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Background: Atrial fibrillation (AF) is associated with a systemic pro-coagulant state. Coagulation involves complex interactions between endothelial and circulating cells, cell-derived microparticles and plasma proteins. Methods: We investigated the levels of endothelial and platelet microparticles, leukocyte and platelet activation, and cell interactions in 48 patients with non-valvular AF and compared to normal controls. We performed flow cytometry in periheral venous blood to measure (1) Platelet expression of P-selectin, (2) Platelet microparticles; (3) Platelet-leukocyte conjugates; (4) Leukocyte expression of CD11b; (5) Endothelial microparticles (EMP) positive for CD31 and negative for CD42 (EMP31+), EMP positive for E-selectin (EMP62E+), CD54 (EMP54+), or CD51 (EMP51+); (6) EMP54+- and EMP62E+-leukocyte conjugates. Atrial fibrillation was confirmed electrocardiographically and left atrial volume was estimated by echocardiography. The mean age of patients with AF was 61.3±12 years. Congestive heart failure was present in 54.2% of patients, hypertension in 72.9%, and diabetes mellitus in 22.9%. Most patients (81%) were receiving anticoagulant therapy and 62.5% were receiving antiplatelet medications. Calcium channel blockers or digoxin were given to 43.8% and 54.2% of patients, respectively. The mean ventricular rate was 85.5±17 beats per minute, and the mean left atrial volume was 97.9 ml. Results: Patients with AF had significantly higher levels of platelet P-selectin expression and platelet-leukocyte conjugates. P-selectin expression strongly correlated with platelet-leukocyte conjugate levels (r=0.77; p Conclusions: Patients with AF have increased levels of platelet and leukocyte activation, circulating endothelial microparticles, and binding of endothelial microparticles and platelets to leukocytes. Platelet activation is a determinant of platelet-leukocyte conjugate formation in AF. The formation of EMP62E-neutrophil conjugates is a major determining factor for circulating leukocyte activation in AF. Further studies are needed to assess the correlation of these markers with the risk of thromboembolism in AF. Figure 1. Figure 1. Figure 2. Figure 2.

Background: Atrial fibrillation (AF) is associated with thromboemboli, which is due to blood stasis in the left atrium and hypercoagulability. Several studies have shown that both platelet and leukocyte activation are increased in AF. Formation of platelet-leukocyte conjugates (PLC) is an important mechanism by which leukocytes contribute to thrombosis. Increased levels of P selectin expression in platelets and platelet-leukocyte conjugates (PLC) have been correlated with the risk of cerebral infarction in AF (Circulation. 1998; 98:1721–7). The mechanisms driving the formation of PLC in AF is unclear. We investigated the levels of PLC, platelet expression of P selectin, and leukocyte activation in patients with non-valvular AF. Methods. Patient population: Fourteen patients with chronic AF (8 men and 6 women; mean age = 62±9 years) were studied. AF was documented by a 12-lead electrocardiogram and all patients underwent an echocardiogram to assess cardiac function and rule out valvular AF. The mean left ventricular ejection fraction was 49±16%. Comorbidities included hypertension (85%), diabetes mellitus (21%), coronary artery disease (35%) and congestive heart failure (28%). The mean heart rate was 80±13 bpm. The mean BP was 127±9 / 75±6 mmHg. All patients were anticoagulated with warfarin and 78% were taking aspirin. Since we have previously shown that digitalis use is associated with platelet activation in this population, patients taking digitalis were excluded. Laboratory methods: Venous blood from patients with AF and from healthy volunteers was examined by flow cytometry using fluorescent mAbs. We measured platelet expression of P selectin and leukocyte expression of CD11b. Coexpression of CD41 and CD45 was used to measure PLC. Results: Patients with AF had markedly increased levels of P selectin (22.1 vs 5.0 fluorescence units; p=0.008), PLC (61.2±13.6% vs 43.1±21.6%; p=0.001) and CD11b expression in leukocytes (16.4 vs. 7.9 fluorescence units; p=0.0003). PLC strongly correlated with P selectin expression (R= 0.80; R2=0.64; p=0.0006) but not with leukocyte activation as measured by CD11b expression (R=0.41; R2= 0.17; p=0.14). Conclusion: Our findings indicate that (1) Patients with AF demonstrate increased levels of platelet and leukocyte activation; (2) Increased PLC formation occurs in AF; (3) Levels of PLC closely correlate with platelet activation but not with leukocyte activation, suggesting than PLC formation is driven by platelet activation rather than by leukocyte activation in this population. Aspirin has been shown to be only marginally effective to prevent thromboembolism in AF. Clopidogrel, but not aspirin, has been shown to decrease the formation of PLC (J Am Coll Cardiol2004;43(11):1982–8). Our data suggests that aspirin use in AF patients would not be anticipated to normalize platelet activation and PLC formation in AF patients, but other therapies aimed at decreasing PLC formation might decrease the thrombotic risk in AF.