Low Molecular Weight Heparins: An Emerging New Class of Glycosaminoglycan Antithrombotics

Freedman, Michael D.

doi:10.1002/j.1552-4604.1991.tb03709.x

Cited by 12 publications

(7 citation statements)

References 69 publications

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“…Finally, we have asked if inhibition of selectin binding can occur at concentrations of heparin that are in the typical range for its use as a therapeutic anticoagulant (61,62). We find that this is indeed the case, and note a striking difference between the activity of the traditional pharmaceutical preparations of unfractionated heparin, and that of some of the currently popular low molecular weight (LMW) heparins (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71).…”

Section: Introductionmentioning

confidence: 99%

Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.

Koenig¹,

Norgard-Sumnicht²,

Linhardt³

et al. 1998

J. Clin. Invest.

377

288

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The selectins are calcium-dependent C-type lectins that bind certain sialylated, fucosylated, sulfated glycoprotein ligands. L-selectin also recognizes endothelial proteoglycans in a calcium-dependent manner, via heparan sulfate (HS) glycosaminoglycan chains enriched in unsubstituted glucosamine units. We now show that these HS chains can also bind P-selectin, but not E-selectin. However, while L-selectin binding requires micromolar levels of free calcium, P-selectin recognition is largely divalent cation-independent. Despite this, HS chains bound to P-selectin are eluted by ethylenediamine tetraacetic acid (EDTA), but only at high concentrations. Porcine intestinal mucosal (mast cell-derived) heparin (PIM-heparin) shows similar properties, with no binding to E-selectin, calcium-dependent binding of a subfraction to L-selectin and to P-selectin, and calcium-independent binding of a larger fraction to P-selectin, the latter being disrupted by high EDTA concentrations. Analysis of defined heparin fragment pools shows a size dependence for interaction, with tetradecasaccharides showing easily detectable binding to L- and P-selectin affinity columns. L-selectin binding fragments include more heavily sulfated and epimerized regions and, as with the endothelial HS chains, they are enriched in free amino groups. The P-selectin binding component includes this fraction as well as some less highly modified regions. Thus, endothelium-derived HS chains and mast cell-derived heparins could play a role in modulating the biology of selectins in vivo. Notably, P- and L-selectin binding to sialyl-Lewisx and to HL-60 cells (which are known to carry the native ligand PSGL-1) is inhibited by unfractionated pharmaceutical heparin preparations at concentrations 12-50-fold lower than those recommended for effective anticoagulation in vivo. In contrast, two low molecular weight heparins currently considered as clinical replacements for unfractionated heparin are much poorer inhibitors. Thus, patients undergoing heparin therapy for other reasons may be experiencing clinically significant inhibition of L- and P-selectin function, and the current switchover to low-molecular weight heparins may come at some loss of this effect. Low-dose unfractionated heparin should be investigated as a treatment option for acute and chronic diseases in which P- and L-selectin play pathological roles.

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Section: Introductionmentioning

confidence: 99%

Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.

Koenig¹,

Norgard-Sumnicht²,

Linhardt³

et al. 1998

J. Clin. Invest.

377

288

View full text Add to dashboard Cite

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“…4,5 Elevations in alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) due to LMWH were first reported by Christiansen et al 6 Although hypertransaminasemia has been observed, it is believed to be a rather benign process as it has not been reported to produce clinical illness. 7 Elevations of serum transaminases are believed to be maximal within the first 7 days of therapy. 8,9 The exact pathogenesis of deranged LFT induced by LMWH is so far unknown.…”

Section: Discussionmentioning

confidence: 99%

Low Molecular Weight Heparin‐Induced Liver Toxicity

Hui

Yuen

et al. 2001

The Journal of Clinical Pharma

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The authors report two cases of hepatotoxicity induced by low molecular weight heparin. A 26-year-old woman and a 33-year-old man were treated with low molecular weight heparin for pulmonary embolism and cerebral infarction, respectively. They both developed derangement in liver function tests a few days after commencement of the low molecular weight heparin. The derangement in liver function tests was associated with a decreased serum complement 3 activity. Their liver functions recovered over a period of 2 to 3 months after low molecular weight heparin was stopped. Liver biopsy in the woman demonstrated balloon degeneration with scattered foci of hepatocytic necrosis, suggesting a complement-mediated hepatocellular damage.

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“…The clinical outcome, cost, and cost-effectiveness of both methods were evaluated The American-Canadian Thrombosis Study randomized 432 patients and found tinzaparin sodium, s.c., to be at least as effective and safe as UFH i.v., but less expensive. The costeffectiveness of the LMWH administration could have been greater if outpatient therapy had been implemented (16). Once again, the results of this study could not be extrapolated to other LMWHs, since their molecular composition and pharmacokinetic profiles differ and their cost may vary considerably (16).…”

Section: Clinical Experiencementioning

confidence: 96%

“…The costeffectiveness of the LMWH administration could have been greater if outpatient therapy had been implemented (16). Once again, the results of this study could not be extrapolated to other LMWHs, since their molecular composition and pharmacokinetic profiles differ and their cost may vary considerably (16).…”

Section: Clinical Experiencementioning

confidence: 96%

“…When used in the lower, more appropriate doses for prevention of thrombosis, LMWHs have not been associated with an increased risk of perioperative bleeding. Other side effects such as thrombocytopenia and skin necrosis also occur with LMWHs, but the occurrence rate appears much lower than with UFH (16). LMWHs inhibit factor Xa activity, thrombin (IIa) activity, and cause release of TFPI at different dose levels (14,44,46) and inhibit clot dynamics regardless of the stimulus (6).…”

Section: Plasmatic Effects At Different Steps In the Coagulation Cascadementioning

confidence: 99%

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The Low Molecular Weight Heparin, Tinzaparin, in Thrombosis and Beyond

Mousa

2002

Cardiovascular Drug Reviews

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Standard unfractionated heparin (UFH) has been in clinical use for over 50 years. The commercial use of low molecular weight heparins (LMWHs) began in the mid 1980s for hemodialysis and the prophylaxis of deep vein thrombosis (DVT). Initially, the clinical development of LMWHs was concentrated on the European continent. Subsequently, LMWHs were introduced in North America as well. In the initial stages of development of these drugs only nadroparin, dalteparin and enoxaparin were used. Subsequently, several other LMWHs such as ardeparin, tinzaparin, reviparin and parnaparin were introduced. LMWHs constitute a group of important medications with total sales reaching nearly 2.5 billion dollars with expanded indications reaching far beyond the initial indications for the prophylaxis of post-surgical DVT. This review highlights the pharmacology of tinzaparin. Unlike other LMWHs, tinzaparin is prepared by enzymatic hydrolysis with heparinase, while various chemical depolymerization methods are used for the synthesis of other LMWHs. As compared with the standard heparin, LMWHs have different pharmacodynamic, and pharmacokinetic properties; they also differ in clinical benefits.

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Low Molecular Weight Heparins: An Emerging New Class of Glycosaminoglycan Antithrombotics

Cited by 12 publications

References 69 publications

Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.

Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents.

Low Molecular Weight Heparin‐Induced Liver Toxicity

The Low Molecular Weight Heparin, Tinzaparin, in Thrombosis and Beyond

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