High fibrinogen gamma ' levels in patient plasma increase clot formation a arterial and venous shear

F.L. Macrae, F. Swieringa, J.W.M. Heemskerk, R.A.S. Ariens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

Fibrinogen gamma' accounts for 3% to 40% of plasma fibrinogen. Earlier studies indicated that fibrinogen gamma' forms altered fibrin dots under static conditions, whereas clinically, altered plasma levels are associated with arterial and venous thrombosis. However, the effects of static vs flow conditions on the role of gamma' throughout the pathophysiological range is unknown. This study explores the effects of gamma' levels on clot formation and structure in static and flow conditions. Coagulation of plasma samples with low (n - 41; 3%), normal (n - 45; 10%), or high (n - 33; 30%) levels were compared with that of purified fibrinogen mixtures with increasing ratios of gamma' (3%, 10%, 30%). Clots were analyzed by confocal microscopy, permeation, turbidity, and lysis techniques. In a novel 2-step flow-perfusion model, fibrinogen-deficient plasma repleted with increasing ratios of gamma' (3%, 10%, 30%) or plasmas with low (n = 5, 3%) or high (n = S, 30%) gamma' were flowed over preformed platelet aggregates at arterial (500 s(-1)) and venous (150 s(-1)) shear rates. Increasing gamma' percentages within the pathophysiological range (3%-30%) did not result in any change in dotformation rates; however, it led to significantly higher clot density, thinner fibers, and slower lysis in static conditions. Under flow at arterial shear, high gamma' (30%) led to faster (+44.1%-75.3%) and increased (+104%-123%) fibrin deposition, with clots exhibiting a larger volume (-253%-655%) and height (+130%-146%). These trends were magnified at venous shear. Overall, our findings demonstrate the significant impact of pathophysiological fibrinogen gamma' levels on clot structure and provide new flow-dependent mechanisms to explain how gamma' increases thrombosis risk.
Original languageEnglish
Pages (from-to)3468-3477
Number of pages10
JournalBlood advances
Volume5
Issue number17
DOIs
Publication statusPublished - 14 Sep 2021

Keywords

  • THROMBIN GENERATION
  • SPLICE VARIANT
  • FACTOR-XIII
  • CHAIN
  • BINDING
  • GENES
  • RISK
  • THROMBOEMBOLISM
  • ASSOCIATION
  • INHIBITION

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