Increased soluble thrombomodulin influences fibrin clot formation in patients with mild to moderate bleeding tendency

Objective A majority of patients with a mild bleeding disorder (MBD) remains without a diagnosis, despite thorough hemostatic investigations (bleeding of unknown cause, BUC). Recently, a coagulopathy with posttraumatic bleeding caused by 100-fold enhanced levels of soluble thrombomodulin (TM) was reported in several cases.

We investigated TM levels in a large and well-characterized cohort of patients with MBDs and healthy controls and how high TM levels affect thrombin generation and plasma clot formation.

Material and Methods TM and thrombin generation (TG) were measured using commercially available kits (ab46508 – TM (CD141) Human ELISA Kit – Abcam UK; TG Technothrombin, Technoclone, Austria). Plasma clot formation/lysis was assessed according to SCC recommendations of the ISTH.

Results TM was not altered in 507 patients, including 358 BUC patients, with MBD when comparing to 90 sex- and age-matched healthy controls (median [IQR] 5.0 [3.8-6.3] vs. 5.1 [3.7-6.4] ng/mL, multiple regression with adjustment for sex p=0.801; Figure 1). Also in the BUC patients no difference was found (TM: 5.05 [3.8-6.3] ng/mL, multiple regression after adjustment for sex p= 0.695). To identify outliers of TM levels in our patients, a cut-off according to the 95th percentile of TM in healthy controls (≥ 14.7 ng/mL) was defined. No increased number of patients above the predefined cut-off was identified (OR [95% CI]: 1.9 [0.6-6.1]). Nevertheless, 2 BUC patients had clearly elevated TM levels (150.1 and 123.4 ng/mL, reference range: 2.9-7.6), but TG and plasma clot properties were not significantly altered.

We identified a prolonged time to peak (TTP) in fibrin clot analysis between patients with TM levels above vs. below the cut-off (mean (SD): 28.7 (31.7) vs. 20.0 (7.4) minutes, p<0.001), which was also significant in subgroup analysis of patients with BUC (Table 1). In the thrombin generation assay no differences could be found. Levels of TM did not correlate with both the Vicenza (rs=-0.052, p=0.239) and the ISTH bleeding score (rs=-0.057, p=0.368).

Conclusion Soluble TM was not increased in patients with MBD or patients with BUC in comparison to healthy controls. Two patients with high TM levels were identified, though levels were not as high as in reported cases of TM-associated coagulopathy. Thus, TM appears not to have an impact on bleeding in patients with MBD and/or BUC.

Abb 1. Scatter plot (including mean and SD) of TM levels in patients and healthy controls. BUC: bleeding of unknown cause; PFD: platelet function defects; VWF: Von Willebrand factor; CFD: clotting factor deficiency

Tab 1. Parameters of fibrin clot formation assay according to TM values (<95th vs. ≥ 95th percentile of the healthy controls).

Publication History

Article published online:
18 June 2021