Interaction with prothrombin

The studies on the mode of interaction of prothrombin with phospholipid monolayers, using complementary methods of surface measurement are reviewed. They were investigated at air-water and Hg-water interfaces respectively by radioactivity and electrochemistry. A process more complex than a simple adsorption could be detected. Indeed, the variation of the differential capacity of a mercury electrode in direct contact with phospholipid monolayer, induced by the interaction with prothrombin could be interpreted as a model of its penetration into the layer this was confirmed by the study of the dynamic properties of the direct adsorption of this protein at the e-lectrode, followed in part by the reduction of S-S bridges at the electrode. It could be also concluded that prothrombin resists complete unfolding at these interfaces. 

The anticoagulant activity of heparin is endowed by its ability to form strong complexes with a variety of blood clotting factors and thus neutralize their action. For instance, heparin interacts with thrombin, fibrinogen, prothrombin, factors IX-XII... 

Interaction of Prothrombin and Ca++ with Phospholipid Monolayers Containing Phosphatidyl Serine... 

In the present work we studied the interaction of prothrombin with lipid monolayers in the presence of Ca++. The stoichiometric relations of the interacting components were determined by measuring surface radioactivity of 3H-labelled prothrombin and 45Ca. The penetration was inferred from the effect of the interaction on the capacitance of the surface layer. 

In Figure 4 the effect of prothrombin on the differential capacity of a PS monolayer is presented. The overall capacitance, which is proportional to the out-of-phase (quadrature) ac current, increases upon interaction with the prothrombin. Moreover, a pseudocapacitance peak (at —0.7 V relative to the N-AgCl electrode) characteristic of cystine-cysteine redox potential appears. The peak potential moves as expected toward more... 

From the previous results one can draw some conclusions with regard to the structure and the arrangements of the prothrombin molecules interacting with a lipid layer consisting of PS. A model based on these conclusions are presented schematically in Figure 7. As seen in this drawing... 

Figure 7. A schematic model of the interaction between prothrombin and the PS monolayer in the presence of calcium on one side, the hydrocarbon chain is in contact with the air or the mercury drop on the other side, the layer of prothrombin protrudes in the aqueous solution. The prothrombin schematic configuration is according to Ref. 8.

Divorce Prothrombin engages in an exchange [of gene piecesl that leaves it with [domains] for binding to fibrin in place of its EGF domains, which are no longer needed for interaction with TF. ... 

A very recent paper by Robertson etal. l 08) explores the utilization of NMR for the study of Mg binding to y-carboxyglutamic acid-containing peptides. These are taken as a model for prothrombin, an enzyme possessing 10 y-carboxyglutamic acid residues and which is known to interact with Mg and Ca. Whereas the addition of the peptide to an aqueous solution of Mg affects the line-width rather than the shift, the Ca line-widths remain almost invariant in the... 

The resultant modified E residues are gamma-carboxyglutamate (gla). This process is most clearly understood for factor II, also called preprothrombin. Prothrombin is modified pre-prothrombin. The gla residues are effective calcium ion chelators. Upon chelation of calcium, prothrombin interacts with phospholipids in membranes and is proteolysed to thrombin through the action of activated factor X (Xa). Dining the carboxylation reaction reduced hydroquinone form of vitamin K is converted to a 2,3-epoxide form. The regeneration of the hydroquinone form requires an uncharacterized reductase. This latter reaction is the site of action of the dicumarol-based anticoagulants such as warfarin. 

Erythromycin can interact with warfarin, resulting in a modest increase in blood concentrations and a rise in the prothrombin time of around 8% (78). 

May interact with monoamine oxidase inhibitors and warfarin (decreased prothrombin time)... 

In two of the five spontaneous bleeding episodes described in Heading 4, medications that can affect platelet function or prothrombin time (PT) (i.e., aspirin and warfarin) were involved. Because GB is known to be an inhibitor of PAF (41), in theory GB could interact with antiplatelet drugs (e.g., aspirin, nonsteroidal anti-inflammatory drugs, clopidogrel, ticlopidine, dipyridamole) or anticoagulants (e.g., warfarin, heparin). EGb 761 was shown to potentiate the antiplatelet effect of ticlopidine in rats (42). However, in two studies in humans, the coadministration of GB with warfarin had no effect on either international normalized ratio or warfarin metabolism (43,44). 

These results show that the ability of these signal peptides to interact with phospholipid monolayers indeed correlates with their in vivo activity. The pressure increases due to the functional signal peptides (8—11 dyn/cm) are in the same range as those caused by proteins known to insert into monolayers (Bougis et al., 1981). In contrast, prothrombin, which binds only to the membrane surface, causes a pressure increase in a phospholipid monolayer of 1.9-2.3 dyn/cm (Mayer et al., 1983). These values are almost identical to those obtained for perturbation of the monolayer by the deletion-mutant signal peptide. 

Aznar J, Vaya A, Estelles A, et al. Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica 2000 85 1271— 1276. 

Hepatic necrosis develops at much lower doses of acetaminophen in some heavy drinkers than would be expected (39), perhaps because of the induction of the CYP2E1 system, depletion of glutathione stores, or aberrations in the primary sulfate and glucuronide conjugation pathways. At 4 g per day, acetaminophen has been reported to potentiate the response to oral anticoagulants, increasing prothrombin time (INR values) two to three times. Interactions with warfarin... 

Interaction of Prothrombin with Phospholipid Monolayers at Air- and Mercury-Water Interfaces... 

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