Antibodies associated with heparin-induced thrombocytopenia (HIT) inhibit activated protein C generation: new insights into the prothrombotic nature of HIT. Blood 2011 Sep 08;118(10):2882-8
Date
07/21/2011Pubmed ID
21772054Pubmed Central ID
PMC3172804DOI
10.1182/blood-2011-02-335208Scopus ID
2-s2.0-80052667085 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
Heparin-induced thrombocytopenia (HIT) is caused by antibodies that recognize complexes between platelet factor 4 (PF4) and heparin or glycosaminoglycan side chains. These antibodies can lead to a limb- and life-threatening prothrombotic state. We now show that HIT antibodies are able to inhibit generation of activated protein C (aPC) by thrombin/thrombomodulin (IIa/TM) in the presence of PF4. Tetrameric PF4 potentiates aPC generation by formation of complexes with chondroitin sulfate (CS) on TM. Formation of these complexes occurs at a specific molar ratio of PF4 to glycosaminoglycan. This observation and the finding that the effect of heparin on aPC generation depends on the concentration of PF4 suggest similarity between PF4/CS complexes and those that bind HIT antibodies. HIT antibodies reduced the ability of PF4 to augment aPC formation. Cationic protamine sulfate, which forms similar complexes with heparin, also enhanced aPC generation, but its activity was not blocked by HIT antibodies. Our studies provide evidence that complexes formed between PF4 and TM's CS may play a physiologic role in potentiating aPC generation. Recognition of these complexes by HIT antibodies reverses the PF4-dependent enhancement in aPC generation and may contribute to the prothrombotic nature of HIT.
Author List
Kowalska MA, Krishnaswamy S, Rauova L, Zhai L, Hayes V, Amirikian K, Esko JD, Bougie DW, Aster RH, Cines DB, Poncz MMESH terms used to index this publication - Major topics in bold
AdultAnimals
Antibodies, Monoclonal
Anticoagulants
Cells, Cultured
Glycosaminoglycans
Heparin
Humans
Integrases
Kidney
Mice
Mice, Inbred C57BL
Mice, Knockout
Platelet Factor 4
Protein C
Protein C Inhibitor
Protein Multimerization
Prothrombin
Recombinant Proteins
Thrombin
Thrombocytopenia
Thrombomodulin
