Low-affinity heparin potentiates the action of high-affinity heparin oligosaccharides

Barrowcliffe, Trevor W.; Merton, R E; Havercroft, S J; Thunberg, Lennart; Lindahl, Ulf; Thomas, Duncan P.

doi:10.1016/0049-3848(84)90069-0

Cited by 76 publications

(34 citation statements)

References 20 publications

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“…Subsequent studies using purified antithrombin confirmed these trends, and it became clear that acceleration of inhibition of thrombin and FXa by heparin had different MW requirements (14,15). This difference was emphasised in studies by Holmer (16) and in our laboratory (17,18 ); high-affinity (for antithrombin) oligosaccharides with chain lengths mostly below 16 units, had very high anti-Xa activity, over 1,000 IU/mg, but their activity in thrombin inhibition and APTT assays was less than 10 IU/ mg.…”

Section: Mw Dependencementioning

confidence: 81%

Heparin and low-molecular-weight heparin

Mulloy,

Barrowcliffe,

Gray

2008

Thromb Haemost

236

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SummaryHeparin is one of the oldest biological medicines, and has an established place in the prevention and treatment of venous thrombosis. Low-molecular-weight heparins (LMWH) have been developed by several manufacturers and have advantages in terms of pharmacokinetics and convenience of adminisKeywords Heparin, low-molecular-weight heparin tration. They have been shown to be at least as effective and safe as unfractionated heparin and have replaced the latter in many indications. In this article the chemistry, mechanisms of action, measurement of anticoagulant activities, and clinical status of heparin and LMWH are reviewed.

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Section: Mw Dependencementioning

confidence: 81%

Heparin and low-molecular-weight heparin

Mulloy,

Barrowcliffe,

Gray

2008

Thromb Haemost

236

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“…Nevertheless, this is possible due to a laboratory artifact (absence of Ca 2+ in the test system). The fraction called LAM [7] with nonsignificant antithrombotic properties can enhance the antithrombotic effect of HAM [7,9]. LAM may also release TFPI from vessel wall and can displace HAM from nonspecific binding sites on cells and plasma proteins, increasing the effect of heparin and can also contribute to bleeding.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Unfractionated Heparin, Low Molecular Weight Heparin and Both Combined for Releasing Total and Free Tissue Factor Pathway Inhibitor

Altman¹,

Scazziota²,

Rouvier³

1998

Pathophysiol Haemos Thromb

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Unfractionated heparin (UFH) exerts its anticoagulant properties by increasing the inactivation of thrombin and activated factor X by antithrombin III. Apart from this main action release of tissue factor pathway inhibitor (TFPI) from endothelial cells could also be important for the antithrombotic activity of heparins. Four different heparin preparations were injected subcutaneously into 5 healthy volunteers 1 week apart: (1) UFH 2,500 IU fix dose (FixUFH), (2) 1 mg/kg body weight of low molecular weight heparin (LMWH), (3) the combined LMWH-adjusted dose plus UFH 2,500 IU fix dose (ComHep) and (4) UFH 2,500 IU/10 kg body weight (UFHvar). Plasma samples were drawn before and 1, 2, 4, 6, 12 and 24 h afterwards. FixUFH did not affect the concentration of total and free TFPI. Total TFPI increased in the 1st hour after LMWH injection from 74 to 124 ng/ml (p < 0.01), after ComHep from 82 to 144 ng/ml (p < 0.01), and after UFHvar from 91 to 113 ng/ml (p < 0.05). All observed elevations were significant at the peak value (± 2 h, p < 0.01 compared with baselines). The increase of free TFPI produced by UFHvar (74.5 and 70.5 ng/ml) was significantly higher than with LMWH (42.8 and 38.0 ng/ml) at 2 and 4 h (p < 0.001 and p < 0.01, respectively). UFHvar and ComHep but not LMWH produced a statistically significant increase of free TFPI compared with FixUFH at 2, 4 and 6 h (p < 0.01). We concluded that at comparable therapeutic doses, subcutaneous UFHvar released more free TFPI than LMWH and ComHep. A synergism between LMWH and low dose of UFH was found in 4-, 6- and 12-hour blood samples.

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“…Barrowcliffe et al (13), however, demonstrated that low-affinity forms of heparin potentiate the antithrombotic effect of high-affinity forms. At a dose of 110 gg/kg, h16 and h12 exerted an antithrombotic effect that lasted until the antiFactor Xa level had decreased by -50%.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the antithrombotic activity of different heparin fragments not only depends on their specific anticoagulant activity, but it also seems to be a function ofthe chain length ofthe fragment (1 1). Furthermore, it has been shown that low-affinity heparin potentiates the antithrombotic effect of high-affinity heparin fragments (13).…”

Section: Introductionmentioning

confidence: 99%

Antithrombotic properties in rabbits of heparin and heparin fragments covalently coupled to human antithrombin III.

Mattsson¹,

Hoylaerts²,

Holmer³

et al. 1985

J. Clin. Invest.

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Clinical grade heparin is a very heterogeneous mucopolysaccharide, containing molecules with M, ranging from 6,000 to 30,000 that have either a high affinity or a low affinity for antithrombin III (AT). In this study, the antithrombotic properties of intact high-affinity heparin (M, = 15,000) and of two heparin fragments (h16, a 16-monosaccharide fragment, with M, = 4,300, and h12, a 12-monosaccharide fragment, with M, = 3,200) and of their functional covalent stoichiometric complexes with human AT were compared in a venous thrombosis stasis model in rabbits. Thrombosis was induced by injection of glass-activated human plasma and measured in a segment of the jugular vein that was isolated between two vascular clamps for 10 min.Injections of 55 Mg/kg resulted in a clear antithrombotic effect for intact heparin, but not for the two fragments. Equivalent amounts (carbohydrate moiety) of covalent complexes of heparin or of both heparin fragments with human AT resulted in an antithrombotic effect lasting for 45-60 min. Injection of 110 Mtg/kg of heparin and of the heparin fragments yielded an antithrombotic effect, lasting 45-60 min; the corresponding amounts of covalent complexes caused an antithrombotic effect for 60-120 min. The free and conjugated framents produced equal antithrombotic effects at equal plasma levels of anti-Factor Xa activity, but the specific antithrombotic activities of free and complexed intact heparin, on a molar basis, were 10-20-fold greater than those of the free and complexed heparin fragments. The plasma half-life of the covalent complexes of the heparin fragments with AT is, however, 10 times longer than that of the complex between intact heparin and AT and 30 times longer than that of free intact heparin. Covalent complexes between AT and heparin fragments could, therefore, be useful to maintain more stable levels of antithrombotic activity in plasma.

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Low-affinity heparin potentiates the action of high-affinity heparin oligosaccharides

Cited by 76 publications

References 20 publications

Heparin and low-molecular-weight heparin

Heparin and low-molecular-weight heparin

Efficacy of Unfractionated Heparin, Low Molecular Weight Heparin and Both Combined for Releasing Total and Free Tissue Factor Pathway Inhibitor

Antithrombotic properties in rabbits of heparin and heparin fragments covalently coupled to human antithrombin III.

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