ISSN:1424-8832    

DOI:10.1159/000216226

出版商:S. Karger AG    

年代:1991

数据来源: Karger

ISSN:1424-8832    

DOI:10.1159/000216227

出版商:S. Karger AG    

年代:1991

数据来源: Karger

ISSN:1424-8832    

DOI:10.1159/000216228

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

A simulation model for the production of thrombin in plasma is presented. Values of the reaction rate constants as determined in purified systems are used and the model is tested by comparison of simulations of factor Xa, factor Va and thrombin generation curves with experimental data obtained in thromboplastin-activated plasma. Simulations of the effect of hirudin indicate that factor V is predominantly activated by thrombin and not by factor Xa. The model predicts a threshold value for the factor Xa production which, if exceeded, results in explosive and complete activation of prothrombinase. The dependence of this threshold value on different negative feedback reactions, e.g. the inactivation of thrombin and factor Xa by antithrombin III (+ heparin), is investigated. The threshold value, for control plasma in the range of 1–10 pM total factor Xa production, can be raised two orders of magnitude by accelerated inactivation of factor Xa and prothrombinase but is hardly affected by a tenfold increase in the rate of thrombin inactivation or by increased production of activated protein C. This latter effect, however, results in a more gradual input-response relation between factor Xa input and the extent of prothrombinase activatio

ISSN:1424-8832    

DOI:10.1159/000216229

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

A simple numerical model of the activation of factor X by factors IXa and VIII has been constructed in order to identify and examine the major controls that operate in a nonflowing system in the presence of (1) inhibitors of factor Xa and (2) feedback activation of factor VIII by factor Xa. The model confirms, and allows parameter estimation for, (1) the control of factor Xa yield by factor Villa decay; (2) the control of generation-curve area by the rate of factor Xa inhibition; and (3) the reduction in the factor Villa decay rate in the presence of factor IXa. Beyond confirmation of existing data, the model also predicts that below a definite, but very low, threshold level of factor IXa (≤ 10 pM), minimal feedback activation of factor VIII will occur. The concentration of factor IXa at which the threshold is observed in simulations is dependent on the rate of inhibition of factor X

ISSN:1424-8832    

DOI:10.1159/000216230

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Extrinsic pathway inhibitor (EPI) is a Kunitz type serine protease inhibitor. EPI is a potent inhibitor of the factor VIIa/thromboplastin (TP) complex in the presence of factor Xa and is also a direct inhibitor of factor Xa. The inhibitory mechanism is complex and is currently thought to involve, in a first step, the formation of a EPI-factor Xa complex, and, in a second step, the formation a quaternary EPI-factor Xa-factor VIIa-TP complex. In the blood vessels, EPI is confined to three different pools. A major pool of EPI is bound to the endothelial surface, and this fraction may be released by heparin. Plasma contains a second, but smaller pool of EPI (≈ 10–50% of the endothelial surface pool) at a concentration of 50–100ng/ml. This pool consists mostly of EPI-lipoprotein complexes and only less than 10% is carrier-free EPI. A third pool of EPI is confined to platelets ( < 10% of the plasma pool). The biological role of these pools has not yet been clarified, but some evidence suggest that the carrier-free EPI is biologically most active. In patients, disseminated intravascular coagulation may continue despite normal or even elevated EPI levels. However, evidence has now been provided to indicate that EPI can inhibit factor VIIa/TP complexes formed in vivo to prevent the effect of limited amounts of TP. Taken together, the present knowledge of EPI indicates that EPI functions as a key inhibitor to feedback control of blood coagulation initiated

ISSN:1424-8832    

DOI:10.1159/000216231

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The polyanions heparin and dermatan sulfate catalyze α-thrombin inhibition and can delay the onset of factor VIII and factor V necessary for intrinsic prothrombin activation to begin in plasma. These polyanions bind α-thrombin at its anion-binding exosite(s), structural domain(s) occupancy of which may alter the properties of the fibrin(ogen) recognition exosite of α-thrombin. We compared how such four polyanions influenced factor VIII and factor V activation during intrinsic coagulation. A pentasaccharide with high affinity for antithrombin III and the C-terminal docedapeptide fragment of hirudin (hirugen) which occupy the anion-binding and fibrin(ogen) recognition exosites of α-thrombin, respectively, could not significantly inhibit factor VIII and factor V activation. In contrast, heparin and a bis-lactobionic acid, both of which catalyzed α-thrombin inhibition, could effectively inhibit factor VIII and factor V activation. These results suggest that occupancy of fibrin(ogen) or anionbinding exosites by itself does not provide a necessary and sufficient condition for catalysis of thrombin inhibition or the inhibition thrombin-mediated amplification react

