Thrombin generation profiling in rare coagulation factor deficiencies: associations with bleeding severity and potential for screening

Background Rare coagulation factor deficiencies (RCFDs) can cause significant bleeding, but activated partial thromboplastin time (APTT) and prothrombin time (PT) may not detect abnormalities, and factor activity measurements do not predict bleeding severity. Thrombin generation assays may better reflect overall hemostatic capacity. Objectives This study investigated whether thrombin generation can detect RCFDs and correlate with bleeding severity in patients with congenital deficiencies of factor (F)II, FV, FV/FVIII, FVII, FX, and FXI. Methods Thrombin generation was measured using the Nijmegen hemostasis assay in patients from the cross-sectional Dutch Rare Bleeding disorders in the Netherlands (RBiN) study (2017-2019). Parameters analyzed included thrombin potential, lag time, and thrombin potential-to-lag time (TP/LT) ratio, normalized using pooled normal plasma and expressed as percentages of the mean from 37 healthy controls. Nijmegen hemostasis assay data were correlated with bleeding severity and compared with APTT and PT. Results We included 106 patients, mostly with mild deficiencies (median factor activity 5%-53%). Overall, thrombin generation in patients was significantly reduced compared with controls, with decreased thrombin potentials (median 58%) and prolonged lag times (150%), resulting in reduced TP/LT ratios (45%). These parameters correlated with bleeding severity; across RCFDs, median TP/LT ratios ranged from 30% to 104% in patients without spontaneous bleeding (bleeding severity grade 0-1), 26% to 49% in mild spontaneous bleeding (grade 2), and 0% to 22% in severe spontaneous bleeding (grade 3). At 95% specificity, TP/LT ratio showed 68% to 100% sensitivity, outperforming APTT and PT (14%-80%) in all RCFDs except FVII and FV/FVIII deficiency. Conclusion Thrombin generation profiling correlated with bleeding severity and showed higher sensitivity than conventional screening assays in detecting RCFDs, supporting its potential in screening and clinical evaluation of RFCDs.