Antithrombin III inhibition of the reaction to thrombin excitation of the anticoagulation system

It has been established that intravenous administration of alpha-thrombin-antithrombin III preparations (1 mkM) has practically no effect on anticoagulation parameters (thrombin time, additive fibrinolytic activity, nonenzymatic fibrinolysis and nonenzymatic fibrinolytic activity). Administration of 1 mkM of alpha-thrombin caused a statistically significant increase of all the parameters. The experiments on perfusion of the humorally isolated sinocarotid area of the rabbit with alpha-thrombin-antithrombin III preparations (1.25 mkM) showed no changes peculiar to the induction of anticoagulation response with thrombin. It is concluded that antithrombin III blocks the ability of thrombin to activate anticoagulation system function.     

Role of intermediate products of prothrombin proteolysis by thrombin in the stimulation of the anticoagulation system of blood]

Two components - the intermediate product 1 (P-1) converting under certain conditions into thrombin, and product 2 (P-2) which possesses no such properties were isolated from the products of prothrombin proteolysis by thrombin. The intravenous injection of the P-1 to rats lengthened the blood coagulation time and plasma recalcification. The sum total fibrinolytic activity proved to increase and the fibrinogen concentration - to decrease. A sharp 5-fold rise of the nonfermentative fibrinolysis was observed. It seems that this effect of the anticoagulating and fibrinolytic potential mobilization was stimulated by the response of the second anticoagulating blood system.     

Participation of the hypophyseal-adrenal cortex system in thrombin clearance during immobilization stress]

The examination carried out with thrombin marked by 131J resulted in a considerable increase of the thrombin clearance rate in healty male rats during the stress (caused by an immobilization lasting 30 minutes) and in an increase of thrombin deposits in the liver. A further increase of thrombin clearance occurred by the combination of immobilization and administration of ACTH. Contrary to ACTH the thrombin clearance is not stimulated in healthy animals by hydrocortisone. Thrombin clearance and thrombin deposits in the liver are lowered in adrenalectomized rats. In these animals the administration of ACTH does not result in an increase of thrombin clearance. The rate of thrombin clearance is normalized in adrenalectomized animals after administering hydrocortisone without as well as under conditions of stress. In adrenalectomized animals having received hydrocortisone as well as in healthy animals the administration of ACTH will results in an increase of thrombin clearance. From these experiments the conclusion can be drawn that ACTH will increase the intensity of thrombin clearance in stress and that hydrocortisone plays a transmitting part here.     

Are factor Xa inhibitors superior to thrombin inhibitors in anticoagulation?

Protease inhibitors are useful tools for increasing the inhibitor potential of plasma. In this context, thrombin inhibitors attracted special interest. However, other clotting enzymes, especially factor Xa, are target enzymes of protease inhibitors besides thrombin. Our studies on structure-activity relationships of benzamidine derivatives resulted in selective inhibitors of thrombin and factor Xa. The use of these inhibitors enabled us to clarify whether the antithrombin activity or the anti-factor Xa activity of a compound is more efficient in anticoagulation. We assessed the concentration-dependent inhibition of the activated partial thromboplastin time by these compounds. If one correlates the inhibitor concentration, which prolonged the clotting time by 60 s, with the dissociation constants one will realize that thrombin inhibition is significantly more efficient in anticoagulation than inhibition of factor Xa.     

Importance of the antithrombin III-heparin complex in the protective reaction to thrombin formation in animal and human blood

The antithrombin III-heparin complex was isolated from albino rat and human blood. The non-enzymatic fibrinolytic activity of the complex during anticoagulation system activation was higher, as compared to analogous activity in normal conditions or in depressed function of anticoagulation system.     

The startle reaction to an acoustic stimulus in the rat: the effect of noradrenaline administered by microinjection into the pontomedullary reticular formation

The effect of the local administration of noradrenaline (NA) by microinjection into the pontomedullary reticular formation on the startle reaction (SR) evoked by an acoustic stimulus was studied in waking, non-immobilized rats. NA (10(-6) mol.l-1 in 2.5 microliters artificial cerebrospinal fluid) was administered 21 times to five animals in 13 experiments. In nine cases (43%), a significant change in the mean amplitude of the SR to a series of 30 stimuli (recorded in the third minute after administering NA) was observed; in eight cases (38%) it rose and in only one (5%) it fell. Binomial statistics confirmed the preponderance of results with an increase in SR amplitude. The results indicated that the potentiating effect of NA could actively help to regulate the function of the pontomedullary part of the neuronal circuit for the acoustic SR.     

Role of adrenergic structures in regulating the release by the intestines of hemocoagulating compounds into the blood stream

Experiments on cats were made to study the capability of adrenaline, tropaphen and propranolol of influencing the intensity of the release of hemocoagulating compounds and anticoagulants from the intestinal vessels and tissues to the bloodstream (perfusate). Adrenaline was found to increase the coagulative activity of the perfusate, provoking an enhanced release into it of thromboplastin, an analogue of plasma factor V and antiheparin compounds and suppressing the release of antithromboplastins. The blockade of the alpha-adrenoreceptors was accompanied by a dramatic increase of antithromboplastins to the intestinal perfusate, whereas the depression of the activity of beta-adrenergic structures by reduction of the release of tissue thromboplastin inhibitors. It is concluded that regulation of the release of antithromboplastins in the intestine is mediated by the structures similar in their characteristics to alpha- and beta-adrenoreceptors.     

The role of blood clotting factor V in the conversion of prothrombin and a decarboxy prothrombin into thrombin

Purified PIVKA-II exhibits some factor II (prothrombin) activity in the one-stage coagulation assay and this factor II activity does not come from residual amounts of factor II but originates from PIVKA-II itself. It is shown that PIVKA-II is converted by a normal prothrombinase complex (factor Va and factor Xa adsorbed onto a phospholipid interface) more readily than by phospholipids and factor Xa alone. This suggests that binding between PIVKA-II and factor Va is an essential feature in the formation of the enzyme . substrate complex and from this we infer that a direct interaction between factor Va and prothrombin plays a r?le in the prothrombinase . prothrombin complex.