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Original Research |

Intravenous immunoglobulin for treatment of severe refractory heparin-induced thrombocytopenia FREE TO VIEW

Anand Padmanabhan, MD PhD; Curtis G. Jones, BS; Shannon M. Pechauer, BS; Brian R. Curtis, PhD; Daniel W. Bougie, PhD; Mehraboon S. Irani, MD; Barbara J. Bryant, MD; Jack B. Alperin, MD; Thomas G. Deloughery, MD; Kevin P. Mulvey, MD; Binod Dhakal, MD; Renren Wen, PhD; Demin Wang, PhD; Richard H. Aster, MD
Author and Funding Information

Guarantor statement:

Anand Padmanabhan MD PhD had full access to all the data in the study and he takes responsibility for the integrity of the data and the accuracy of the data analysis

1Department of Pathology, Medical College of Wisconsin, Milwaukee, WI

2Medical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI

3Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI

4Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin, Milwaukee, WI

5Department of Pathology, University of Texas Medical Branch, Galveston, TX

6Internal Medicine, University of Texas Medical Branch, Galveston, TX

7Knight Cancer Center, Oregon Health & Science University, Portland, OR

8Department of Medicine, Kootenai Health, Coeur d'Alene, ID

9Department of Medicine, Medical College of Wisconsin, Milwaukee, WI

Corresponding Author: Anand Padmanabhan 8733 Watertown Plank Road Milwaukee, WI 53226-3548.


Copyright 2017, . All Rights Reserved.


Chest. 2017. doi:10.1016/j.chest.2017.03.050
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Abstract

Background  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 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.

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 (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).

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


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