Platelet GP IIb/IIIa receptor blockade versus selective inhibition of platelet signal transduction: Which approach is better to protect platelets during extracorporeal circulation?

  • Dr Andreas Straub, Dept. of Thoracic, Cardiac and Vascular Surgery, University Hospital of Tübingen, Germany
  • Dr Hans-Peter Wendel, Dept. of Thoracic, Cardiac and Vascular Surgery, University Hospital of Tübingen, Germany
  • Dr Ruben Azevedo, Dept. of Thoracic, Cardiac and Vascular Surgery, University Hospital of Tübingen, Germany
  • Daniela Schiebold, Dept. of Thoracic, Cardiac and Vascular Surgery, University Hospital of Tübingen, Germany
  • Prof Karlheinz Peter, Baker IDI Heart and Diabetes Institute, Melbourne, Australia
  • Dr Simone Schoenwaelder, Australian Centre for Blood Diseases, Melbourne, Australia
  • Prof Gerhard Ziemer, Germany

    • Objective: Blood contact with extracorporeal circulation (ECC) and hypothermia as used in cardiac surgery cause platelet dysfunction possibly followed by severe bleeding as well as thrombotic complications. Platelet glycoprotein (GP) IIb/IIIa blockers protect platelets during ECC but may cause prolonged platelet inhibition. An alternative may be selective inhibition of platelet signal transduction using the new phosphoinositide-3-kinase-p110β inhibitor TGX-221 that inhibits shear-induced platelet activation without affecting the bleeding time.
    Methods: Heparinized blood of healthy volunteers was treated in-vitro with GP IIb/IIIa blockers (tirofiban [half-life:1.5-2 hours], eptifibatide [half-life:1.5 hours], FK633 [half-life:0.52 hours]), TGX-221 or as control and circulated in an ECC model at normothermia (37°C) and hypothermia (18°C). Before and after circulation platelet aggregation and activation (P-selectin expression and β-thromboglobulin release) and platelet-ECC adsorption were investigated in flow cytometry and by ELISA.
    Results: All investigated GP IIb/IIIa blockers and TGX-221 inhibited platelet activation and aggregation at normothermia. At hypothermia, however, platelet P-selectin expression was decreased by tirofiban to 19.5% of control values but augmented by FK633 and eptifibatide to 269% and 163% of control values respectively (p<0.0001). Compared to control values tirofiban and TGX-221 decreased platelet-ECC adsorption to 11.6% and 29.5% respectively (p<0.05).
    Conclusions: FK633 is the most suitable GP IIb/IIIa blocker to protect platelets during normothermic ECC especially regarding its short half-life that may facilitate therapy control. However, at hypothermia prothrombotic side effects of GP IIb/IIIa blockers should be considered. TGX-221 is a promising alternative and may be safer for clinical use because of its selective mode of action.