American Journal of Therapeutics 24, e689–e692 (2017)

Immune Modulatory Therapy Causing Acute

Coronary Syndrome

Yashwant Agrawal, MD,1* Chris Jacob, DO,1 Nathan Demchuk, MS4,1

Richa Tikaria, MD,2 Shanti Virupannavar, MD,2 Bhavik Khajuria, MS4,1
and Jagadeesh K. Kalavakunta, MD3

Intravenous immunoglobulin (IVIG) is a therapeutic preparation of pooled polyspecific IgG used

effectively in immune thrombocytopenic purpura (ITP), autoimmune diseases, and inflammatory
diseases. We present a case of a 67-year-old male who presented with diffuse petechiae and was
diagnosed with immune thrombocytopenic purpura with platelet count less than 10,000 per milli-
liter. Treatment was initiated with IVIG. When the third dose of IVIG was being administered he
developed hypertensive urgency and non-ST segment elevation myocardial infarction. He was
deemed not to be a candidate for cardiac catheterization and was treated conservatively. IVIG can
cause major thrombotic adverse events such as deep vein thrombosis, myocardial infarction and
stroke, which are attributed to thrombosis and hyperviscocity. Decreasing the dosage of IVIG,
administration of anticoagulants are proposed treatments for such events. We propose that patients
receiving high-dose IVIG with previous coronary artery disease require meticulous cardiac moni-
toring. Further research is needed to determine the true adverse effects of high-dose IVIG and
prophylaxis regimens to decrease the risk.

Keywords: intravenous immunoglobulin, immune thrombocytopenic purpura, acute coronary

