Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides

Summary

Eczematous lesions, resulting from type IV sensitizations are well-known and relatively frequent cutaneous adverse effects of s.c. heparin therapy. If anticoagulation is further required intravenous heparin, heparinoids or lepirudin may be used as a substitute. However, these alternatives are not optimal in terms of practicability and/or safety-profiles. As molecular weight of different heparin preparations has repetitively been implied to determine the frequency of sensitization, we hypothesized, that due to its low molecular weight the pentasaccharide fondaparinux may provide a practicable and safe anticoagulant therapy in patients with delayed type hypersensitivity reactions (DTH) to heparin and other oligosaccharides. To test this concept, patients referred for diagnosis of cutaneous reactions after s.c. anticoagulant treatment underwent a series of in vivo skin allergyand challenge-tests with unfractionated heparin, a series of low molecular weight heparins (nadroparin, dalteparin, tinzaparin, enoxaparin and certoparin), the heparinoid danaparoid and the synthetic pentasaccharide fondaparinux. In total, data from twelve patients was evaluated. In accordance with previously published data, we report a high crossreactivity among heparins and heparinoids. In contrast – and in support of our initial hypothesis – sensitization towards the synthetic pentasaccharide fondaparinux was rarely observed. Plotting the cumulative incidence against the determined molecular weight of the individual anticoagulant preparations, shows that molecular weight generally is a key determinant of sensitization towards heparins and other oligosaccharides (r²=0.842, p=0.009). Hence, fondaparinux may be used as a therapeutic alternative in patients with cutaneous DTH relations towards heparin and other polysaccharides.

Keywords

Heparins / glycosaminoglycans - clinical trials - heparins / LMWH - immunity (auto-)

• References

• 1 Gaigl Z, Pfeuffer P, Raith P. et al Tolerance to intravenous heparin in patients with delayed-type hypersensitivity to heparins: a prospective study. Br J Haematol 2005; 128: 389-92.
• 2 Boehncke WH, Weber L, Gall H. Tolerance to intravenous administration of heparin and heparinoid in a patient with delayed-type hypersensitivity to heparins and heparinoids. Contact Dermatitis 1996; 35: 73-5.
• 3 Jappe U, Reinhold D, Bonnekoh B. Arthus reaction to lepirudin, a new recombinant hirudin, and delayedtype hypersensitivity to several heparins and heparinoids, with tolerance to its intravenous administration. Contact Dermatitis 2002; 46: 29-32.
• 4 Irion R, Gall H, Peter RU. Delayed-type hypersensitivity to heparin with tolerance of its intravenous administration. Contact Dermatitis 2000; 43: 249-50.
• 5 Grassegger A, Fritsch P, Reider N. Delayed-type hypersensitivity and cross-reactivity to heparins and danaparoid: a prospective study. Dermatol Surg 2001; 27: 47-52.
• 6 Fagiolo U, Cancian M, Bertollo L. P et al Inhibitory effect of heparin on skin reactivity to autologous serum in chronic idiopathic urticaria. J Allergy Clin Immunol 1999; 103: 1143-7.
• 7 Alban S, Greinacher A. Role of sulfated polysaccharides in the pathogenesis of heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A. Heparin-Induced Thrombocytopenia. 3rd edition. Marcel Dekker; New York: 2004: 197-221;
• 8 Ludwig RJ, Beier C, Lindhoff-Last E. et al Tolerance of fondaparinux in a patient allergic to heparins and other glycosaminoglycans. Contact Dermatitis 2003; 49: 158-9.
• 9 Lane DA. Heparin binding and neutralizing proteins. In: Lane DA, Lindahl U. editors Heparin: London Edward Arnold; 1989: 363-91.
• 10 Alban S. From heparins to factor Xa inhibitors and beyond. Eur J Clin Invest 2005; 35 (Suppl. 01) 12-20.
• 11 Turpie AG, Eriksson BI, Lassen MR. et al Fondaparinux, the first selective factor Xa inhibitor. Curr Opin Hematol 2003; 10: 327-32.
• 12 Berkun Y, Haviv YS, Schwartz LB. et al Heparininduced recurrent anaphylaxis. Clin Exp Allergy 2004; 34: 1916-8.
• 13 Hirsch K, Ludwig RJ, Lindhoff-Last E. et al Intolerance of fondaparinux in a patient allergic to heparins. Contact Dermatitis 2004; 50: 383-4.
• 14 Zacharski LR, Ornstein DL. Heparin and cancer. Thromb Haemost 1998; 80: 10-23.
• 15 Wagner L, Yang OO, Garcia-Zepeda EA. et al Betachemokines are released from HIV-1-specific cytolytic T-cell granules complexed to proteoglycans. Nature 1998; 391: 908-11.
• 16 Vives RR, Sadir R, Imberty A. et al A kinetics and modeling study of RANTES(9–68) binding to heparin reveals a mechanism of cooperative oligomerization. Biochemistry 2002; 41: 14779-89.
• 17 Caballero MR, Fernandez-Benitez M. Allergy to heparin: a new in vitro diagnostic technique. Allergol Immunopathol 2003; 31: 324-8.
• 18 Wang L, Brown JR, Varki A. et al Heparin’s anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. J Clin Invest 2002; 110: 127-36.
• 19 Ludwig RJ, Boehme B, Podda M. et al Endothelial P-selectin as a target of heparin action in experimental melanoma lung metastasis. Cancer Res 2004; 64: 2743-50.
• 20 Kim YJ, Borsig L, Varki NM. et al P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci U S A 1998; 95: 9325-30.