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A genetic modifier of venous thrombosis in zebrafish reveals a functional role for fibrinogen A?E in early hemostasis.

ABSTRACT: Plasma fibrinogen molecules comprise 2 copies of A?, B?, and ? chains folded into a hexameric protein. A minor fibrinogen isoform with an extended A? chain (A?E) is more abundant in newborn human blood than in adults. Larval zebrafish produce predominantly A?E-containing fibrinogen, but its functional significance is unclear. In 3-day-old zebrafish, when hemostasis is reliant on fibrinogen and erythrocyte-rich clotting but is largely thrombocyte-independent, we measured the time to occlusion (TTO) in a laser-induced venous thrombosis assay in 3 zebrafish strains (AB, TU, and AB × TL hybrids). AB larvae showed delayed TTO compared with the TU and AB × TL strains. Mating AB with TU or TL produced larvae with a TU-like TTO. In contrast to TU, AB larvae failed to produce fibrinogen A?E, due to a mutation in the A?E-specific coding region of fibrinogen ?-chain gene (fga). We investigated whether the lack of A?E explained the delayed AB TTO. Transgenic expression of A?E, but not A?, shortened the AB TTO to that of TU. A?E rescued venous occlusion in fibrinogen mutants or larvae with morpholino-targeted fibrinogen ?-chain messenger RNA, but A? was less effective. In 5-day-old larvae, circulating thrombocytes contribute to hemostasis, as visualized in Tg(itga2b:EGFP) transgenics. Laser-induced venous thrombocyte adhesion and aggregation is reduced in fibrinogen mutants, but transgenic expression of A? or A?E restored similar thrombocyte accumulation at the injury site. Our data demonstrate a genetic modifier of venous thrombosis and a role for fibrinogen A?E in early developmental blood coagulation, and suggest a link between differentially expressed fibrinogen isoforms and the cell types available for clotting.

SUBMITTER: Freire C

PROVIDER: S-EPMC7656923 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A genetic modifier of venous thrombosis in zebrafish reveals a functional role for fibrinogen AαE in early hemostasis.

Freire Cristina C Fish Richard J RJ Vilar Rui R Di Sanza Corinne C Grzegorski Steven J SJ Richter Catherine E CE Shavit Jordan A JA Neerman-Arbez Marguerite M

Blood advances 20201101 21

Plasma fibrinogen molecules comprise 2 copies of Aα, Bβ, and γ chains folded into a hexameric protein. A minor fibrinogen isoform with an extended Aα chain (AαE) is more abundant in newborn human blood than in adults. Larval zebrafish produce predominantly AαE-containing fibrinogen, but its functional significance is unclear. In 3-day-old zebrafish, when hemostasis is reliant on fibrinogen and erythrocyte-rich clotting but is largely thrombocyte-independent, we measured the time to occlusion (TT ...[more]

PMID: 33166405

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Project description:ObjectiveWhile D-dimer can successfully diagnose venous thrombosis due to its excellent negative predictive value (NPV), it cannot be used to detect venous thromboembolism (VTE) because of its low positive predictive value (PPV). This study aims to investigate if a combination of using D-dimer and fibrinogen can improve PPV in the VTE diagnosis.MethodsWe retrospectively analyzed various data including D-dimer, fibrinogen, C-reactive protein, ultrasound, and others collected from 10775 traumatic fracture patients and categorized them into two groups of VTE and non-VTE. By comparing the difference between the two groups, we employ multiple logistic regression to find risk factors that are useful to detect VTE. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic yield of using fibrinogen, D-dimer, and their combination, respectively. Also, these data were classified into quartiles by patient age. We perform the same analysis on the quartiles and find if the patient's age has an impact on diagnosing VTE.ResultsThe univariate analysis demonstrated that five factors of age, D-dimer, fibrinogen, C-reactive protein, and high-density lipoprotein cholesterol were significant to predict VTE. ROC showed that D-dimer was more useful than fibrinogen for the diagnosis of VTE, while the area under the curve (AUC) was 0.7296 for D-dimer and 0.5209 for fibrinogen. The cutoff point of D-dimer and fibrinogen was 424.89 ng/ml and 3.543 g/L, respectively. The specificity of fibrinogen was 0.777 which was better than D-dimer, while the sensitivity of fibrinogen was lower than that of D-dimer. Both PPV and NPV were similar in D-dimer and fibrinogen. The PPV of combining D-dimer and fibrinogen in ages Q3 (60 < age ≤ 70) and Q4 (age > 70) was better than using either D-dimer or fibrinogen.ConclusionsFibrinogen is a promising strategy for the diagnosis of subclinical VTE and postoperative VTE. In particular, a combination of D-dimer and fibrinogen can improve the PPV to successfully diagnose VTE in traumatic fracture patients who are more than 60 years old. Levels of Evidence. This assay is a diagnostic test at level II.

Dataset Information

A genetic modifier of venous thrombosis in zebrafish reveals a functional role for fibrinogen A?E in early hemostasis.

Publications

A genetic modifier of venous thrombosis in zebrafish reveals a functional role for fibrinogen AαE in early hemostasis.

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