Associations Between Thrombin Generation and the Risk of Cardiovascular Disease in Elderly Patients: Results From the PROSPER Study

Loeffen, R.; Winckers, Kristien; Ford, Ian; Jukema, J. Wouter; Robertson, Michele; Stott, David J.; Spronk, Henri M. H.; Cate, Hugo Ten; Lowe, G. D. O.

doi:10.1093/gerona/glu228

Cited by 35 publications

(31 citation statements)

References 28 publications

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“…This is in keeping with inverse relationship observed in other studies following acute myocardial infarction (AMI) and stroke [15, 31]. Conversely, in another study, thrombin generation following acute stroke measured within 2 weeks and at 1 month after stroke showed elevated ETP and peak thrombin concentrations [16, 32], similar to other hypercoagulable states such as VTE and age in hormone replacement therapy [18, 20, 29, 33].…”

Section: Discussionsupporting

confidence: 83%

Thrombin Generation in Acute Ischaemic Stroke

Balogun

Roberts

Patel

et al. 2016

Stroke Research and Treatment

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Introduction. Stroke remains a global leading cause of death and disability. Traditional description of plasma biology in the aftermath of acute ischaemic stroke favours development of hypercoagulability, resulting from complex interplay between plasma and endothelial factors. However, no single assay measures the overall global coagulation process. We postulate that thrombin generation would assist in identifying coagulation abnormalities after acute stroke. Aim. To investigate the coagulation abnormalities after acute ischaemic stroke using thrombin generation. Methods. We evaluated thrombin generation, measured with calibrated automated thrombography in stroke of different aetiological types (n = 170) within 48 hours of symptoms onset (baseline) and in the second week (time 2) and in normal healthy volunteers (n = 71). Results. Two-point thrombin generation assays showed prolonged lag time and time to peak at baseline (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.005) and (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.002), respectively, and at time 2 (3.5 (2.9, 4.2) versus 4.0 (3.1, 4.9); p = 0.004) and (5.9 (5.3, 6.6) versus 6.8 (5.8, 7.7) p = 0.05), respectively, in cardioembolic stroke (n = 39), when compared to noncardioembolic stroke (n = 117). The result was reproduced in multiple comparisons between acute ischaemic stroke subgroups and normal healthy volunteers. Endogenous thrombin potential and peak thrombin did not indicate hypercoagulability after acute ischaemic stroke, and thrombolytic therapy did not affect thrombin generation assays. Conclusion. Our findings suggest that thrombin generation in platelet poor plasma is not useful in defining hypercoagulability in acute ischaemic stroke. This is similar to observed trend in coronary artery disease and contrary to other hypercoagulable states.

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Section: Discussionsupporting

confidence: 83%

Thrombin Generation in Acute Ischaemic Stroke

Balogun

Roberts

Patel

et al. 2016

Stroke Research and Treatment

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“…The unaltered capacity to generate thrombin in spite of increased levels of formed thrombin suggests a hypercoagulability characterized by consumption of coagulation proteins diminishing the capacity to generate more thrombin. Such a phenomenon (lower levels of thrombin generation capacity in plasma) has recently also been suspected to be present in patients with PAD by others (16), as well as in a controlled study of cardiovascular complications in elderly subjects (17). Our study is the first to also show such an inverse association between thrombin generation, in WB, and thrombotic outcomes.…”

Section: Discussionmentioning

confidence: 89%

Increased Clot Formation in the Absence of Increased Thrombin Generation in Patients with Peripheral Arterial Disease: A Case–Control Study

Kleinegris

Konings

Daemen

et al. 2017

Front. Cardiovasc. Med.

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BackgroundIn peripheral arterial disease (PAD), activation of the hemostatic system may contribute to atherosclerosis progression and atherothrombotic events.ObjectiveThis case–control study assesses the overall coagulation status in PAD patients by evaluating coagulation markers in combination with thrombin generation potential, whole blood (WB) clot formation, and fibrinolysis.MethodsIn blood from 40 PAD patients (n = 20 with cardiovascular event within 1 year after initial diagnosis, n = 20 without) and 40 apparently healthy controls, thrombin generation was determined in WB and platelet-poor plasma. Whole blood rotational thromboelastometry (ROTEM) measurements were triggered with tissue factor with/without tissue plasminogen activator.ResultsWe observed increased levels of erythrocyte sedimentation rate, leukocytes, eosinophil granulocytes, vWF antigen, fibrinogen, and D-dimer in PAD patients (p < 0.05). Markers of thrombin generation potential showed no difference between patients and healthy controls. In PAD patients with event compared to patients without, WB-thrombin generation showed a lower thrombin potential when triggered with 0 and 2.5 pM tissue factor. The ROTEM clotting assay showed significantly faster clot formation and increased clot firmness in PAD patients compared to controls. No significant differences were found for parameters of clot degradation.ConclusionThere are no significant differences between the thrombin generation profiles of PAD patients and healthy controls. Between PAD patients with and without cardiovascular event, the WB thrombin generation appears to differ. Mechanistically, PAD patients show an increased ability to form a stable clot in WB in comparison to healthy controls. This is most likely due to the increased fibrinogen levels related to the inflammation in atherosclerosis, confirming the importance of the inflammation-coagulation axis.

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“…In the LURIC study, the event‐free survival in the quartile of individuals with the lowest ETP was much lower than those with the highest ETP ( P =0.004) 50. In elderly subjects from the PROSPER study (on the effects of pravastatin), only an increased normalized peak height was significantly associated with incident coronary heart disease (hazard ratio 1.17 [95% CI: 1.06–1.28], P =0.002) 51. In the selected population of survivors from in‐stent thrombosis, TG was significantly increased with reduced APC sensitivity, as compared to those without recurrent stent thrombosis 52.…”

Section: Literature Studiesmentioning

confidence: 98%

“…In more recent studies, after the clinical introduction of semi‐automated methods, Carcaillon et al observed that ETP and peak height were positively associated with risk of acute stroke (hazard ratio 1.16 and 1.31, respectively, for 1 SD increase), more obvious in women 47. In contrast, Loeffen et al51 found a highly statistically significant but inverse association between ETP as well as peak height in a similar cohort study, albeit in older subjects than in the study by Carcaillon et al.…”

Section: Literature Studiesmentioning

confidence: 99%