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An analysis of the contact phase of blood coagulation: effects of shear rate and surface are intertwined.

This work analyzes, for the first time, the combined role of blood flow, protein transport and the reaction network of the contact phase up to the "common pathway" of the blood coagulation cascade. The model is comprised of a set of 20 dominant reactions with 11 components. Systems of ODEs reducible to 4 coupled equations describe rigorously the dynamic behavior, while systems of algebraic equations, reducible to a single polynomial equation, model the steady state concentrations of the coagulants. The analysis showed that there is never more than one stable steady state. This is in contrast to the analysis of common pathway that gives rise to multiple concentration states. It also revealed a general robustness of the system to changes in procoagulant concentrations, inhibition rates and most activation rate constants. The system is largely impervious to the level of activated Factor XII, given that a trace (non-zero) level is present. In contrast, the system displays a dual response to flow and surface activity: A change in either of these factors alone can promote, have no effect on, or (in the case of flow) impede the progress of coagulation, depending on the value of the other factor. Their effects must therefore be examined in unison. These results may help resolve contradictory findings attributed to one or the other factor alone.

Blood Coagulation

Alkaloids of tobacco and blood coagulation: effect of nicotine on thrombin and fibrinogen.

An alkaloid of tobacco, nicotine, affected the clot-formation property of the enzyme, thrombin, on the substrate, plasma or fibrinogen (thrombin time). Higher concentrations of nicotine retarded the clot-formation property of thrombin. By decreasing the nicotine concentration in the clotting mixture, the clotting time of thrombin was accelerated. Nicotine also modified the clot formation property of plasma or fibrinogen to thrombin, and this effect was dose dependent. From this experimental evidence, it is suggested that nicotine does alter the clot-forming properties of thrombin on fibrinogen.

Alkaloids

Hemophilia as a defect of the tissue factor pathway of blood coagulation: effect of factors VIII and IX on factor X activation in a continuous-flow reactor.

The effect of factors VIII and IX on the ability of the tissue factor-factor VIIa complex to activate factor X was studied in a continuous-flow tubular enzyme reactor. Tissue factor immobilized in a phospholipid bilayer on the inner surface of the tube was exposed to a perfusate containing factors VIIa, VIII, IX, and X flowing at a shear rate of 57, 300, or 1130 sec-1. Factor Xa in the effluent was determined by chromogenic assay. The flux of factor Xa (moles formed per unit surface area per unit time) was strongly dependent on wall shear rate, increasing about 3-fold as wall shear rate increased from 57 to 1130 sec-1. The addition of factors VIII and IX at their respective plasma concentrations resulted in a further 2- to 3-fold increase. The direct activation of factor X by tissue factor-factor VIIa could be virtually eliminated by the lipoprotein-associated coagulation inhibitor; however, when factors VIII and IX were present at their approximate plasma concentrations, factor Xa production rates were enhanced 15- to 20-fold. These results suggest that the tissue factor pathway, mediated through factors VIII and IX, produces significant levels of factor Xa even in the presence of an inhibitor of the tissue factor-factor VIIa complex; moreover, the activation is dependent on local shear conditions. These findings are consistent both with a model of blood coagulation in which initiation of the system results from tissue factor and with the bleeding observed in hemophilia.

Blood Coagulation

Progestational agents and blood coagulation. VIII. Effect of low-dose, alternate-day, estrogen-progestin combinations on blood coagulation factors in man, with a special note on the effect of freezing of blood samples.

Changes in the blood coagulation system were studied in three groups of 20 patients each. The first group received 0.5 mg. of norethindrone daily, plus 0.06 mg. of ethinyl estradiol on alternate days from cycle Day 5 through 25. The second group, all of whom had been fitted with an intrauterine contraceptive device (IUD), received no hormonal treatment and served as a control group. The third group received 0.5 mg. of norethindrone daily, combined with 0.045 mg. of ethinyl estradiol given on alternate days from cycle Day 5 through 25. Blood samples were drawn prior to the initiation of the study and after three months of treatment. Tests of the following parameters of the blood coagulation system were performed: direct platelet count; platelet adhesiveness; prothrombin time; thrombin time; fibrinogen; factor II assay; activity of factors V, VII, VIII, IX, and X; antithrombin III; and fibrin/fibrinogen degradation products. For a number of these factors, both fresh and frozen blood samples were examined. It was concluded that the two treatment regimens, with the use of alternate-day estrogen administration over a three-month period, had no clinically significant effect on the blood coagulation system.

