Thrombin generation was greatly influenced by preanalytic conditions, demonstrating the need for an international standardized protocol.

Summary.  Although the link between blood coagulation and atherogenesis has been long postulated, only recently, and through the extensive work on transgenic mice, crossbred on an atherogenic background, has the direction of this interaction become visible. In general, hypercoagulability in mice tends to increase atherosclerosis, whereas hypocoagulability reduces the atherosclerotic burden, depending on the mouse model used. The information on a direct relationship between coagulation and atherosclerosis in humans, however, is not that clear. Almost all coagulation proteins, including tissue factor, are found in atherosclerotic lesions in humans. In addition to producing local fibrin, a matrix for cell growth, serine proteases such as thrombin may be very important in cell signaling processes, acting through the activation of protease‐activated receptors (PARs). Activation of PARs on vascular cells drives many complex processes involved in the development and progression of atherosclerosis, including inflammation, angiogenesis, and cell proliferation. Although current imaging techniques do not allow for a detailed analysis of atherosclerotic lesion phenotype, hypercoagulability, defined either by gene defects of coagulation proteins or elevated levels of circulating markers of activated coagulation, has been linked to atherosclerosis‐related ischemic arterial disease. New, high‐resolution imaging techniques and sensitive markers of activated coagulation are needed in order to study a causal contribution of hypercoagulability to the pathophysiology of atherosclerosis. Novel selective inhibitors of coagulation enzymes potentially have vascular effects, including inhibition of atherogenesis through attenuation of inflammatory pathways. Therefore, we propose that studying the long‐term vascular side effects of this novel class of oral anticoagulants should become a clinical research priority.

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We demonstrate that a delayed and decreased thrombin generation is a strong and independent predictor for stroke in elderly people at increased risk of vascular disease. However, no convincing consistent association could be demonstrated between thrombin generation and incident CHD.

ObjectiveIn acute coronary syndrome (ACS) cardiac cell damage is preceded by thrombosis. Therefore, plasma coagulation markers may have additional diagnostic relevance in ACS. By using novel coagulation assays this study aims to gain more insight into the relationship between the coagulation system and ACS.MethodsWe measured plasma thrombin generation, factor XIa and D-dimer levels in plasma from ACS (n = 104) and non-ACS patients (n = 42). Follow-up measurements (n = 73) were performed at 1 and 6 months. Associations between coagulation markers and recurrent cardiovascular events were calculated by logistic regression analysis.ResultsThrombin generation was significantly enhanced in ACS compared to non-ACS patients: peak height 148±53 vs. 122±42 nM. There was a significantly diminished ETP reduction (32 vs. 41%) and increased intrinsic coagulation activation (25 vs. 7%) in ACS compared to non-ACS patients. Furthermore, compared to non-ACS patients factor XIa and D-dimer levels were significantly elevated in ACS patients: 1.9±1.1 vs. 1.4±0.7 pM and 495(310–885) vs. 380(235–540) μg/L. Within the ACS spectrum, ST-elevated myocardial infarction patients had the highest prothrombotic profile. During the acute event, thrombin generation was significantly increased compared to 1 and 6 months afterwards: peak height 145±52 vs. 100±44 vs. 98±33 nM. Both peak height and factor XIa levels on admission predicted recurrent cardiovascular events (OR: 4.9 [95%CI 1.2–20.9] and 4.5 [1.1–18.9]).ConclusionACS patients had an enhanced prothrombotic profile, demonstrated by an increased thrombin generation potential, factor XIa and D-dimer levels. This study is the first to demonstrate the positive association between factor XIa, thrombin generation and recurrent cardiovascular events.

This study presents the first application of a new thrombin generation based factor XIa assay, showing significantly increased factor XIa levels in AMI patients on admission compared to 6 months after the event and compared to healthy controls. The factor XIa concentration was not associated with the risk of recurrence.

ObjectiveCoronary stent thrombosis is a devastating complication after percutaneous coronary intervention (PCI). The mechanisms underlying stent thrombosis are multifactorial. Whether the coagulation system is involved in the pathophysiology of stent thrombosis is unclear. We hypothesised that thrombin generation, reflecting the coagulation potential, is enhanced in patients with stent thrombosis.MethodsA case–control study was performed, including 63 patients with PCI: 23 cases (stent thrombosis) and 40 controls (no stent thrombosis). Thrombin generation was measured using 0, 1 and 5 pM tissue factor (TF) triggers. Active site-inhibited factor VIIa (ASIS) and recombinant thrombomodulin were added to study the contact activation system and the protein C pathway, respectively.ResultsThrombin generation was significantly increased for all TF triggers in cases compared with controls. Addition of ASIS to the measurement without exogenous TF revealed significantly enhanced contact activation in cases compared with controls; mean peak height: 241 vs 183 nM. Thrombin generation was also significantly increased in cases compared with controls in the presence of exogenous TF; mean peak height: 263 vs 233 nM (5 pM TF). Addition of thrombomodulin reduced thrombin generation by 23% in cases and 31% in controls (p<0.018), suggesting alterations in the protein C pathway in cases.ConclusionsThis is the first study that suggests the involvement of the coagulation system in stent thrombosis. Stent thrombosis patients showed a hypercoagulable state, most likely caused by enhanced contact activation and attenuation of anticoagulation by the protein C pathway.