prothrombin gene of amino acid Arg596 of exon 14 to Leu596, Gln596, or Trp596 caused the appearance of a thrombophilic state and venous thrombosis. These mutated FII are not associated with bleeding, but only with venous thrombosis. Furthermore, they are all heterozygotes for the mutations. No missense mutation associated with thrombosis has been discovered so far for FV. As a consequence, the prothrombotic activity of FII is the result of a polymorphism and of a missense mutation, whereas that of FV derives only from a polymorphism. The observation that a clotting factor defect may be associated with both bleeding or venous thrombosis depending on the site of the mutation has caused an extensive reevaluation of the blood clotting mechanism.

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“…Prothrombin Belgrade mutation (c.1787G>A, p.Arg596Gln) was detected in two families in Serbia, with 10 members being heterozygous carriers, and six of them developing recurrent thrombotic disorders at a young age 4 . Prothrombin Belgrade mutation was also detected in American, Japanese, Chinese, and Indian population 5–8 . Apart from influencing thrombin‐antithrombin interactions, prothrombin Belgrade mutation impacts the sodium binding region, which is important for maintenance of hemostatic balance.…”

Section: Introductionmentioning

confidence: 99%

“…4 Prothrombin Belgrade mutation was also detected in American, Japanese, Chinese, and Indian population. [5][6][7][8] Apart from influencing thrombinantithrombin interactions, prothrombin Belgrade mutation impacts the sodium binding region, which is important for maintenance of hemostatic balance. Binding of sodium improves the procoagulant function of prothrombin due to the increased fibrinogen affinity, that is, affected by the presence of prothrombin Belgrade, and therefore, may lead to a disruption of normal coagulation.…”

mentioning

confidence: 99%

Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties

Dunjic Manevski,

Cumbo,

Pruner

et al. 2023

Int J Lab Hematology

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IntroductionProthrombin Belgrade mutation is the result of the c.1787G>A substitution in the prothrombin gene. It is located in the antithrombin and sodium binding site and leads to impaired inactivation of thrombin by antithrombin, resulting in antithrombin resistance and thrombotic disorders. However, it negatively affects sodium binding and may have hypocoagulant effects. Considering that prothrombin Belgrade mutation mechanism is still not fully elucidated and that sodium binding is important for thrombin affinity towards fibrinogen, our aim was to determine whether this mutation affects fibrin clot formation and lysis.MethodsUsing HEK293T cell line, recombinant wild type and mutated prothrombin were generated by transient transfection. Samples that correspond to plasma of a non‐carrier, heterozygous and homozygous carriers were reconstituted using prothrombin deficient plasma and recombinant proteins. Reconstituted samples were used in OHP assay (Overall Hemostasis Potential) to determine kinetic profiles of coagulation and fibrinolysis. Clot turbidity assay was performed to observe kinetics of clot formation and lysis more closely. Fibrin clots formed in reconstituted plasma samples were analyzed by confocal microscopy to determine density of fibrin network. Fibrin clots were additionally observed using electron microscopy to determine thickness of individual fibrin fibers.ResultsNo significant difference found in OHP, OCP, OFP, and fibrin network density between wild type, heterozygous, and homozygous carrier reconstituted plasma samples. There were significant differences between samples for slope and slope time parameters in kinetic profiles and fibrin fiber thickness.ConclusionsResults indicate that prothrombin Belgrade mutation has no significant impact on fibrinolysis, however it may affect kinetics of clot formation and its architecture.

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Screening and functional exploration of prothrombin Arg596 related mutations in Chinese venous thromboembolism patients

Cited by 8 publications

References 25 publications

Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance

Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance

Prothrombin: Another Clotting Factor After FV That Is Involved Both in Bleeding and Thrombosis

Effect of prothrombin Belgrade mutation, causing antithrombin resistance, on fibrin clot properties

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