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

Abstract

BackgroundEffective 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.MethodsIn 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).ResultsLevels 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).ConclusionsAntithrombin, 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.

Plasmatic Coagulation Capacity Correlates With Inflammation and Abacavir Use During Chronic HIV Infection

“…40 Furthermore, in the hallmark randomized controlled SMART trial investigating CD4guided treatment interruption, in silico TG was lower in PLHIV without ART and ongoing viral replication compared with that in cART-treated PLHIV. 41,42 Although D-dimer mirrors coagulation and fibrinolysis in vivo, in vitro TG reflects actual hemostatic potential of the plasmatic coagulation pathways. 22 We confirmed that D-dimers indeed correlated with endothelial activation (eg, vWF) and inflammation (eg, sCD163), but found no such relation with TG parameters in PLHIV.…”

Platelets in HIV: A Guardian of Host Defence or Transient Reservoir of the Virus?

“…Molecules like VWF, thrombin, fibrin, fibrinogen (and Ddimer, are associated with (hyper)coagulation, and closely linked to the development of coagulopathies, thrombocytopenia and microvascular disease noted in HIV-1 infections (42,(103)(104)(105). Increased D-dimer concentrations found in HIV-1 infection (119) are also associated with poor cardiovascular and other clinical outcomes in people with HIV-1 infection (120). Similarly, an increase in thrombin and coagulation factors are also present in HIV patients, while decreased levels of antithrombin and protein C, and increased levels of Factor V, Factor VIII, were also previously noted (121).…”

In Silico Hemostasis Modeling and Prediction

“…91 In these simulations hypothermia delayed the onset of thrombin generation and increased thrombin generation (both endogenous thrombin potential and thrombin peak). Another group used the legacy model to describe how changes in blood coagulation factor balance in human immunodeficiency virus patients shift the hemostasis to hypercoagulation, 92 or in patients with hemophilia C, 93 hemophilia A, 94 or deep vein thrombosis, 95 and what is the variation of thrombin generation in healthy individuals. 96 Although the computer simulations of thrombin generation often demonstrate the same trends in response to parameters' variations as in vitro experiments, the thorough comparison of the outputs can show that the discrepancy in the in vitro and in silico is still present, 97 and it is as high as 30 to 50% of values of thrombin peak, or time to peak.…”