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PubMed1993

Antithrombin-III plasma activity during and after prolonged use of heparin in unstable angina.

Heparin effectively prevents the complications of unstable angina but disease reactivation has been documented following its discontinuation. To investigate whether this could be related to antithrombin-III depletion, 50 patients with unstable angina had serial determinations of activated partial thromboplastin time and of the plasma levels of heparin, antithrombin-III activity and of the thrombin-antithrombin-III complex before, during and, in a subgroup of 8 patients, 4 hours after heparin discontinuation. Heparin was administered intravenously at therapeutic doses for a mean of 7.6 +/- 4.1 days. Plasma antithrombin-III activity decreased rapidly from 1.05 +/- 0.03 to 1.0 +/- 0.03 U/ml (p < 0.03) following heparin initiation with no further significant subsequent decrease. Antithrombin-III activity returned to the control values 4 hours after the discontinuation of heparin. Thus, heparin treatment is associated with small, non-cumulative and rapidly reversible decrease in antithrombin-III activity. Reactivation of unstable angina after discontinuation of heparin must be explained by a mechanism other than antithrombin-III deficiency.

Angina, Unstable↗

PubMed1986

A fragment of antithrombin that binds both heparin and thrombin.

In order to identify the regions of antithrombin that interact with heparin and thrombin, it was degraded with CNBr and the activities of the isolated products were investigated. These fragments did not exhibit direct thrombin-neutralizing activity; however, one unique fragment was found to bind to heparin-Sepharose and also to interfere with the inhibition of thrombin by intact antithrombin. This fragment was identified as the one consisting of three disulphide-linked polypeptide chains containing residues 1-17, 104-251 and 424-432. At a concentration of 46 nM, this product decreased the heparin-enhanced thrombin-inhibitory activity of antithrombin by half, and completely abolished this inhibition when above 300 nM. In the absence of heparin, the action of antithrombin was not completely nullified by the fragment, even when present at relatively high concentrations. At a given fragment concentration, the extent of inhibition was independent of antithrombin concentration over the range tested. It was found that the fragment decreased the second-order rate constant for the antithrombin-thrombin reaction. Reduction and alkylation of the fragment showed that the above properties reside primarily in the peptide with residues 104-251. It is concluded that this peptide possesses portions of the antithrombin molecule that bind to heparin as well as to a site on thrombin.

Alkylation↗

PubMed1982

Antithrombin III transfusion in patients with hepatic cirrhosis.

This study was designed to examine the effect of selective correction of antithrombin III activity on the increased turnover of fibrinogen, which occurs in patients with liver cirrhosis supposedly due to disseminated intravascular coagulation. Human antithrombin III concentrates were therefore transfused in seven patients with cirrhosis and antithrombin III deficiency (less than 80%). Fibrinogen half-life and the fractional catabolic rate constant were calculated from the turnover of 125I-fibrinogen which was represented by a two-compartment model. Prior to antithrombin III transfusion, 125I-fibrinogen half-life was 76.7 +/- 15.2 h and the fractional catabolic rate constant was 0.33 +/- 0.11 of the plasma fibrinogen pool per day. In six healthy adult controls these values were significantly different: 109.4 +/- 8.8 h and 0.19 +/- 0.01 respectively. Correction of antithrombin III activity with human antithrombin III concentrate reduced the increased turnover of radiolabelled fibrinogen to normal. The 125I-fibrinogen half-life became 108.4 +/- 17.6 h and the fractional catabolic rate constant decreased to 0.23 +/- 0.06. These observations indicate that decreased antithrombin III activity contributes in an important way to the increased 125I-fibrinogen turnover in patients with cirrhosis and this might reflect intravascular coagulation.

Adult↗

PubMed2004

Mutations in the shutter region of antithrombin result in formation of disulfide-linked dimers and severe venous thrombosis.

