International Journal of Cardiology 172 (2014) e24–e25

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Letter to the Editor

Thrombin induced platelet–fibrin clot strength measured by thrombelastography is a novel marker of platelet activation in acute myocardial infarction☆ Hongyi Wu, Juying Qian, Qibing Wang, Haichen Lv, Aijun Sun, Junbo Ge ⁎ Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China

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Article history: Received 21 September 2013 Accepted 21 December 2013 Available online 5 January 2014 Keywords: Acute myocardial infarction Platelet activation Thrombelastography Marker

After disruption of coronary arteriosclerotic plaques, platelet activation plays a causal role in the subsequent thrombus formation, leading to acute myocardial infarction (AMI) [1]. Although many attempts have been made to monitor platelet activity to detect atherothrombotic process, thus far an easy, useful and specific assay has not been discovered. As a point-of-care testing, thrombelastography (TEG) specifically evaluates the contribution of platelet to thrombosis. Of the TEG parameters, thrombin-induced platelet–fibrin clot strength (MAthrombin) has been shown to reflect the maximal potential platelet reactivity [2]. Interestingly, it has been demonstrated that MAthrombin exhibited significant correlation with other prothrombotic markers and with C-reactive protein and were increased in patients with angina as compared to asymptomatic patients [3]. Taken together, these findings suggest the potential of MAthrombin for diagnostic evaluation of pathophysiological state of hypercoagulability in AMI patients. However, the association between MAthrombin and AMI has not yet been clarified. In the present study, we investigated the level of MAthrombin in patients with AMI and other forms of coronary atherosclerosis disease (CAD) and found that there is a dynamic elevation of MAthrombin after the onset of myocardial infarction. From March 2011 to July 2013, 399 Chinese patients were enrolled in this prospective observational single centre study. Exclusion criteria were: more than 75 years of age, with a history of peripheral arterial ☆ Funding: This work was supported by the National Basic Research Program of China [2011CB503905]. ⁎ Corresponding author at: 180 Fenglin Road, Shanghai 200032, China. Tel.: + 86 2164041990x2745; fax: +86 21 64223006. E-mail address: [email protected] (J. Ge). 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.092

disease, anaemia, malignant disease, severe renal or hepatic insufficiency, total platelet count b 100 × 109/L, and increased risk of bleeding and hematologic disorder. The patients were grouped according to the type of clinical presentation. AMI group comprised 100 patients who had acute myocardial infarction within 1 week of the onset of chest pain. SMI group included 44 individuals with subacute (14–30 days) myocardial infarction. OMI group consisted of 57 stable subjects with old (more than 2 months) myocardial infarction. SAP group included 170 individuals with stable CAD without prior myocardial infarction. The last group was a control group without CAD (n = 28). The study protocol was approved by the hospital's medical ethics committee, and informed consent was obtained from each patient. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. The magnitude of MAthrombin was assessed by Thrombelastograph Hemostasis Analyzer (Haemoscope Corp., Niles, Illinois) with PlateletMapping. The Food and Drug Administration-approved TEG relies on the measurement of activator-induced clot strength to enable a quantitative analysis of the contribution of platelet–fibrin interactions to thrombosis [4,5]. Continuous variables were expressed as mean ± SD. Categorical variables were expressed as frequencies and percentage. For analysis of relations between categorical variables we used the chi-square test or Fisher's exact test when appropriate. Student's t-test was used for the univariate analysis of the continuous variables. Mean values were compared by analysis of variance among different groups. All tests were 2-sided with a significance level of P b 0.05. All statistical analyses were performed with SPSS software package, version 17 (SPSS Inc., Chicago, Illinois). As demonstrated in Table 1, baseline cardiovascular risk factors were well balanced among control group, SAP group and AMI group. There was a progressive increase of MAthrombin in patients with no CAD, with SAP and with AMI (P b 0.001, Table 1). MAthrombin level was significantly elevated in AMI subjects compared to patients with SAP (68.0 ± 4.8 vs. 63.4 ± 3.9 mm, P b 0.001; Fig. 1) or compared to controls (68.0 ± 4.8 vs. 60.0 ± 2.9 mm, P b 0.001; Fig. 1). Moreover, individuals with SAP had considerably higher mean MAthrombin than individuals without CAD (63.4 ± 3.9 vs. 60.0 ± 2.9 mm, P b 0.001; Fig. 1). When the comparison was made among the three groups as AMI, SMI, and OMI, we found that MAthrombin level was associated with the stages of myocardial infarction (P b 0.001, Table 1). The mean value of

H. Wu et al. / International Journal of Cardiology 172 (2014) e24–e25

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Table 1 Baseline characteristics and the level of MAthrombin in the study population. Characteristics

CONTROL N = 28

SAP N = 170

AMI N = 100

SMI N = 44

OMI N = 57

Age Male Hypertension Diabetes mellitus Hypercholesterolemia Current smoking MAthrombin Mean value (mm) Quartiles Q1 (b62.7 mm) Q2 (62.7–66.0 mm) Q3 (66.0–70.2 mm) Q4 (N70.2 mm)

