Procoagulant imbalance in Klinefelter syndrome assessed by thrombin generation assay and whole blood thromboelastometry

Context Klinefelter syndrome (KS) is a condition at increased risk of thrombosis compared to 46,XY men. Objective To investigate the coagulation balance of KS patients by thrombin generation assay (TGA) and thromboelastometry. Design Observational, cross-sectional study. Setting Three tertiary endocrinological centers in Milan, Italy. Patients or other participants 58 KS patients and 58 age-matched healthy controls were included. Anticoagulant or antiplatelet therapy and known coagulation disorders were exclusion criteria. Interventions TGA was performed in platelet-poor plasma (PPP) and platelet-rich plasma (PRP). Whole-blood thromboelastometry and activities of coagulation factors were assessed. Main Outcome Measures Endogenous thrombin potential (ETP), i.e. the area under the thrombin generation curve, assessed with and without thrombomodulin (ETP-TM + and ETP-TM -), and their ratio (ETP-ratio) were considered as indexes of procoagulant imbalance. Results Patients with KS displayed higher PPP-ETP-TM + (mean 1528vs.1315nMxmin; p<0.001), PPP-ETP-ratio (0.78vs.0.70, p<0.001), factor (F)VIII (135%vs.107%; p=0.001), fibrinogen (283vs.241 mg/dL; p<0.001) and FVIII/protein C ratio (1.21vs.1.06; p<0.05) compared to controls. Protein C was comparable in the two groups. Similar results were observed in PRP. ETP-ratio was positively associated with FVIII (rho=0.538, p<0.001) in KS. Thromboelastometry parameters confirmed evidence of hypercoagulability in KS. Conclusions Patients with KS display a procoagulant imbalance expressed by increased thrombin generation both in PPP and PRP, which is at least in part explained by increased FVIII levels. The procoagulant imbalance, which was confirmed by thromboelastometry, may be responsible for the thrombotic events observed in these patients. Further investigation on the benefit/risk ratio of antithrombotic prophylaxis is warranted.