title: HIV replication alters the composition of extrinsic pathway coagulation factors and increases thrombin generation.
abstract: BACKGROUND
  HIV infection leads to activation of coagulation, which may increase the risk for atherosclerosis and venous thromboembolic disease. We hypothesized that HIV replication increases coagulation potentially through alterations in extrinsic pathway factors.
  
  
  RESULTS
  Extrinsic pathway factors were measured among a subset of HIV participants from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial. Thrombin generation was estimated using validated computational modeling based on factor composition. We characterized the effect of antiretroviral therapy (ART) treatment versus the untreated state (HIV replication) via 3 separate analyses: (1) a cross-sectional comparison of those on and off ART (n=717); (2) a randomized comparison of deferring versus starting ART (n=217); and (3) a randomized comparison of stopping versus continuing ART (n=500). Compared with viral suppression, HIV replication consistently showed short-term increases in some procoagulants (eg, 15% to 23% higher FVIII; P<0.001) and decreases in key anticoagulants (eg, 5% to 9% lower antithrombin [AT] and 6% to 10% lower protein C; P<0.01). The net effect of HIV replication was to increase coagulation potential (eg, 24% to 48% greater thrombin generation from computational models; P<0.01 for all). The pattern of changes from HIV replication was reversed with ART treatment and consistent across all 3 independent comparisons.
  
  
  CONCLUSIONS
  HIV replication leads to complex changes in extrinsic pathway factors, with the net effect of increasing coagulation potential to a degree that may be clinically relevant. The key influence of changes in FVIII and AT suggests that HIV-related coagulation abnormalities may involve changes in hepatocyte function in the context of systemic inflammation.
authors.affiliation: Hennepin County Medical Center, Minneapolis, MN.
authors.forename: Jason V
authors.initials: JV
authors.lastname: Baker
authors.forename: Kathleen
authors.initials: K
authors.lastname: Brummel-Ziedins
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Neuhaus
authors.forename: Daniel
authors.initials: D
authors.lastname: Duprez
authors.forename: Nathan
authors.initials: N
authors.lastname: Cummins
authors.forename: David
authors.initials: D
authors.lastname: Dalmau
authors.forename: Jack
authors.initials: J
authors.lastname: DeHovitz
authors.forename: Clara
authors.initials: C
authors.lastname: Lehmann
authors.forename: Ann
authors.initials: A
authors.lastname: Sullivan
authors.forename: Ian
authors.initials: I
authors.lastname: Woolley
authors.forename: Lewis
authors.initials: L
authors.lastname: Kuller
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D003198:Computer Simulation; D003430:Cross-Sectional Studies; D005260:Female; D006678:HIV / Q000187:drug effects / Q000254:growth & development*; D015658:HIV Infections / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D013917:Thrombin / Q000378:metabolism*; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D013917:Thrombin
keywords: HIV infection; HIV replication; antiretroviral therapy; coagulation; inflammation; thrombin generation
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