Adolescent

Fasting (acute energy deprivation) in man: effect on blood coagulation and fibrinolysis.

Blood coagulation and fibrinolysis parameters were studied during 10 days of total fasting in healthy, normal weight males. A reduction of plasma levels of factor VIII activity with a concomitant decrease in factor VIII antigen was found, without other laboratory evidence for a disseminated intravascular coagulation. The effect of 10 days' starvation on blood coagulation appears to be small but the effect of more prolonged starvation might implicate impaired hemostasis.

Adult

Effect on blood coagulation and fibrinolysis in women using norethisterone or a combination of ethinyloestradiol and quingestianol.

Oral contraceptives of the combined type and contraceptives containing only progestagen were studied for their effect on blood coagulation and fibrinolysis. Several blood parameters were determined in 13 women before and during the 3rd month of use of either 0.3 mg norethisterone alone or 0.05 mg ethinyloestradiol combined with 0.5 mg quingestianol. Blood samples were obtained on days 2--4, 9--11, 16--18 and 23--25 of the menstrual cycle. Except on days 16--18, a significantly increased fibrinolytic activity and a significantly increased variation in plasminogen were observed in women using the combined type of contraceptives, but not in the women using contraceptives containing only norethisterone. The other variables studied were not significantly changed, which might be due to the doses and types of progestagens used in the present series.

Adult

[Study on effects of cefminox sodium on blood coagulation system].

Effects of cefminox (CMNX) on hemostasis and blood coagulation system were studied. Adult in-patients admitted to 237 centers (310 clinics) nationwide in Japan during the period from April 1988 to March 1989 were followed up using a newly designed uniformed protocol. Case cards recovered were inspected by an evaluation committee and patients to be included in analysis were determined according to the protocol. Presence or absence of abnormalities in the hemostasis and blood coagulation system was examined objectively using criteria for evaluation prepared by the committee. Out of 1,374 patients included in analysis, 10 patients were judged as having abnormalities which were suspected to have causal relationships with CMNX. Prolongation in prothrombin time was observed in 4 cases (0.29%), prolongation in activated partial thromboplastin time in 4 cases (0.29%), and decrease in fibrinogen in 2 cases (0.15%). Decrease in platelet count was not detected in any of the cases. Cross-sectional analysis according to background factors in these 10 cases revealed that abnormalities of the hemostasis and blood coagulation systems were significantly higher (P less than 0.01) for the group positive for underlying disease or complications ("positive" group) than the "negative" group. Five out of 9 patients of the positive group had malignant neoplasm. Other than this factor, no items showed statistically significant differences. From these results it is considered that the administration of CMNX is nearly free of effects on the hemostasis and blood coagulation system and development of laboratory abnormalities is chiefly due to the patients' condition.

Adolescent

An experimental study on the effect of plasma expanders on blood coagulability.

The effect of various plasma expanders on blood coagulation was studied using the thromboelastography (TEG). Solutions of 5, 10, 20, and 50% concentration of each expander (6% low molecular weight hydroxyethyl-starch (6% Hespander), 3% dextran-40, 6% high molecular weight hydroxyethyl-starch (6 HES), and 6% dextran-70) or solvent (lactated Ringer solution and normal saline) in blood were prepared and their coagulability was examined by TEG. In the low molecular weight plasma expanders (6% Hespander and 3% dextran-40), in general, the coagulability decreased when the concentration was increased. In the high molecular weight plasma expanders (6 HES and 6% dextran-70), the coagulability increased slightly at low and high concentrations and the coagulability was reduced. As a conclusion, at clinically used concentrations of less than 20% in blood, changes in the TEG of the plasma expanders are minimum and have no clinical significance.

Blood Coagulation

Degradation products of fibrinogen by elastase-like neutral protease from human granulocytes. Characterization and effects on blood coagulation in vitro.

