Circulating Extracellular Vesicle Tissue Factor Activity During Orthohantavirus Infection Is Associated With Intravascular Coagulation

• Published in: The Journal of infectious diseases 2020-10, Vol.222 (8), p.1392-1399
• Main Authors: Schmedes, Clare M, Grover, Steven P, Hisada, Yohei M, Goeijenbier, Marco, Hultdin, Johan, Nilsson, Sofie, Thunberg, Therese, Ahlm, Clas, Mackman, Nigel, Fors Connolly, Anne-Marie
• Format: Article
• Language: English
• Subjects: Adult; Biomarkers - blood; Blood Coagulation; Disseminated intravascular coagulation; Disseminated Intravascular Coagulation - blood; Endothelial cells; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Fibrinogen; Fibrinolysis; Hemorrhage; Hemorrhagic fever with renal syndrome; Hemorrhagic Fever with Renal Syndrome - blood; Humans; Kinetics; Major and Brief Reports; Male; Middle Aged; Monkeys & apes; Orthohantavirus; Plasminogen Activator Inhibitor 1 - blood; Plasminogen activator inhibitors; Prothrombin; Puumala virus - pathogenicity; Sensitivity and Specificity; t-Plasminogen activator; Thromboembolism; Thromboplastin - metabolism; Thrombosis; Tissue factor; Tissue Plasminogen Activator - blood; Venous Thromboembolism - blood
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiz597

Abstract Background Puumala orthohantavirus (PUUV) causes hemorrhagic fever with renal syndrome (HFRS). Patients with HFRS have an activated coagulation system with increased risk of disseminated intravascular coagulation (DIC) and venous thromboembolism (VTE). The aim of the study was to determine whether circulating extracellular vesicle tissue factor (EVTF) activity levels associates with DIC and VTE (grouped as intravascular coagulation) in HFRS patients. Methods Longitudinal samples were collected from 88 HFRS patients. Patients were stratified into groups of those with intravascular coagulation (n = 27) and those who did not (n = 61). We measured levels of circulating EVTF activity, fibrinogen, activated partial prothrombin time, D-dimer, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and platelets. Results Plasma EVTF activity was transiently increased during HFRS. Levels of EVTF activity were significantly associated with plasma tPA and PAI-1, suggesting that endothelial cells could be a potential source. Patients with intravascular coagulation had significantly higher peak EVTF activity levels compared with those who did not, even after adjustment for sex and age. The peak EVTF activity value predicting intravascular coagulation was 0.51 ng/L with 63% sensitivity and 61% specificity with area under the curve = 0.63 (95% confidence interval, 0.51–0.76) and P = .046. Conclusions Plasma EVTF activity during HFRS is associated with intravascular coagulation. We found increased rates of infection-related hospitalization and decreased cellular responses to the tetanus vaccine among HIV-exposed, uninfected compared with HIV-unexposed infants. Incomplete treatment of maternal HIV, but not early infant CMV infection, was associated with decreased vaccine responses.