HIV infection is associated with decreased thrombin generation

Abstract

Background: Excess risk of cardiovascular disease occurs in effectively treated individuals with human immunodeficiency virus (HIV) infection. Although elevated plasma D-dimer levels are associated with increased morbidity and mortality, the impact of HIV infection on coagulation in vivo has not been well studied.

Methods: We measured D-dimers, antithrombin, endogenous thrombin potential (ETP; a functional measure of thrombin generation in vitro), thrombin/antithrombin complexes (TAT; a measure of thrombin generation in vivo), tissue factor, prothrombin fragment 1 + 2 (F1+2), and normalized APC sensitivity ratio (nAPCsr) in 199 HIV-positive men who were receiving antiretroviral therapy and had an undetectable HIV RNA level, in 79 HIV-positive untreated men, and in 39 uninfected controls.

Results: Median antithrombin levels were higher while the ETP was lower among HIV-infected adults (treated and untreated), compared with controls. There were few differences between coagulation markers in the 2 HIV groups. Compared with controls, the nAPCsr was lower in treated men and the TAT level was lower in untreated individuals. We observed little difference among measured levels of D-dimer, tissue factor, or F1+2 between HIV-infected individuals and controls. Antiretroviral therapy exposure was associated with a lower antithrombin level, a lower nAPCsr, and a lower ETP, while history of opportunistic infection was associated with a higher nAPCsr.

Conclusions: HIV infection is associated with decreased thrombin generation, as measured by the ETP, and an increased antithrombin level. These data suggest that HIV infection may not be associated with increased propensity toward clotting, as has been suggested on the basis of isolated measures of D-dimer levels.

Figure 1.

Coagulation pathway. We assessed the following 7 components of the coagulation cascade: (1) D-dimer, fibrin degradation product (FDP); (2) antithrombin III (antithrombin, AT), circulating inhibitor of thrombin; (3) endogenous thrombin potential (ETP), functional measure of thrombin generation in vitro; (4) thrombin-antithrombin complexes (TAT), antibodies to the thrombin-antithrombin complex, which is a measure of thrombin generation in vivo; (5) tissue factor (TF), protein needed for initiation of thrombin formation; (6) prothrombin fragment 1 + 2 (F1+2), activation peptide generated during conversion of prothrombin to thrombin; and (7) normalized activated protein C (APC) sensitivity ratio (nAPCsr), ETP with and without addition of APC, which is a measure of resistance to the enzymatic activity of APC.