Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation

Su, Kankan; Jin, Yanhui; Miao, Zhihai; Cheng, Xiaoli; Yang, Lihong; Wang, Mingshan

doi:10.1080/10245332.2017.1287332

Cited by 5 publications

(2 citation statements)

References 24 publications

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“…Although this view is novel, to our knowledge, its elements are in good agreement with previous reports. All results of this study in its homogeneous model are well in line with previous reports on the sensitivity of the clotting cascade to coagulation factor deficiency (11,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The decrease in clotting sensitivity to coagulation factor deficiency with the increase in TF activation level is also well documented (34).…”

Section: Discussionsupporting

confidence: 91%

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Kuprash

Shibeko

Vijay

et al. 2018

Biophysical Journal

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Blood coagulation is a delicately regulated space-and time-dependent process that leads to the formation of fibrin clots preventing blood loss upon vascular injury. The sensitivity of the coagulation network was previously investigated without accounting for transport processes. To investigate its sensitivity to coagulation factor deficiencies in a spatial reactiondiffusion system, we combined an in vitro experimental design with a computational systems biology model. Clot formation in platelet-free plasma supplemented with phospholipids was activated with identical amounts of tissue factor (TF) either homogeneously distributed (concentration 5 pM, homogeneous model) or immobilized on the surface (surface density 100 pmole/m 2 , spatially heterogeneous model). Fibrin clot growth and thrombin concentration dynamic in space were observed using video microscopy in plasma of healthy donors or patients with deficiencies in factors (F) II, FV, FVII, FVIII, FIX, FX, or FXI. In the spatially heterogeneous model, near-activator thrombin generation was decreased in FV-, FVII-, and FX-deficient plasma. In the homogeneous model, clotting was not registered in these samples. The simulation and experiment data showed that the coagulation threshold depended on the TF concentration. Our data indicate that the velocity of spatial clot propagation correlates linearly with the concentration of thrombin at the clot wave front but not with the overall thrombin wave amplitude. Spatial clot growth in normal plasma at early stages was neither reaction nor diffusion limited but became diffusion limited later. In contrast, clot growth was always diffusion limited in FV-, FVII-, and FX-deficient plasma and reaction limited in FVIII-, FIX-, and FXI-deficient plasma. We conclude that robustness of the spatially heterogeneous coagulation system was achieved because of the combination of 1) a local high TF surface density that overcomes activation thresholds, 2) diffusion control being shared between different active factors, and 3) an early saturated stimulus-response dependence of fibrin clot formation by thrombin.

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Section: Discussionsupporting

confidence: 91%

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Kuprash

Shibeko

Vijay

et al. 2018

Biophysical Journal

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“…12 In addition, thrombin participates in the anticoagulation process as it activates protein C. It plays a role in inflammation, cell proliferation, and tissue repair mechanisms. 13 For an unclear reason, prothrombin mutations are more prevalent in patients from a Latin/Hispanic origin (Puerto Rico, Spain, France, etc.). 2,11 Prothrombin deficiency is classified into severe (when factor level <5%), moderate (factor level 5%-10%), and mild (factor level >10%).…”

Section: Discussionmentioning

confidence: 99%

A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

Mansory¹,

Bhai²,

Stuart³

et al. 2021

Research and Practice in Thrombosis and Haemostasis

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Congenital prothrombin deficiency is an extremely rare, autosomal recessive bleeding disorder with a prevalence of 1 in 2 million individuals. Here, we report a case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene (F2), affecting the heavy B chain. The patient presented with a history of multiple bleeding events in his youth that are mostly trauma associated, with a family history of prothrombin deficiency. Laboratory analysis showed a prolonged activated partial thromboplastin time and a prothrombin activity level of 5%. Genetic analysis of the F2 gene identified two heterozygous variants; one is a previously reported pathogenic deletion (c.1814_1815del; p.His605Argfs*13), and the other is a novel missense variant (c.1147C>T; p.Arg383Trp). In silico analysis predicted that p.Arg383Trp is likely to be disease causing, as it affects one of the anion‐binding exosites‐I of the B chain. This case highlights the significance of molecular findings in confirming the diagnosis of patients with congenital prothrombin deficiency.

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Congenital Bleeding Disorders: Diagnosis and Management

Dorgalaleh,

Daneshi,

Dabbagh

et al. 2023

Congenital Bleeding Disorders

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Phenotypic and genetic analysis of dysprothrombinemia due to a novel homozygous mutation

Abstract: This was the first report of such a mutation in the position which was associated with dysprothrombinemia.

Cited by 5 publications

References 24 publications

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

A case of congenital prothrombin deficiency with two concurrent mutations in the prothrombin gene

Congenital Bleeding Disorders: Diagnosis and Management

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