Regular ArticleEndogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment
Introduction
Plaque disruption with subsequent thrombin generation and superimposed thrombosis is the main cause of acute coronary events [1]. Thrombin formation enhance the activation of the coagulation cascade, platelet activation and may also contribute to the development of the atheromatous lesion itself [2], [3].
Prothrombin fragment 1+2 (F1+2) is a specific molecular marker of thrombin generation in the body. Circulating levels have previously been reported to be a marker of both acute venous and arterial thrombotic events [4], [5] and also to be a predictor for new thrombotic events and mortality [6], [7]. Growing evidence support the concept that tissue factor (TF)–induced thrombin formation in plasma ex vivo by the endogenous thrombin potential (ETP), and notably parameters of the thrombogram, are useful in assessing the risk of bleeding, thrombosis and anticoagulant treatment [8]. The calibrated automated thrombogram (CAT) method displays the thrombin activity over time in clotting plasma. This is monitored by a fluorescent product released by cleavage of a flourogenic substrate and calibrated by comparison with a known thrombin activity in a parallel non–clotting sample [9]. Thus, the thrombogram allow assessment of the initiation phase (lag–time) and propagation phase (endogenous thrombin potential–ETP) of coagulation. As clotting occurs at the start of the explosive burst of thrombin formation, clotting times is a good estimate of the duration of the lag phase, whereas ETP reflects the potential thrombin–forming capacity of a non–triggered system in any given situation, e.g. at site of plaque disruption.
Aspirin inhibits thromboxane–induced platelet activation by irreversible inhibition of cyclooxygenase [10], whereas warfarin inhibits the vitamin K–dependent post–translational carboxylation of glutamate residues on the N–terminal regions of coagulation factors II, VII, IX and X by inhibiting the conversion of vitamin K 2, 3–epoxide to reduced vitamin K [11]. Several randomized controlled studies have reported superior efficacy in secondary prevention of fatal and non–fatal MI and stroke of oral anticoagulant treatment alone or in combination with antiplatelet treatment over antiplatelet treatment alone in survivors of acute myocardial infarction (AMI) [12], [13], [14], [15]. Warfarin treatment is reported to decrease factor VII coagulant activity (FVIIc) [16], [17] and factor VII mass (FVIIAg) [18], whereas activated factor VII (FVIIa) are reported unchanged [19] or decreased [20] in patients on anticoagulant treatment. The aims of the present study were to investigate the effect of warfarin and aspirin treatment on thrombin generation, assessed by the ETP, and study the relation between coagulation parameters and ETP in patients with AMI.
Section snippets
Study population and design
This is a part of the WARIS–II trial [13], a national multicenter study in which patients with an AMI were randomly assigned to treatment with warfarin alone (Marevan®, Nycomed Pharma, Asker, Norway) with target INR 2.8–4.2, aspirin alone (Albyl–E®, Nycomed Pharma) 160 mg d–1 or aspirin 75 mg d–1 and warfarin with target INR 2.0–2.5. Randomization was stratified by centre. The study protocol was approved by the Regional Ethics Committee and all patients gave written informed consent for the
Results
Baseline characteristics of the study population are given in Table 1. Mean age was 61.4 years and 78% of the patients were men. The three treatment groups were comparable with respect to all the listed variables except for the prevalence of diabetes which was significantly higher in the group of patients receiving combined aspirin and warfarin treatment. The mean INRs (range) obtained in patients treated with warfarin alone were 3.0 (1.9–5.5) and 2.3 (1.3–4.1) in those receiving combined
Discussion
The present study shows a significant reduction of thrombin generation both in vivo, assessed by the levels of F1+2, and ex vivo, assessed by ETP, during 6 weeks anticoagulant treatment with warfarin after an AMI. Thrombin formation is known to play a crucial role in coagulation as well as platelet activation with subsequent thrombus formation during acute coronary events [22]. Thus, it is likely to assume that inhibited thrombin generation during warfarin treatment contributed substantially to
Acknowledgements
CART is supported by an independent grant from Pfizer.
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