Validation of the Low-Molecular-Weight Heparin Standard

Fareed, J.; Walenga, Jeanine M.; Coyne, Erwin; Hoppensteadt, D.; Racanelli, A.; Messmore, Harry L.; Huan, Xia‐Juan

doi:10.1159/000215889

Cited by 2 publications

(3 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another finding of immediate practical relevance is that the LMW heparins currently in vogue as preferred anticoagulants over unfractionated heparins (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71) may not be achieving the same degree of selectin inhibition at the levels currently recommended for their use. Indeed, the IC 50 values of these compounds against selectin-PSGL-1 interactions are so close to or even above the recommended target range for anticoagulation that the degree of selectin inhibition in a given patient would be hard to predict.…”

Section: Discussionmentioning

confidence: 99%

“…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: 97%

See 1 more Smart Citation

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.

376

288

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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.

376

288

View full text Add to dashboard Cite

show abstract

“…The question of whether to use a common standard for LMWHs, however, is being strongly debated. 3,4,90,[144][145][146][147][148][149][150][151] The data presented here suggest that standardization practices for unfractionated heparin are not valid in the case of LMWHs. The key issue on the standardization of LMWHs can be summarized in the following: There is considerable concern over the current use of the first LMWH standard.…”

Section: Standardization Of Low Molecular Weight Heparinsmentioning

confidence: 99%