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Mathematical model of thrombin generation and bleeding phenotype in Amish carriers of Factor IX:C deficiency vs. controls.

ABSTRACT: INTRODUCTION:Factor IX:C (FIX:C) levels vary in hemophilia B carriers even in pedigrees with a unifying genetic defect. Analyzing the balance between pro-and anticoagulants might increase our understanding of carriers' bleeding potential. AIM:In this research study, we evaluated bleeding scores (BS) and a novel mathematical model of thrombin generation (TG) in Amish FIX:C deficient carriers and controls. METHODS:Blood samples and BS were obtained from post-menarchal females, including 59 carriers and 57 controls from the same extended pedigree. Factors II, V, VII, VIII, IX, X, antithrombin, tissue factor pathway inhibitor and protein C were assayed to generate mathematical models of TG in response to 5pM tissue factor (TF) and for TF?+?thrombomodulin. BS was based on a modification of the MCMDM-1VWD scoring system. RESULTS:Carriers had a lower mean FIX:C (68% vs. 119%), von Willebrand factor antigen (108 vs.133) and Tissue activatable fibrinolysis inhibitor (103 vs. 111) compared to controls; both groups had a similar mean BS. Carriers demonstrated significantly lower TG parameters on both mathematical models compared to controls. Carriers with FIX:C???50% had lower TG curves than those >50% but similar BS. CONCLUSION:Thrombin generation showed significant differences between carriers and controls, between low (?50%) and high (>50%) FIX:C carriers, and specifically in the TF?+?thrombomodulin model, between high FIX:C carriers and controls, although the BS were not different.

SUBMITTER: Gupta S

PROVIDER: S-EPMC7071813 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Mathematical model of thrombin generation and bleeding phenotype in Amish carriers of Factor IX:C deficiency vs. controls.

Gupta S S Bravo M C MC Heiman M M Nakar C C Brummel-Ziedins K K Miller C H CH Shapiro A A

Thrombosis research 20190808

<h4>Introduction</h4>Factor IX:C (FIX:C) levels vary in hemophilia B carriers even in pedigrees with a unifying genetic defect. Analyzing the balance between pro-and anticoagulants might increase our understanding of carriers' bleeding potential.<h4>Aim</h4>In this research study, we evaluated bleeding scores (BS) and a novel mathematical model of thrombin generation (TG) in Amish FIX:C deficient carriers and controls.<h4>Methods</h4>Blood samples and BS were obtained from post-menarchal females ...[more]

PMID: 31446339

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Project description:BackgroundHeterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding.ObjectivesThe objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia.MethodsThe Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis.ResultsIn total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively.ConclusionA decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity.

Project description:Thrombin is an enzyme produced during blood coagulation that is crucial to the formation of a stable clot. Thrombin cleaves soluble fibrinogen into fibrin, which polymerizes and forms an insoluble, stabilizing gel around the growing clot. A small fraction of circulating fibrinogen is the variant γA/γ′, which has been associated with high-affinity thrombin binding and implicated as a risk factor for myocardial infarctions, deep vein thrombosis, and coronary artery disease. Thrombin is also known to be strongly sequestered by polymerized fibrin for extended periods of time in a way that is partially regulated by γA/γ′. However, the role of γA/γ′-thrombin interactions during fibrin polymerization is not fully understood. Here, we present a mathematical model of fibrin polymerization that considered the interactions between thrombin, fibrinogen, and fibrin, including those with γA/γ′. In our model, bivalent thrombin-fibrin binding greatly increased thrombin residency times and allowed for thrombin-trapping during fibrin polymerization. Results from the model showed that early in fibrin polymerization, γ′ binding to thrombin served to localize the thrombin to the fibrin(ogen), which effectively enhanced the enzymatic conversion of fibrinogen to fibrin. When all the fibrin was fully generated, however, the fibrin-thrombin binding persisted but the effect of fibrin on thrombin switched quickly to serve as a sink, essentially removing all free thrombin from the system. This dual role for γ′-thrombin binding during polymerization led to a paradoxical decrease in trapped thrombin as the amount of γ′ was increased. The model highlighted biochemical and biophysical roles for fibrin-thrombin interactions during polymerization and agreed well with experimental observations. Author summary We developed a mathematical model of fibrin polymerization that explicitly incorporated thrombin-fibrin(ogen) interactions, including the γ′ variant of fibrin(ogen). This variant is associated with clots that are more resistant to fibrinolysis and is therefore implicated as a risk factor in cardiovascular disease. However, the underlying mechanism it is not completely understood. We previously modeled γ′-thrombin interactions in a preformed fibrin clot and hypothesized that some thrombin became physically trapped within the clot during its formation (fibrin polymerization). We developed the model in this study to test that hypothesis and determine the role of γ′ during polymerization. The new model showed the plausibility of large amounts of thrombin being trapped within fibrin fibers during polymerization and suggested a dual role for γ′ during polymerization: localization of thrombin to the fibrin(ogen) during an initial early phase of polymerization and sequestration of thrombin during the later phase. The model results suggested a new regulatory mechanism for fibrin polymerization.

Dataset Information

Mathematical model of thrombin generation and bleeding phenotype in Amish carriers of Factor IX:C deficiency vs. controls.

Publications

Mathematical model of thrombin generation and bleeding phenotype in Amish carriers of Factor IX:C deficiency vs. controls.

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