Correlation between plasma clot properties, thrombin generation and whole blood fibrinolytic assays in patients presenting with STEMI

Abstract

Abstract Background Impaired endogenous fibrinolysis is a novel risk factor for recurrent adverse cardiovascular events in acute coronary syndrome (ACS) patients. This is independent of conventional cardiovascular risk factors and unaffected by dual antiplatelet therapy (DAPT). The mechanism underlying impaired endogenous fibrinolysis in ACS patients is currently unclear. Aim To identify the relationship between whole blood fibrinolysis, plasma fibrinolysis and thrombin generation in samples from STEMI patients. Methods In a large, prospective, observational study of 500 patients presenting with ST-segment elevation myocardial infarction (STEMI), blood samples were taken on arrival, after DAPT loading, and before administration of heparin or PPCI. Non-anticoagulated venous whole blood was analysed using the point-of-care Global Thrombosis Test, which assesses the time taken for occlusive thrombus formation under high shear (occlusion time, OT) and time required for spontaneous restart of flow as a measure of endogenous fibrinolysis (lysis time, LT). Patients were divided into 4 groups based on quartiles (Q) of whole blood LT (Q1: LT<1500s, Q2:1501–3000s, Q3:3001–4500s, Q4:>4500s). Plasma samples (20 per quartile) were examined in a thrombin generation assay using 1pM tissue factor to initiate and using a turbidity assay to determine the plasma clot lysis time (CLT). Results Clinical characteristics of patients were similar in the four groups. The whole blood LT in the 4 groups were Q1: 1194 (1125–1329) s, Q2: 1859 (1634–2157) s, Q3: 3638 (3252–3962) s, Q4: 6000 (5523–6000) s. As LT increased, there was a trend towards longer plasma CLT (50% CLT Q2: 88.5 [73.5–102] vs. Q4: 100 [85–128.5] min, p=0.088). As a continuous variable, there was no significant relationship between whole blood LT and plasma CLT, or between endogenous thrombin potential (ETP) and either whole blood LT or plasma CLT. There was a significant negative correlation between OT and velocity index (r=−0.425, p=0.0138), ETP (r=−0.519, p=0.002), peak thrombin generation (r=−0.390, p=0.0247) and a positive correlation with lag-time (r=0.427, p=0.013). There was positive correlation between CLT and white cell count (WCC, r=0.388, p=0.026), C-reactive protein (CRP, r=0.477, p=0.005) and maximum absorbance (MA, r=0.530, p=0.002). MA correlated with WCC (r=0.436, p=0.011) and platelet count (r=0.357, p=0.042). There was a negative correlation between OT and WCC (r=−0.537, p=0.001) and CRP (r=−0.381, p=0.029). Conclusion In patients with STEMI, increased platelet reactivity (shorter OT) correlated with increased thrombin generation (higher ETP, peak thrombin generation, velocity index and reduced lag time), demonstrating the key role of thrombin in occlusive thrombus formation. Fibrinolysis in whole blood was poorly related to plasma CLT or thrombin generation, suggesting that cellular components such as platelets, erythrocytes and neutrophil extracellular traps may significantly influence endogenous fibrinolysis. Funding Acknowledgement Type of funding source: None