Anand Padmanabhan1, Curtis G Jones2, Shannon M Pechauer3, Brian R Curtis4, Daniel W Bougie3, Mehraboon S Irani5, Barbara J Bryant6, Jack B Alperin7, Thomas G Deloughery8, Kevin P Mulvey9, Binod Dhakal10, Renren Wen3, Demin Wang3, Richard H Aster11. 1. Medical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI; Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI. Electronic address: anand.padmanabhan@bcw.edu. 2. Medical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI. 3. Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI. 4. Platelet and Neutrophil Immunology Laboratory, BloodCenter of Wisconsin, Milwaukee, WI. 5. Medical Sciences Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Pathology, Medical College of Wisconsin, Milwaukee, WI. 6. Department of Pathology, University of Texas Medical Branch, Galveston, TX. 7. Department of Pathology, University of Texas Medical Branch, Galveston, TX; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX. 8. Knight Cancer Center, Oregon Health & Science University, Portland, OR. 9. Department of Medicine, Kootenai Health, Coeur d'Alene, ID. 10. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. 11. Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI.
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.
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.
Authors: Anand Padmanabhan; Curtis G Jones; Brian R Curtis; Daniel W Bougie; Mia J Sullivan; Namrata Peswani; Janice G McFarland; Daniel Eastwood; Demin Wang; Richard H Aster Journal: Chest Date: 2016-02-19 Impact factor: 9.410
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