Inherited and Acquired Thrombophilia in Patients with Previous Thrombosis: An Integrated Analysis of Thrombophilic Profiles and Their Combined Associations
Gianluca Gessoni *
Division of Transfusion Medicine, Ospedale dell’Angelo, Via Paccagnella 11, 30172 Mestre (Venice), Italy.
Sara Valverde
Division of Laboratory Medicine, Ospedale Madonna della Navicella, Chioggia (Venice), Italy.
Francesca Gessoni
Division of Radiation Oncology, Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy.
Roberto Valle
Division of Cardiology and Intensive Care Unit, Ospedale Madonna della Navicella, Chioggia (Venice), Italy.
*Author to whom correspondence should be addressed.
Abstract
Background: Thrombosis is a multifactorial condition in which inherited thrombophilic abnormalities, acquired haemostatic disturbances, and other clinical factors may coexist and contribute to thrombotic susceptibility. Because multiple abnormalities can occur within the same individual, their relative and combined associations with previous thrombosis require integrated evaluation, particularly when inherited thrombophilia and antiphospholipid antibody profiles are considered together.
Aims: To characterise the integrated thrombophilic phenotype associated with previous thrombosis, identify abnormalities retaining an independent association after multivariable adjustment, and investigate the contribution and heterogeneity of antiphospholipid antibodies (aPL).
Study Design: Analytical re-analysis of a previously assembled observational case-control cohort.
Methodology: We re-analysed 623 subjects, comprising 292 individuals with previous thrombosis and 331 thrombosis-free consanguineous controls. A complete univariate screen was followed by Firth penalised logistic regression. The primary non-aPL model included age modelled with a 4-df natural cubic spline, sex, antithrombin deficiency, factor V Leiden (FVL) carrier status and factor II G20210A carrier status. Aggregate antiphospholipid antibody positivity (APA), ≥1 positive non-LAC aPL assay, seven individual non-LAC aPL specificities and cumulative aPL burden were analysed separately.
Results: In the primary non-aPL model, FVL carrier status was associated with previous thrombosis (adjusted OR 3.40, 95% CI 2.32–4.99; P<.001), as was factor II G20210A carrier status (OR 5.29, 95% CI 2.88–9.71; P<.001) and antithrombin deficiency (OR 4.31, 95% CI 1.13–16.49; P=.033). Aggregate APA positivity showed an adjusted OR of 7.53 (95% CI 4.61–12.31; P<.001), while ≥1 positive non-LAC aPL assay showed an adjusted OR of 7.58 (95% CI 4.60–12.48; P<.001). Six of seven individual non-LAC aPL specificities remained significant after false-discovery-rate correction.
Conclusion: Previous thrombosis was associated with an integrated pattern of inherited and acquired thrombophilic abnormalities. FVL and factor II G20210A were the principal inherited associations, while antithrombin deficiency and the antiphospholipid phenotype provided additional information. The aPL findings support a multimarker interpretation rather than attribution of the thrombotic phenotype to a single antibody specificity.
Keywords: Thrombosis, thrombophilia, factor V Leiden, prothrombin G20210A, antithrombin, antiphospholipid antibodies, multimarker analysis, Firth logistic regression