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Venous Thrombosis and Thrombocyte Activity in Zebrafish Models of Quantitative and Qualitative Fibrinogen Disorders.

ABSTRACT: Venous thrombosis occurs in patients with quantitative and qualitative fibrinogen disorders. Injury-induced thrombosis in zebrafish larvae has been used to model human coagulopathies. We aimed to determine whether zebrafish models of afibrinogenemia and dysfibrinogenemia have different thrombotic phenotypes. Laser injuries were used to induce venous thrombosis and the time-to-occlusion (TTO) and the binding and aggregation of fluorescent Tg(itga2b:EGFP) thrombocytes measured. The fga^-/- larvae failed to support occlusive venous thrombosis and showed reduced thrombocyte binding and aggregation at injury sites. The fga^+/- larvae were largely unaffected. When genome editing zebrafish to produce fibrinogen A? R28C, equivalent to the human A? R35C dysfibrinogenemia mutation, we detected in-frame skipping of exon 2 in the fga mRNA, thereby encoding A?^?19-56. This mutation is similar to Fibrinogen Montpellier II which causes hypodysfibrinogenemia. A?^+/?19-56 fish had prolonged TTO and reduced thrombocyte activity, a dominant effect of the mutation. Finally, we used transgenic expression of fga R28C cDNA in fga knock-down or fga^-/- mutants to model thrombosis in dysfibrinogenemia. A? R28C expression had similar effects on TTO and thrombocyte activity as A?^+/?19-56. We conclude that thrombosis assays in larval zebrafish can distinguish between quantitative and qualitative fibrinogen disorder models and may assist in anticipating a thrombotic phenotype of novel fibrinogen mutations.

SUBMITTER: Fish RJ

PROVIDER: S-EPMC7826895 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Venous Thrombosis and Thrombocyte Activity in Zebrafish Models of Quantitative and Qualitative Fibrinogen Disorders.

Fish Richard J RJ Freire Cristina C Di Sanza Corinne C Neerman-Arbez Marguerite M

International journal of molecular sciences 20210111 2

Venous thrombosis occurs in patients with quantitative and qualitative fibrinogen disorders. Injury-induced thrombosis in zebrafish larvae has been used to model human coagulopathies. We aimed to determine whether zebrafish models of afibrinogenemia and dysfibrinogenemia have different thrombotic phenotypes. Laser injuries were used to induce venous thrombosis and the time-to-occlusion (TTO) and the binding and aggregation of fluorescent <i>Tg(itga2b:EGFP)</i> thrombocytes measured. The <i>fga<s ...[more]

PMID: 33440782

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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

Venous Thrombosis and Thrombocyte Activity in Zebrafish Models of Quantitative and Qualitative Fibrinogen Disorders.

Publications

Venous Thrombosis and Thrombocyte Activity in Zebrafish Models of Quantitative and Qualitative Fibrinogen Disorders.

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