Tissue factor pathway inhibitor: a possible mechanism of action.

We have analyzed several mathematical models that describe inhibition of the factor VIIa-tissue factor complex (VIIa-TF) by tissue factor pathway inhibitor (TFPI). At the core of these models is a common mechanism of TFPI action suggesting that only the Xa-TFPI complex is the inhibitor of the extrinsic tenase activity. However, the model based on this hypothesis could not explain well all the available experimental data. Here, we show that a good quantitative description of all experimental data could be achieved in a model that contains two more assumptions. The first assumption is based on the hypothesis originally proposed by Baugh et al. [Baugh, R.J., Broze, G.J. Jr & Krishnaswamy, S. (1998) J. Biol. Chem. 273, 4378-4386], which suggests that TFPI could inhibit the enzyme-product complex Xa-VIIa-TF. The second assumption proposes an interaction between the X-VIIa-TF complex and the factor Xa-TFPI complex. Experiments to test these hypotheses are suggested.

Invertebrate compounds acting on the hemostatic mechanism.

Physiological secretions from some invertebrates have toxic effects on mammalian blood coagulation and fibrinolytic systems. Some of these effects occur because the substances contained in the secretions resemble the components of the hemostatic system. Some of the substances have been characterized, and have been found to have similar molecular weights or sequences, which may indicate a common ancestry. The components can be divided into five groups: antithrombic agents (group I); inhibitors and activators of the prothrombinase complex (group II); substances that affect platelet function (group III); substances that affect the fibrinolytic mechanism (group IV); and a group of miscellaneous agents whose activities are difficult to group together (group V). In group I special mention of the antithrombin agents in Hirudo medicinalis should be made. In group II, the agents affecting the prothrombinase complex are antistasin from Haementeria officinalis, ghilanten from Haementeria Ghiliani and the tick anticoagulant protein from Ornithodoros moubata, a factor V activator/inhibitor from Lonomia achelous and factor II and factor X activators from L. achelous and Lonomia obliqua. Examples of factors which affect platelet function (group III) are glossina from the black fly Glossina morsitans, calin from H. medicinalis, decorsin (a desintegrin) from Macrobdella decorsa, and FAGA from Stichopus japonicus selenka. The first three of these are inhibitors of platelet aggregation, and the last is an inducer. The plasminogen activators (group IV) from the L. achelous caterpillar and Eutriatoma maculata trigger the fibrinolytic system, whereas hementin from H. officinalis and hementerin from Haementeria depressa are directly fibrinolytic. The last group of substances (group V) include those with factor-XIIa-like activity from D. farinae, kallikrein-like activity and a factor XIII degrading enzyme from L. achelous, destabilase from H. medicinalis and prolixin S (nitroforin 2, or anti-factor-IXa) from Rhodnius prolixus. Some of these components have been well characterized, cloned and prepared in recombinant form, and seem to be very promising from the therapeutic point of view.

Prothrombin and factor X activator activities in the venoms of Viperidae snakes.

A Ca(2+)-dependent prothrombin activator, carinactivase-1 (CA-1), was previously found in the venom of Echis carinatus leucogaster. In the present study, the activities of CA-1-like enzymes were screened in the venoms of various Viperidae snakes. The addition of 1 mM Ca2+ ions to the venoms of only Echis snakes in Viperidae produced considerably high prothrombin activator activity, indicating that only the Echis snake venoms contain not only the Ca(2+)-independent prothrombin activator, ecarin, but also Ca(2+)-dependent activator(s). CA-1-like activators and ecarin in the venom of each Echis snake were efficiently separated by Blue Sepharose column chromatography. The venoms of the various Viperidae snakes were also examined for factor X activator activity. The venoms of genera Daboia, Vipera, Cerastes, Echis, Calloselasma and Bothrops contained factor X activator activity in the presence of Ca2+ ions. Cerastes cerastes and Calloselasma rhodostoma venoms also had Ca(2+)-independent factor X activator activity.