Decreased Activity of the Protein C Anticoagulant Pathway in the Early Hours of Paroxysmal Atrial Fibrillation

Abstract

Background: Increased coagulation activity has been established in paroxysmal atrial fibrillation (PAF), but data on the anticoagulant system are scarce. Purpose: To examine the protein C anticoagulant pathway in the early hours of the disease. Materials and Methods: Fifty-one patients (26 men and 25 women; mean age 59.84 + 1.60 years) and 52 controls (26 men and 26 women; mean age 59.50 + 1.46 years) were selected for the study. Protein C antigen and its activity, total protein S, free protein S and its activity, soluble forms of endothelial protein C receptor (sEPCR), and thrombomodulin (sTM) were examined in the plasma. Results: The indicators were studied in patients between the 2nd and the 24th hour after the onset of arrhythmia. Levels of protein C were significantly elevated in patients compared to controls (111.40% + 6.66% vs 94.83% + 4.47%; P ¼ .039). Protein C activity showed significant reduction in PAF (73.13% + 5.80% vs 103.3% + 3.80%; P < .001). Total protein S levels did not differ significantly (108.20% + 4.07% vs 102.40% + 3.65%; P ¼ .30). Free protein S (76.81% + 6.01% vs 122.10% + 3.97%; P < .001) and its activity (71.39% + 6.27% vs 119.50% + 6.54%; P < .001) were reduced in patients. Higher levels of sEPCR (203.10 + 10.33 vs 133.10 + 7.37 ng/mL; P < .001) and sTM (6.50+0.40 vs 4.48+0.28 ng/mL; P < .001) were measured in PAF. Conclusion: Protein C activity is reduced still in the first hours (until the 24th hour) of PAF clinical manifestation, determining reduced activity of the anticoagulant pathway as a whole. The established low levels of free protein S and its activity as well as low sEPCR and sTM levels are a possible explanation of the changes in protein C activity.

Thrombin in complex with dabigatran can still interact with PAR‐1 via exosite‐I and instigate loss of vascular integrity

“…Another determinant present in our system is the APC pathway, as the endothelium is a potential source of TM and EPCR, which in concert with PC and protein S will provide a negative feedback loop by inactivating FVa and FVIIIa. However, TNF‐α stimulation attenuated surface expression of TM and EPCR already at 1 ng/ml TNF‐α (Figure 1E), which is consistent with the literature, 26 thus potentially suppressing this pathway, which has been confirmed in patients with AF 27 . When assessing the contribution of APC to thrombin generation, inhibition of activation of PC using antibody HPC4 showed no detectable effect.…”

“…However, TNF‐α stimulation attenuated surface expression of TM and EPCR already at 1 ng/ml TNF‐α (Figure 1E ), which is consistent with the literature, 26 thus potentially suppressing this pathway, which has been confirmed in patients with AF. 27 When assessing the contribution of APC to thrombin generation, inhibition of activation of PC using antibody HPC4 showed no detectable effect.…”

Cerebral microembolism during atrial fibrillation ablation can result from the technical aspects and mostly does not cause permanent neurological deficit

“…The presence of micro-thrombi may result from coagulopathy. Potentially enhanced endogenous anticoagulant activity and the "consumption" of C and S proteins consequently lead to impaired anticoagulant protection [25]. Additionally, the activation of inflammatory processes may be of some importance.…”