ISSN:1424-8832    

DOI:10.1159/000216232

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

A simple model of the initiation of thrombin formation in plasma as a response to factor Xa generation was constructed. In this model factor Xa is considered as an input with a constant concentration. Substrate depletion and inactivation by activated protein C are neglected. The resulting linear model allows a closed form solution by standard methods. With values of the reaction rate constants, as determined in purified systems, this model predicts a highly explosive and complete activation of factor V and prothrombin as a response to any given (steady state) factor Xa concentration even in situations where prothrombinase and(&slash;or) thrombin are rapidly inactivated. However, the time delay to rapid thrombin production becomes longer at lower factor Xa concentrations. Analysis of this time delay as a function of the factor Xa concentration indicates that the gain of the feedback loop of factor V activation by thrombin is so high that the contribution of factor V activation by factor Xa is relatively unimportant for factor Xa concentrations in the nanomolar range. It appears that the time lag is mainly determined by the gain of this feedback loop: similar proportional reductions of each of these reaction rates causes a similar effect. The effects of moderately enhanced inhibition rates of thrombin and prothrombinase on the time delay depend strongly on factor Xa concentration. Only a minor prolongation of the delay is predicted for factor Xa concentrations in the nanomolar range, but for factor Xa concentrations in the 1–10 pM range, the enhanced decay will cause considerable delays. Simultaneous reduction of the turnover rate of prothrombinase results in much larger delays for the entire range of factor Xa concentration

ISSN:1424-8832    

DOI:10.1159/000216233

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Heparinization of blood inhibited the generation of fibrinopeptide A (FPA) after addition of thromboplastin (TP). Heparinization was more effective when performed in vivo than in vitro; the amounts of FPA at 60 s incubation were 8% and 32%, respectively, of control values in nonheparinized blood. When monospecific, neutralizing IgG against extrinsic pathway inhibitor (anti-EPI) were added to heparinized blood prior to TP, the amount of FPA increased to 65%. When monospecific IgG blocking antithrombin (anti-AT) was used, the amount of FPA increased to values similar to those in nonheparinized blood. When anti-AT and anti-EPI were both added to heparinized blood, FPA was generated about 25% faster than in normal blood. These results show that EPI contributes significantly to the anticoagulant effect of heparin in human blood.

ISSN:1424-8832    

DOI:10.1159/000216234

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

We define a standard independent unit (SIU) of heparin as that amount that, in plasma containing 1 μmol of ATIII, raises the (pseudo-)first-order breakdown constant of factor Xa by 1 min-1• These units measure all material with a high affinity for ATIII (HAM); only material above the critical chain length of 17 monosaccharide units (above critical chain length material; ACLM) catalyzes the inactivation of thrombin. An SIU of ACLM is therefore analogously defined as the amount that, in plasma containing 1 μmol of ATIII, will raise the (pseudo-)first-order breakdown constant of thrombin by 1 min-1• Of any given heparin preparation one can determine the specific HAM and ACLM activities in terms of SlU/mg. On the basis of the factor Xa and thrombin breakdown constants found in a plasma sample one can then determine the levels of HAM and ACLM. Preliminary experiments were carried out in plasma samples obtained after subcutaneous injection of unfractionated heparin (UFH) and of two types of low-molecular-weight heparin (LMWH). About three times more of UFH activity than of LMWH activity has to be injected to obtain the same levels of ACLM in the plasma. Only with the LMWHs significant amounts of BCLM are found, which rises higher and persists longer than the ACLM. We determined the course of thrombin generation in platelet-rich plasma (PRP) and in platelet-poor plasma (PPP), as well as in the PPP factor Xa generation curve and the course of prothrombin conversion. The observed inhibitions correlated much better with the levels of ACLM than with those of below critical chain length material. The difference between UFH and LMWHs can therefore not be explained in terms of antithrombin and anti-factor-Xa activity. The essential difference between UFH and LMWH appears in the feedback effect of thrombin in PRP, where thrombin generation is both inhibited and retarded by LMWH, while it is only retarded but hardly inhibited b

ISSN:1424-8832    

DOI:10.1159/000216235

出版商:S. Karger AG    

年代:1991

数据来源: Karger