Use of dermatan sulfates and/or desulfated heparins to treat or prevent heparinoid-induced autoimmune responses

Abstract

Dermatan sulfates and/or O-desulfated heparins useful in treating and preventing heparinoid-induced autoimmune responses, in particular heparin-induced thrombocytopenia (HIT) and its associated disease states. The dermatan sulfates comprise repeating disulfated and/or trisulfated disaccharide units of L-iduronic acid and N-acetyl-D-galactosamine. The O-desulfated heparins comprise heparin molecules selectively O-desulfated at the 2-O and/or 3-O positions of the uronic acid and glucosamine saccharide residues. Particularly effective dermatan sulfate HIT antagonists have a mean molecular weight of from about 2000 to about 10,000 Daltons.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application makes reference to the following co-pending U.S. Provisional Patent Application No. 60 / 572,364, filed May 19, 2004. The entire disclosure and contents of the above application is hereby incorporated by reference.GOVERNMENT INTEREST STATEMENT [0002] This invention was made in part with Government support under Grant No. HL-66-646-01 and HL-70-453-01 awarded by the National Institute of Health, National Heart, Lung & Blood Institute. The Government may have certain rights to the invention.BACKGROUND [0003] 1. Field of the Invention [0004] The present invention relates to treating and / or preventing heparinoid-induced autoimmune responses with certain dermatan sulfates and / or certain O-desulfated heparins. The present application particularly relates to the treatment and / or prevention of heparin-induced thrombocytopenia (HIT) and its associated disease states with certain dermatan sulfate and / or certain O-desulfated heparin...

AI Technical Summary

Benefits of technology

[0020] The dermatan sulfates and/or O-desulfated heparins of this invention unexpectedly prevent the activation of platelets and endothelial cell damage caused by the immune complexes of HIT, even in the presence of administered heparin, a property or activity referred to as “HIT antagonism.” The HIT antagonist properties of the dermatan sulfates and/or O-desulfated heparins of this invent

Problems solved by technology

In contrast to the hemorrhagic thrombocytopenia disease states, HIT is associated with an increased risk of thrombosis.

Historically, about 40% of these HIT patients develop a life-threatening thrombosis or HITT syndrome that produces devastating complications including necrosis of the extremities, stroke, myocardial infarction and pulmonary embolism.

Thus, it has been previously concluded that hyper- or oversulfation of GAGs is an inappropriate approach to anticoagulation based on the HIT inducing potential of sulfated GAGs, and that to reduce the ability of a GAG to induce a HIT response: (i) the nature of the glycosidic bond is unimportant; (ii) the molecule should be unbranched; (iii) the molecule should have a degree of sulfation (i.e., the number of sulfate groups/monosaccharide) of less than 0.60 (i.e., a sulfate to carboxylate (S/C) ratio of no more than 1.2) for chain lengths greater than 10 monosaccharides (i.e., greater than 3000 Daltons); (iv) the molecule should be smaller than 2400 Daltons if its degree of sulfation is 1.0-1.3; and (v)

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