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Platelet anaesthesia during extracorporeal circulation: Differential effects of GP IIb/IIIa blockers on platelet activation marker P-selectin expression at hypothermia

https://doi.org/10.1016/j.thromres.2008.01.001Get rights and content

Abstract

Introduction

Blood contact with artificial surfaces of extracorporeal circulation (ECC) and hypothermia as applied in cardiac surgery cause platelet dysfunction possibly followed by bleeding complications. “Platelet anaesthesia” is a pharmacological strategy to protect platelets against ECC-induced damage using a GP IIb/IIIa blocker, which should be short acting to achieve maximal therapy control thereby avoiding post-ECC haemorrhage. However, GP IIb/IIIa blockers can paradoxically induce platelet activation, which may limit their efficiency as anti-platelet drugs. This in-vitro study investigated potentially platelet-activating effects of short-acting GP IIb/IIIa blockers during normothermic and hypothermic ECC.

Materials and methods

Control (untreated) and treated (using either FK633 [half-life: 0.52 h], tirofiban [half-life: 1.5–2 h], or eptifibatide [half-life: 1.5 h]) heparinized blood was circulated in an ECC-model at normothermia (37 °C) and hypothermia (18 °C). Percentages of platelet aggregates and P-selectin-expressing (activated) platelets, platelet-counts and Thrombin–Antithrombin (TAT) complex formation were determined before (baseline) and after ECC. Statistical analysis was performed using multifactorial ANOVA after log-transforming the data.

Results

GP IIb/IIIa blockade inhibited ECC-induced platelet aggregation and platelet loss and decreased P-selectin expression at normothermia. During hypothermic ECC P-selectin was decreased by tirofiban but augmented by FK633 and eptifibatide. TAT formation was only decreased by FK633.

Conclusions

Especially regarding its ultra-short half-life FK633 has the best properties for platelet protection during normothermic ECC. However, at hypothermia FK633 and eptifibatide induce platelet activation. In relation with “platelet anaesthesia” possible hypothermia-associated prothrombotic side effects of GP IIb/IIIa blockers should be considered.

Introduction

Contact of blood with an extracorporeal circulation circuit (ECC) and exposure of blood to hypothermia as employed in cardiac surgery causes persistent activation and subsequent dysfunction of platelets [1], [2], [3]. Temporary blockade of the main platelet receptor GP IIb/IIIa (αIIbβ3) during ECC, also termed “platelet anaesthesia”, is an experimental pharmacological strategy to protect platelets during ECC [4]. It is not yet routinely employed but may be very beneficial for the clinical setting and improve the outcome of operations employing ECC. Several studies have shown that cardiac surgery can be performed without an increase of bleeding complications after administration of short-acting GP IIb/IIIa blockers [5], [6], [7]. A desirable property of a GP IIb/IIIa blocker used as “platelet anaesthetic” is a short half-life. Thereby platelets are inhibited only during ECC and full platelet function is restored shortly after ECC to provide full functioning platelets for haemostasis at the end of surgery. According to this criterion the “ultra-short acting” GP IIb/IIIa blocker FK633 would be very suitable because of its half-life of only 0.52 h [8]. GP IIb/IIIa blockers that are also candidates for “platelet anaesthesia” are the commercially available agents tirofiban and eptifibatide. Nevertheless, both are not optimal for the desired indication because of their half-lives of 1.5–2 h [9]. Therefore, it is not clear which agent would be most suitable for “platelet anaesthesia”. This issue is very important not only in terms of half-life of the desired agent but also regarding the fact that GP IIb/IIIa blockers may induce platelet activation under certain conditions [10], [11], [12], [13]. In general, a platelet-activating property may limit the efficiency of an anti-platelet drug. The aim of this study was to investigate potentially platelet-activating effects of the GP IIb/IIIa blockers FK633, tirofiban and eptifibatide under conditions of ECC at normothermia and hypothermia as employed in cardiac surgery.

Section snippets

Blood sampling

Blood from non-medicated healthy male subjects, definitely free of platelet-affecting drugs for 14 days, was collected by venipuncture with a 21 gauge butterfly needle from an antecubital vein. The first 5 mL of blood was discarded before additional blood samples were drawn for analysis. All blood samples were anti-coagulated with 3 U/mL heparin. Blood sampling procedures were approved by the ethics committee of the University of Tübingen, Germany (project-numbers 410/2004 V and 193/2002 V).

Sample preparation

In

Expression of the platelet activation marker P-selectin

During ECC platelet activation is induced by contact activation of platelets at the artificial ECC surface. A strong temperature-associated effect was observed regarding the action of GP IIb/IIIa blockers on P-selectin:

After 30 and 90 min of normothermic ECC FK633 inhibited P-selectin expression in unstimulated and ADP-stimulated samples (Fig. 1a). During hypothermic ECC FK 633 treatment increased P-selectin expression 3.2-fold in unstimulated samples (after 30 min) and 2.7-fold (after 90 min)

Discussion

Blood circulation in an ECC circuit and hypothermia in temperature ranges as applied in cardiac surgery leads to damage and dysfunction of platelets [2], [3]. Previous reports have stated that pharmacological platelet anaesthesia using a blocker of the main platelet receptor GP IIb/IIIa can protect platelets against ECC-induced damage [4], [15]. The principle of platelet anaesthesia comprises that a GP IIb/IIIa blocker is administered temporarily before or during ECC to protect platelets

Conclusion

Ultra-short acting GP IIb/IIIa blockade with FK633 is a promising experimental strategy to inhibit platelet activation and thereby conserve platelet function during normothermic ECC. However, in temperature ranges of deep hypothermia that may be applied during cardiac surgery GP IIb/IIIa inhibitors like FK633 and eptifibatide induce expression of the platelet activation marker P-selectin which suggests a prothrombotic side effect of these agents. Therefore, a potential GP IIb/IIIa blocker for

References (23)

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This work has been presented at the Annual Scientific Meeting of the Australian Vascular Biology Society at Bellinzona, Hepburn Springs, Victoria on the 7th of September 2007.

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