scholarly journals The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin

1981 ◽  
Vol 193 (2) ◽  
pp. 395-400 ◽  
Author(s):  
E Holmer ◽  
K Kurachi ◽  
G Söderström
Keyword(s):  
Molecular Weight ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Clotting Factors ◽  
Factor Ixa ◽  
Molecular Weight Dependence ◽  
Factor Xiia ◽  
Factor Xia ◽  
Heparin Fractions ◽  
Inhibition Of Thrombin

Heparin fractions of different molecular weight and with high affinity for antithrombin were studied with respect to their ability to potentiate the inhibition of activated clotting factors by antithrombin. Inhibition of thrombin, Factor IXa and Factor XIa showed similarities in the dependence on the molecular weight of heparin and was found to decrease with decreasing molecular weight. Inactivation of Factor Xa, Factor XIIa and kallikrein was, however, less dependent on the size of the polysaccharide and, to a great extent, was potentiated even by low-molecular-weight heparin fractions that had virtually no effect on the inhibition of thrombin, Factor IXa and Factor XIa.

Accelerating ability of synthetic oligosaccharides on antithrombin inhibition of proteinases of the clotting and fibrinolytic systems Comparison with heparin and low-molecular-weight heparin

2004 ◽  
Vol 92 (11) ◽  
pp. 929-939 ◽  
Author(s):  
Steven Olson ◽  
Richard Swanson ◽  
Elke Raub-Segall ◽  
Tina Bedsted ◽  
Morvardi Sadri ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Rate Constants ◽  
Factor Xa ◽  
Common Mechanism ◽  
Low Molecular Weight ◽  
Thrombin Inhibition ◽  
High Affinity ◽  
Factor Ixa ◽  
Contrast Factor ◽  
Synthetic Oligosaccharides

SummaryThe abilities of three synthetic oligosaccharides to accelerate antithrombin inhibition of ten clotting or fibrinolytic proteinases were compared with those of unfractionated, fractionated high-affinity and low-molecular-weight heparins. The results show that the anticoagulant effects of the latter three heparins under conditions approximating physiologic are exerted almost exclusively by acceleration of the inactivation of thrombin, factor Xa and factor IXa to near diffusion-controlled rate constants of ∼106 – 107 M−1·s−1. All other proteinases are inhibited with at least 20-fold lower rate constants. The anticoagulant ability of the synthetic regular (fondaparinux) and high-affinity (idraparinux) pentasaccharides is due to a common mechanism, involving acceleration of only factor Xa inhibition to rate constants of ∼106 M−1·s−1. A synthetic hexadecasaccharide, containing both the pentasaccharide sequence and a proteinase binding site, exerts its anticoagulant effect by accelerating antithrombin inactivation of both thrombin and factor Xa to rate constants of ∼106 – 107 M−1·s−1, although thrombin appears to be the more important target. In contrast, factor IXa inhibition is appreciably less stimulated. The conformational change of antithrombin induced both by the pentasaccharides and longer heparins contributes substantially, ∼150–500-fold, to accelerating the inactivation of factors Xa, IXa and VIIa and moderately, ∼50-fold, to that of factor XIIa and tissue plasminogen activator inhibition. The bridging effect due to binding of antithrombin and proteinase to the same, long heparin chain is dominating, ∼1000–3000-fold, for thrombin inhibition and is appreciably smaller, although up to ∼250-350-fold, for the inactivation of factors IXa and XIa. These results establish the proteinase targets of heparin derivatives currently used in or considered for thrombosis therapy and give new insights into the mechanism of heparin acceleration of antithrombin inhibition of proteinases.

scholarly journals On the molecular-weight-dependence of the anticoagulant activity of heparin

1979 ◽  
Vol 181 (1) ◽  
pp. 241-243 ◽  
Author(s):  
L Thunberg ◽  
U Lindahl ◽  
A Tengblad ◽  
T C Laurent ◽  
C M Jackson
Keyword(s):  
Molecular Weight ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Molecular Weights ◽  
High Affinity ◽  
Polysaccharide Chain ◽  
Molecular Weight Dependence ◽  
Heparin Fractions

The inactivation of thrombin and factor Xa by antithrombin was determined in the presence of heparin fractions of different molecular weights and with high affinity for antithrombin. The ability to potentiate the inactivation of either coagulation factor increased with increasing length of the polysaccharide chain.

