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 Bryant, Jack B. Alperin, Thomas G. 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; Alperin, Jack B.; Deloughery, Thomas G.; 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, B, Alperin, JB, Deloughery, TG, 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 ; Alperin, Jack B. ; Deloughery, Thomas G. ; 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.
@article{bd80bea7ffab4584baddbbdb8f01c8be,
title = "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, heparin, HIT, IVIg, thrombocytopenia, thrombosis",
author = "Anand Padmanabhan and Jones, {Curtis G.} and Pechauer, {Shannon M.} and Curtis, {Brian R.} and Bougie, {Daniel W.} and Irani, {Mehraboon S.} and Barbara Bryant and Alperin, {Jack B.} and Deloughery, {Thomas G.} and Mulvey, {Kevin P.} and Binod Dhakal and Renren Wen and Demin Wang and Aster, {Richard H.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.chest.2017.03.050",
language = "English (US)",
volume = "152",
pages = "478--485",
journal = "Chest",
issn = "0012-3692",
publisher = "American College of Chest Physicians",
number = "3",

}

TY - JOUR

T1 - IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia

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

AU - Alperin, Jack B.

AU - Deloughery, Thomas G.

AU - Mulvey, Kevin P.

AU - Dhakal, Binod

AU - Wen, Renren

AU - Wang, Demin

AU - Aster, Richard H.

PY - 2017/9/1

Y1 - 2017/9/1

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.

KW - DOAC

KW - heparin

KW - HIT

KW - IVIg

KW - thrombocytopenia

KW - thrombosis

UR - http://www.scopus.com/inward/record.url?scp=85028972116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028972116&partnerID=8YFLogxK

U2 - 10.1016/j.chest.2017.03.050

DO - 10.1016/j.chest.2017.03.050

M3 - Article

VL - 152

SP - 478

EP - 485

JO - Chest

JF - Chest

SN - 0012-3692

IS - 3

ER -