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J Thorac Cardiovasc Surg 2001;122:405-406
© 2001 The American Association for Thoracic Surgery
Letters to the Editor |
Department of Cardiothoracic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlandsa, Department of Clinical Chemistry, Leiden University Medical Center, Leiden, The Netherlandsb
Reply to the Editor
Poullis and associates
1 showed that the thrombin-induced activation of platelets in vitro, as mediated by proteolysis of the protease-activated receptor 1 (PAR1), is inhibited by aprotinin. The authors also demonstrated that the platelets, in the presence of aprotinin, still respond to collagen and epinephrine. However, this in vitro study using washed platelets cannot easily be extended to our in vivo situation in the pericardial cavity, as proposed by Landis and Taylor. They propose that platelets in the pericardial blood become activated by adenosine diphosphate (ADP) and collagen from the surgical wound and not by thrombin, that is, by a process that is not inhibited by aprotinin, as shown by Poullis and associates. 1 First, it would seem from their letter that thrombin is especially being formed by contact between blood and the bypass circuit in the systemic circulation. Several studies indicated that thrombin generation is especially pronounced in the pericardial blood, a process most likely mediated by the tissue factor–factor VII pathway and not by the contact activation pathway. 2 Second, as also noted by Poullis and coworkers, 1 thrombin not only activates platelets via PAR1 proteolysis, but also via proteolysis of the PAR4 receptor and nonproteolytically via glycoprotein Ib. 3,4 Although the platelet-activating compounds ADP and collagen are likely to be present in the wound area of the pericardial cavity to activate platelets by an aprotinin-insensitive pathway, the synergistic effect 5 of individual platelet agonists, including thrombin, on the overall platelet response can easily be underestimated in the in vivo situation. Thus, only complete inhibition of thrombin would preclude a synergistic action between residual thrombin activity and other agonists. This may well involve other stimulus-response coupling mechanisms than solely the PAR1 receptor. Third, aprotinin may prohibit platelet activation not only via the inhibition of thrombin, but also by inhibition of plasmin. 5-8 Plasmin is present at high concentrations in pericardial blood and is known to activate platelets. 9 The exact mechanism leading to the observed platelet activation in the pericardial blood therefore remains to be established, that is, thrombin-, plasmin-, ADP-, collagen-mediated, or by a combination of those agonists. Because platelet activation, as measured by the disappearance of glycoprotein Ib from the platelet surface or the formation of platelet microparticles, is far more extensive in the pericardial blood than in the systemic circulation, pericardial blood may be a suitable target for therapeutic intervention if this blood has to be returned into the patient.
In conclusion, our finding that topical administration of aprotinin into the pericardial blood does not inhibit platelet activation 10 could not be anticipated beforehand. Also, this topical administration of aprotinin may still have a favorable effect on the overall systemic hemostatic process by inhibition of, for example, hyperfibrinolysis in this pericardial wound blood before being returned into the patient.
12/8/115697
References
-thrombin binding site on platelet glycoprotein Ib. J Biol Chem. 1994;269:6478-84.
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