thromboplastin and Atrial-Fibrillation

From acute coronary syndrome (ACS) to the prevention of cardioembolic events in patients with atrial fibrillation and thrombosis of mechanical heart valves, there is a quest to develop a new generation of anticoagulants. Perhaps the 'holy grail' of antithrombotic therapy is not only a drug that will prevent coagulation without promoting bleeding but also an anticoagulant that is easily reversible should the clinical need arise. Further, an optimally designed anticoagulant would have broad applications to include arterial, venous, hybrid conditions (atrial flutter and fibrillation) and nonbiological materials. Factor (F)IXa plays a pivotal part in tissue factor (TF)-mediated thrombin generation, and therefore represents a potentially promising target for drug development. FIXa activity has been targeted by multiple modalities, including oral inhibitors, RNA aptamers, monoclonal antibodies and synthetic active-site-blocking competitive inhibitors. Herein, we summarize the biochemistry of FIXa as it applies to thrombotic disorders and conditions, as well as the evolution of targeted therapies.

Topics: Acute Coronary Syndrome; Animals; Anticoagulants; Atrial Fibrillation; Drug Design; Factor IXa; Hemorrhage; Humans; Thrombin; Thromboplastin; Thrombosis

Anticoagulants are effective at preventing and treating thrombosis, but can cause bleeding. For decades, vitamin K antagonists (VKAs) have been the only available oral anticoagulants. The development of non-VKA oral anticoagulants (NOACs), which inhibit either factor Xa or thrombin stoichiometrically, has provided alternatives to VKAs for several indications. The results of recent large-scale randomised controlled trials comparing NOACs with VKAs for the prevention of stroke in patients with non-valvular atrial fibrillation (AF) have produced some unexpected results. As a group, NOACs showed similar efficacy as warfarin, but a reduced risk of major bleeding. The reduction in bleeding with NOACs was greatest with intracranial hemorrhage. In contrast, the relative risk of gastro-intestinal bleeding was increased with some NOACs. In this review, we explore the potential mechanisms as well as the implications of these organ-specific bleeding patterns.

Topics: Anticoagulants; Atrial Fibrillation; Blood Coagulation Factors; Endothelium, Vascular; Factor Xa Inhibitors; Gastrointestinal Hemorrhage; Hemorrhage; Humans; International Normalized Ratio; Intestinal Absorption; Intracranial Hemorrhages; Organ Specificity; Randomized Controlled Trials as Topic; Stroke; Thrombophilia; Thromboplastin; Vitamin K; Warfarin

Topics: Animals; Atrial Appendage; Atrial Fibrillation; Blood Flow Velocity; Drug Delivery Systems; Endothelium, Vascular; Factor Xa; Fibrinolytic Agents; Gene Expression Regulation; Humans; Intracranial Embolism; Mice; Mice, Inbred C57BL; Thrombin; Thromboembolism; Thromboplastin; Thrombosis

Atrial fibrillation (AF) is the commonest sustained cardiac arrhythmia, which confers a high risk of mortality and morbidity from stroke and thromboembolism. The precise mechanisms by which AF causes thromboembolism and subsequent cerebrovascular events have attracted much research interest, and are yet to be fully elucidated. Nonetheless, it is well recognised that AF fulfils Virchow's triad for thrombogenesis, with abnormal flow conditions with loss of atrial contractility and an irregularly irregular cardiac output, (i. e. flow abnormalities), as well as structural heart disease with endocardial damage (i. e. abnormal vessel wall) and abnormalities in platelet and haemostatic variables (i. e. abnormal blood constituents). This review is to summarise the evidence so far for the role of coagulation and fibrinolytic components, platelets and inflammation (that is blood constituents) in the generation of the prothrombotic state in AF, with particular focus on the endothelium and AF.

