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HIV infection is associated with decreased thrombin generation.

ABSTRACT: 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.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.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.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.

SUBMITTER: Hsue PY

PROVIDER: S-EPMC3309887 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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HIV infection is associated with decreased thrombin generation.

Hsue Priscilla Y PY Scherzer Rebecca R Grunfeld Carl C Nordstrom Sarah M SM Schnell Amanda A Kohl Louis P LP Nitta Elaine E Martin Jeffrey N JN Deeks Steven G SG Weiss Ethan J EJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20120401 8

<h4>Background</h4>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.<h4>Methods</h4>We measured D-dimers, antithrombin, endogenous thrombin potential (ETP; a functional measure of thrombin generation in vitro), thrombin/antithrombin complexes (TA ...[more]

PMID: 22438347

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Project description:BackgroundHeterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding.ObjectivesThe objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia.MethodsThe Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis.ResultsIn total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively.ConclusionA decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity.

Project description:BackgroundThe haemostatic balance is an equilibrium of pro- and anticoagulant factors that work synergistically to prevent bleeding and thrombosis. As thrombin is the central enzyme in the coagulation pathway, it is desirable to measure thrombin generation (TG) in order to detect possible bleeding or thrombotic phenotypes, as well as to investigate the capacity of drugs affecting the formation of thrombin. By investigating the underlying processes of TG (i.e., prothrombin conversion and inactivation), additional information is collected about the dynamics of thrombin formation.ObjectivesTo obtain reference values for thrombin dynamics (TD) analysis in 112 healthy donors using an automated system for TG.MethodsTG was measured on the ST Genesia, fibrinogen on the Start, anti-thrombin (AT) on the STA R Max and α2Macroglobulin (α2M) with an in-house chromogenic assay.ResultsTG was measured using STG-BleedScreen, STG-ThromboScreen and STG-DrugScreen. The TG data was used as an input for TD analysis, in combination with plasma levels of AT, α2M and fibrinogen that were 113% (108-118%), 2.6 μM (2.2 μM-3.1 μM) and 2.9 g/L (2.6-3.2 g/L), respectively. The maximum rate of the prothrombinase complex (PCmax) and the total amount of prothrombin converted (PCtot) increased with increasing tissue factor (TF) concentration. PCtot increased from 902 to 988 nM, whereas PCmax increased from 172 to 508 nM/min. Thrombin (T)-AT and T-α2M complexes also increased with increasing TF concentration (i.e., from 860 to 955 nM and from 28 to 33 nm, respectively). PCtot, T-AT and T-α2M complex formation were strongly inhibited by addition of thrombomodulin (-44%, -43%, and -48%, respectively), whereas PCmax was affected less (-24%). PCtot, PCmax, T-AT, and T-α2M were higher in women using oral contraceptives (OC) compared to men/women without OC, and inhibition by thrombomodulin was also significantly less in women on OC (p < 0.05).ConclusionsTG measured on the ST Genesia can be used as an input for TD analysis. The data obtained can be used as reference values for future clinical studies as the balance between prothrombin conversion and thrombin inactivation has shown to be useful in several clinical settings.

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HIV infection is associated with decreased thrombin generation.

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HIV infection is associated with decreased thrombin generation.

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