We investigated the effect of elastase-like neutral protease isolated from human granolocytes on human fibrinogen. Dependent on enzyme concentration and time of incubation, the elastase-like protease induced a progressive degradation of fibrinogen. Analysis of the remaining polypeptide chains showed a high susceptibility of the Aalpha- and low susceptibility of the gamma-chain of fibrinogen towards the proteolytic action of the enzyme. The split products were characterized by polyacrylamide gel electrophoresis and two-dimensional immunoelectrophoresis. They showed antigenic determinants of fibrinogen and of plasmin-induced proteolysis products D and E. The cleavage fragments isolated by gel chromatography had distinct molecular weights. Coagulability of fibrinogen by thrombin was inhibited according to the concentration of the protease and the time of incubation. Split products of fibrinogen with higher molecular weight prolonged the coagulation time of native fibrinogen, whereas low molecular weight fragments were ineffective.

Blood Coagulation

[Nature, properties and the mechanism of the effect on blood coagulation of the preparation obtained from Pulmonaria officinalis].

The non-dialyzable fraction of the ammonia extract from Pulmonaria officinalis contains the anticoagulant glycopeptide. The anticoagulant in doses reducing total coagulation activity of the blood 4-5-fold, does not change the animals' behaviour, hypocoagulemia remains at a high level up to 6 h after intravenous administration of the anticoagulant, and diminishes only after 24 h. The anticoagulant reduces the death rate of the animals with exogenous thromboplastinemia by suppressing the blood coagulation activity. The inhibitor effect is realized mainly at the stage of fibrinogen conversions.

Animals

Amidinosemicarbazido derivatives of pyrazole: synthesis and inhibitory effect on blood coagulation and platelet aggregation.

Amidinosemicarbazido derivatives of pyrazole having various substituents on pyrazole ring were prepared and their effect on platelet function and blood coagulation was determined in vitro. Platelet aggregation and serotonin release induced by ADP, collagen, arachidonic acid and thrombin were markedly inhibited by pyrazole derivatives at mM concentrations. Compounds with a hydrophobic nucleus at position 1 of the pyrazole ring showed the most potent antiplatelet activity. On the contrary, their effect on blood coagulation was faintly inhibitory.

Anticoagulants

Effect of blood coagulation and platelet aggregation on perfusable capillaries and arterioles in ischemic and nonischemic myocardium.

The aim of this study was to determine the effect of blood coagulation and platelet aggregation on the perfusability of arterioles (19-50 micron) and capillaries in subepicardial and subendocardial ischemic and nonischemic myocardium of anesthetized open-chest rabbits. Fluorescein isothiocynate-dextran (MW 150,000) was injected intravenously to label perfusable myocardial microvessels of rabbits that were subjected to 60 min of coronary artery occlusion. Fluorescent microscopy was used to identify the perfusable vessels and an alkaline phosphatase stain was employed to locate the total microvasculature of the heart. Stereological principles were utilized to determine various morphometric parameters. About 25% of the capillaries were incapable of being perfused but virtually all arterioles were perfusable in occluded myocardium of the control group. Essentially all capillaries and arterioles were perfusable in nonoccluded myocardium. Collagen infusion produced a perfusion defect in 14% of the capillaries and arterioles in nonoccluded myocardium and in 33% of the capillaries and arterioles in occluded myocardium. Heparin, prostaglandin E1 (PGE1), or PGE1 + heparin did not prevent the perfusion defect in capillaries of occluded myocardium. It is concluded that while promotion of blood coagulation and platelet aggregation was able to produce microvessel obstruction, these hemostatic mechanisms were not primarily responsible for the capillary obstruction observed during myocardial ischemia in the rabbit heart.

Alprostadil

Synthesis of N1-substituted benzamidines. Effects on blood coagulation, platelet aggregation and antiarrhythmic activity.

A series of N1-substituted-4-alkoxybenzamidines was synthesized and tested in vitro for their inhibitory effects on blood coagulation and agonist induced platelet aggregation. The antiarrhythmic activity against chloroform-induced arrhythmias in mice was also evaluated. The biological activity of the title compounds is reported in comparison with that of procainamide; among the new products described, IVi and IVe were found to have the most potent anti-platelet and antiarrhythmic activity, respectively. The structure-activity relationships are discussed.

Action Potentials