Topics: Atrial Fibrillation; Cyclic GMP; Endothelium, Vascular; Fibrinolysis; Hemostasis; Humans; Nitric Oxide; Stroke; Thromboembolism; Thromboplastin; von Willebrand Factor

Topics: Atrial Fibrillation; Brain Ischemia; Fibrinolytic Agents; Humans; Intracranial Embolism and Thrombosis; Platelet Aggregation Inhibitors; Recurrence; Thromboplastin; von Willebrand Factor

Thrombi form mainly in the left rather than the right atria of patients with atrial fibrillation (AF), the reason of this predilection being unknown.. The purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation, and tissue factor activity occur in patients with AF.. Twenty-two patients (16 men, 6 women; age 56 ± 8 years; 16 paroxysmal AF, 6 persistent AF) with AF undergoing pulmonary vein isolation were investigated. Blood samples from the left and the right atrium were obtained at the start of the procedure. Microparticles (MPs) released by apoptotic/stimulated cells were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin were determined (endothelium, platelet, leukocyte). Platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet P-selectin (CD62P), active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using ADP, TRAP and collagen-induced whole blood aggregometry.. There were no atrial-specific differences in the levels of total procoagulant MPs, leukocyte-derived-MPs or platelet-derived MPs. Conversely, endothelial-derived MPs and tissue factor activity and collagen-induced platelet aggregation were slightly elevated in the right atrium (P < 0.05).. Our data show no evidence for increased thrombogenic status in the left atrium that would account for its greater propensity for thrombus formation in patients with AF.

Topics: Atrial Fibrillation; Cell-Derived Microparticles; Endothelium, Vascular; Female; Heart Atria; Humans; Leukocytes; Male; Middle Aged; Platelet Activation; Thromboplastin; Thrombosis

Angiotensin receptor blockers (ARBs) are widely used for the treatment of hypertension. It has been reported that the ARB losartan has antiplatelet, anticoagulant and profibrinolytic effects experimentally. These properties could be desirable to treat hypertensive patients with high atherothrombotic and/or thromboembolic risk. To examine the antithrombotic effects of losartan in hypertension, 20 consecutive patients with hypertension complicated by atrial fibrillation (AF) were enrolled in this study. The patients were treated with losartan 50 mg for 8 weeks followed by 100 mg for 4 weeks. Blood samples were obtained from each patient at 0 (pretreatment), 8 and 12 weeks after initiating treatment. Platelet aggregability, plasma levels of tissue factor (TF) and type 1 plasminogen activator inhibitor (PAI-1) activity levels were measured. The area under the curve for small platelet aggregability decreased from 100 to 42.8% at 12 weeks (P<0.0001). TF levels (ng ml(-1)) and PAI-1 activity (IU ml(-1); mean±s.d.) also changed from 14.2±3.6 to 10.9±4.5 at 12 weeks (P=0.0299) and from 11.7±3.6 to 8.5±3.1 at 12 weeks (P=0.0122), respectively. Losartan inhibited platelet activity and coagulation factors in a dose- and time-dependent manner in patients with hypertension complicated by AF, whereas the fibrinolytic capacity was increased. The use of losartan could be advantageous in the treatment of hypertensive patients with high atherothrombotic risk.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Atrial Fibrillation; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Humans; Hypertension; Losartan; Male; Middle Aged; Pilot Projects; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Risk Factors; Thromboembolism; Thromboplastin; Time Factors; Treatment Outcome

Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state.. We studied 25 patients with AF (20 men; mean+/-SD age, 62+/-13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60+/-9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60+/-12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay.. VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (P<0.001, P=0.022, and P=0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman's r=0.65, P<0.001) and sFlt (r=0.54, P=0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (r=0.39, P=0.02). There were no significant correlations among the healthy control subjects.. Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.

