Limited Ability to Activate Protein C Confers Left Atrial Endocardium A Thrombogenic Phenotype

Abstract

Background and Purpose-Atrial fibrillation is the most important risk factor for cardioembolic stroke. Thrombi form in the left atrial appendage rather than in the right. The causes of this different thrombogenicity are not well-understood. The goal herein was to compare the activation of the anticoagulant protein C and the thrombomodulin and endothelial protein C receptor/activated protein C receptor expression on the endocardium between right and left atria. Methods-We harvested the atria of 6 monkeys (Macaca fascicularis) and quantified their ability to activate protein C ex vivo and we measured the thrombomodulin and endothelial protein C receptor expression by immunofluorescence. Results-We found the ability to activate protein C decreased by half (Pϭ0.028) and there was lower expression of thrombomodulin in the left atrial endocardium than the right (52.5Ϯ19.9 and 72.1Ϯ18.8 arbitrary intensity units, meanϮstandard deviation; Pϭ0.028). No differences were detected in endothelial protein C receptor expression. Conclusions-Impaired protein C activation on the left atrial endocardium attributable to low thrombomodulin expression may explain its higher thrombogenicity and play a role in cardioembolic stroke. (Stroke. 2011;42:2622-2624.)Key Words: anticoagulation Ⅲ embolic stroke Ⅲ embolism Ⅲ endothelium Ⅲ protein C anticoagulant system Ⅲ thrombomodulin A trial fibrillation is the most commonly sustained cardiac arrhythmia and the most important risk factor for cardioembolic stroke. 1 The left atrium, particularly the left atrial appendage (LAA), is the most frequent location of the embolic thrombi even when the right atrium undergoes the same pathological process. 2 The blood stasis at the LAA and the right atrial appendage (RAA) is similar, 3 so this cannot explain the higher propensity of thrombi to be formed in the LAA. In the search for additional factors to explain the difference between the 2 atria in thrombogenicity, study of their endothelial phenotypes deserves consideration. Attention recently has focused on the functional consequences of endothelial heterogeneity among different vascular beds. 4 Endothelium has been classically considered a thromboresistent surface because of the presence of receptors involved in several antithrombotic pathways. Among these, thrombomodulin and the endothelial protein C/activated protein C receptor (EPCR) play a crucial role in the protein C anticoagulant pathway. 5 EPCR expression is high in large arteries and veins but is virtually absent in capillaries. 6 Thrombomodulin expression is particularly high in the pulmonary endothelium and is low in the brain endothelium. 7 Differences also have been reported within 1 vessel: in veins, both EPCR and thrombomodulin are expressed more in the valvular sinus endothelium as opposed to the vein lumenal endothelium. 8 The association between protein C deficiency and thrombosis is well-documented. 9 For this reason, we propose the hypothesis that the left atrium has a lower ability to activate protein C than the right one. Mate...

Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice

“…Endothelial dysfunction has been implicated in the increased risk for thrombus formation within the failing heart. Given the critical endogenous anticoagulant role of APC [ 23 , 26 ], we examined APC generation on the LV endocardial surface. Our results show a striking decrease in the APC generating ability of the endocardium.…”

“…This attenuation is paralleled by increased thrombin generation on the endocardial surface in acute decompensated HF mice. An attenuation of APC generation in the left atrial appendage, as compared to the right, has been postulated as a possible reason for the increased formation of thrombi within the left atria in atrial fibrillation [ 26 ]. In the latter study, however, thrombi numbers were not quantified.…”

“…Decreased PC expression, or mutations in TM, increases the risk for vascular and atrial endocardial thrombus formation [ 25 – 27 ]. Indeed, decreased APC activation in the left atrial endocardium may promote thrombosis in atrial fibrillation [ 26 ]. Therefore, regulation of endothelial TM and EPCR is a critical part of endothelial cell anticoagulant function that may be disrupted in HF.…”

Evaluating the Atrial Myopathy Underlying Atrial Fibrillation

“…Activated protein C is one of the most potent natural anticoagulants; protein C binds to the endothelial protein C receptor where it is activated by a complex of thrombin and thrombomodulin. Cervero et al 163 reported a significant underexpression of thrombomodulin by the left as compared to the right atrial endocardium, and less than half the ability to activate protein C. In pigs with induced AF, PAI-1 protein expression was increased in the LA but not the right atrium, and the LA increase was accompanied by a decrease in nitric oxide. 164 In patients with chronic AF, thrombin generation is increased in the LA compared to the periphery.…”

Atrial thrombogenesis in atrial fibrillation

“…(PAI) 1, von Willebrand factor (vWF), and adhesion molecules (ICAM, VCAM, selectins) [5,16,20]. There is clinical evidence that AF-induced thrombogenicity of the left atrium is much greater compared with the right atrium [9]. This helps to explain why AF induces predominantly systemic emboli and stroke rather than pulmonary emboli.…”