Immunologic Research

, Volume 66, Issue 6, pp 668–674 | Cite as

Intravenous immunoglobulins for rheumatic disorders and thromboembolic events—a case series and review of the literature

  • Merav Lidar
  • Sewar Masarwa
  • Pnina Rotman
  • Or Carmi
  • Noa Rabinowicz
  • Yair LevyEmail author
Original Article


To report the temporal association between a series of thromboembolic events and intravenous immunoglobulin infusion in patients with rheumatic diseases, and to review the literature on the subject. The clinical presentation, course, and outcome of thromboembolic events occurring post-immunoglobulin infusion in nine patients is described. A web-based literature review using the PubMed database from 1996 to 2017 was performed, searching for the keywords: thrombosis, thromboembolism, intravenous immunoglobulin, pulmonary embolism, deep vein thrombosis, cerebrovascular event, and acute myocardial infarction. Nine patients who had suffered a thromboembolic event within a week after receiving an intravenous immunoglobulin infusion (Omr-IgG-am™, OMRIX) were identified among our joint cohort. All patients except one were female ranging in age from 22 to 69 years. Five had progressive systemic sclerosis (one of them had progressive systemic sclerosis with antiphospholipid syndrome, and another had an overlap of progressive systemic sclerosis with systemic lupus erythematosus), the sixth had monoclonal IgM autoimmune neuropathy, the seventh had systemic lupus erythematosus with antiphospholipid syndrome, the eighth had granulomatosis with polyangiitis (GPA) and the ninth had overlap autoimmune syndrome. Six of the patients had an arterial thrombosis: an acute myocardial infarction in four, a brachial artery thrombosis in the fifth, and a cerebrovascular attack in the sixth. Three patients sustained a venous thrombosis and/or an acute pulmonary embolism (one of them had a DVT with the PE). Two events occurred during the IVIG infusion, three within an hour after the last infusion of the 5-day course, one occurred a few hours after the initiation of the IVIG therapy, another occurred 3 days after receiving the final infusion of the 10th course, and two events occurred a week after the treatment course has ended. Fifty-five percent of the patients had no thrombogenic risk factors other than their rheumatic condition, and most of them had received numerous, uneventful IVIG treatment courses before sustaining the thromboembolic event. No immediate deaths occurred among this cohort. Thromboembolic events after IVIG infusions, although infrequent, may occur in rheumatic patients, even in the absence of other recognizable risk factors for thromboembolism. The reported events had occurred despite complying with recommended guidelines for IVIG administration, which include a lengthy 8-h infusion and division of the total dose. No correlation was found between the number and frequency of the infusions to the thromboembolic events. Heightened awareness of possible thromboembolic events in rheumatic patients is encouraged for at least a week following IVIG administration.


Intravenous immunoglobulin Myocardial infarction Thromboembolic events Cerebrovascular accident Pulmonary embolism 


Compliance with ethical standards

Conflict of interests

The authors declare that they have no conflict of interest.