Topics: Anticoagulants; Atrial Fibrillation; Blood Pressure; Case-Control Studies; Chronic Disease; Coronary Artery Disease; Cross-Sectional Studies; Demography; Endothelial Growth Factors; Female; Humans; Lymphokines; Male; Middle Aged; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Thrombophilia; Thromboplastin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Warfarin

 Atrial fibrillation (AF) is associated with a prothrombotic state. Presence of active tissue factor (TF), activated factor IX (FIXa) and FXIa in circulating blood contributes to thrombosis. We investigated a prognostic value of these factors in AF patients..  In this cohort study, 284 AF patients (aged 63.3 ± 8.8 years) treated with oral anticoagulants were enrolled. Plasma levels of active coagulation factors were evaluated using thrombin generation assay. Concentrations of fibrinogen, D-dimer, interleukin-6 (IL-6), and endothelial damage markers, including von Willebrand factor (VWF) and soluble (s)E-selectin, were also measured. Ischemic stroke and cardiovascular death, analyzed separately or as a composite endpoint, were recorded during a mean follow-up of 47 months..  Cerebrovascular events were observed in 20 patients (1.8%/year) who had at baseline higher fibrinogen, D-dimer, and VWF levels. Active TF and FXIa at enrollment were detectable in 12 (60%) and 15 (75%) patients who experienced ischemic stroke during follow-up. The composite endpoint observed in 23 patients (2.1%/year) was associated with increased concentrations of the above laboratory variables, along with 26% higher IL-6 levels. sE-selectin did not differ between the studied groups. On multivariable regression analysis, advanced age, anticoagulation discontinuation, and detectable FXIa, but not active TF, independently predicted the composite endpoint. No associations of FIXa with the study endpoints were observed..  FXIa present in circulating blood is associated with increased risk of ischemic stroke and cardiovascular death in anticoagulated AF patients during long-term follow-up. FXIa inhibition could be useful in cardiovascular prevention in AF beyond the current oral anticoagulation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cohort Studies; Factor XI; Fibrinogen; Humans; Interleukin-6; Ischemic Stroke; Middle Aged; Risk Factors; Thromboplastin; von Willebrand Factor

The risk of thrombus formation in the left atrial appendage (LAA) in patients with atrial fibrillation (AF) may result from blood stasis, local endocardial changes, and/or changed blood composition. Extracellular vesicles (EVs), especially subtypes exposing tissue factor (TF), have procoagulant capacity. We hypothesized that blood concentrations of TF-bearing EVs and other procoagulant biomarkers are elevated in AF patients, particularly in the LAA lumen.. From 13 AF patients and 12 controls a venous blood sample was drawn prior to cardiac surgery. Intraoperatively, venous blood and blood directly from the LAA was drawn. Plasma levels of EVs, including TF- and cell type specific antigen-bearing EVs, were measured using a protein microarray platform. Plasma levels of TF, von Willebrand factor (vWF), cell free deoxyribonucleic acid (cf-DNA), procoagulant phospholipids (PPLs), and total submicron particles were also evaluated.. Significantly higher EV levels, including a several-fold higher median level of TF-bearing EVs were measured in AF patients compared with controls. Median concentrations of TF and vWF were approximately 40% and 30% higher, respectively, in the AF group than in the control group, while no significant differences in levels of cf-DNA, PPLs, or total submicron particles were observed. No significant differences in levels of any of the measured analytes were observed between intraoperative venous and LAA samples.. Increased plasma concentrations of TF in AF patients are accompanied and probably at least partly explained by increased levels of TF-bearing EVs, which may be mechanistically involved in increased thrombogenicity in AF patients.

Topics: Aged; Aged, 80 and over; Atrial Appendage; Atrial Fibrillation; Extracellular Vesicles; Female; Humans; Male; Middle Aged; Monocytes; Thromboplastin; Thrombosis; von Willebrand Factor

The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Case-Control Studies; Dabigatran; Factor Xa Inhibitors; Female; Fibrin Clot Lysis Time; Heparin, Low-Molecular-Weight; Humans; Linear Models; Male; Middle Aged; Phenprocoumon; Plasma; Pyrazoles; Pyridones; Rivaroxaban; Thromboplastin; Tissue Plasminogen Activator

