Why thrombin PAR1 receptors are important to the cardiac surgical patient

Abstract

Targeting of the high-affinity thrombin receptor protease-activated receptor-1 (PAR1) on platelets represents an exciting strategy to curb the pro-thrombotic complications of cardiac surgery without interfering with the hemostatic benefits of thrombin in the coagulation cascade. The first dedicated PAR1 antagonist to complete safety trials this year has justified expectations, showing no increased risk of bleeding when added to standard anti-platelet therapy but halving major adverse cardiovascular events after percutaneous coronary intervention. In the setting of cardiothoracic surgery with cardiopulmonary bypass, an FDA-approved drug already exists with anti-PAR1 properties: aprotinin has been shown to inhibit thrombin-induced platelet activation in vitro and clinically, through sparing of PAR1 receptor cleavage and activation. Because aprotinin also exerts anti-fibrinolytic effects through blockade of plasmin, this indicates a subtle clinical mechanism of action that is simultaneously anti-thrombotic yet hemostatic. PAR1 antagonists would also be expected to exert anti-inflammatory properties through targeting of PAR1 on endothelium, and this principle has been validated in vitro for aprotinin and newer peptidomimetric antagonists. PAR1 antagonism is likely to remain an active and exciting area of research in cardiac surgery, with newer generations of PAR1 antagonists and recombinant aprotinin variants entering clinical development.

Figure 1.

Anti-fibrinolytics and PAR1 antagonists in cardiac surgery. (Left) A concern in cardiothoracic surgery is that, although antifibrinolytics are effective at reducing bleeding, might they not also present a concomitant risk of thrombosis? (Middle) The promise of PAR1 antagonists is that they can inhibit the action of thrombin on platelets while maintaining the hemostatic properties of thrombin in the coagulation cascade. (Right) The TRA-PCI study (phase II safety trial) seems to have borne out this early promise by noting no increase in TIMI bleeding but a 46% reduction in major adverse cardiovascular events after percutaneous coronary intervention. Aprotinin exhibits anti-thrombotic properties in on- and off-pump surgery by inhibiting thrombin-induced platelet activation through PAR1, yet it exhibits simultaneous hemostatic properties by blocking plasmin in the fibrinolytic pathway. tbn, thrombin.