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Introduction: Patients with coronary artery disease (CAD) display a prothrombotic fibrin clot phenotype, involving low permeability and resistance to lysis. The determinants of this phenotype remain elusive. Circulating tissue factor (TF) and activated factor XI (FXIa) are linked to arterial thromboembolism. We investigated whether detectable active TF and FXIa influence fibrin clot properties in CAD. Methods: In 118 CAD patients (median age 65 years, 78% men), we assessed Ks, an indicator of clot permeability, and clot lysis time (CLT) in plasma‐based assays, along with the presence of active TF and FXIa. We also analysed proteins involved in clotting and thrombolysis, including fibrinogen, plasminogen activator inhibitor‐1 (PAI‐1) and thrombin activatable thrombolysis inhibitor (TAFI). During a median 106 month (interquartile range 95–119) follow‐up, myocardial infarction (MI), stroke, systemic thromboembolism (SE) and cardiovascular (CV) death were recorded. Results: Circulating TF and FXIa, detected in 20.3% and 39.8% of patients, respectively, were associated with low Ks and prolonged CLT. Solely FXIa remained an independent predictor of low Ks and high CLT on multivariable analysis. Additionally, fibrinogen and PAI‐1 were associated with low Ks, while PAI‐1 and TAFI—with prolonged CLT. During follow‐up low Ks and prolonged CLT increased the risk of MI and the latter also a composite endpoint of MI, stroke/SE or CV death. Conclusions: To our knowledge, this study is the first to show that circulating FXIa is associated with prothrombotic fibrin clot properties in CAD, suggesting additional mechanisms through which FXIa inhibitors could act as novel antithrombotic agents in CAD. [ABSTRACT FROM AUTHOR]

Background: Coronary artery disease (CAD) is associated with a prothrombotic tendency including increased factor (F) VIIa‐antithrombin (FVIIa‐AT) complexes, a measure of tissue factor (TF) exposure, and activated FXI (FXIa). We investigated whether increased FVIIa–AT complexes are associated with FXIa and active TF and if major adverse clinical outcomes are predicted by the complexes in CAD. Methods: In 120 CAD patients, we assessed FVIIa–AT complex concentrations and the presence of circulating FXIa and active TF. Levels of 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α), interleukin‐6, high‐sensitivity C reactive protein, prothrombin fragment 1 + 2, and free Tissue Factor Pathway Inhibitor were determined. Myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SE), and cardiovascular (CV) death were recorded separately and as a composite endpoint, during follow‐up. Results: FVIIa–AT complexes were positively associated with current smoking and multivessel CAD. Elevated FVIIa–AT complexes characterized patients with circulating FXIa and/or active TF in association with increased plasma isoprostanes but not with thrombin generation or inflammatory markers. During a median follow‐up of 106 months (interquartile range 95–119), high baseline levels of FVIIa–AT complexes predicted ischemic stroke/SE (HR 4.61 [95% CI 1.48–18.42]) and a composite endpoint of MI, stroke/SE, and CV death (HR 7.47 [95% CI 2.81–19.87]). Conclusions: This study is the first to show that high FVIIa–AT complexes characterize advanced CAD patients with detectable FXIa and active TF, which is, in part, driven by oxidative stress. High FVIIa–AT complexes were associated with the risk of ischemic stroke/SE during long‐term follow‐up, highlighting the need for effective antithrombotic agents in CAD. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2011 Abstract Background Elevated factor (F)XI and tissue factor (TF) have been reported to occur in patients with acute ischemic stroke (AIS). We sought to investigate whether circulating activated FXI (FXIa) and TF on admission can predict clinical outcomes in patients with acute cerebrovascular events. Materials and methods In the observational study, we evaluated 205 consecutive patients aged 70 years or less within the first 72 h of acute event, including 140 with AIS and 65 with transient ischemic attack (TIA). Plasma TF and FXIa activity were determined on admission in clotting assays by measuring the response to inhibitory monoclonal antibodies. Results Active TF and FXIa activity were detected in 58 (28·9%) and 132 (64·4%) patients on admission, respectively. Active TF was detected in 45 of the 136 AIS patients with available TF levels (33·1%) and 13 of the 65 patients with acute TIA (20%; P = 0·05). Corresponding values for FXIa were 99 of the 140 (70·7%) and 33 of the 65 (50·8%; P = 0·006), respectively. Patients with detectable TF were more frequently women and hypertensive, while subjects with detectable FXIa had more often diabetes and higher levels of fibrinogen, C-reactive protein and interleukin-6 (all P < 0·05). Patients with detectable FXIa but not TF had higher National Institutes of Health Stroke Scale score, higher modified Rankin scale score and lower Barthel Index at discharge (all P < 0·05). Conclusions Circulating active TF and FXIa occur frequently in acute cerebrovascular ischemic events. Active FXIa in plasma might be useful as a novel risk marker of worse functional outcomes in patients with acute cerebrovascular events. [ABSTRACT FROM AUTHOR]

