Response of plasma tissue factor pathway inhibitor to diet-induced hypercholesterolemia in crab-eating monkeys.

Abstract

Tissue factor pathway inhibitor (TFPI), a protease inhibitor associated with lipoproteins in plasma and endothelial cells, can inhibit the initial reactions of the tissue factor-mediated coagulation pathway. A positive relationship between TFPI and cholesterol has been demonstrated in human plasma. To investigate this relation in more detail, in the present study we measured TFPI in the plasma of monkeys on a high-cholesterol diet. After diet treatment, cholesterol levels and TFPI activity were increased 3-and 1.5-fold, respectively. Three forms of TFPI, low-density lipoprotein (LDL)/very-low-density lipoprotein (VLDL)-associated TFPI, high-density lipoprotein (HDL)-associated TFPI, and free TFPI, were measured after gel filtration of plasma. In hypercholesterolemic monkeys, levels of TFPI activity and T he extrinsic blood coagulation pathway is triggered by the interaction between tissue factor (TF) and factor VII, which leads to activation of the precursors of the serine proteases, factor VII, factor IX, factor X, and prothrombin, resulting in the generation of thrombin. (For a review see References 1 and 2.) These reactions are regulated by several different mechanisms, eg, inactivation of cofactors by activated protein C and inactivation of activated proteases by protease inhibitors such as antithrombin III. TF pathway inhibitor (TFPI), a protease inhibitor with three tandem Kunitz-type inhibitory domains, inhibits factor Vila and factor Xa in the presence of TF, so that TFPI is an inhibitor of the initial reaction of the extrinsic pathway. (For reviews see References 3 through 7.)The most striking characteristics of TFPI are its association with lipoproteins in plasma and endothelial cells. It has been demonstrated that three forms of TFPI, low-density lipoprotein (LDL)/very-low-density lipoprotein (VLDL)-associated TFPI, high-density lipoprotein (HDL)-associated TFPI, and the free form of TFPI, can be detected by gel filtration of human plasma; it has also been shown that heparin infusion markedly increases the free form of TFPI, which is thought to be derived from

Tissue factor pathway inhibitor: structure, biology and involvement in disease

“…The homology of the Kunitz‐type domains of TFPI among the three species is 57%, 86% and 69% in the first, second and third domains 57. The differences between rabbit and rat TFPI and those of human or monkey may be due to differences in the amino acid sequence, post‐transitional modification of TFPI, or species differences in the properties of the lipoproteins 60. The cDNA and predicted protein sequence for the full‐length mouse TFPI show significant homology to that of rat 61.…”

“…Cloning and expression of the mouse TFPI gene may offer useful information and material for coagulation studies performed in a mouse model system. However, in studying the regulatory roles of TFPI in thrombosis and atherosclerosis, species differences should be taken into consideration, especially if rabbits and rats are to be used as the animal model 60. Recently, a two‐Kunitz (Ixolaris) and a five‐Kunitz (Penthalaris) molecule with TFPI‐like properties have been described in the tick saliva from Ixodes scapularis 62, 63.…”

Oxidized low-density lipoprotein impairs the anti-coagulant function of tissue-factor-pathway inhibitor through oxidative modification by its high association and accelerated degradation in cultured human endothelial cells

“…The final concentration of TFPI under the present assay conditions ranged from 0.01 to 0.1 nM. It has been widely accepted that the C-terminus of TFPI is a major site for interactions of heparin, lipoproteins and phospholipids ; the significance of this region in anti-coagulant function has also been demonstrated [35,36]. Hansen et al [37] have reported that the lipoprotein-associated form of TFPI, which was estimated to account for 70-85 % of the circulating TFPI in human plasma, does not possess anti-coagulant function when the activity is determined in terms of diluted prothrombin time.…”

Olive oil and the haemostatic system

“…The principal role of TFPI appears to be to inhibit small amounts of TF, which are probably essential for the maintenance of normal haemostatic balance. A previous study has shown that TFPI in the plasma of crab-eating monkeys increases markedly in response to a high-cholesterol diet [52]. The effects of diets enriched with fats from various sources were explored by Larsen et al in a randomised crossover study that compared three dietary periods based on an olive oil-enriched diet, a sunflower oil diet and a rapeseed oil diet respectively [46].…”