In silico thrombin generation: Plasma composition imbalance and mortality in human immunodeficiency virus


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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.

Original languageEnglish (US)
Pages (from-to)708-717
Number of pages10
JournalResearch and Practice in Thrombosis and Haemostasis
Issue number4
StatePublished - Oct 2018

Bibliographical note

Funding Information:
We'd like to thank the participants and investigators for the SMART and ESPRIT trials (see [42] for the complete list of SMART investigators and [44] for the complete list of ESPRIT investigators). The SMART study was funded by NIH grants U01-AI068641, U01-AI046362, and U01-AI042170. The ESPRIT study was funded by NIH grants U01-AI068641 and U01-AI46957. The ARRA-2 grant was funded by NIH Grants 3U01-AI068641-0451 and 3U01-AI06841-0551. This project is also supported by NIH grant R01-HL126542, United States Navy contract W911QY-15-C-0027, and by the UVM Department of Biochemistry. AHB is supported by Lundbeckfonden (grant R219-2016-762). AHB's institution is supported by a grant from the Danish National Research Foundation (grant number DNRF126). Portions of this research were presented at the 2016 American Society of Hematology Annual Meeting.

Publisher Copyright:
© 2018 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.


  • HIV
  • blood coagulation factors
  • in silico
  • inflammation
  • mathematical model
  • mortality
  • thrombin generation


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