Pharmacological Studies on the Antithrombotic Action of Synthetic low Molecular Weight Inhibitors of Clotting Enzymes

1979 ◽  
Author(s):  
F. Markwardt
Keyword(s):  
Molecular Weight ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Repeated Administration ◽  
Inhibitory Effect ◽  
Blood Levels ◽  
Low Molecular Weight ◽  
Clotting Factors ◽  
Pharmacological Studies ◽  
Competitive Inhibitors

Biochemical investigations allowed the identification of benzamidine derivatives as highly effective competitive inhibitors of clotting enzymes. Their anticoagulant effect is not only based on the inhibition of the thrombin-fibnn reaction, but also on that of thrombin-induced platelet reactions and activation of clotting factors. The inhibitory effect on factor Xa potentiates the anticoagulant action. However, the inhibitors interfere with the antithrombin III reaction.Selected benzamidine derivatives are critically observed from the aspect of their use as antithrombotics. The pharmacokinetic behaviour was studied using radiolabelled compounds. Due to the relatively rapid elimination from the blood repeated administration is required in order to maintain an adequate concentration in blood. Experimental, venous, arterial, and microthromboses in rats could be prevented by infusion of the inhibitors. Their protective effect was dependent on the affinity for the clotting enzymes (Ki-values) and on the blood levels. Synthetic low molecular weight inhibitors of serine proteinases are considered therapeutically relevant compounds.

Effects of heparin fractions of different affinities to antithrombin III and thrombin on the inactivation of thrombin and factor Xa by antithrombin III

1984 ◽  
Vol 62 (10) ◽  
pp. 975-983 ◽  
Author(s):  
Andrew L. Cerskus ◽  
Kathy J. Birchall ◽  
Frederick A. Ofosu ◽  
Jack Hirsh ◽  
Morris A. Blajchman
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Similar Rate ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
High Affinity ◽  
Relative Contribution ◽  
Heparin Fractions

To investigate the relative contribution of heparin-binding thrombin and antithrombin III to the enhancement of the rate of inactivation of thrombin by antithrombin III, standard heparin was fractionated on matrix-linked thrombin and (or) antithrombin III. There was a good correlation between heparin affinity for antithrombin III and its ability to enhance the inactivation of thrombin and factor Xa. In addition, there was a good correlation between affinity of heparin for thrombin and its catalytic activity on the inactivation of thrombin by antithrombin III. Thus fractions with high affinity to thrombin had similar rate-enhancing activity for thrombin inactivation to that of fractions with high affinity to antithrombin III. Fractions with high affinity to both proteins were more potent than fractions with high affinity to either protein alone. No significant differences in mean molecular weight were observed among the various heparin fractions. A heparin fraction with very low affinity to thrombin and high affinity to antithrombin III was prepared by repeated fractionation of a low molecular weight heparin on the two affinity columns. This fraction had very weak rate-enhancing activity for the inactivation of thrombin by antithrombin III, but retained substantial activity for the inactivation of factor Xa. The results of these studies support the concept that, for both standard and low molecular weight heparin, the enhancement of the inactivation of thrombin by antithrombin III requires the interaction of the heparin with both thrombin and antithrombin III.

Markers of Hemostatic System Activation in Acute Deep Venous Thrombosis-Evolution during the First Days of Heparin Treatment

1993 ◽  
Vol 70 (06) ◽  
pp. 0909-0914 ◽  
Author(s):  
Keyword(s):  
Molecular Weight ◽  
Venous Thrombosis ◽  
Deep Venous Thrombosis ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Dose Adaptation ◽  
Heparin Treatment ◽  
Lung Scan

