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A mathematical model of coagulation under flow identifies factor V as a modifier of thrombin generation in hemophilia A.

Authors
  • Link, Kathryn G1
  • Stobb, Michael T2
  • Sorrells, Matthew G3
  • Bortot, Maria4
  • Ruegg, Katherine5
  • Manco-Johnson, Marilyn J5, 6
  • Di Paola, Jorge A5, 6
  • Sindi, Suzanne S2
  • Fogelson, Aaron L1, 7
  • Leiderman, Karin8
  • Neeves, Keith B4, 5, 6
  • 1 Department of Mathematics, University of Utah, Salt Lake City, UT, USA.
  • 2 Department of Applied Mathematics, University of California Merced, Merced, CA, USA.
  • 3 Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, USA.
  • 4 Department of Bioengineering, University of Colorado, Aurora, CO, USA.
  • 5 Hemophilia and Thrombosis Center, University of Colorado, Aurora, CO, USA.
  • 6 Department of Pediatrics, University of Colorado, Aurora, CO, USA.
  • 7 Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.
  • 8 Department of Applied Mathematics and Statistics, Colorado School of Mines, Golden, CO, USA.
Type
Published Article
Journal
Journal of thrombosis and haemostasis : JTH
Publication Date
Feb 01, 2020
Volume
18
Issue
2
Pages
306–317
Identifiers
DOI: 10.1111/jth.14653
PMID: 31562694
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown. To use a previously validated mathematical model of flow-mediated coagulation as a screening tool to identify parameters that are most likely to enhance thrombin generation in the context of FVIII deficiency. We performed a global sensitivity analysis (GSA) on our mathematical model to identify potential modifiers of thrombin generation. Candidates from the GSA were confirmed by calibrated automated thrombography (CAT) and flow assays on collagen-tissue factor (TF) surfaces at a shear rate of 100 per second. Simulations identified low-normal factor V (FV) (50%) as the strongest modifier, with additional thrombin enhancement when combined with high-normal prothrombin (150%). Low-normal FV levels or partial FV inhibition (60% activity) augmented thrombin generation in FVIII-inhibited or FVIII-deficient plasma in CAT. Partial FV inhibition (60%) boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies. These effects were amplified by high-normal prothrombin levels in both experimental models. These results show that low-normal FV levels can enhance thrombin generation in hemophilia A. Further explorations with the mathematical model suggest a potential mechanism: lowering FV reduces competition between FV and FVIII for factor Xa (FXa) on activated platelet surfaces (APS), which enhances FVIII activation and rescues thrombin generation in FVIII-deficient blood. © 2019 International Society on Thrombosis and Haemostasis.

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