BACKGROUND: Missense mutations causing conformational alterations in serpins can be responsible for protein deficiency associated with human diseases. However, there are few data about conformational consequences of mutations affecting antithrombin, the main hemostatic serpin. OBJECTIVES: To investigate the conformational and clinical effect of mutations affecting the shutter region of antithrombin. PATIENTS AND METHODS: We identified two families with significant reduction of circulating antithrombin displaying early and severe venous thrombosis, frequently associated with pregnancy or infection. Mutations were determined by standard molecular methods. Biochemical studies were performed on plasma samples. One variant (P80S) was purified by heparin-affinity chromatography and gel filtration, and evaluated by proteomic analysis. Finally, we modelled the structure of the mutant dimer. RESULTS: We identified two missense mutations affecting the shutter region of antithrombin: P80S and G424R. Carriers of both mutations presented traces of a similar abnormal antithrombin, supporting inefficiently expressed rather than non-expressed variants. The abnormal antithrombin purified from P80S carriers is an inactive disulfide-linked dimer of mutant antithrombin whose properties are consistent with head-to-head insertion of the reactive loop. CONCLUSIONS: Our data support the conclusion that missense mutations affecting the shutter region of serpins have specific conformational effects resulting in the formation of mutant oligomers. The consequent inefficiency of secretion explains the accompanying deficiency and loss of function, but the severity of thrombosis associated with these mutations suggests that the oligomers also have new and undefined pathological properties that could be exacerbated by pregnancy or infection.

Adult↗

PubMed1992

Cerebral infarction in a heterozygote with variant antithrombin III.

BACKGROUND: We report a heterozygous case of familial qualitative deficiency of antithrombin III associated with cerebral infarction. CASE DESCRIPTION: A 33-year-old man had a history of recurrent transient ischemic attacks from the age of 28. Cerebral computed tomography at age 29 disclosed a low-density area in the left frontal lobe, and an internal carotid angiogram showed branch occlusion of the right anterior cerebral artery and stenosis of the left middle cerebral artery. Occlusion of the right middle cerebral artery developed thereafter. The plasma antithrombin III antigen concentration and progressive antithrombin activity were normal, but plasma heparin cofactor activity was low in the patient and his father. Nucleotide sequence analysis of the proband's deoxyribonucleic acid showed no mutation in exons II and VI of antithrombin III. CONCLUSIONS: We conclude that abnormal antithrombin III with defective heparin binding, even though heterozygous, may cause ischemic stroke in young adults. We named this antithrombin III variant "Antithrombin III Nagasaki."

Adult↗

PubMed1994

Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp)

A new variant of antithrombin (Rouen-VI, 187 Asn-->Asp) with increased heparin affinity was shown to have normal inhibitory activity which decreased slowly at 4 degrees C and rapidly at 41 degrees C. On electrophoresis the freshly isolated variant had an anodal shift relative to native antithrombin due to the mutation. A further anodal transition occurred after either prolonged storage at 4 degrees C or incubation at 41 degrees C due to the formation of a new inactive uncleaved component with properties characteristic of L-form (latent) antithrombin. At the same time, polymerization also occurred with a predominance of di-, tri-, and tetra-mers. These findings fit with the observed mutation of the conserved asparagine (187) in the F-helix destabilizing the underlying A-sheet of the molecule. Evidence of A-sheet perturbation is provided by the increased rate of peptide insertion into the A-sheet and by the decreased vulnerability of the reactive loop to proteolysis. The spontaneous formation of both L-antithrombin and polymers is consistent with our crystal structure of intact antithrombin where L-form and active antithrombin are linked together as dimers. The nature of this linkage favors a mechanism of polymerization whereby the opening of the A-sheet, to give incorporation of the reactive center loop, is accompanied by the bonding of the loop of one molecule to the C-sheet of the next. The accelerated lability of antithrombin Rouen-VI at 41 versus 37 degrees C provides an explanation for the clinical observation that episodes of thrombosis were preceded by unrelated pyrexias.

Adult↗

PubMed1985

[Howie's antithrombin activity and thrombin inhibitors in the nephrotic syndrome].

