Antithrombin-III mitigates thrombin-mediated endothelial cell contraction and sickle red blood cell adhesion in microscale flow.

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  • Additional Information
    • Source:
      Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 0372544 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2141 (Electronic) Linking ISSN: 00071048 NLM ISO Abbreviation: Br J Haematol Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Wiley-Blackwell
      Original Publication: Oxford : Blackwell Scientific Publications
    • Subject Terms:
      Anemia, Sickle Cell* ; Thrombin*/metabolism ; Thrombin*/pharmacology; Anticoagulants/pharmacology ; Antithrombins/metabolism ; Antithrombins/pharmacology ; Cell Adhesion ; Endothelial Cells ; Endothelium, Vascular/metabolism ; Erythrocytes ; Humans
    • Abstract:
      Individuals with sickle cell disease (SCD) have persistently elevated thrombin generation that results in a state of systemic hypercoagulability. Antithrombin-III (ATIII), an endogenous serine protease inhibitor, inhibits several enzymes in the coagulation cascade, including thrombin. Here, we utilize a biomimetic microfluidic device to model the morphology and adhesive properties of endothelial cells (ECs) activated by thrombin and examine the efficacy of ATIII in mitigating the adhesion of SCD patient-derived red blood cells (RBCs) and EC retraction. Microfluidic devices were fabricated, seeded with ECs, and incubated under physiological shear stress. Cells were then activated with thrombin with or without an ATIII pretreatment. Blood samples from subjects with normal haemoglobin (HbAA) and subjects with homozygous SCD (HbSS) were used to examine RBC adhesion to ECs. Endothelial cell surface adhesion molecule expression and confluency in response to thrombin and ATIII treatments were also evaluated. We found that ATIII pretreatment of ECs reduced HbSS RBC adhesion to thrombin-activated endothelium. Furthermore, ATIII mitigated cellular contraction and reduced surface expression of von Willebrand factor and vascular cell adhesion molecule-1 (VCAM-1) mediated by thrombin. Our findings suggest that, by attenuating thrombin-mediated EC damage and RBC adhesion to endothelium, ATIII may alleviate the thromboinflammatory manifestations of SCD.
      (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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    • Grant Information:
      U01 HL117659 United States HL NHLBI NIH HHS; R01 HL133574 United States HL NHLBI NIH HHS; TL1 TR002549 United States TR NCATS NIH HHS; OT2 HL152643 United States HL NHLBI NIH HHS; TL1 TR000441 United States TR NCATS NIH HHS; T32 GM007250 United States GM NIGMS NIH HHS; T32 HL134622 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: antithrombin; coagulation; microfluidics; sickle cell disease; thrombin; vascular endothelium
    • Accession Number:
      0 (Anticoagulants)
      0 (Antithrombins)
      EC 3.4.21.5 (Thrombin)
    • Publication Date:
      Date Created: 20220713 Date Completed: 20220823 Latest Revision: 20230427
    • Publication Date:
      20231215
    • Accession Number:
      PMC9542057
    • Accession Number:
      10.1111/bjh.18328
    • Accession Number:
      35822297