Nonleukoreduced units of red blood cells (RBCs) contain activated platelets (PLTs) that interact with white blood cells (WBCs) and may promote inflammation and thrombosis in the recipient. The aim of this study was to characterize PLT-WBC interactions (PLT-WBC aggregates [PLAs]), WBC apoptosis, WBC death, and the development of procoagulant activity in RBCs during storage. RBCs were prepared from volunteer donor blood and stored. Samples were analyzed with flow cytometry between Days 1 and 15 to measure PLT-monocyte aggregate (PMA) and PLT-neutrophil aggregate (PNA) formation, WBC apoptosis (annexin V binding), and cell death (binding of 7-aminoactinomycin D). Procoagulant activity in the supernatant of four RBC preparations was assessed between Days 1 and 39 using a clotting assay with and without the addition of an inhibitory anti-tissue factor (TF) antibody, αTF-5. PLA formation was extensive and maximal on Day 3 of storage (PNA, 23 ± 13%; PMA, 93 ± 4%; n = 6). Apoptosis was progressive throughout storage, with 95 ± 4% of neutrophils and 73 ± 19% of monocytes binding annexin V on Day 15. Cell death became measurable after apoptosis. Procoagulant activity was observed in all RBCs but with varying temporal patterns. It was partially TF dependent and removed with high-speed centrifugation, suggestive of an association with microparticles. The activation of PLTs during the storage of RBCs induces PLA formation that precedes WBC apoptosis and death. Procoagulant activity, likely associated with microparticles derived from apoptotic WBCs, may contribute to adverse effects of stored, nonleukoreduced RBCs. [ABSTRACT FROM AUTHOR]

Therapeutic agents that regulate blood coagulation are critical to the management of thrombotic disorders and surgical intervention. Many new compounds that were plausible in terms of target, relative specificity, mechanism and kinetic and thermodynamic properties have failed to perform as expected when assessed, at significant expense, in vivo. Our current deterministic mathematical model (Hockin et al. J. Biol. Chem. 2002, 277: 18322) describes the dynamic biochemical repair process that emerges in response to vascular injury and allows us to incorporate hypothetical inhibitors/enhancers at their proposed sites of interaction, thus providing an assessment of their efficacy. In conjunction with our coagulation proteome model (a synthetic reconstruction using purified protein of the components described in the computational model), we evaluated a set of anticoagulants currently in clinical use (unfractionated heparin, synthetic low molecular weight heparins, factor Xa inhibitors and thrombin inhibitors). The interactions of each anticoagulant with its target(s) were mathematically incorporated into the overall mathematical description of the reaction pathways. Outcomes for each anticoagulant at clinically relevant concentrations were generated and validated by comparisons with the synthetic coagulation proteome. Our results show that this type of mathematical methodology can lead to insights into drug performance and to rationalizing the differing properties that an ideal anticoagulant would require in therapeutic vs. prophylactic settings. [ABSTRACT FROM AUTHOR]