A prospective study was carried out on a group of 28 patients affected by nephrotic syndrome in order to compare the antithrombin activity, measured by the technique of Howie, the antithrombin III, measured with chromogenic substrate and by radial immunodiffusion, the alpha 2-macroglobulin and the alpha 1-antitrypsin. An increased level of alpha 2-macroglobulin and of the antithrombin activity, measured by the technique of Howie and a reduction of the level of antithrombin III and of alpha 1-antitrypsin was observed. It is suggested that the increased antithrombin activity is related to the increase of alpha 1-antitrypsin was observed. It is suggested that the increased antithrombin activity is related to the increase of alpha 2-macroglobulin concentration in spite of the simultaneous decrease of antithrombin III.

Adolescent↗

PubMed1993

[Abnormal antithrombin III: abnormalities of heparin or protease binding domain].

Two patients with abnormal antithrombin III manifested abnormality in heparin binding activity (abnormal antithrombin III "Toyma") or protease binding activity (abnormal antithrombin III "Aomori"). Antithrombin III "Toyama" is hereditarily homozygous with Arg47 to Cys47 (TGC-->TGT) mutation, and antithrombin III "Aomori" is hereditarily heterozygous with Arg393 to His393 (CGT-->CAT). The former is classified as type II-c, and the latter as type II-b according to Lane's classification2). Both patients showed cerebral thrombosis after age 20. Heparin cofactor II activity in the former case was slightly higher than normal. Oral anticoagulant therapy was used in the both cases. These cases were examined by biological and immunological assay, heparin sepharose column chromatography, binding activity to cultured porcine endothelial cells, restriction fragment length polymorphysm and polymerase chain reaction. The authors developed an antithrombin III assay method to be able to estimate real activity without the influence of heparin cofactor II activity11), and to apply the low molecular weight heparin to prevent relapse of thrombosis, and finally to find an anticoagulant substance in an interesting case of hepatocellular carcinoma (Edmondson type 1) producing normal antithrombin III30).

Adult↗

PubMed1995

Antithrombin activity of surface-bound heparin studied under flow conditions.

Polyacrylamide-grafted polyetherurethane sheets were modified by end-point and multipoint attachment of heparin. The surface-bound heparin was firmly attached. No release of heparin activity could be detected when the surface was rinsed at a wall shear rate of 2000 s-1. Uptake of antithrombin and thrombin inactivation were investigated under well-defined flow conditions by the use of a spinning device with an attached disk-shaped heparinized surface. It is demonstrated that the rate of thrombin inactivation at the antithrombin-heparin surface equals the maximal rate of transport of thrombin toward the surface when the surface coverage of antithrombin exceeds 10 pmol/cm2. This result indicates that a higher intrinsic catalytic efficiency of a surface does not necessarily result in a higher antithrombin activity. We varied the heparin content of the surfaces between 0 and 35 micrograms/cm2 by increasing the number of functional groups to which heparin could be covalently attached. The uptake of antithrombin increased with the heparin content of the surface, but the stoichiometry decreased from 2 to 0.5 pmol antithrombin/micrograms heparin. Apparently, antithrombin could not bind to heparins buried in the poly(acrylamide) layer. The rate of thrombin inactivation at surfaces with low heparin content (2 micrograms/cm2) fells below the transport limit of thrombin and became proportional with the heparin content of the surface. Although the contribution of surface-bound heparin to the neutralization of fluid-phase thrombin was found to be negligible compared with the effect of fluid-phase antithrombin at physiologic relevant concentrations, these heparinized surfaces markedly delayed the onset of thrombin generation in platelet-rich plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombins↗

PubMed1997

Effect of individual carbohydrate chains of recombinant antithrombin on heparin affinity and on the generation of glycoforms differing in heparin affinity.