High mobility group box 1 (HMGB1) is a member of the HMGB family that is involved in inflammatory disease-related thrombosis. We hypothesize that HMGB1 and its downstream factors are associated with thrombosis in atrial fibrillation (AF).. Our experimental materials were the left atrial appendage (LAA) tissues from patients undergoing valve replacement. The samples were divided into 3 groups: a sinus rhythm group (n = 15), an AF(+)thrombus(-)group (n = 15), and an AF(+) thrombus (+)group (n = 15). The expression of HMGB1, Toll-like receptor 4 (TLR4), advanced glycation end product (RAGE), myeloid differentiation factor 88 (MyD88), nuclear factor κB (NFκB), p-NFκB, and tissue factor (TF) were detected by Western blot and immunohistochemical (IHC) staining. The expressions of interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha were detected by quantitative real-time PCR.. The Western blots revealed significantly higher expressions of HMGB1, MyD88, p-NFκB/NFκB, and TF in the AF(+)thrombus(+) group than in the other 2 groups. However, no differences in TLR4 or RAGE expression were found between the groups. IHC staining also revealed higher expressions of HMGB1 and TF in the AF(+)thrombus(+) group. The increased mRNA expressions of classic inflammatory factors (i.e., interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha) in AF(+)thrombus(+) group further validated the correlation between inflammation and thrombi in atrial fibrillation.. HMGB1 was associated with thrombosis in patients with AF via the MyD88/NFκB pathway after adjustment for cardiac and extra cardiac inflammation variables.

Topics: Adult; Aged; Atrial Fibrillation; Case-Control Studies; Coronary Thrombosis; Female; Glycation End Products, Advanced; HMGB1 Protein; Humans; Interleukins; Male; Middle Aged; Myeloid Differentiation Factor 88; NF-kappa B; Thromboplastin; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha

The mechanism underlying thrombosis in atrial fibrillation (AF) is not yet clearly understood. Oncostatin M (OSM), as a member of IL-6 family, is involved in atherosclerosis-mediated thrombosis. The present study hypothesizes that OSM and its downstream factors play a role in thrombogenesis in AF.The specimens of left atrial appendages collected from patients with rheumatic mitral stenosis who underwent valve replacement were divided into 3 groups: sinus rhythm, AF(+)/thrombus(-), and AF(+)/thrombus(+) group. The macrophage infiltration in atrial tissue was assessed by immunohistochemistry, and the amount of OSM, tissue factor (TF), and tissue factor pathway inhibitors (TFPIs) was detected by Western blot.The infiltration of the M1 macrophages was significantly increased in the AF with thrombus group compared with the sinus rhythm group (P = .03). Moreover, the expression of OSM and TF was much higher in the AF with thrombus group compared with the sinus rhythm group (P = .02, .009, respectively) while the TFPI was decreased in the AF with thrombus group (P = .04).OSM might be correlated with thrombosis in patients with AF mediated by TF and TFPI.

Topics: Atrial Fibrillation; Blotting, Western; Heart Atria; Heart Valve Prosthesis Implantation; Humans; Immunohistochemistry; Lipoproteins; Macrophages; Mitral Valve Stenosis; Oncostatin M; Rheumatic Heart Disease; Thromboplastin; Thrombosis

Oral anticoagulation is considered standard therapy for stroke prevention in atrial fibrillation (AF). Endocardial activation triggers expression of pro-thrombotic mediators including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), and contributes to thrombus formation in the left atrial appendage (LAA) of AF patients. Recently, pleiotropic effects of specific P2Y12 receptor antagonists were demonstrated; however, whether these drugs possess antithrombotic effects on LAA endocardial cells currently remains unknown.. LAA were obtained from 14 patients with known AF undergoing elective cardiac surgery including LAA removal at the University Hospital Zurich. LAA endocardial cells were isolated and pre-incubated with ticagrelor (10-7, 10-6, 10-5M) or clopidogrel active metabolite (CAM) (1.5 × 10-8, 1.5 × 10-7, 1.5 × 10-6 M) before stimulation with tumour necrosis factor-alpha (TNF-α) (10 ng/mL). Finally, TF and PAI-1 expression and activity were analysed. Ticagrelor, unlike CAM, concentration dependently decreased TNF-α-induced TF expression and TF activity in LAA endocardial cells. Further, ticagrelor, but not CAM reduced PAI-1 expression and enzyme activity in TNF-α-stimulated LAA endocardial cells. In contrast, TF pathway inhibitor (TFPI) remained unaffected by both dugs.. Ticagrelor, but not CAM, reduces expression and activity of TF and PAI-1 in LAA endocardial cells isolated from patients with AF, indicating possible local antithrombotic effects. Such pleiotropic properties of ticagrelor may contribute to a reduction in thromboembolic complications in patients with AF.

