Depletion of Systemic Concentrations of Coagulation Factors in Blood From Patients with Atherosclerotic Vascular Disease
Authors: Brummel-Ziedins Kathleen E. , Lam Philip , Gauthier Eric , Schneider David 
Published: October 2019

Abstract
Abstract 1231

Introduction.
Thrombosis complicating the rupture of atherosclerotic plaques leads to arterial occlusion. Tissue factor (Tf), a membrane-bound glycoprotein, is expressed to a greater extent in atherosclerotic plaques and is likely a key mediator of micro and macro thrombosis. Atherosclerotic vascular disease is a widespread process that can lead to stroke, myocardial infarction and peripheral artery occlusion. Because thrombosis consumes coagulation factors, the goal of the present study was to determine whether the extent of atherosclerosis correlated with the concentration or activity of coagulation factors in blood and to relate, using novel computational approaches, the thrombin generation potential of the arterial blood to the extent of atherosclerosis. Methods. Patients scheduled for diagnostic cardiac catheterization (n=57) for clinical indications were enrolled. The average age was 65 (range 35–92) with a predominance of males (71%). Most patients were treated with aspirin (54/57 – 95%) and a small group had been treated with both aspirin plus clopidogrel (7/57 – 12%). After review of their angiograms, patients were divided into 3 groups based on their maximal extent of stenosis, 1) no coronary artery disease (no CAD, n=10), 2) coronary arterial stenosis <50% (CAD<50%, n=9), and 3) coronary arterial stenosis >50% (CAD>50%, n=38). For patients with CAD>50%, we evaluated those not treated with clopidogrel (n=31) separately from the group taking clopidogrel (n=7). Blood was taken from catheters placed in the femoral artery before administration of anticoagulants. Thrombin and factor Xa generation was assessed computationally based on measurements of plasma coagulation factors (II, V, VII, IX, X) and inhibitors (antithrombin and free tissue factor pathway inhibitor, TFPI) in all patients. Results. Plasma composition was not significantly different between individuals with no CAD versus CAD. In individuals with CAD, the concentrations of fX and prothrombin were significantly less in blood from patients with more than 50% stenosis. This difference was apparent in both those taking clopidogrel and those not taking clopidogrel. Thrombin and fXa generation after a 5 pM Tf initiator was significantly increased in all individuals compared to a physiologic control. Individuals with >50% CAD had significantly lower total thrombin then individuals with CAD<50% (83±16μM.s vs. 96 ±20μM.s, respectively). Kinetic analysis suggested that depletion of fX and prothrombin would decrease the amount of thrombin generated in patients with CAD>50%. To determine whether selected factors influenced the generation of fXa and thrombin, linear regression analysis was performed. The concentrations in blood of TFPI and fVIII were strongly associated (R2=0.5) with the time to the maximum rate of thrombin generation and maximum concentration of fXa generated. In simulations performed with increasing Tf concentrations (12.5 pM and 25 pM) TFPI and fVIII continued to correlate with thrombin and fXa generation. Also, at increasing Tf concentrations, fXa generation had greater (11 fold range) power to resolve each individual's thrombin generation profile (4 fold range). Conclusions. In summary, a reduced concentration of prothrombin and fX was observed in patients with more severe CAD, which could reflect greater consumption of these coagulation factors, reduced production or some combination. The computational analyses indicated important roles for TFPI and fVIII in the thrombin generation potential of individuals with CAD. The kinetics of fXa and thrombin generation suggests that the lower concentrations of fX and prothrombin may have functional implications consistent with clinical observations of patients with severe CAD having a narrower therapeutic window when treated with vitamin K antagonists.

Disclosures:
No relevant conflicts of interest to declare.