IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

Abstract

Background: Heparin-induced thrombocytopenia (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.

Methods: We describe three patients with HIT who had severe thromboembolism and prolonged thrombocytopenia refractory to standard treatment but who achieved an immediate and sustained response to IVIg therapy. The mechanism of action of IVIg was evaluated in these patients and in five additional patients with severe HIT. The impact of a common polymorphism (H/R 131) in the platelet IgG receptor FcγRIIa on IVIg-mediated inhibition of platelet activation was also examined.

Results: 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 (platelet factor 4 enzyme-linked immunoassay). The H/R131 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 therapy with direct oral anticoagulants.

Conclusions: These studies suggest that IVIg treatment should be considered in patients with HIT who have severe disease that is refractory to standard therapies.

Keywords: DOAC; HIT; IVIg; heparin; thrombocytopenia; thrombosis.

Figure 1

IVIg treatment led to prompt recovery of platelet counts. Left ordinate denotes (A-C) PEA, PEA (low PF4), and (A) SRA test results. Right ordinate depicts platelet count. PEA (open circle) and PEA (Low PF4, closed circle) results shown are the average of duplicate measurements, and SRA (open triangles) and platelet counts (open squares) shown are single determinations. Orange arrows and dashes denote IVIg treatment (1g/kg body weight). Api = apixaban; Arg = argatroban; Biv = bivalirudin; Dab = dabigatran; PEA = PF4-dependent P-selectin expression assay; PF4 = platelet factor 4; Riv = rivaroxaban.

Figure 2

Effect of IVIg on HIT antibody-mediated platelet activation. A and B, IVIg was added to patient serum to produce a final IgG concentration equivalent to that achieved after treatment at 2 g/kg (blue bars) or no treatment (red bars). A, PEA or (B) PEA (low PF4) was then performed and is depicted by the ordinate. Figures show mean + 1 SD of triplicate measurements. Mean values were compared with results obtained with untreated serum using the Student t test. Asterisks denote P < .01 (**), P < .001 (***), and P < .0001 (****). See Figure 1 legend for expansion of abbreviations.

Figure 3

Effect of IVIg, Fc, and Fab fragments on HIT antibody-mediated platelet activation in the PEA (low PF4) and SRA. A, IVIg equivalent to the concentration achieved in vivo following treatment with 2 g/kg (red bars), Fc fragments (blue bars), or Fab fragments (gray bars) were added to serum samples obtained from five patients who had severe HIT (Fc and Fab fragments were used at equimolar and twice-molar amounts relative to IgG, respectively). Samples were tested in the PEA (low PF4) shown on the ordinate. Figures show mean + 1 SD of triplicate measurements. Mean values were compared with results obtained with untreated serum using the Student t test. Asterisks denote P < .05 (*), P < .01 (**), P < .001, (***), and P < .0001 (****). B, IVIg equivalent to the concentration achieved in vivo following treatment with 2 g/kg (closed circles and closed squares) or buffer (open circles and open squares) was added to serum samples obtained from three patients experiencing severe HIT (HIT patients 2-4). The SRA, shown on the ordinate, was measured as a single determination in the absence of heparin (circles) or in the presence of 0.1 units/mL unfractionated heparin (squares). The dotted line (20%) indicates the cutoff for a positive result. Fab = fragment antigen-binding; Fc = fragment crystallizable; HIT = heparin-induced thrombocytopenia; SRA = serotonin release assay; UFH = unfractionated heparin. See Figure 1 legend for expansion of other abbreviations.

Figure 4

FcγRIIa HH131 platelets are most susceptible to inhibition by IVIg. IVIg was added to serum from two patients with severe HIT (A, HIT patient 1 and B, HIT patient 2) to produce IgG concentrations achieved after treatment with IVIg at doses shown on the abscissa (see Methods section). Samples were then tested in the PEA (low PF4) using platelets from donors with RR, HR, and HH131 FcγRIIa genotypes. P-selectin expression (percent of value obtained with untreated serum) is shown on the ordinate. Figures show mean + 1 SD of triplicate measurements. Mean values were compared using the Student t test. Asterisks denote P < .05 (*), P < .01 (**), P < .001, (***), and P < .0001 (****). See Figures 1 and 3 legends for expansion of abbreviations.