58 ± 7 23(82.1%) 14(50.0%) 4(14.3%) 6(21.4%) 8(28.6%)

61 ± 8 140(82.4%) 105(61.8%) 36(21.2%) 33(19.4%) 80(47.1%)

60 ± 10 84(84.0%) 59(59.0%) 30(30.0%) 27(27.0%) 56(56.0%)

57 ± 12 40(90.9%) 24(54.5%) 7(15.9%) 6(13.6%) 27(61.4%)

59 ± 9 51(89.5%) 25(43.9%) 11(19.3%) 10(17.5%) 33(57.9%)

60.0 ± 2.9

63.4 ± 3.9

68.0 ± 4.8

66.2 ± 4.2

63.6 ± 3.8

25(89.3%) 2(7.1%) 1(3.6%) 0

74(43.5%) 52(30.6%) 35(20.6%) 9(5.3%)

16(16.0%) 20(20.0%) 28(28.0%) 36(36.0%)

9(20.5%) 13(29.5%) 10(22.7%) 12(27.3%)

25(43.9%) 19(33.3%) 11(19.3%) 2(3.5%)

P1

P2

P3

0.278 0.936 0.492 0.123 0.348 0.033

0.311 0.426 0.186 0.119 0.139 0.835

0.087 0.203 0.018 0.762 0.755 0.157

b0.001 b0.001

b0.001 b0.001

0.863 0.932

b0.001

b0.001

0.735

Data are expressed mean ± SD or number of patients (percentage). P1: the comparison was made among control, SAP and AMI groups; P2: the comparison was made among AMI, SMI and OMI groups; P3: the comparison was made between SAP and OMI groups.

Fig. 1. Thrombin induced platelet–fibrin clot strength in the five study groups. ★P b 0.001, §P b 0.05 as compared with the previous group.

MAthrombin was significantly decreased in patients with subacute myocardial infarction compared to AMI patients (66.2 ± 4.2 vs. 68.0 ± 4.8 mm, P = 0.030; Fig. 1). Additionally, further decrease in MAthrombin was observed in OMI participants (63.6 ± 3.8 vs. 66.2 ± 4.2 mm, P = 0.003; Fig. 1). However, MAthrombin level remained significantly elevated in SMI subjects in comparison with subjects presenting with SAP (66.2 ± 4.2 vs. 63.4 ± 3.9 mm, P b 0.001; Fig. 1). Interestingly, we did not observe a significant difference in MAthrombin between OMI subjects and SAP subjects (P = 0.863, Table 1). Distribution of MAthrombin quartiles (Q1 to Q4) within the study groups was shown in Table 1. A high MAthrombin was defined as a value in the highest quartile (N 70.2 mm). Our results demonstrated that 36.0% (36/100) of the subjects with AMI displayed high MAthrombin, whereas none of the controls and only 5.3% (9/170) of the SAP patients displayed high MAthrombin (P b 0.001, Table 1). Additionally, the prevalence of high MAthrombin decreased gradually in participants with

AMI, with subacute myocardial infarction, and with OMI (P b 0.001, Table 1). To the best of our knowledge, few data have been reported about the association of the MAthrombin level with AMI. We noticed an abrupt elevation of MAthrombin in patients with AMI and a progressive decrease of platelet activation with time after the event. Interestingly, we did not observe a significant difference in MAthrombin between stable CAD subjects with OMI and those without prior myocardial infarction. Although these correlations are not surprising, our results support the concept that platelet activation plays an important role in the pathophysiology of AMI and suggest that MAthrombin may be a useful candidate marker allowing for easy identification of patients who are in a platelet hyperaggregability state. In fact, a reliable serum biochemical marker for determination of platelet activation in various stages of CAD is desirable. Additionally, the result that the elevation of MAthrombin persists even in the subacute phase of MI supports the view that long-term dual antiplatelet therapy is essential to reduce the risk of recurrent ischaemic events in patients with AMI. Of note, a recent study has suggested that MAthrombin parameter provided additional information for risk assessment after percutaneous coronary intervention [2]. However, little is known about the effect of antiplatelet treatment on the level of MAthrombin. Further investigation may be needed to understand whether MA represents a potential therapeutic target. References [1] Trip MD, Cats VK, van Capelle FJL, et al. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med 1990;322:1549–54. [2] Gurbel PA, Bliden KP, Guyer K, et al. Adenosine diphosphate-induced platelet-fibrin clot strength: a new thrombelastographic indicator of long-term poststenting ischemic events. Am Heart J 2010;160(2):346–54. [3] Tantry US, Bliden KP, Suarez TA, et al. Hypercoagulability, platelet function, inflammation and coronary artery disease acuity: results of the Thrombotic RIsk Progression (TRIP) study. Platelets 2010;21(5):360–7. [4] Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005;46(10):1820–6. [5] Wu H, Qian J, Xu J, et al. Besides CYP2C19, PON1 genetic variant influences postclopidogrel platelet reactivity in Chinese patients. Int J Cardiol 2013;165(1):204–6 [30].