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Ham-Wasserman Lecture

Program: General Sessions
Saturday, December 9, 2023: 12:30 PM-1:30 PM
Hall A (San Diego Convention Center)
Robert A. Brodsky, MD, Johns Hopkins University
Brodsky: Alexion, AstraZeneca Rare Disease: Research Funding.
Platelet-activating antibodies of IgG class against the chemokine, platelet factor 4 (PF4), can induce some of the most prothrombotic disorders encountered in clinical practice. Heparin-induced thrombocytopenia (HIT) is the prototypic anti-PF4 disorder. HIT is mediated by strong IgG-induced activation of platelets through their FcγIIa (IgG) receptors. Concomitant pancellular activation (monocytes, neutrophils, endothelium) triggers thrombo-inflammation with resulting hypercoagulability and associated high risk for venous and arterial thrombosis. HIT requires anticoagulation with a non-heparin anticoagulant. Understanding HIT, and its atypical variants, permitted rapid understanding of the mechanisms underlying the rare adverse effect of adenovirus vector COVID-19 vaccines, vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT is also caused by anti-PF4 IgG, but in contrast to most cases of HIT, VITT is a predominantly heparin-independent platelet-activating disorder. VITT requires both therapeutic-dose anticoagulation and inhibition of FcγRIIa-mediated cell activation, currently achieved by high-dose intravenous immunoglobulin (IVIG). Recent development of new assays to distinguish between HIT and VITT-like anti-PF4 antibodies has led to recognition of patients with severe acute (sometimes chronic, recurrent) thrombosis and thrombocytopenia, where VITT-mimicking (rather than HIT-mimicking) anti-PF4 antibodies are implicated, independent of proximate heparin exposure or vaccination.

Dr. Greinacher will conceptualize anti-PF4 antibody mediated disorders as a misdirected pathogen defense mechanism causing uncontrolled thrombo-inflammation. He will explain how biophysical techniques helped to uncover the underlying mechanisms by which the endogenous protein, PF4, becomes immunogenic. The lecture will outline new options for detecting anti-PF4 antibodies, both heparin-dependent and heparin-independent, and discuss the key concept that heparin-independent, platelet-activating anti-PF4 antibodies require (besides anticoagulation) adjunct treatment with high-dose IVIG to deescalate the severe anti-PF4 IgG-mediated hypercoagulability state.

Andreas Greinacher, MD

Transfusion Medicine, University Medicine Greifswald, University of Greifswald, Greifswald, Germany

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