Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Krystin Krauel,
  2. Christine Hackbarth,
  3. Birgitt Fürll, and
  4. Andreas Greinacher*
  1. 1 Institut fuer Immunologie und Transfusionsmedizin, Universitaetsmedizin Greifswald, Germany
  1. * Corresponding author; email: greinach{at}uni-greifswald.de

Abstract

Heparin is a widely used anticoagulant. Due to its negative charge it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG antibodies. 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 two 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 antibodies with platelets. Neither dabigatran nor rivaroxaban had any effect on the interaction of PF4 or anti-PF4/heparin antibodies 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, inhibited anti-PF4/heparin antibody 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 antigens, and, when given together with heparin, may have the potential to reduce the risk for HIT during treatment with heparin.

  • Submitted May 10, 2011.
  • Accepted October 30, 2011.