Complement activation as a biomarker for platelet-activating antibodies in heparin-induced thrombocytopenia.

BACKGROUND: Immunoglobulin G antibodies (Abs) to platelet factor 4 (PF4) complexed to heparin (PF4/H) commonly occur after H exposure but cause life-threatening complications of H-induced thrombocytopenia (HIT) in only a few patients. Presently, only platelet activation assays reliably distinguish anti-PF4/H Abs that cause disease (HIT Abs) from those likely to be asymptomatic (AAbs). OBJECTIVES: Recent studies indicate that complement activation is an important serologic property of HIT Abs and is essential for IgG Fc receptor IIA-mediated cellular activation. As platelet activation by HIT Abs also relies on IgG Fc receptor IIA activation, we correlated the complement- and platelet-activating properties of anti-PF4/H Abs in a clinically annotated patient cohort. METHODS: Clinical and laboratory features of patients with HIT (n = 8) and AAbs+ (n = 14) were correlated with properties of complement, platelet, and monocyte/neutrophil activation. RESULTS: Expected clinical and laboratory differences were seen between HIT and AAb+ patients, with HIT patients having lower mean platelet counts, greater percentage drop in platelet counts, higher 4T and HIT expert probability scores, higher anti-PF4 polyclonal and immunoglobulin G Ab levels, and serotonin release assay positivity. Ex vivo assays revealed significant differences in complement activation by HIT vs AAb+ patients, with the extent of complement activation closely correlated with percent serotonin release by anti-PF4/H Abs and matrix metalloproteinase-9 and interleukin-8 release in whole blood. CONCLUSION: These findings suggest that complement activation strongly correlates with cellular activation endpoints, including platelet and monocyte/neutrophil activation, and if confirmed in a larger prospective study, may serve as a "functional" biomarker for pathogenic HIT Abs.

Duke Scholars

Author Sanjay Khandelwal Medicine, Hematology

Author Gowthami Morey Arepally Medicine, Hematology

Author Maragatha Kuchibhatla Biostatistics & Bioinformatics, Division of Biostatistics

Author Grace Ming Lee Medicine, Hematology