Desulfated Heparin Blocks Platelet Activation Induced by HIT Antibodies / Heparin: A New Approach to Patient Management.

Heparin-induced thrombocytopenia (HIT) represents a disease spectrum triggered by an immune response to heparin. The most dramatic clinical expression of HIT is HIT antibody-driven thrombosis. Direct thrombin inhibitors (DTIs) are a promising new class of drugs for treatment of the acute phase of HIT; however, they have a narrow safety/efficacy window (high bleeding risk) and morbidity/mortality have not been eliminated. In addition, the high probability of developing thrombosis in HIT combined with extreme mortality, has led to a bias for prophylactic treatment. Thus, there remains a clinical need to identify optimal treatment options for patients with HIT. A new concept is to use an agent that can effectively compete with heparin in a manner that prevents the HIT antibody from inducing platelet activation, i.e., amelioration. We evaluated a 2-O, 3-O desulfated heparin (ParinGenix, Inc.; Tucson, AZ) to determine its ability to ameliorate HIT antibody/heparin induced platelet activation. The test agent was added to a mixture of known-reactive platelets and pre-formed immune complexes (heparin, PF4, HIT antibodies), and SRA and flow cytometry were performed. Due to the inherent biological variability of HIT antibodies, sera from four different patients (clinically diagnosed as HIT; SRA positive) were used. Two concentrations of heparin which reflect typical prevention (0.1 U/ml) and treatment (0.5 U/ml) clinical doses were used. The 2-O, 3-O desulfated heparin produced an amelioration of HIT antibody/heparin induced platelet activation as demonstrated in the SRA by inhibition of ¹⁴C serotonin release from activated platelets, and in flow cytometric analysis by inhibition of platelet microparticle formation and platelet cell surface P-selectin expression. Significant amelioration activity was initiated at 6.25 μg/ml 2-O, 3-O desulfated heparin and complete inhibition of the induced platelet activation (equal to the 100 U/ml heparin HIT assay ‘no response’) was achieved with 50 μg/ml of the agent. Since this new treatment approach blocks platelet activation caused by HIT antibody/heparin (not a characteristic of DTIs), we propose that a non-anticoagulant glycosaminoglycan (GAG) may be useful in improving the clinical management of patients with HIT. The concept of amelioration differs from all previous options for the clinical management of patients with HIT including the use of danaparoid, fondaparinux, DTIs and other drugs that target thrombin/thrombin generation inhibition. Although not directed at platelet activation inhibition, this type of GAG effects an inhibition of HIT antibody mediated platelet activation, which is the source of the pathophysiology of HIT. The data of this study suggest that this 2-O, 3-O desulfated heparin may be effective as either an adjunct or sole treatment of an ongoing HIT pathology, or as a preventive measure in patients who will be exposed to heparin.