Topics: Adenosine; Antithrombins; Atrial Appendage; Atrial Fibrillation; Clopidogrel; Endocardium; Heart Atria; Humans; Plasminogen Activator Inhibitor 1; Purinergic P2Y Receptor Antagonists; Thromboplastin; Ticagrelor; Ticlopidine; Tumor Necrosis Factor-alpha

Topics: Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation; Case-Control Studies; Cerebral Hemorrhage; Dabigatran; Humans; Thromboplastin; Warfarin

Atrial fibrillation is a potent risk factor for stroke, and the administration of anticoagulant therapy is important for preventing thromboembolism. Dabigatran is the first new oral anticoagulant developed as an alternative to warfarin. However, serious major gastrointestinal bleeding events have been observed in elderly patients in post-market case reports. We therefore retrospectively investigated elderly cases of the use of anticoagulant therapy with dabigatran.. Twenty-eight patients over 80 years of age were treated with anticoagulant therapy at our satellite hospital. Nine of the patients received dabigatran, and all others received warfarin. We evaluated the CHADS2 score, HAS-BLED score, renal function and incidence of adverse effects in nine patients treated with dabigatran.. All of the nine patients received 220 mg/day of dabigatran, with no antiplatelet agents. Seven patients continued to receive dabigatran. One patient had an impaired renal function (Cr 1.55 mg/dl, Ccr 30 ml/min). However, the activated partial thromboplastin time (APTT) was not prolonged and neither major bleeding nor stroke were noted in seven patients. Although two patients were unable to continue dabigatran treatment due to APTT prolongation, no serious complications were observed during the administration of dabigatran.. No serious adverse effects of dabigatran anticoagulant therapy were detected in our elderly patients. Although it is necessary to monitor the risk of bleeding, renal dysfunction, effects of drug combination and so on, some elderly patients with atrial fibrillation are good candidates for dabigatran treatment.

Topics: Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Female; Humans; Male; Retrospective Studies; Thromboplastin

Atrial fibrillation (AF) is associated with a prothrombotic state. The aim of this study was to analyze platelet activation and tissue factor (TF) induction in mononuclear cells (MNCs) and granulocytes downstream of cell-cell interactions in AF patients.. Blood samples were obtained from patients with paroxysmal AF (n=14) at sinus rhythm and at 15 min after induction of AF during an electrophysiological study, and from control subjects (n=13) and patients with chronic AF (n=14) in the outpatient clinic. The expression of CD41a, CD42b, P-selectin, and P-selectin glycoprotein ligand-1 (PSGL-1) on platelets and microparticles in platelet-rich plasma (PRP), and on MNCs and granulocytes in whole blood were examined by flow cytometry. MNC-platelet interaction was investigated ex vivo.. The expression of CD41a and CD42b on platelets and microparticles was comparable between the control and chronic AF groups, and unchanged after AF induction. Acute induction of AF significantly increased the expression of P-selectin on platelets and microparticles, and to a similar extent, P-selectin-positive MNCs and granulocytes and P-selectin/PSGL-1-double positive MNCs. However, AF induction had no effect on platelet-MNC interactions ex vivo or TF expression on MNCs and granulocytes. Only patients with chronic AF showed platelet-MNC interaction ex vivo and TF overexpression on MNCs.. Acute-onset AF activates platelets within minutes to initiate platelet-MNC interaction. The subsequent platelet binding induced TF expression in patients with chronic AF. These findings support the efficacy of anticoagulant therapeutics in chronic AF and suggest the underlying utility of antiplatelet therapeutics in early phase of AF occurrence.

