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

  • Brummel-Ziedins, Kathleen E1
  • Gissel, Matthew1
  • Neuhaus, Jacqueline2
  • Borges, Álvaro H3, 4
  • Chadwick, David R5
  • Emery, Sean6, 7
  • Neaton, James D2
  • Tracy, Russell P1, 8
  • Baker, Jason V9, 10
  • 1 Department of Biochemistry University of Vermont Colchester Vermont USA.
  • 2 Department of Biostatistics University of Minnesota Minneapolis Minnesota USA.
  • 3 Centre of Excellence for Health, Immunity, and Infections (CHIP) Department of Infectious Diseases, Rigshospitalet University of Copenhagen Copenhagen Denmark. , (Denmark)
  • 4 Institute for Clinical Medicine University of Copenhagen Copenhagen Denmark. , (Denmark)
  • 5 James Cook University Hospital Middlesbrough UK.
  • 6 Faculty of Medicine University of Queensland Brisbane Australia. , (Australia)
  • 7 The Kirby Institute University of New South Wales Sydney Australia. , (Australia)
  • 8 Department of Pathology and Laboratory Medicine University of Vermont Burlington Vermont USA.
  • 9 Department of Medicine University of Minnesota Minneapolis Minnesota USA.
  • 10 Department of Infectious Diseases Hennepin County Medical Center Minneapolis Minnesota USA.
Published Article
Research and practice in thrombosis and haemostasis
Publication Date
Oct 01, 2018
DOI: 10.1002/rth2.12147
PMID: 30349890


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. 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). 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). 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.

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