Impaired thrombin generation as a reproducible feature of bleeding disorder of unknown cause

Thrombin generation (TG) has previously been investigated in patients with bleeding disorder of unknown cause (BDUC) with discrepant results.

To investigate whether previously reported impairments of TG in BDUC patients can be resproduced using a automated TG analysed at different tissue factor concentrations.

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).

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.

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.