Topics: Acute Disease; Atrial Fibrillation; Blood Platelets; Case-Control Studies; Cell Communication; Chronic Disease; Female; Flow Cytometry; Granulocytes; Humans; Leukocytes, Mononuclear; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Glycoprotein GPIb-IX Complex; Platelet Membrane Glycoprotein IIb; Thromboplastin

Atrial fibrillation (AF) is a common complication of coronary artery bypass grafting (CABG). We sought to determine the diagnostic validity of plasma biomarkers of i) inflammation (marked by interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP]), ii) extracellular matrix remodelling (matrix metalloproteinase [MMP-9], tissue inhibitor of matrix metalloproteinase [TIMP-1]) and iii) the prothrombotic state (tissue factor and von Willebrand factor [vWF]) in the risk prediction of post-operative AF. Samples were obtained preoperatively from peripheral/femoral vein and from intracardiac chambers (right atrium [RA], the right atrial appendage [RAA], the left atrium [LA] and the left atrial appendage [LAA]) amongst 100 consecutive patients free of AF and inflammatory disease undergoing elective CABG. Biomarker concentrations were related to incident AF (30 days). At 30 days post CABG, 30 patients were proven to have had AF. Concentrations of tissue factor (TF) and vWF were unrelated to postoperative AF. Peripheral (p=0.018), and intracardiac levels (RAA (p=0.029) and LA (p=0.026)) of hs-CRP were associated with the presence of AF after CABG. Intracardiac levels of IL-6 in samples from the RAA (p=0.031), LA (p=0.042) and LAA (p=0.006), and MMP-9 in the LAA sample were also associated with AF (p=0.007). Our data suggest that an intra-cardiac inflammatory environment that is manifest peri-operatively may predispose to the development of post-operative AF. This intracardiac inflammatory state was reflected by increased peripheral hs-CRP levels. These differences may indicate local substrate abnormalities contributing to the development of AF post-operatively.

Topics: Aged; Atrial Fibrillation; Biomarkers; C-Reactive Protein; Coronary Artery Bypass; Coronary Artery Disease; Female; Humans; Inflammation; Interleukin-6; Male; Matrix Metalloproteinase 9; Middle Aged; Postoperative Complications; Predictive Value of Tests; Prognosis; Reproducibility of Results; Thromboplastin

The precise pathophysiologic processes underlying the prothrombotic or hypercoagulable state in patients with atrial fibrillation (AF) remain uncertain. We hypothesized a relationship among abnormal platelet activation, angiogenic factors, and coagulation, thereby contributing to increased thrombogenecity.. Plasma levels of soluble CD40 ligand (sCD40L [an index of platelet activation]) and tissue factor (TF [an index of coagulation]), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin (Ang)-1, and Ang-2, were measured by enzyme-linked immunosorbent assay in 59 patients with chronic AF. Data were compared to 40 age-matched and sex-matched healthy control subjects who were in sinus rhythm.. AF patients had significantly higher levels of sCD40L (p = 0.038), VEGF (p = 0.023), and Ang-2 (p < 0.001), but not Ang-1 (p = 0.363), compared to control subjects. In non-anticoagulated AF patients (n = 28), TF levels were also higher (p = 0.043), in addition to high sCD40L, VEGF, and Ang-2, compared to control subjects. Among AF patients, sCD40L levels correlated strongly with levels of VEGF (r = 0.919; p < 0.001) and Ang-2 (r = 0.546; p = 0.002). VEGF levels were significantly correlated with levels of Ang-2 (r = 0.490; p < 0.001) and TF (r = 0.298; p = 0.044). In multivariate regression analysis, sCD40L levels were independently associated with levels of VEGF (p = 0.003) and Ang-2 (p = 0.005).. Plasma levels of sCD40L are elevated in patients with AF, and are related to levels of VEGF, Ang-2, and TF. This interaction among platelets, angiogenic markers, and TF may play a role in the generation of the prothrombotic state associated with AF.

