title: Heparin-induced thrombocytopenia: in vitro studies on the interaction of dabigatran, rivaroxaban, and low-sulfated heparin, with platelet factor 4 and anti-PF4/heparin antibodies.
abstract: Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). HIT requires treatment with alternative anticoagulants. Approved for HIT are 2 direct thrombin inhibitors (DTI; lepirudin, argatroban) and danaparoid. They are niche products with limitations. We assessed the effects of the DTI dabigatran, the direct factor Xa-inhibitor rivaroxaban, and of 2-O, 3-O desulfated heparin (ODSH; a partially desulfated heparin with minimal anticoagulant effects) on PF4/heparin complexes and the interaction of anti-PF4/heparin Abs with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin Abs with platelets. In contrast, ODSH inhibited PF4 binding to gel-filtered platelets, displaced PF4 from a PF4-transfected cell line, displaced PF4/heparin complexes from platelet surfaces, and inhibited anti-PF4/heparin Ab binding to PF4/heparin complexes and subsequent platelet activation. Dabigatran and rivaroxaban seem to be options for alternative anticoagulation in patients with a history of HIT. ODSH prevents formation of immunogenic PF4/heparin complexes, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin.
authors: Institut für Immunologie und Transfusionsmedizin, Universitä Greifswald, Sauerbruchstrasse, Greifswald, Germany.
authors: Krystin
authors: K
authors: Krauel
authors: Christine
authors: C
authors: Hackbarth
authors: Birgitt
authors: B
authors: Fürll
authors: Andreas
authors: A
authors: Greinacher
mesh_terms: D000906:Antibodies / Q000494:pharmacology*; D000925:Anticoagulants / Q000009:adverse effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D000069604:Dabigatran; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D057809:HEK293 Cells; D006493:Heparin / Q000009:adverse effects* / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D010978:Platelet Factor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000069552:Rivaroxaban; D013431:Sulfates / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000139:chemically induced*; D014162:Transfection; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000906:Antibodies; D000925:Anticoagulants; D001562:Benzimidazoles; D009025:Morpholines; D013431:Sulfates; D013876:Thiophenes; D015091:beta-Alanine; D010978:Platelet Factor 4; D006493:Heparin; D000069552:Rivaroxaban; D000069604:Dabigatran