Protein Foundry’s CXCL4 Used to Identify Antibodies That Cause Heparin-Induced Thrombocytopenia

A recent study published in Blood from scientists at @BloodCenterWI and @MayoClinic reveals structural differences between platelet-activating and non-activating antibodies from HIT patients, all of which bind heparin-bound CXCL4.

Heparin-induced thrombocytopenia (HIT) was first diagnosed in patients treated with heparin more than 60 years ago and today affects >20,000 people annually in the United States. The molecular basis for HIT pathogenesis is incomplete, as some patients who test positive for anti-CXCL4/heparin antibodies exhibit clinical signs of HIT. Using recombinant CXCL4 protein (also known as platelet factor-4 or PF4) from Protein Foundry, Zhu et al. measured binding and platelet activation for a panel of 54 antibodies from 6 HIT patients. The platelet-activating (PA) antibodies contained an unusually long CDR3 loop and one of two PA sequence motifs (RKH or Y5), either of which could be incorporated into a non-activating anti-CXCL4/heparin antibody to confer PA activity. Thus, there is an obvious structural feature associated with the antibodies most likely to cause HIT. While ELISA easily detects antibodies that bind CXCL4/heparin complexes and is widely used as a diagnostic test for HIT, this study helps explain why other assays that detect antibodies capable of inducing platelet activation produce results correlating much more closely with the clinical condition. Discovery of the molecular signature of pathogenic antibodies could enable the creation of biologic drugs to significantly reduce HIT-related injuries and deaths.