Total Plasma Protein S Is a Prothrombotic Marker in People Living with HIV

Martha M.S. Sim, Meenakshi Banerjee, Thein Myint, Beth A. Garvy, Sidney W. Whiteheart, Jeremy P. Wood

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background:HIV-1 infection is associated with multiple procoagulant changes and increased thrombotic risk. Possible mechanisms for this risk include heigthened expression of procoagulant tissue factor (TF) on circulating monocytes, extracellular vesicles, and viral particles and/or acquired deficiency of protein S (PS), a critical cofactor for the anticoagulant protein C (PC). PS deficiency occurs in up to 76% of people living with HIV-1 (PLWH). As increased ex vivo plasma thrombin generation is a strong predictor of mortality, we investigated whether PS and plasma TF are associated with plasma thrombin generation.Methods:We analyzed plasma samples from 9 healthy controls, 17 PLWH on first diagnosis (naive), and 13 PLWH on antiretroviral therapy (ART). Plasma thrombin generation, total and free PS, PC, C4b-binding protein, and TF activity were measured.Results:We determined that the plasma thrombin generation assay is insensitive to PS, because of a lack of PC activation, and developed a modified PS-sensitive assay. Total plasma PS was reduced in 58% of the naive and 38% of the ART-treated PLWH samples and correlated with increased thrombin generation in the modified assay. Conversely, plasma TF was not increased in our patient population, suggesting that it does not significantly contribute to ex vivo plasma thrombin generation.Conclusion:These data suggest that reduced total plasma PS contributes to the thrombotic risk associated with HIV-1 infection and can serve as a prothrombotic biomarker. In addition, our refined thrombin generation assay offers a more sensitive tool to assess the functional consequences of acquired PS deficiency in PLWH.

Original languageEnglish
Pages (from-to)463-471
Number of pages9
JournalJournal of Acquired Immune Deficiency Syndromes
Volume90
Issue number4
DOIs
StatePublished - Aug 1 2022

Bibliographical note

Funding Information:
Supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1TR001998. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also supported by NHLBI grants HL056652, HL138179 (S.W.W.), HL129193 (J.P.W.), and VA Merit I01BX003877 (S.W.W.).

Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.

Keywords

  • HIV-1
  • protein S deficiency
  • thrombin
  • thrombomodulin
  • thrombosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

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