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Methods and models to evaluate shear-dependent and surface reactivity-dependent antithrombotic efficacy.

K S Sakariassen1, S R Hanson, Y Cadroy

  • 1Department of Lead Pharmacology, Pharmacia Corporation, Uppsala and Stockholm, Sweden. kjell.sakariassen@serono.com

Thrombosis Research
|October 24, 2001
PubMed
Summary

Understanding blood flow and surface reactivity is crucial for evaluating antithrombotic drugs. These factors influence drug efficacy in various thrombosis models, aiding in predicting human responses.

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Area of Science:

  • Pharmacology
  • Biomedical Engineering
  • Hematology

Background:

  • Thrombosis research requires accurate models to assess antithrombotic drug efficacy.
  • Flow-dependent thrombosis models have evolved since the 1970s for in vitro, ex vivo, and in vivo studies.
  • Perfusion chambers exposing thrombogenic surfaces to flowing blood are key components of these models.

Purpose of the Study:

  • To evaluate the impact of blood flow and surface reactivity on antithrombotic drug measurement.
  • To provide essential information for the proper assessment of antithrombotic drug profiles.
  • To suggest recommendations for experimental conditions in antithrombotic efficacy testing.

Main Methods:

  • Utilizing flow-dependent thrombosis models, including in vitro and ex vivo studies with native or anticoagulated blood.

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  • Employing perfusion chambers inserted into arteriovenous (AV) shunts in animal models (baboon, pig, dog, rabbit).
  • Testing antithrombotic drugs under well-defined shear conditions and on various thrombogenic surfaces (e.g., tissue factor-rich, collagen-rich).

    • Main Results:

    • Shear-dependent efficacy was observed for anticoagulants (heparin, LMWH, thrombin/Xa/VIIa inhibitors) and some platelet antagonists (aspirin, TxA2 inhibitors, vWf inhibitors).
    • The degree of shear dependency varied with thrombogenic surface type and shear rate (e.g., more pronounced on TF-rich surfaces at low shear).
    • Platelet ADP antagonists (clopidogrel) and GPIIb-IIIa antagonists showed shear-independent efficacy, even at high arterial shear rates.

    Conclusions:

    • Blood flow and surface reactivity significantly influence antithrombotic drug efficacy measurements.
    • Model systems effectively mimic and predict antithrombotic efficacy in humans.
    • Established data support recommendations for optimizing experimental conditions in antithrombotic drug testing.