Original Paper Cerebrovasc Dis 2014;38:182–190 DOI: 10.1159/000365652

Received: December 27, 2013 Accepted: July 2, 2014 Published online: October 9, 2014

Thrombelastography Maximal Clot Strength Could Predict One-Year Functional Outcome in Patients with Ischemic Stroke Xiaoying Yao Quan Dong Yeping Song Yanqing Wang Ye Deng Yansheng Li

Key Words Thrombelastography · Maximal clot strength · Maximum amplitude · Ischemic stroke · Clinical outcome

Abstract Background: Elevated maximal clot strength, measured by thrombelastography (TEG) maximum amplitude (MA) has been associated with a higher risk for ischemic events in patients with coronary artery diseases. However, it has not been investigated in patients with cerebrovascular diseases. In the current study, we aimed to evaluate the predictive ability of TEG-MA in assessing the risk for ischemic event recurrence and the functional outcome after index ischemic stroke. Methods: This was a prospective observational study. Consecutive eligible patients with acute ischemic stroke were included and followed up for one year. Patients were stratified into tertile groups based on MA levels. TEG-hypercoagulability was defined as an MA of ≥69 mm. Ischemic events were defined as a composite of ischemic stroke, myocardial infarction, or vascular death (excluding hemorrhagic death). The functional outcome was evaluatewd by modified Rankin Scale (mRS). Unfavorable functional outcome was defined as mRS ≥2. Results: Two hundred and eleven

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patients were enrolled with 27 lost to follow-up at one year contact. At baseline, 38 (18.0%) patients were TEG-hypercoagulopathy after the treatment of antiplatelets. Patients with higher tertile of MA were more likely to be females, and had lower hemoglobin levels, higher platelet counts, higher fibrinogen levels, higher white blood cell counts, as well as higher ESR and hsCRP levels. Patients in the third tertile group were more likely to have intracranial artery stenosis and large-vessel subtype stroke than those in the other two groups. Higher tertile of MA was also related to stroke severity in acute phase (higher NIHSS scores on admission and longer in-hospital stay). At one year of follow-up, a higher percentage of unfavorable functional outcome and a nonsignificant trend of higher ischemic event rate were observed in higher MA tertile groups. Multivariate logistic analysis revealed that higher MA level (OR = 1.192, p = 0.022) was an independent predictor for unfavorable one-year functional outcome. Other independent predictors included old age (OR = 1.119, p = 0.001), diabetes mellitus (DM) (OR = 4.280, p = 0.014), previous ischemic stroke/TIA history (OR = 4.953, p = 0.008), and higher NIHSS scores on admission (OR  = 1.437, p = 0.001). Conclusions: We found that higher TEG-MA levels could predict an unfavorable functional outcome after index ischemic stroke. Further, large-

Yansheng Li, MD Department of Neurology, Ren Ji Hospital 1630 Dongfang Road Pudong District, Shanghai 200127 (China) E-Mail lliyans @ hotmail.com

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Department of Neurology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Introduction

Thrombelastography (TEG) is a whole-blood viscoelastic assay that has been widely used in the assessment of coagulation and fibrinolysis [1]. TEG, unlike conventional coagulation tests, assesses the hemostasis as a dynamic process from the time of the initial platelet-fibrin interaction, through platelet aggregation, clot strengthening and fibrin cross linkage to eventual clot lysis [1]. Maximum amplitude (MA), probably the most important information provided by TEG, is taken to represent the maximal clot strength [2]. High MA, indicative of hypercoagulability, can be attributed to persistence of high platelet reactivity and generation of thrombin on the surface of activated platelets [3, 4]. Therefore, TEG might be a potentially useful test for predicting thromboembolic events such as ischemic stroke, myocardial infarction (MI), cerebral venous thrombosis, pulmonary embolus and deep vein thrombosis. Previous results have suggested that MA could predict risk for ischemic events after coronary stenting, coronary artery bypass graft (CABG) surgery, or other non-cardiac surgeries [3–8]. However, there are limited data about TEG-MA in acute ischemic stroke; Ettinger et al. and Elliott et al. reported that acute ischemic stroke patients were hypercoagulable compared to normal controls [9, 10], and Elliott et al. further proved that the treatment with tissue plasminogen activator resulted in reduction of clot strength [10]. We hypothesized that TEG-MA could also predict the ischemic event recurrence after index ischemic stroke. Moreover, since a hypercoaguable state is linked to compromised microcirculation and generation of new thrombi at the surface of plaque rupture [11], it could be expected that high MA might be associated with progressive stroke and be able to predict stroke severity and functional outcome in ischemic stroke patients. Therefore, in the current study, we intended: (1) to learn the distribution of TEG-MA in acute ischemic stroke patients under antiplatelet treatment; (2) to investigate the association between MA and baseline clinical, laboratory and radiological data; (3) to evaluate the predictive ability of MA in assessing the risk for ischemic event recurrence; (4) and to establish a possible relationship between MA and stroke severity and functional outcome. Predicting Outcome of Ischemic Stroke by TEG Clot Strength

