Reduced ADAMTS13 in children with severe meningococcal sepsis is associated with severity and outcome

Abstract

Multiple organ failure is a common feature of pediatric meningococcal sepsis and is associated with an imbalance of coagulation and fibrinolysis. This is partly due to an increased secretion of prothrombotic ultra-large von Willebrand factor (VWF) as the result of vascular endothelial damage. Another factor that may contribute is ADAMTS13, which converts VWF into smaller, less active, VWF multimers and thus influences VWF activity in plasma. We investigated the role of ADAMTS13 and VWF in the severity and outcome of sepsis. In 58 children with severe meningococcal sepsis we measured ADAMTS13 activity and antigen, VWF collagen binding activity (VWF:CB) and antigen levels (VWF:Ag), VWF propeptide and factor VIII at different time points during their stay in the paediatric intensive care unit. In the acute phase, both ADAMTS13 activity and antigen were decreased (median 23.4% and 33.7% of normal, respectively) and VWF:CB and VWF:Ag levels were strongly increased (325% and 348%, respectively.) ADAMTS13 antigen (23.9% vs. 34.6%; p=0.06) and VWF:CB (240% and 340% p<0.001) were lower in non-survivors than in survivors. ADAMTS13 activity and VWF:CB were both correlated with the severity of the disease, as indicated by the Pediatric Risk of Mortality score (R(s)= -0.38 and R(s)= -0.50, p=0.01, respectively, p<0.001). In the acute phase of severe sepsis decreased levels of ADAMTS13 and increased levels of VWF are observed, and the changes are related to severity of disease and outcome. This may contribute to the formation of microthrombi and the severity of thrombotic sequelae of sepsis.

Development of a Hyperactive Primary Hemostatic System During Off-Pump Lung Transplantation Resulting From an Unbalance Between von Willebrand Factor and Its Cleaving Protease ADAMTS13

“…This process may ultimately result in organ dysfunction as described previously in several other pathologies and invasive procedures including TTP and liver transplantation (4,5,(20)(21)(22)(23)(24). We speculate that the development of a VWF/ADAMTS13 unbalance during lung transplantation also facilitates thrombus formation within the allograft.…”

Biomarkers of endothelial activation/dysfunction in infectious diseases

“…Despite promising findings in animal models, studies in human subjects have yielded decidedly mixed results. In a study of 58 children with severe meningococcal sepsis, decreased levels of ADAMTS13 were observed, correlating with disease severity based on the Pediatric Risk of Mortality score 46 . Levels were also lower in non-survivors as compared with survivors.…”

Do Aspirin and Other Antiplatelet Drugs Reduce the Mortality in Critically Ill Patients?

“…During systemic inflammation and infection platelets become activated as indicated by an increase in the number of CD62P-positive platelets and platelet-leukocyte conjugates [7–9]. Different mechanisms may contribute to platelet activation, including imbalance between plasma level of high molecular weight von-Willebrand factor and its cleaving protease, ADAMTS-13 [10–13], and binding of endotoxins to specific receptors at the platelet surface [14–16]. Adhesion of activated platelets within the microcirculation and formation of platelet aggregates contributes to vascular hyperpermeability as well as hypoperfusion [17–20].…”