SummaryFibrin D-Dimer (D-Di), prothrombin activation fragment (F 1+2) and thrombin-antithrombin III complexes (TAT) were measured using ELISA procedures in the plasma of patients with an acute deep venous thrombosis (DVT), at presentation and on days 2, 6 and 10 after initiation of heparin treatment. Patients were randomly allocated into two treatment groups: 44 patients received adapted doses of continuous intravenous unfractionated heparin (UH) whereas 47 received 1 mg/kg every twelve hours of a low molecular weight heparin (enoxaparin) subcutaneously. A phlebography and a perfusion lung scan were performed before inclusion and on day 10. Failure of therapy (n = 9) was defined by venogram worsening or confirmed pulmonary embolism. Improvement (n = 44) or stationary state (n = 38) were defined by venogram evolution in the absence of new leg scan defects.At presentation, D-Di, F 1 + 2 and TAT were above cut-off values in 97, 66 and 89% of patients respectively. D-Di levels correlated with the extent of venous thrombosis whereas TAT and F 1 + 2 did not. Mean levels of D-Di decreased sharply during the first days of treatment but were still abnormal on day 10. A secondary increase of D-Di on days 6 or 10 by more than 3 μg/ml occurred in 4 of the 9 patients who developed a thromboembolic recurrence but in none of the 72 patients who had a more favorable outcome. F 1 + 2 and TAT time-courses were not related to clinical evolution. In the Enoxaparin group, there was no relationship between antifactor Xa activities and any biological markers. TAT and F 1 + 2 levels fell on day 2 and remained stable until day 10. In contrast, in the UH group, TAT and F 1 + 2 did not significantly decrease on day 2, probably due to a delay in dose adaptation, but they declined slowly until day 10.In conclusion, D-Di displays a higher sensitivity than F 1 + 2 or TAT for the diagnosis of D\T. D-Di, but not TAT or F 1 + 2, follow-up seems to be of potential value for early detection of recurrency. Hemostatic activation is controlled earlier by fixed doses of a low molecular weight heparin, irrespective of the plasma anti-factor Xa activities, than by unfractionated heparin at adapted doses.

Comparison of the Non-Specific Binding of Unfractionated Heparin and Low Molecular Weight Heparin (Enoxaparin) to Plasma Proteins

1993 ◽  
Vol 70 (04) ◽  
pp. 625-630 ◽  
Author(s):  
Edward Young ◽  
Benilde Cosmi ◽  
Jeffrey Weitz ◽  
Jack Hirsh
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Plasma Proteins ◽  
Low Molecular Weight Heparin ◽  
Specific Binding ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Heparin Binding ◽  
Fixed Amount

SummaryThe non-specific binding of anticoagulantly-active heparin to plasma proteins may influence its anticoagulant effect. We used low affinity heparin (LAH) essentially devoid of anti-factor Xa activity to investigate the extent and possible mechanism of this non-specific binding. The addition of excess LAH to platelet-poor plasma containing a fixed amount of unfractionated heparin doubled the anti-factor Xa activity presumably because it displaces anticoagulantly-active heparin from plasma proteins. Although dextran sulfates of varying molecular weights also increased the anti-factor Xa activity, less sulfated heparin-like polysaccharides had no effect. These findings suggest that the ability to displace active heparin from plasma protein binding sites is related to charge and may be independent of molecular size. In contrast to its effect in plasma containing unfractionated heparin, there was little augmentation in anti-factor Xa activity when LAH was added to plasma containing low molecular weight heparin (LMWH), indicating that LMWH binds less to plasma proteins than unfractionated heparin. This concept is supported by studies comparing the anticoagulant activity of unfractionated heparin and LMWH in plasma with that in buffer containing antithrombin III. The anti-factor Xa activity of unfractionated heparin was 2-fold less in plasma than in the purified system. In contrast, LMWH had identical anti-factor Xa activity in both plasma and buffer, respectively. These findings may be clinically relevant because the recovered anti-factor Xa activity of unfractionated heparin was 33% lower in plasma from patients with suspected venous thrombosis than in plasma from healthy volunteers. The reduced heparin recovery in patient plasma reflects increased heparin binding to plasma proteins because the addition of LAH augmented the anti-factor Xa activity. In contrast to unfractionated heparin, there was complete recovery of LMWH added to patient plasma and little increase of anti-factor Xa activity after the addition of LAH. These findings may explain why LMWH gives a more predictable dose response than unfractionated heparin.

Chrono-Pharmacological Study of Once Daily Curative Dose of a Low Molecular Weight Heparin (200IU antiXa/kg of Dalteparin) in Ten Healthy Volunteers

1995 ◽  
Vol 74 (02) ◽  
pp. 660-666 ◽  
Author(s):  
P Mismetti ◽  
J Reynaud ◽  
B Tardy-Poncet ◽  
S Laporte-Simitsidis ◽  
M Scully ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Healthy Volunteers ◽  
Low Molecular Weight Heparin ◽  
Pharmacological Study ◽  
Area Under The Curve ◽  
Factor Xa ◽  
Similar Efficacy ◽  
Low Molecular Weight ◽  
Thrombin Time ◽  
Once Daily