Two major glycoforms of recombinant antithrombin which differ 10-fold in their affinity for the effector glycosaminoglycan, heparin, were previously shown to be expressed in BHK or CHO mammalian cell lines (I. Björk, et al., 1992, Biochem. J. 286, 793-800; B. Fan et al., 1993, J. Biol. Chem. 268, 17588-17596). To determine the source of the glycosylation heterogeneity responsible for these different heparin-affinity forms, each of the four Asn residue sites of glycosylation, residues 96, 135, 155, and 192, was mutated to Gln to block glycosylation at these sites. Heparin-agarose chromatography of the four antithrombin variants revealed that Gln 96, Gln 135, and Gln 192 variants still displayed the two functional heparin-affinity forms previously observed with the wild-type inhibitor, whereas the Gln 155 variant showed only a single functional high heparin affinity form. These results demonstrate that heterogeneous glycosylation of Asn 155 of recombinant antithrombin is responsible for generating the low heparin affinity glycoform. Analysis of heparin binding to the higher heparin affinity forms of the four variants showed that all exhibited increased heparin affinities of two- to sevenfold compared to wild-type higher heparin affinity form or to plasma antithrombin, with the Gln 135 variant showing the largest effect on this affinity. The extent of heparin-affinity enhancement was correlated with the distance of the mutated glycosylation site to the putative heparin-binding site in the X-ray structure of antithrombin. All variants displayed normal kinetics of thrombin inhibition in the absence and presence of saturating heparin, indicating that the carbohydrate chains solely affected heparin binding and not heparin-activation or proteinase-binding functions. These results indicate that all carbohydrate chains of recombinant antithrombin adversely affect heparin-binding affinity to an extent that correlates with their relative proximity to the putative heparin-binding site in antithrombin.

Animals↗

PubMed1981

Decreased production or increased turnover of antithrombin III in severe acquired coagulopathy?

During the course of severe coagulopathy in an infant suffering from septicaemia and shock, antithrombin III levels were determined repeatedly before and during substitution therapy with human antithrombin. By mathematical analysis of these data, using a biexponential function, the plasma elimination half-life of the antithrombin III was estimated to be 7.5-10.5 h. Compared with known plasma half-lives of radioactively labelled antithrombin III in adults the increase was five-to ten-fold. This indicates that the significantly decreased levels of antithrombin III in this case of coagulopathy were at least partly due to an accelerated consumption of antithrombin III. The estimation of the plasma elimination half-life of antithrombin III helps to differentiate decreased production from increased consumption in cases of severe coagulopathy. Thus, a more precise diagnosis of disseminated intravascular coagulation can be made whilst taking advantage of substitution therapy and avoiding the hazards of radioactive tracer proteins.

Antithrombin III↗

PubMed1989

Antithrombin inactivation by neutrophil elastase requires heparin.

In certain thrombotic states, large declines in the levels of functional circulating antithrombin occur, which may reflect the highly active nature of the endothelial surface in suppressing excessive amounts of activated coagulation enzymes. Alternatively, we have recently observed an unexpected and paradoxical in vitro functioning of heparin that could result in the inactivation of antithrombin in pathologic conditions. Specifically, antithrombin was rendered nonfunctional as an inhibitor of clotting enzymes as a result of a limited, heparin-dependent cleavage by neutrophil elastase. This inactivation occurred only in the presence of the active anticoagulant heparin fraction, which suggested that the heparin-antithrombin complex was the substrate for elastase attack. Interestingly, neutrophil elastase was found to bind tightly to heparin and heparin-like materials. Neutrophil elastase has been previously linked to nonspecific proteinolysis occurring in inflammatory thrombotic reactions. This affinity of both antithrombin and elastase for heparin suggests a novel mechanism of potential specificity. An important component of this hypothesis is the localization of the elastase/antithrombin reaction away from the high circulating levels of elastase inhibitors. The proposed inactivation of antithrombin on the vascular surface would likely occur only in pathologic states associated with neutrophil sequestration and activation. Nevertheless, this mechanism could lead to a localized reversal of the nonthrombogenic nature of the endothelium and potentially lead to significant reductions of functional antithrombin in certain disease states.

Antithrombins↗

PubMed1983

Antithrombin in vertebrate species: conservation of the heparin-dependent anticoagulant mechanism.