Materials and Methods Study Population This was a prospective observational study of consecutive patients with acute ischemic stroke admitted to a Neurological Department at a tertiary level hospital in China (Shanghai Ren Ji Hospital) from January 1, 2012 to July 31, 2012. Shanghai Ren Ji Hospital is a major teaching hospital of the Medical School of Shanghai Jiao Tong University. Nearly 60–80 acute ischemic stroke patients were admitted to the department every month. Eligible patients were included in the study at hospital admission and followed up for one year. Patients meeting one of the following criteria were excluded: age below 18 years; missing admission TEG; no cranial MRI performed within 7 days after disease onset; after thrombolysis therapy; history of hematologic diseases; prothrombin time greater than 1.5 times control; platelet count less than 100,000/mm3; patients taking anticoagulant therapy; patients refusing to participate in the current study or refusing the follow-ups. The study was approved by the Ethics Committee of Ren Ji Hospital. Informed consent was obtained from all the included patients. Baseline Data Collection Hypertension was defined as the use of antihypertensive agents or systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. Diabetes mellitus (DM) was defined as the use of oral hypoglycemic agents, insulin, or a fasting serum glucose level higher than 7.0 mmol/l on at least two separate occasions. Hyperlipidemia was defined as the use of lipid-lowering agents or a serum total cholesterol level ≥5.7 mmol/l or LDL cholesterol level ≥3.4 mmol/l. Ischemic heart disease was defined as a history of acute myocardial infarction or angina pectoris. Atrial fibrillation was present if the patient was previously diagnosed by a cardiologist or if the arrhythmia was found on an EKG record performed after admission. TEG was part of the routine analysis in patients with cerebrovascular diseases admitted to the Neurology Department of our institute. Other routine tests after admission included blood cell count, urianalysis, renal and liver function tests, electrolytes, blood glucose, hemoglobin A1c (HbA1c), lipid profile, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), fibrinogen, erythrocyte sedimentation rate (ESR) and hypersensitive C-reactive protein (hsCRP). 12-lead electrocardiography and echocardiography were routinely performed. All patients underwent cranial MRI except where there were contradictions or patients could not cooperate. Intracranial arteries were evaluated by cranial MRA or CTA. Extracranial arteries were screened by Doppler ultrasound, and if any artery stenosis was suspected, cervical MRA or CTA was ordered. MRI studies were performed on a 1.5 or 3.0 T magnetic resonance scanner. MRA was conducted according to the three-dimensional time-of-flight method. CTA was performed on a 128-slice CT system. The percentage diameter stenosis was calculated by the method described previously [12]. Intracranial/extracranial artery stenosis was defined as ≥50% stenosis in the intracranial or extracranial arteries according to MRA or CTA imaging [13, 14]. White matter lesions (WMLs) were considered present when visible as hyperintensity on fluid-attenuated inversion recovery sequence, without prominent hypointensity on T1-weighted images.

Cerebrovasc Dis 2014;38:182–190 DOI: 10.1159/000365652

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scale studies are required to investigate the relationship between MA levels and risk of recurrent ischemic events in © 2014 S. Karger AG, Basel ischemic stroke patients.

Blood Sampling and Thromboelastography Analysis Blood samples for the test of TEG were obtained after the application of antiplatelet agents for at least three days to reach the steady blood concentrations. Whole blood was collected in a 3.2% sodium citrate vacutainer tube (BD) and TEG was performed within 90 min after collection using a computerized TEG coagulation analyzer according to the manufacturer’s instructions (TEG model 5000; Haemoscope Corporation, Niles, Ill., USA). Citrate plasma was mixed with kaolin, inverted five times, and then loaded in a heparinise-coated cup. Thrombelastography was stopped after maximal fibrin clot strength was recorded. Maximum amplitude (MA, mm) of the TEG tracing represents the maximum clot strength. Patients were divided into three tertile groups according to MA levels. TEG-hypercoagulability was defined as an MA of ≥69 mm according to the manufacturer. Follow-Ups and Clinical Outcomes Patients were contacted by telephone by one investigator (Yanqing Wang) who was blinded to laboratory and radiological data 12 months after the index event to determine the recurrence of ischemic events and functional outcomes. Ischemic events were defined as a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal myocardial infarction, or other vascular death (excluding hemorrhagic death). If patients or their family members reported the recurrence of ischemic events, source medical documents were reviewed to make further confirmation. The functional outcome was evaluated by modified Rankin Scale (mRS) with a validated questionnaire [17]. Unfavorable functional outcome was defined as mRS ≥2. Statistical Analysis Categorical variables were summarized as counts (percentage) and continuous variables as means (SE) or medians (interquartile ranges (IQR)), if not distributed normally. Statistical comparisons among three tertile groups were performed using one-way ANOVA with LSD post hoc test, Kruskal-Wallis test and Wilcoxon rank sum (Bonferroni adjusted post hoc) for continuous variables, as well as the χ2 and Fisher’s exact tests for categorical variables, as appropriate. Correlations between continuous variables were assessed by Spearman’s correlation coefficient. All variables with a p less than 0.05 on univariate analysis were entered into stepwise logistic regression analysis. Kaplan-Meier curves for time from index stroke onset to the first occurrence of any ischemic events were plotted for three MA tertile groups and compared by Log-rank test. A two-tailed probability value

Thrombelastography maximal clot strength could predict one-year functional outcome in patients with ischemic stroke.

Elevated maximal clot strength, measured by thrombelastography (TEG) maximum amplitude (MA) has been associated with a higher risk for ischemic events...
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