Topics: Aged; Angiopoietins; Atrial Fibrillation; Case-Control Studies; CD40 Ligand; Chi-Square Distribution; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Neovascularization, Pathologic; Platelet Activation; Regression Analysis; Statistics, Nonparametric; Thromboplastin; Thrombosis; Vascular Endothelial Growth Factor A

Topics: Atrial Fibrillation; C-Reactive Protein; Echocardiography, Transesophageal; Heart Atria; Humans; Inflammation; Interleukin-6; Intracranial Embolism; Risk Factors; Thrombophilia; Thromboplastin

The precise pathophysiological processes underlying the prothrombotic or hypercoagulable state in atrial fibrillation (AF) remain uncertain. We hypothesized a relationship between abnormal endothelial damage/dysfunction, coagulation, and angiogenic factors, thereby contributing to increased thrombogenicity.. Plasma levels of von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and tissue factor (TF, an index of coagulation), as well as the angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), were measured by enzyme-linked immunosorbant assay (ELISA) in 59 chronic AF patients. Data were compared to 40 age- and sex-matched healthy controls in sinus rhythm.. Plasma vWF, VEGF and Ang-2 were significantly higher in AF patients compared to healthy controls (P=0.005, P=0.0055 and P<0.0001 respectively) but there were no significant differences in plasma Ang-1 or TF levels between the two groups (P=0.925 and P=0.121 respectively). Significant correlations were found between VEGF and vWF levels (Spearman, r=0.262, P=0.011) and between VEGF and Ang-2 (r=0.333, P=0.001).. Raised VEGF in association with Ang-2 and vWF may reflect a link between abnormal endothelial damage/dysfunction and angiogenic factors. These may act together to alter TF expression and endothelial integrity, thereby contributing to the prothrombotic state in AF.

Topics: Aged; Angiogenesis Inducing Agents; Angiopoietin-2; Atrial Fibrillation; Endothelium; Female; Humans; Male; Middle Aged; Thromboplastin; Thrombosis; Vascular Endothelial Growth Factor A; von Willebrand Factor

Thromboembolism secondary to atrial fibrillation accounts for approximately one-fourth of all strokes. Although considerable resources have been targeted to pharmacologic prophylaxis, neither the cellular nor the biochemical composition of atrial thrombi is known. Quantitative immunohistochemistry was undertaken to define the composition of atrial thrombi and to explore morphological differences between atrial appendage thrombi and those that embolize.. Serial sections of thrombi obtained during valve replacement surgery or embolectomy from 22 patients with atrial fibrillation were stained with antibodies against fibrin, integrin beta3, or tissue factor and analyzed with NIH-image.. Thrombi showed distinct regions staining for either fibrin or platelets and on average, the fibrin-rich regions predominated (P < 0.0001). The platelet content of embolized thrombi was nearly twice that of atrial thrombi (P = 0.02). Non-staining amorphous material comprised nearly half of atrial thrombi in situ, but was rare in embolized thrombi (P < 0.001). Tissue factor colocalized to areas rich in platelets and granulocytes.. The abundance of fibrin relative to platelets underscores the enhanced efficacy of warfarin prophylaxis in clinical trials. The finding of tissue factor localized to platelet-leukocyte clusters suggests its blood-borne origin. Compositional differences between in situ and embolized thrombi suggest directions for investigating propensity for embolization.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Platelets; Female; Fibrin; Heart Valve Prosthesis; Humans; Immunohistochemistry; Integrin beta3; Male; Thromboembolism; Thromboplastin; Thrombosis; Warfarin

