Abstract Number: OC 02.4
Meeting: ISTH 2021 Congress
Background: The resolution of arterial thrombi is critically dependent on the endogenous fibrinolytic system.
Aims: To investigate the endogenous fibrinolytic potential of tissue-type plasminogen activator (tPA) and the intra-thrombus distribution of fibrinolytic proteins formed ex vivo under shear.
Methods: Established and complementary whole blood models, with tPA present at physiologically relevant concentrations, were used to monitor fibrinolysis using a FITC-labelled fibrinogen tracer. Thrombi were formed from anticoagulated blood using a Chandler Loop and from non-anticoagulated blood perfused over specially-prepared porcine aorta strips under low (212 s-1) and high shear (1690 s-1) conditions in a Badimon Chamber. Plasminogen, tPA, plasminogen activator inhibitor-1 (PAI-1), and D-dimer concentrations were measured by ELISA. The association of PAI-1 and tPA was further examined in thrombi extracts and serum by zymography.
Results: Fibrin formation and fibrinolysis occurred simultaneously during thrombus formation as evidenced by the presence of D-dimers in the serum from the closed loop model thrombi. Endogenous tPA concentrations significantly enhanced the rate of lysis and there was a strong correlation of D-dimer concentrations with fluorescence release. tPA-PAI-1 complex was abundant within the serum of Chandler model thrombi. In contrast, within thrombi, free tPA was evident in the head which directly correlated with fibrinolytic activity. Thrombi formed under high shear conditions in the Badimon chamber showed lower fluorescence release and D-dimer concentrations and were more resistant to fibrinolysis than those formed at low shear. Plasminogen and tPA concentrations were elevated in thrombi formed at low shear, while PAI-1 concentrations were augmented at high shear rates.
Conclusions: Active tPA is concentrated within the head of thrombi. Thrombi formed at high shear incorporate less tPA and plasminogen than those at low shear. In contrast, the inhibitor PAI-1, is elevated. Together these factors contribute to the resistance of thrombi formed at high shear to fibrinolytic degradation.
To cite this abstract in AMA style:Whyte C, Mostefai A, M Baeten K, J Lucking A, E Newby D, A Booth N, J Mutch N. Role of Shear Stress and tPA Concentration in the Fibrinolytic Potential of Thrombi [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/role-of-shear-stress-and-tpa-concentration-in-the-fibrinolytic-potential-of-thrombi/. Accessed September 24, 2021.
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