SummaryLow molecular weight heparin (LMWH) is currently prescribed for the treatment of deep vein thrombosis at the dose of 100 IU antiXa/kg twice daily or at a dose of 175 IU antiXa/kg once daily with a similar efficacy. We decided to study the chrono-pharmacology of curative dose of LMWH once daily administrated according to the one previously described with unfractionated heparin (UFH).Ten healthy volunteers participated in an open three-period crossover study according to three 24 h cycles, separated by a wash-out interval lasting 7 days: one control cycle without injection, two cycles with subcutaneous injection of 200 IU antiXa/kg of Dalteparin (Fragmin®) at 8 a.m. or at 8 p.m. Parameters of heparin activity were analysed as maximal values and area under the curve.Activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and tissue factor pathway inhibitor (TFPI) were higher after 8 p.m. injection than after 8 a.m. injection (p <0.05) while no chrono-pharmacological variation of anti factor Xa (AXa) activity was observed. Thus the biological anticoagulant effect of 200 IU antiXa/kg of Dalteparin seems to be higher after an evening injection than after a morning injection.A chrono-therapeutic approach with LMWH, as prescribed once daily, deserves further investigation since our results suggest that a preferential injection time may optimise the clinical efficacy of these LMWH.

In Vivo Studies on the Inhibition of Coagulation by Fractionated Heparin and by a Heparin Analogue I. Effects of Heparin Fractions

1981 ◽  
Vol 46 (03) ◽  
pp. 612-616 ◽  
Author(s):  
U Schmitz-Huebner ◽  
L Balleisen ◽  
F Asbeck ◽  
J van de Loo
Keyword(s):  
Molecular Weight ◽  
Day Treatment ◽  
Gel Filtration ◽  
Weight Fraction ◽  
In Vivo Studies ◽  
Low Molecular Weight ◽  
High Molecular Weight Fraction ◽  
Platelet Factor ◽  
Heparin Fractions

SummaryHigh and low molecular weight heparin fractions obtained by gel filtration chromatography of sodium mucosal heparin were injected subcutaneously into six healthy volunteers and compared with the unfractionated substance in a cross-over trial. Equal doses of 5,000 U were administered twice daily over a period of three days and heparin activity was repeatedly controlled before and 2, 4, 8 hrs after injection by means of the APTT, the anti-Xa clotting test and a chromogenic substrate assay. In addition, the in vivo effect of subcutaneously administered fractionated heparin on platelet function was examined on three of the volunteers. The results show that s.c. injections of the low molecular weight fraction induced markedly higher anti-Xa activity than injections of the other preparations. At the same time, APTT results did not significantly differ. Unfractionated heparin and the high molecular weight fraction enhanced ADP-induced platelet aggregation and collagen-mediated MDA production, while the low molecular weight fraction hardly affected these assays, but potently inhibited thrombin-induced MDA production. All heparin preparations stimulated the release of platelet Factor 4 in plasma. During the three-day treatment periods, no side-effects and no significant changes in the response to heparin injections were detected.

Covalent Complexes Between Low Molecular Weight Heparin Fragments and Antithrombin III – Inhibition Kinetics and Turnover Parameters

1983 ◽  
Vol 49 (02) ◽  
pp. 109-115 ◽  
Author(s):  
M Hoylaerts ◽  
E Holmer ◽  
M de Mol ◽  
D Collen
Keyword(s):  
Molecular Weight ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Life Time ◽  
Low Molecular Weight ◽  
High Affinity ◽  
Plasma Half Life ◽  
Covalent Complex

SummaryTwo high affinity heparin fragments (A/r 4,300 and M, 3,200) were covalently coupled to antithrombin III (J. Biol. Chem. 1982; 257: 3401-3408) with an apparent 1:1 stoichiometry and a 30-35% yield.The purified covalent complexes inhibited factor Xa with second order rate constants very similar to those obtained for antithrombin III saturated with these heparin fragments and to that obtained for the covalent complex between antithrombin III and native high affinity heparin.The disappearance rates from plasma in rabbits of both low molecular weight heparin fragments and their complexes could adequately be represented by two-compartment mammillary models. The plasma half-life (t'/j) of both low Afr-heparin fragments was approximately 2.4 hr. Covalent coupling of the fragments to antithrombin III increased this half-life about 3.5 fold (t1/2 ≃ 7.7 hr), approaching that of free antithrombin III (t1/2 ≃ 11 ± 0.4 hr) and resulting in a 30fold longer life time of factor Xa inhibitory activity in plasma as compared to that of free intact heparin (t1/2 ≃ 0.25 ± 0.04 hr).

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