HIT complicated by severe thrombocytopenia and thrombosis can pose significant treatment challenges. Use of alternative anticoagulants in this setting may increase bleeding risks, especially in patients who have a protracted disease course. Additional therapies are lacking in this severely affected patient population.
We describe three HIT patients who had severe thromboembolism and prolonged thrombocytopenia refractory to standard treatment but achieved an immediate and sustained response to intravenous immunoglobulin G (IVIg) therapy. The mechanism of action of IVIg was evaluated in these and in five additional patients with severe HIT. The impact of a common polymorphism (131 H/R) in the platelet IgG receptor, FcγRIIa, on IVIg-mediated inhibition of platelet activation was also examined.
At levels attained in vivo, IVIg inhibits HIT antibody-mediated platelet activation. The constant domain of IgG (Fc) but not the antigen-binding portion (Fab) is required for this effect. Consistent with this finding, IVIg had no effect on HIT antibody binding in a solid phase HIT immunoassay (PF4 ELISA). The R/H131 polymorphism in FcγRIIa influences the susceptibility of platelets to IVIg treatment, with the HH131 genotype being most susceptible to IVIg-mediated inhibition of antibody-induced activation. However, at high doses of IVIg, activation of platelets of all FcγRIIa genotypes was significantly inhibited. All three patients did well on long-term anticoagulation with direct oral anticoagulants (DOACs).
These studies suggest that IVIg treatment should be considered in HIT patients with severe disease refractory to standard therapies.