Thrombogenesis in lone atrial fibrillation: a role for soluble P-selectin?

This editorial refers to ‘A study of blood soluble P-selectin, fibrinogen, and von Willebrand factor levels in idiopathic and lone atrial fibrillation’ by R. Fu et al., on page 31 Irrespective of whether atrial fibrillation (AF) is paroxysmal or sustained, this common arrhythmia substantially increases the risk of stroke and thrombo-embolism 5-fold, and hence, much interest has been directed towards the underlying pathophysiological processes associated with this risk.1,2 Virchow's triad for thrombogenesis is fulfilled in AF, as evident by altered flow patterns in the left atrium with stasis within the left atrial appendage (‘flow abnormalities’), as well as structural and endothelial/endocardial damage or dysfunction (‘vessel wall abnormalities’) and abnormalities of blood constituents (e.g. platelets, increased fibrin turnover).3 To date, most studies that have explored prothrombotic or thrombogenic markers in AF patients have related these biomarkers to poor outcomes, although many published cohorts have included subjects with associated comorbities.3 Thus, AF may further enhance risk and worsen outcome, although it has often been debated whether the presence of AF is simply a marker of a ‘sick heart’ from underlying cardiovascular disorders or risk factors. For example, stroke associated with AF becomes more common with age, but the latter is intimately associated with an increasing prevalence of other cardiovascular disorders (e.g. hypertension, diabetes, coronary artery disease, heart failure, etc.) which themselves lead to an enhanced prothrombotic state.3 As patients with lone AF do not manifest any other cardiovascular disease, this group has been deemed to have a favourable prognosis with respect to thrombo-embolism and mortality. Thus, when studying the prothrombotic state associated with AF, careful evaluation of lone AF patients would be one approach. Some evidence supports the contribution of platelet activation in the development and persistence of AF, based on higher levels of soluble P-selectin (sP-selectin), an endothelial and platelet glycoproteins appear essential in the adhesion of leucocytes to the endothelium.4,5 In addition, indices of endothelial damage/dysfunction [e.g. von Willebrand factor (vWF), E-selectin] and clotting (e.g. fibrinogen, fibrin D-dimer) markers have been investigated in AF.3,6 Nonetheless, several risk factors (age, gender, hypertension, diabetes, hyperlipidaemia) may also increase these haemostatic index levels, affecting the prothrombotic state in AF.3,7 Indeed, genetics might also influence the thrombo-embolic risk in AF patients, but the data are still limited.8 Although it is uncertain to what extent each of the above comorbidities might contribute to the pathogenesis of thrombogenesis in AF, several plasma markers have been used as biomarkers to refine the predictive value of stroke risk in AF.9 In other studies, the fibrin degradation product, D-dimer, has also been related to outcomes in AF.6,10 Fu et al.11 examined whether patients with lone and idiopathic AF display thrombogenic aspects promoting a hypercoagulable state. Lone AF and idiopathic AF are clearly distinguished here based on patient age and the absence of identified cardiovascular pathologies, and are also compared with matched controls. The study has shown that patients with idiopathic AF had higher levels of soluble P-selectin and fibrinogen, compared with controls, which confirms the prothrombotic state and enhanced platelet activation in AF, irrespective of associated risk factors. However, these data are in conflict with other studies in AF with only local platelet activation,4 or with systemic platelet activation.12 In the subgroup of 60 patients with lone AF (age of <60 years), there was only a significant difference in soluble P-selectin, but not in plasma fibrinogen or vWF levels. Thus, the hypercoagulable state in lone AF might be more related to platelet activation (P-selectin) rather than the endothelium (vWF) per se. This is despite endothelial perturbation in AF that may contribute to the prothrombotic state.13 Although plasma levels of soluble P-selectin are unrelated to stroke risk in AF,14 the paper by Fu et al.11 proposed that platelet activation involvement in idiopathic and lone AF may be evident. Does this translate to clinical benefits? In the Japan Atrial Fibrillation Stroke Trial,15 patients with lone AF were randomized to aspirin 150–200 mg/day or control without antithrombotic therapy. There was no significant difference in primary outcomes (3.1% per year in the aspirin-treated group vs. 2.4% per year in the control group), as well as a non-significant increased risk of major bleeding (1.6%) compared with control (0.4%). Oral anticoagulation is also far more effective than antiplatelet therapy at reducing stroke risk with no significant difference in major bleeding risks.16,17 Nonetheless, this view has been much debated,18,19 but recent data from the AVERROES (Apixaban vs. Acetylsalicylic Acid to Prevent Strokes) trial have clearly shown that an oral anticoagulant drug (apixaban, an oral Factor Xa inhibitor) was superior to aspirin for stroke prevention in AF with no significant difference in major bleeding rates between apixaban and aspirin, and importantly, aspirin was less well tolerated.20 Other antiplatelet agents such as indobufen and triflusal have been investigated in AF, with the suggestion of some benefit, but more data are still required. Supporting the overwhelming benefit of oral anticoagulation therapy in the reduction of thrombo-embolism in AF patients, atrial thrombi tend to be fibrin-rich (so-called red thrombi) compared with thrombi associated with acute coronary syndromes, which are platelet-rich (so-called white thrombi).1 Thus, thrombogenesis in AF is rather dependent upon the coagulation pathway, but this does not preclude a role for platelets . Thus, the results in the paper by Fu et al.11 are intriguing, given that the antiplatelet drug management of lone AF does not seem to confer any significant benefits, but, possibly, harm from the risk of bleeding. Conflict of interest: S.M.G. and F.M. have no conflicts of interest. G.Y.H.L. has received funding for research, educational symposia, consultancy, and lecturing from many different manufacturers of drugs used for the treatment of atrial fibrillation.