  1. 1.
    Levy Y, Amital H, Langevitz P, Nacci F, Righi A, Conforti L, et al. Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum. 2004;50:1005–7.CrossRefGoogle Scholar
  2. 2.
    Sanges S, Rivière S, Mekinian A, Martin T, le Quellec A, Chatelus E, et al. Intravenous immunoglobulin in systemic sclerosis: data from a French nationwide cohort of 46 patients and review of the literature. Autoimmun Rev. 2017;16:377–84.CrossRefGoogle Scholar
  3. 3.
    Zandman-Goddard G, Levy Y, Shoenfeld Y. Intravenous immunoglobulin therapy and systemic lupus erythematosus. Clin Rev Allergy Immunol. 2005;29:219–28.CrossRefGoogle Scholar
  4. 4.
    Dalakas MC. The role of high-dose immune globulin intravenous in the treatment of dermatomyositis. Int Immunopharmacol. 2006;6:550–6.CrossRefGoogle Scholar
  5. 5.
    Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. Qjm. 2000;93:433–9.CrossRefGoogle Scholar
  6. 6.
    Shoenfeld Y, Katz U. IVIG therapy in autoimmunity and related disorders: our experience with a large cohort of patients. Autoimmunity. 2005;38:123–37.CrossRefGoogle Scholar
  7. 7.
    Brannagan TH 3rd, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology. 1996;47:674–7.CrossRefGoogle Scholar
  8. 8.
    Stangel M, Kiefer R, Pette M, Smolka MN, Marx P, Gold R. Side effects of intravenous immunoglobulin in neurological autoimmune disorders--a prospective study. J Neurol. 2003;250:818–21.CrossRefGoogle Scholar
  9. 9.
    Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol. 2005;29:173–84.CrossRefGoogle Scholar
  10. 10.
    Stenton SB, Dalen D, Wilbur K. Myocardial infarction associated with intravenous immune globulin. Ann Pharmacother. 2005;39:2114–8.CrossRefGoogle Scholar
  11. 11.
    Zaidan R, Al Moallem M, Wani BA, et al. Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurol. 2003;10:367–72.CrossRefGoogle Scholar
  12. 12.
    Fruchter O, Blich M, Jacob G. Fatal acute myocardial infarction during severe thrombocytopenia in a patient with idiopathic thrombocytopenic purpura. Am J Med Sci. 2002;323:279–80.CrossRefGoogle Scholar
  13. 13.
    Paran D, Herishanu Y, Elkayam O, Shopin L, Ben-Ami R. Venous and arterial thrombosis following administration of intravenous immunoglobulin. Blood Coagul Fibrinolysis. 2005;16:313–8.CrossRefGoogle Scholar
  14. 14.
    Marie I, Maurey G, Herve F, Hellot MF, Levesque H. Intravenous immunoglobulin-associated arterial and venous thrombosis; report of a series and review of the literature. Br J Dermatol. 2006;155:714–21.CrossRefGoogle Scholar
  15. 15.
    Tam PY, Richardson M, Grewal S. Fatal case of bilateral internal jugular vein thrombosis following IVIG infusion in an adolescent girl treated for ITP. Am J Hematol. 2008;83:323–5.CrossRefGoogle Scholar
  16. 16.
    Marie I, Herve F, Kerleau JM, et al. Intravenous immunoglobulin-associated vena cava thrombosis. Thromb Haemost. 2006;96:849–51.CrossRefGoogle Scholar
  17. 17.
    Daniel GW, Menis M, Sridhar G, Scott D, Wallace AE, Ovanesov MV, et al. Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion. 2012;52:2113–21.CrossRefGoogle Scholar
  18. 18.
    Ammann EM, Jones MP, Link BK, et al. Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy. Blood. 2016;127:200–7.CrossRefGoogle Scholar
  19. 19.
    Ramírez E, Romero-Garrido JA, López-Granados E. Symptomatic thromboembolic events in patients treated with intravenous- immunoglobulins: results from a retrospective cohort study. Thromb Res. 2014;133:1045–51.CrossRefGoogle Scholar
  20. 20.
    Ammann EM, Haskins CB, Fillman KM, Ritter RL, Gu X, Winiecki SK, et al. Intravenous immune globulin and thromboembolic adverse events: a systematic review and meta-analysis of RCTs. Am J Hematol. 2016;91:594–605.CrossRefGoogle Scholar
  21. 21.
