Open AccessIn silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus
Author(s) -
BrummelZiedins Kathleen E.,
Gissel Matthew,
Neuhaus Jacqueline,
Borges Álvaro H.,
Chadwick David R.,
Emery Sean,
Neaton James D.,
Tracy Russell P.,
Baker Jason V.
Publication year - 2018
Publication title -
research and practice in thrombosis and haemostasis
Language(s) - English
Resource type - Journals
ISSN - 2475-0379
DOI - 10.1002/rth2.12147
Subject(s) - antithrombin , thrombin , in silico , tissue factor , immunology , medicine , direct thrombin inhibitor , thromboplastin , tissue factor pathway inhibitor , anticoagulant , area under the curve , human immunodeficiency virus (hiv) , coagulopathy , heparin , pharmacology , gastroenterology , coagulation , biology , biochemistry , platelet , dabigatran , warfarin , gene , atrial fibrillation
Background Effective HIV treatment with antiretroviral therapy has prolonged survival and shifted causes of death to non‐ AIDS illnesses such as cardiovascular disease. We have shown that inflammation and HIV viral load associate with pro‐ and anticoagulant factor imbalances resulting in increased thrombin generation when mathematically modeled. We explore the hypothesis that factor compositional imbalance, corresponding to increased in silico thrombin generation, predicts mortality among HIV + persons. Methods In a nested case‐control study of HIV + individuals on continuous antiretroviral therapy in two large trials, we evaluated cases (any non‐violent mortality, n = 114) and matched controls (n = 318). Thrombin generation in response to a tissue‐factor initiator for each individual was calculated by a mathematical model incorporating levels of factors (F) II , V, VII , VIII , IX , X, antithrombin, tissue factor pathway inhibitor, and protein C ( PC ) measured at study entry to the trials. In silico thrombin generation metrics included clot time, maximum rate (MaxR), maximum level (MaxL), and area under the curve ( AUC ). Results Levels of antithrombin and PC decreased, while FV and FVIII were higher in cases vs controls. This resulted in a more procoagulant phenotype with increased MaxR, MaxL, and AUC in cases compared to controls ( P < 0.05 for all). Conclusions Antithrombin, FV , FVIII , and PC were the major contributors to the increased thrombin generation associated with mortality risk. Our results suggest that mortality in HIV is associated with an increase in in silico thrombin generation via altered balance of pro‐ and anticoagulant factors, likely due to an inflammatory response signal, and resulting coagulopathy.