Thrombin Generation in Children after Acute Venous Thromboembolism

Introduction: Venous thromboembolism (VTE) is a major and growing problem in children. The annual rate of VTE has increased by 70% in the U.S hospitalized children in the past decade. Accompanying this increase in VTE is the attendant increase in chronic, post-thrombotic sequeale of VTE. Strategies to identify children at high risk of developing poor outcomes after initial management of VTE are unclear. We hypothesized that 'global coagulation assessment' may identify children likely to suffer from poor thrombosis outcomes following an initial event. In this pilot study, we therefore, evaluated thrombin generation (TG) after an acute episode of provoked VTE in children.

Methods: Baseline patient, thrombus characteristics and thrombophilia testing were prospectively collected for 50 consecutive children with acute, provoked VTE after informed consent. Subjects with cancer, protein C, protein S and antithrombin deficiency, persistent antiphospholipid positivity and inflammatory disorders were excluded. Thrombin generation, using corn trypsin inhibited treated plasma by calibrated automated thrombogram was measured in the presence and absence of thrombomodulin (TM), 4 weeks after completion of anticoagulation therapy, and compared to 50 healthy controls. All cases were treated according to the 9th edition of American College of Chest Physicians Clinical Practice Guidelines.

Results: The mean age of VTE cases was 14 years (range: 6 weeks to 18 years). Two thirds (33/50) of VTE cases consisted of deep venous thrombosis of the limbs and/or pulmonary embolism, and nearly 20% (10/50) were cerebral sinovenous thrombosis. Thrombin generation of subjects showed significantly higher endogenous thrombin potential (ETP) compared to healthy controls (1150 ± 281 vs. 763 ± 274 nM.min; p <0.001). There were no significant differences in the other TG parameters (lag time and thrombin peak) between VTE cases and healthy controls. Inhibition by TM was attenuated in patients compared to controls (22% vs. 45.5% p<0.001). A significant negative correlation was found between those with elevated FVIII levels (>150%) at end of therapy and TM induced reduction of ETP (r=0.297 vs. 0.171; p<0.01).

In conclusion, a novel finding in children with provoked VTE was persistent elevation of TG after successful completion of anticoagulation therapy. A role for FVIII as an important cause of hypercoagulability after anticoagulation therapy is reflected by the reduced inhibitory effect of TM at high FVIII levels. Further studies are ongoing to determine the utility of TG as a biomarker for predicting poor outcomes after VTE in children.