    Elkayam O, Paran D, Milo R, Davidovitz Y, Almoznino-Sarafian D, Zeltser D, et al. Acute myocardial infarction associated with high dose intravenous immunoglobulin infusion for autoimmune disorders. A study of four cases. Ann Rheum Dis. 2000;59:77–80.CrossRefGoogle Scholar
  22. 22.
    Zandman-Goddard G, Tweezer-Zaks N, Shalev T, et al. A novel overlap syndrome: systemic sclerosis associated with antiphospholipid syndrome--a case series. Ann N Y Acad Sci. 2007;1108:497–504.CrossRefGoogle Scholar
  23. 23.
    Levy Y, Sherer Y, Langevitz P, Lorber M, Rotman P, Fabrizzi F, et al. Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin--a preliminary report. Clin Rheumatol. 2000;19:207–11.CrossRefGoogle Scholar
  24. 24.
    Amital H, Rewald E, Levy Y, Bar-Dayan Y, Manthorpe R, Engervall P, et al. Fibrosis regression induced by intravenous gammaglobulin treatment. Ann Rheum Dis. 2003;62:175–7.CrossRefGoogle Scholar
  25. 25.
    Ihn H, Mimura Y, Yazawa N, Jinnin M, Asano Y, Yamane K, et al. High-dose intravenous immunoglobulin infusion as treatment for diffuse scleroderma. Br J Dermatol. 2007;156:1058–60.CrossRefGoogle Scholar
  26. 26.
    Hefer D, Jaloudi M. Thromboembolic events as an emerging adverse effect during high-dose intravenous immunoglobulin therapy in elderly patients: a case report and discussion of the relevant literature. Ann Hematol. 2004;83:661–5.CrossRefGoogle Scholar
  27. 27.
    Sztajzel R, Le Floch-Rohr J, Eggimann P. High-dose intravenous immunoglobulin treatment and cerebral vasospasm: a possible mechanism of ischemic encephalopathy? Eur Neurol. 1999;41:153–8.CrossRefGoogle Scholar
  28. 28.
    Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44:223–6.CrossRefGoogle Scholar
  29. 29.
    Baba R, Shibata A, Tsurusawa M. Single high-dose intravenous immunoglobulin therapy for Kawasaki disease increases plasma viscosity. Circ J. 2005;69:962–4.CrossRefGoogle Scholar
  30. 30.
    Alexandrescu DT, Dutcher JP, Hughes JT, Kaplan J, Wiernik PH. Strokes after intravenous gamma globulin: thrombotic phenomenon in patients with risk factors or just coincidence? Am J Hematol. 2005;78:216–20.CrossRefGoogle Scholar
  31. 31.
    Roemisch JR, Kaar W, Zoechling A, et al. Identification of activated FXI as the major biochemical root cause in IVIG batches associated with thromboembolic events. Analytical and experimental approaches resulting in corrective and preventive measures implemented into the Octagam® manufacturing process. WebmedCentral. 2011:2.Google Scholar
  32. 32.
    Wolberg, AS, Kon RH, Monroe DM et al. Coagulation factor FXI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol, 2000; 65: 30–34.Google Scholar
  33. 33.
    Etscheid M, Breitner-Ruddock SGA, et al. Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. Vox Sang. 2012;102:40–6.CrossRefGoogle Scholar
  34. 34.
    Park DH, Kang GB, Kang DE, et al. A new manufacturing process to remove thrombogenic factors (II, VII, IX, X, and XI) from intravenous immunoglobulin gamma preparations. Biologicals. 2017;45:1–8.CrossRefGoogle Scholar
  35. 35.
    Salge-Bartels U, Heiden M, Groß N, Seitz R. Significance of platelet and monocyte activation for therapeutic immunoglobulin-induced thromboembolism. Thromb Res. 2014;133:244–53.CrossRefGoogle Scholar
  36. 36.
    Yu CF, Hou JF, Shen LZ, Gao K, Rao CM, Yang PY, et al. Acute pulmonary embolism caused by highly aggregated intravenous immunoglobulin. Vox Sang. 2016;110:27–35.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Merav Lidar
    • 1
    • 2
  • Sewar Masarwa
    • 2
    • 3
  • Pnina Rotman
    • 2
    • 3
  • Or Carmi
    • 2
    • 3
  • Noa Rabinowicz
    • 2
    • 3
  • Yair Levy
    • 2
    • 3
    Email author
  1. 1.Rheumatology UnitSheba Medical CenterRamat GanIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Department of Medicine EMeir Medical CenterKfar-SabaIsrael

Personalised recommendations