Heparin is thought to regulate the rate of mammalian blood clotting by enhancing the activity of antithrombin, an inhibitor of coagulation enzymes. The present study establishes that this same inhibitor is present in the blood plasma of each of the terrestrial vertebrate groups including mammals, birds, reptiles, and amphibians. In each case, an inhibitor with remarkably similar properties to human antithrombin was isolated by affinity chromatography on immobilized porcine heparin. The purified vertebrate inhibitors all show the following physical and functional homologies to human antithrombin: (i) heparin-enhanced inhibition of both bovine thrombin and human Factor Xa, (ii) molecular masses of approximately 60,000, and (iii) heparin-induced increases in ultraviolet fluorescence. Also, the heparin-binding interaction of vertebrate antithrombins is highly selective with each demonstrating the same rigid specificity for heparin species fractionated on the basis of their affinity for human antithrombin. This common ability of vertebrate antithrombins to discriminate among heparins is accomplished by a nearly unvarying equilibrium binding constant for the high-affinity heparin species. Thus, the present results suggest that the anticoagulant relationship of heparin and antithrombin was established at an early point in the evolution of the coagulation system and has been highly conserved since that time.

Animals↗

PubMed2005

Characterization of the structure of antithrombin-binding heparan sulfate generated by heparan sulfate 3-O-sulfotransferase 5.

The 3-O-sulfation of glucosamine is a key modification step during the biosynthesis of anticoagulant heparan sulfate (HS). Both heparan sulfate 3-O-sulfotransferase -1 (3-OST-1) and 3-O-sulfotransferase-5 (3-OST-5) transfer sulfate to the 3-OH group of glucosamine to generate antithrombin-binding heparan sulfate (HS(act)). Here, we reported the isolation and characterization of the antithrombin-binding HS oligosaccharides generated by 3-OST-5 (3-OST-5 oligo(act)). (3)H-labeled HS of Chinese hamster ovary cells was exhaustively modified by 3-OST-1 to remove the 3-OST-1 modification sites followed by antithrombin-affinity fractionation. The non-antithrombin-binding fraction of 3-OST-1 pretreated HS was further modified by 3-OST-5 to generate additional antithrombin-binding HS, which was designated as 3-OST-5 HS(act). Structural analysis of 3-OST-5 HS(act) revealed that the antithrombin-binding site of 3-OST-5 HS(act) is located within a domain clustered with N-sulfated glucosamine units. We also isolated 3-OST-5 antithrombin-binding oligosaccharides (3-OST-5 oligo(act)) from high pH nitrous acid degraded 3-OST-5 HS(act). A disaccharide analysis revealed that 3-OST-5 oligo(act) were composed of multiple 3-O-sulfated glucosamine units. Our results provide additional insights on the relationship between the anticoagulant activity and structure of HS.

Animals↗

PubMed2005

Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass.

OBJECTIVES: We sought to evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization. RESULTS: Six (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients ( P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group. CONCLUSION: Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.

Adult↗

PubMed1982

Estrogen-induced deficiency and decrease in antithrombin III activity in patients with prostatic cancer.

Plasma antithrombin III activity was studied in 22 patients with prostatic cancer who were on estrogen therapy. Normal plasma antithrombin III activity varies between 0.80 and 1.40 U. per ml. A loading dose of 15 mg. diethylstilbestrol daily resulted in a marked decrease in plasma antithrombin III activity (mean 0.24 U. per ml.). Patients with the lower end of normal range of pre-treatment plasma antithrombin III activity may suffer acquired antithrombin III deficiency and, thus, a concomitantly increased risk of thromboembolic complications as a result of estrogen treatment. Patients on maintenance therapy of approximately 1 mg. daily appear to have normal plasma antithrombin III levels. The results obtained suggest that plasma antithrombin III activity should be monitored before and during estrogen therapy in patients with prostatic cancer.

Aged↗

PubMed1998

Mechanism of factor IXa inhibition by antithrombin in the presence of unfractionated and low molecular weight heparins and fucoidan.

