Effect of Cholesterol Lowering on Intravascular Pools of TFPI and Its Anticoagulant Potential in Type II Hyperlipoproteinemia

Abstract

Tissue factor pathway inhibitor (TFPI) inhibits the extrinsic coagulation system. A major pool of TFPI is associated with the vascular endothelium and can be mobilized into the circulation by heparin. In circulating blood, TFPI is mainly associated with LDL (80%), whereas 10% to 20% is carrier free. In this study, heparin administration caused a 2.2-fold and a 7.5-fold increase in TFPI activity and TFPI antigen, respectively, in 25 patients with phenotypes IIa and IIb hyperbetalipoproteinemia. Because the antigen determination of TFPI almost exclusively measures carrier-free TFPI, more than 90% of the heparin-induced increase in TFPI activity was caused by mobilization of carrier-free TFPI from the vascular endothelium. Therapeutic lowering of total cholesterol (a decrease of 31.1 +/- 11.6%, P < .001) by 40 mg/d lovastatin in 17 patients with hyperbetalipoproteinemia was accompanied by a parallel decrease in TFPI activity (of 27.7 +/- 24.2%, P < .001) because of a reduction in LDL-TFPI complexes. However, drug intervention did not affect carrier-free TFPI or the magnitude of the vascular pool of TFPI that could be mobilized into the circulation by heparin. Moreover, this reduction of LDL-TFPI complexes did not reduce the anticoagulant potency of TFPI in plasma or of the vascular endothelial pool. The results of this study may imply that the anticoagulant potency of TFPI is associated with its carrier-free form in plasma or on the endothelium and that downregulation of LDL affects neither the size nor the anticoagulant potency of the endothelial pool of TFPI.

Statins and Blood Coagulation

“…However, conflicting results have been reported. 5,8 Lovastatin, 69 fluvastatin, 70 simvastatin, 36 and atorvastatin 36 have been found to decrease TFPI activity, caused by reduction in the LDL-TFPI complexes, and total TFPI levels without any change in free TFPI in hyperlipidemic individuals. The reported lower TFPI antigen levels as a result of the HMG-CoA reductase inhibitors are likely to reflect normalization of the disturbed functions of the endothelium, but not suppression of the anticoagulant potency of the endothelial pool of free TFPI, mobilized by heparin, as shown by Hansen et al 69 The available data indicate a lack of significant changes in TFPI levels and/or activity during statin therapy.…”

Detection of the Three Kunitz-Type Single Domains of Membrane-Bound Tissue Factor Pathway Inhibitor (TFPI) by Flow Cytometry

“…The cells were washed three times in phosphate-buffered saline at 4 °C to remove traces of culture medium, then resuspended in phosphate-buffered saline at an approximate cell concentration of 2xl0 9 /l. The suspension (50-ΙΟΟμΙ) was pipetted onto a premarked area of silanized glass slides and allowed to settle for 10 ! )…”

“…It functions as a potent natuation with ^'Proteins remains unclear (9). It has been ral anticoagulant that regulates tissue factor-mediated su gS ested that domain 3 is involve d in the binding to coagulation inhibition in the extrinsic pathway (1 -3).…”

Comparison of the Inhibitory Effects of ApoB100 and Tissue Factor Pathway Inhibitor on Tissue Factor and the Influence of Lipoprotein Oxidation

“…14 In fact, most circulating TFPI has been found to be associated with low-density LDL and HDL subfractions. [15][16][17] Oxidation of lipoproteins and LDL in particular has been closely associated with atherogenesis. 18 The inhibitory effect of LDL, arising from the ApoB100 moiety, can be compromised by oxidation.…”