Severe Dengue Is Associated with Consumption of von Willebrand Factor and Its Cleaving Enzyme ADAMTS-13

Abstract

BackgroundThrombocytopenia, bleeding and plasma leakage are cardinal features of severe dengue. Endothelial cell activation with exocytosis of Weibel-Palade bodies (WPBs) may play an etiological role in this condition.Methods and Principal FindingsIn a cohort of 73 Indonesian children with dengue hemorrhagic fever (DHF), of which 30 with dengue shock syndrome (DSS), we measured plasma levels of the WPB constituents von Willebrand factor antigen (VWF:Ag), VWF propeptide and osteoprotegerin (OPG), together with activity levels of the VWF-cleaving enzyme ADAMTS-13 and the amount of VWF in a platelet binding conformation (VWF activation factor). Compared with healthy controls (n = 17), children with DHF/DSS had significantly higher levels of VWF:Ag, VWF propeptide and OPG and decreased ADAMTS-13 activity. The VWF activation factor was also significantly higher in DHF/DSS and highest in children who died. There were significant differences in the kinetics of the various WPB constituents: VWF propeptide and OPG levels decreased toward discharge, while VWF:Ag levels were lower than expected at enrollment with plasma levels increasing toward discharge. Moreover, VWF propeptide levels correlated better with markers of disease severity (platelet count, liver enzymes, serum albumin and pleural effusion index) than corresponding VWF levels. Together, these findings suggest that there is consumption of VWF in DHF/DSS. In 4 out of 15 selected children with low ADAMTS-13 levels on admission, we found a remarkable reduction in the large and intermediate VWF multimers in the discharge blood samples, consistent with an acquired von Willebrand disease.ConclusionThese findings suggest that severe dengue is associated with exocytosis of WPBs with increased circulating levels of VWF:Ag, VWF propeptide and OPG. High circulating levels of VWF in its active conformation, together with low ADAMTS-13 activity levels, are likely to contribute to the thrombocytopenia and complications of dengue. During the convalescence phase, qualitative defects in VWF with loss of larger VWF multimers may develop.

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.…”

Imbalance of Angiopoietin-1 and Angiopoetin-2 in Severe Dengue and Relationship with Thrombocytopenia, Endothelial Activation, and Vascular Stability

“…12 The finding of high levels of von Willebrand factor, the most abundant WPB constituent, in dengue patients, supports the notion that endothelial cell activation with WPB exocytosis is an important feature of dengue infection. 15,20 Although the exact mechanisms of increased WPB exocytosis with subsequent Ang-2 release in dengue are unknown, we hypothesize that endothelial activation caused by increased pro-inflammatory cytokines is centrally involved. 21 In addition to the effect of inflammatory cytokines, other mechanisms may also be involved, including direct interaction of dengue virus with endothelial cells, release of mast cell products, and pro-coagulant factors such as thrombin.…”

Rising Mean Platelet Volume (MPV) Heralding Platelets Recovery in Dengue?

“…ADAMTS13 cleaves the UL-vWF in healthy individuals and prevents the formation of such micro plugs and consequent vasculopathy (microangiopathy). [40] As dengue illness can result in an excess of UL-vWF and deficiency of ADAMTS13, the transfusion of platelets alone without replacement of ADAMTS13 may lead to further platelet plugs and microangiopathy. Or in other words, platelet transfusion may cause more harm than good and add insult to the ongoing injury.…”