Atrial fibrillation (AF) has been shown to confer a prothrombotic or hypercoagulable state, which could be related to inflammation. Factor XIII (FXIII) catalyses the cross-linking of fibrin monomers, increasing clot resistance; specifically, a common polymorphism, Val34Leu, in the FXIII-A subunit gene has been associated with more rapid FXIII activation. We hypothesised a role for this polymorphism in the prothrombotic state and inflammation in AF, and tested this hypothesis by measurement of indices of coagulation (tissue factor (TF) and fibrinogen), inflammation (interleukin-6 (IL6)) and platelet activation (soluble P selectin (sPsel)).. We studied 90 stable outpatients (73 +/- 8 years) with persistent AF. The FXIII Val34Leu polymorphism was determined by polymerase chain reaction-allelic specific restriction assay (PCR-ASRA). Prevalence of Val34Leu polymorphism of patients was compared to 585 unrelated subjects from the same geographical area. Plasma fibrinogen (Clauss), TF, IL6 and sPsel (all ELISA) were quantified in patient group. Research indices were compared to 74 controls in sinus rhythm with similar clinical characteristics.. There were no statistical differences in FXIII polymorphism prevalence between AF patients and controls. Patients carrying the Leu34 allele had higher plasma levels of TF, IL6 and sPsel (all P < 0.05) compared to controls. Plasma IL6 and TF levels were significantly correlated (Spearman coefficient, r = 0.33, P < 0.01). On multivariate analysis, the Leu34 allele was independently associated with IL6 levels (P < 0.01), whereas TF levels were only associated with IL6 concentrations. However, sPsel and fibrinogen levels were not related to Leu34 allele.. FXIII Val34Leu polymorphism was independently associated with IL6 levels in AF. The Leu34 allele may potentially influence the prothrombotic state in these patients by modulating the inflammatory state.

Topics: Aged; Aged, 80 and over; Alleles; Amino Acid Substitution; Atrial Fibrillation; Factor XIII; Female; Fibrinogen; Genetic Predisposition to Disease; Humans; Inflammation; Interleukin-6; Male; P-Selectin; Polymorphism, Genetic; Thromboplastin

Topics: Atrial Fibrillation; Endocardium; Endothelium, Vascular; Heart Atria; Humans; Thromboplastin; Thrombosis

Tissue factor plays a key role in the extrinsic coagulation pathway and is induced by inflammatory cytokines. Atrial myocarditis has been detected recently in some patients with lone atrial fibrillation. Virchow's triad of low blood flow, hypercoagulability, and endothelial dysfunction, enhances thrombus formation. The present study was designed to elucidate the role of endothelial dysfunction in thrombogenesis associated with nonvalvular atrial fibrillation.. We investigated tissue factor expression in the endothelia of left atrial appendages obtained from seven patients with nonvalvular atrial fibrillation and cardiogenic thromboembolism. Tissues were divided into 7-13 sections and compared with control specimens from four patients who died of noncardiac events. Expression of tissue factor, von Willebrand factor and tissue factor pathway inhibitor was evaluated by immunohistochemistry.. Histopathologically, inflammatory cells infiltrated the endocardium and all seven patients showed features of persistent myocarditis. Activated T cells [15.3+/-9.4 cells/high power field (HPF, mean+/-S.D.) vs. control 2.2+/-4.4/HPF (P=0.0294)] and a few macrophages [5.1+/-8.4 cells/HPF vs. control 2.4+/-3.5 cells/HPF (P=NS)] infiltrated the endocardium. Tissue factor was overexpressed in the endothelia particularly in tissues containing inflammatory cells and denuded matrix of the endocardium, compared with the control group. Von Willebrand factor, but not tissue factor pathway inhibitor, was also overexpressed in these tissues.. Tissue factor expression induced by local inflammation is involved in the pathogenesis of thrombosis in patients with nonvalvular atrial fibrillation.

Topics: Aged; Atrial Fibrillation; Endocardium; Endothelium, Vascular; Female; Heart Atria; Humans; Immunohistochemistry; Inflammation; Male; Middle Aged; Myocarditis; Thromboplastin; von Willebrand Factor