Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis

Abstract

Background Previous clinical evidence correlates levels of von Willebrand factor (VWF) and its cleaving protease ADAMTS13 with outcome in septic patients. No previous studies addressed if VWF and ADAMTS13 affected the outcome of Staphylococcus aureus sepsis. Objectives We studied the role of VWF and ADAMTS13 in S. aureus sepsis both in patients and in mice. Methods VWF levels and ADAMTS13 activity levels were measured in plasma samples from 89 S. aureus bacteremia patients by chemiluminescent assays and were correlated with clinical sepsis outcome parameters. In wild‐type mice and mice deficient in VWF and ADAMTS13, we investigated the outcome of S. aureus sepsis and quantified bacterial clearance and organ microthrombi. Results In patients with S. aureus bloodstream infections, high VWF levels and low ADAMTS13 activity levels correlated with disease severity and with parameters of inflammation and disseminated intravascular coagulation. In septic mice, VWF deficiency attenuated mortality, whereas ADAMTS13 deficiency increased mortality. Bacterial clearance was enhanced in VWF‐deficient mice. The differences in mortality for the studied genotypes were associated with differential loads of organ microthrombi in both liver and kidneys. Conclusions In conclusion, this study reports the consistent relation of VWF, ADAMTS13 and their ratio to disease severity in patients and mice with S. aureus sepsis. Targeting VWF multimers and/or the relative ADAMTS13 deficiency that occurs in sepsis should be explored as a potential new therapeutic target in S. aureus endovascular infections.

Staphylococcus aureus and Neutrophil Extracellular Traps: The Master Manipulator Meets Its Match in Immunothrombosis

“…In pathological conditions, however, this balance is often impaired. 79 PAD4, which is released on NETs, can citrullinate ADAMTS13 and subsequently abolish its activity, promoting ultra-large VWF-platelet string formation, such as in sepsis 80 (Figure 3 ). VWF, in turn, by binding to platelet GPIbα and neutrophil αMβ2, also facilitates platelet interaction with neutrophils and platelet-induced NET formation.…”

Emerging Concepts in Immune Thrombotic Thrombocytopenic Purpura

“…Associations between infection and iTTP must be made with caution. One must differentiate between secondary iTTP due to infection (that is, anti-ADAMTS13 autoantibodies developed due to the presence of the infectious microorganism) from secondary TTP caused either by the systemic inflammation and/or endothelial damage which commonly accompanies infections ( 13 , 52 , 115 ), or secondary TTP caused by drugs, or liver cirrhosis, or excessive alcohol intake ( 116 , 117 ), as well as from other coagulation disorders well known to occur with infectious diseases ( 118 , 119 ). The presence of autoantibodies together with ADAMTS13 activity < 10% is the defining factor for this differentiation.…”

Biomarkers Predicting Tissue Pharmacokinetics of Antimicrobials in Sepsis: A Review

“…Another essential anticoagulant protein is antithrombin. Most of these coagulation biomarkers have been related to a worse prognosis: thrombomodulin [111,112], plasminogen activator inhibitor 1 [113], vWf [114][115][116], ADAMTS-13 [116][117][118], and thrombocytopenia [119,120]. A prolonged coagulation time is frequent in critically ill patients, and prothrombin time and activated partial thromboplastin time have been found to be predictors of sepsis and mortality [107,121].…”