Heparin exerts its anticoagulant activity by catalysing the inhibition of coagulation proteases by antithrombin (AT). Its main target is thrombin but it also catalyses the inhibition of the other serine-proteases of the coagulation cascade, such as factor IXa (fIXa). The aim of this study was to compare the catalysis of inhibition of blood fIXa by antithrombin in the presence of several sulfated polysaccharides with anticoagulant activity, i.e. heparin, three widely used in therapeutics low molecular weight heparins (LMWH) and fucoidan. Plots of the second-order rate constants of the fIXa-antithrombin reaction vs. the concentration of added heparin and LMWH are bell-shaped and fit the kinetic model established for thrombin-antithrombin reaction by Jordan R., Beeler D., Rosenberg R. (1979) J. Biol. Chem., 254, 2902-2913. In the ascending branch, the catalyst (C) binds quickly to the inhibitor (I) to form a catalyst-inhibitor (CI) complex which is more reactive towards the enzyme (E) than the free inhibitor, leading to the formation of an inactive enzyme-inhibitor complex (EI) and the release of free catalyst, in a rate-limiting second step. After a maximum corresponding to an optimal catalyst concentration, the decrease in the reaction rate was in keeping with the formation of a catalyst-enzyme (CE) complex, whose inactivation by the CI complex was slower than that of the free enzyme. Maximum second-order rate constants for the inhibition of fIXa by AT were 105, 6.8, 12.24 and 22 microM-1 min-1 with heparin, Enoxaparin, Fraxiparin and Fragmin, respectively, leading to 3500-, 225-, 405- and 728-fold increases in the inhibition rate in the absence of polysaccharide, respectively. Fucoidan yielded 23-fold increase in the fIXa-antithrombin interaction rate. The kinetic profiles obtained with this polysaccharide exhibited ascending branch which correlated well with the kinetic model based on the formation of binary complexes (CI or CE). Fucoidan was covalently conjugated with a fluorescent probe (DTAF) and used in conjunction with fluorescence anisotropy to follow its binding to antithrombin, heparin cofactor II (HCII), thrombin and fIXa. The binding of fucoidan to these proteins occurred with low affinities when compared to heparin and LMWH. Fucoidan had higher affinity for the inhibitor HCII compared to antithrombin and enzymes. These data suggest that binding of heparins and fucoidan to the inhibitor (CI) is required for the polysaccharide-dependent enhancement in the rate of neutralization of the enzyme by the inhibitor.

Anticoagulants↗

PubMed2001

Antithrombin binding of low molecular weight heparins and inhibition of factor Xa.

Fluorescence and stopped flow methods were used to compare clinically used heparins with regard to their ability to bind to antithrombin and to accelerate the inactivation of factor Xa. Titration of antithrombin with both low molecular weight heparin (LMWH) (enoxaparin, fragmin and ardeparin) and unfractionated heparin (UFH) produced an equivalent fluorescence increase and indicates similar affinity of all heparin preparations to antithrombin. However, relative to UFH enoxaparin, the LMWH with the smallest average molecular mass, contained only 12% material with high affinity for antithrombin. The rate of factor Xa inhibition by antithrombin increased with the concentration of the examined heparins to the same limiting value, but the concentration required for maximal acceleration depended on the preparation. According to these data the high affinity fraction of the heparin preparations increased the intrinsic fluorescence and inhibitory activity equally without additional effects by variations in chain length and chemical composition. In contrast, in the presence of Ca UFH accelerated the inhibition of factor Xa by antithrombin 10-fold more efficiently than comparable concentrations of the high affinity fractions of enoxaparin and fragmin. The bell-shaped dependence of this accelerating effect suggests simultaneous binding of both proteins to heparin. In conclusion, under physiologic conditions the anti-factor Xa activity of heparin results from a composite effect of chain length and the content of material with high affinity to antithrombin. Thus, the reduced antithrombotic activity of LMWH relative to UFH results from a smaller content of high affinity material and the absence of a stimulating effect of calcium.

Animals↗