IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

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

    Research output: Contribution to journalArticle

    31 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)478-485
    Number of pages8
    JournalChest
    Volume152
    Issue number3
    DOIs
    StatePublished - Sep 1 2017

    Fingerprint

    Thrombocytopenia
    Heparin
    Platelet Activation
    Therapeutics
    Anticoagulants
    Antibodies
    Blood Platelets
    Genotype
    Platelet Factor 4
    IgG Receptors
    Thromboembolism
    Immunoenzyme Techniques
    Immunoassay
    Thrombosis
    Immunoglobulin G
    Hemorrhage
    Antigens
    Population

    Keywords

    • DOAC
    • heparin
    • HIT
    • IVIg
    • thrombocytopenia
    • thrombosis

    ASJC Scopus subject areas

    • Pulmonary and Respiratory Medicine
    • Critical Care and Intensive Care Medicine
    • Cardiology and Cardiovascular Medicine

    Cite this

    Padmanabhan, A., Jones, C. G., Pechauer, S. M., Curtis, B. R., Bougie, D. W., Irani, M. S., ... Aster, R. H. (2017). IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest, 152(3), 478-485. https://doi.org/10.1016/j.chest.2017.03.050

    IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. / Padmanabhan, Anand; Jones, Curtis G.; Pechauer, Shannon M.; Curtis, Brian R.; Bougie, Daniel W.; Irani, Mehraboon S.; Bryant, Barbara J.; Alperin, Jack B.; Deloughery, Thomas; Mulvey, Kevin P.; Dhakal, Binod; Wen, Renren; Wang, Demin; Aster, Richard H.

    In: Chest, Vol. 152, No. 3, 01.09.2017, p. 478-485.

    Research output: Contribution to journalArticle

    Padmanabhan, A, Jones, CG, Pechauer, SM, Curtis, BR, Bougie, DW, Irani, MS, Bryant, BJ, Alperin, JB, Deloughery, T, Mulvey, KP, Dhakal, B, Wen, R, Wang, D & Aster, RH 2017, 'IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia', Chest, vol. 152, no. 3, pp. 478-485. https://doi.org/10.1016/j.chest.2017.03.050
    Padmanabhan A, Jones CG, Pechauer SM, Curtis BR, Bougie DW, Irani MS et al. IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest. 2017 Sep 1;152(3):478-485. https://doi.org/10.1016/j.chest.2017.03.050
    Padmanabhan, Anand ; Jones, Curtis G. ; Pechauer, Shannon M. ; Curtis, Brian R. ; Bougie, Daniel W. ; Irani, Mehraboon S. ; Bryant, Barbara J. ; Alperin, Jack B. ; Deloughery, Thomas ; Mulvey, Kevin P. ; Dhakal, Binod ; Wen, Renren ; Wang, Demin ; Aster, Richard H. / IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. In: Chest. 2017 ; Vol. 152, No. 3. pp. 478-485.
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    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.",
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    AU - Padmanabhan, Anand

    AU - Jones, Curtis G.

    AU - Pechauer, Shannon M.

    AU - Curtis, Brian R.

    AU - Bougie, Daniel W.

    AU - Irani, Mehraboon S.

    AU - Bryant, Barbara J.

    AU - Alperin, Jack B.

    AU - Deloughery, Thomas

    AU - Mulvey, Kevin P.

    AU - Dhakal, Binod

    AU - Wen, Renren

    AU - Wang, Demin

    AU - Aster, Richard H.

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    N2 - 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.

    AB - 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.

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