Polyphosphate/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia.

Abstract

Heparin-induced thrombocytopenia (HIT) is a thrombotic disorder initiated by antibodies to complexes between platelet factor 4 (PF4) and heparin. The risk of recurrent thromboembolism persists after heparin is cleared and platelet activation leading to release of PF4 has dissipated. We asked whether antigenic complexes between polyphosphates and PF4 released from activated platelets might intensify or sustain the prothrombotic phenotype of HIT. PF4 forms stable, ultralarge complexes with polyphosphates of various sizes, including those released from platelets, which are recognized by the HIT-like monoclonal KKO, an immunoglobulin G2bκ monoclonal heparin/PF4 binding antibody, and by human HIT antibodies. KKO helps to protect PF4/polyphosphate complexes from degradation by phosphatases. Complement is activated when HIT antibodies bind to PF4/polyphosphate complexes and PF4 reverses the inhibition of complement by polyphosphates. Polyphosphates and PF4 are stored primarily in separate granules in resting platelets, but they colocalize when the cells are activated. Platelets activated by subaggregating doses of thrombin receptor activating peptide release polyphosphates and PF4, which form antigenic complexes that allow KKO to further activate platelets in the absence of heparin and exogenous PF4. These studies suggest that thrombin- or immune complex-mediated release of endogenous antigenic PF4/polyphosphate complexes from platelets may augment the prothrombotic risk of HIT and perpetuate the risk of thrombosis after heparin has been discontinued.

• Authors: Douglas B Cines, Serge V Yarovoi, Sergei V Zaitsev, Tatiana Lebedeva, Lubica Rauova, Mortimer Poncz, Gowthami M Arepally, Sanjay Khandelwal, Victoria Stepanova, Ann H Rux, Adam Cuker, Cecilia Guo, Linnette Mae Ocariza, Richard J Travers, Stephanie A Smith, Hugh Kim, James H Morrissey, Edward M Conway
• Journal: Blood advances (Blood Adv) Vol. 1 Issue 1 Pg. 62-74 (Nov 29 2016) ISSN: 2473-9529 [Print] United States
• PMID: 29296696 (Publication Type: Journal Article)