Abstract
BACKGROUND: Thrombin generation (TG) has previously been investigated in patients with bleeding disorder of unknown cause (BDUC) with discrepant results. OBJECTIVE: To investigate whether previously reported impairments of TG in BDUC patients can be resproduced using a automated TG analysed at different tissue factor concentrations. METHODS: In this case-control cohort study, TG was measured in patients with BDUC and age- and sex-matched healthy controls using the fully automated Ceveron S100 assay with 2 trigger reagents: reagent B (RB; very low tissue factor concentration) and reagent C-low (RC; low tissue factor concentration). RESULTS: In total, 62 patients and 22 controls were analyzed. In both reagents, patients compared with healthy controls had longer time to peak (RB: 16.2 vs 12.8 seconds; RC-low: 10.3 vs 8.5 seconds; P < .001), lower peak thrombin (RB: 209.0 vs 300.7 nM; P < .001; RC-low: 243.6 vs 299.2 nM; P = .011), and lastly a lower velocity index (RB: 25.6 vs 45.9 nM/min; P < .001; RC-low: 34.6 vs 54.3 nM/min; P = .001). The lag time was only significantly prolonged in patients in RB (7.6 vs 6.1 seconds; P < .001), but not with RC-low (3.2 vs 3.0 seconds; P = .403), as was the area under the curve (RB: 2776.9 vs 3276.3 nM × min; P < .001; RC-low: 2824.7 vs 2842.7 nM × min; P = .072). Crossvalidated receiver operating characteristic analysis showed an area under the curve of 0.74 (95% CI, 0.62-0.86) for RB and 0.76 (95% CI, 0.65-0.87) for RC-low. However, there was no association between the bleeding score and any TG parameters after adjustment for factor [F]VIII and FIX activity. CONCLUSION: This study highlights the reproducibility of impaired TG in patients with BDUC. Given that BDUC pathophysiology remains largely unknown, these findings suggest impaired TG may represent a common underlying feature of BDUC and underscore the need for further validation in independent cohorts and clinical settings.