syndrome

CASE REPORT patient denied hemoptysis, hematuria, melena, and

A 67-year-old male with a history of coronary artery
disease, pulmonary embolism, traumatic splenectomy
due to sarcoidosis, hypothyroidism, and biopsy con-
firmed immune thrombocytopenic purpura (ITP) pre-
sented to the hospital with complaints of generalized
painless petechiae and blood blisters. On arrival, the
1
Department of Internal Medicine & Pediatrics, Western Michi-
gan University Homer Stryker M.D. School of Medicine, Kalama-
zoo, MI; 2Department of Internal Medicine, Michigan State
University, Lansing, MI; and 3Department of Cardiology, Borgess
Medical Center, Kalamazoo, MI.
The authors have no conflicts of interest to declare.
*Address for correspondence: 1521 Shaffer Road, Borgess Medical
Center, Kalamazoo, MI 49004. E-mail: yashwantagrawal.
agrawal@gmail.com
1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
hematochezia. Computed tomography of the head was
negative for acute hemorrhage. The patient was started
on intravenous steroids and subsequently transitioned
to oral prednisone at 100 mg/d. Paroxysmal nocturnal
hemoglobinuria and flow cytometry were negative.
Over the first 2 weeks of hospitalization, platelet
counts were less than 10,000 per milliliter. The patient
received multiple platelet transfusions and addition-
ally was started on 400 mg of danazol orally twice
daily. He received 2 doses of intravenous immunoglo-
gulin (IVIG), at 1 g$kg21$d21, on the second and third
days of admission, without any complications. The
third dose of IVIG at 1 g$kg21$d21, a week later, dur-
ing which he began having new onset hypertension,
with blood pressures as high as 190/131 mm Hg and
chest pain. He was normotensive before the event. The
chest pain was located in the anterior left and central
chest, with radiation to the back. Computed tomogra-
phy of abdomen and chest was obtained and
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e690
dissection was ruled out. Troponin levels increased
from less than 0.02 to 0.14–4.75 ng/mL. Creatine kinase
increased from 57 to 226 U/L. The patient was started
on nitroglycerin and nicardipine continuous infusions.
Electrocardiogram showed an incomplete right bundle
branch block, left ventricular hypertrophy, and antero-
lateral ST segment depression, which were new
changes from previous electrocardiogram obtained 1
week ago (Figures 1, 2). The patient was deemed not
to be a candidate for heart catheterization because of
thrombocytopenia. He was continued on home medica-
tions, including metoprolol, amlodipine, and lisinopril.
Aspirin was not initiated because of thrombocytopenia.
The patient was started on rituximab weekly for 4
doses. The patient was discharged 1 week after the car-
diac event and platelets were 25,000 per milliliter. The
patient denied any further episodes of chest pain after
the cardiac event.
DISCUSSION
IVIG is an amalgamation of immunoglobulins from
thousands of donors. The mechanism of action of IVIG
is multifactorial and consists of multiple reactions that
act together to perform immunomodulation, especially
at high doses.1 This function of IVIG enables its use in
autoimmune and inflammatory conditions.2 This con-
trasts with administration in immunocompromised
FIGURE 1. Electrocardiogram performed 1 week before IVIG infusion, in the absence of symptoms.
American Journal of Therapeutics (2017) 24(6)
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Agrawal et al
patients which requires smaller dosing given over lon-
ger periods of time.3
IVIG is a therapeutic preparation of pooled polyspe-
cific IgG obtained from the plasma of a large number
of healthy individuals. In 1981, patients with Wiskott–
Aldrich syndrome receiving high-dose IVIG showed
an increase in their platelet count. IVIG has been since
used effectively in ITP, autoimmune diseases, and
other systemic inflammatory diseases.1,4,5
There are various adverse effects of IVIG infusion
which include fever, rash, chills, hypotension, hypo-
thermia, irritability, vomiting, chest pain, and throm-
botic events. Most of these adverse reactions are seen
within the first few hours of infusion. The half-life of
IVIG is 18–32 days; hence adverse effects may appear
or persist several days after infusion administration.6
Thrombotic complications such as venous thromboem-
bolism, stroke, and myocardial infarctions have also
been reported in 0.6%–13% of cases.7
Thrombotic complications due to IVIG administra-
tion are attributed to thrombocytosis, platelet aggrega-
tion promoting hyperviscosity, procoagulant activity
in the presence of activated factor XI or antiphospho-
lipid antibodies, alteration in cytokine profile with
localized synthesis of vasoactive cytokines leading to
thrombosis and arterial vasospasm.8–10
A case report of myocardial infarction with IVIG
infusion was reported in a young patient with risk
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Rare Cause of Acute Coronary Syndrome
FIGURE 2. Electrocardiogram performed immediately after starting IVIG infusion, whereas patient was experiencing
chest discomfort.
factors which included hypertension, hyperlipidemia,
a previous cardiac event, and the presence of antiphos-
phospholipid antibodies.11 In our patient, cardiac risk
factors were present, including a history of coronary
artery disease and smoking.
Another question raised from our case is whether
IVIG dosing is related to incidence of cardiac events.
Despite known cardiac risk factors, our patient received
high dosing of IVIG of 1 g$kg21$d21 for 2 days. It has
been reported previously that there may indeed be an
association between rate of infusion and risk for myo-
cardial infarction.8,12 Therefore, investigators in these
cases and investigations into side effect profiles8,12,13
suggested using a slow scheme of IVIG administration,
of 2 g/kg of body weight over 5 days.11 Anticoagula-
tion may play a role in limiting the adverse thrombotic
events seen by high-dose administration.10
Therefore, it is important for us to proceed with
extreme caution in use of this agent. We should, at
the very least, consider lower dosing of IVIG especially
in patients with cardiac risk factors.
CONCLUSIONS
Although there is still little concrete evidence linking
high-dose administration of IVIG and coronary events,
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e691
it seems as though there is a plethora of anecdotal evi-
dence to suggest further investigation of the correlation
between them. Although the background and details
surrounding the reported cases remains highly variable,
it seems as though cardiac monitoring could be benefi-
cial. It can be initiated on a precautionary basis for pa-
tients who are considered at risk especially who already
have coronary disease. It is unclear at this time if there is
any benefit of cardiovascular screening in preparation
for IVIG administration. If cardiac disease is found, an
added prophylactic dose of anticoagulation may prove
to be beneficial. Further research is needed to determine
the true adverse effects of administering high-dose IVIG
and prophylaxis regimens to decrease the risk.
REFERENCES
1. Vani J, Elluru S, Negi V-S, et al. Role of natural antibod-
ies in immune homeostasis: IVIg perspective. Autoimmun
Rev. 2008;7:440–444.
2. Kamali S, Cefle A, Sayarlioglu M, et al. Experience with
monthly, high-dose, intravenous immunoglobulin ther-
apy in patients with different connective tissue diseases.
Rheumatol Int. 2005;25:211–214.
3. Gold R, Stangel M, Dalakas MC. Drug insight: the use of
intravenous immunoglobulin in neurology—therapeutic
American Journal of Therapeutics (2017) 24(6)
e692
considerations and practical issues. Nat Clin Pract Neurol.
2007;3:36–44.
4. Imbach P, Barandun S, d’Apuzzo V, et al. High-dose
intravenous gammaglobulin for idiopathic thrombocyto-
penic purpura in childhood. Lancet. 1981;1:1228–1231.
5. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, et al.
Monoclonal antibody and intravenous immunoglobulin
therapy for rheumatic diseases: rationale and mecha-
nisms of action. Nat Clin Pract Rheumatol. 2007;3:262–272.
6. Marie I, Maurey G, Herve F, et al. Intravenous
immunoglobulin-associated arterial and venous throm-
bosis; report of a series and review of the literature. Br
J Dermatol. 2006;155:714–721.
7. Darnige L, Lillo-Le Louet A. Treatments with immuno-
globulin and thrombotic adverse events. Rev Med Interne.
2014;35:39–44.
8. Duhem C, Dicato MA, Ries F. Side-effects of intravenous
immune globulins. Clin Exp Immunol. 1994;97(Suppl 1):
79–83.
American Journal of Therapeutics (2017) 24(6)
Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Agrawal et al
9. Palabrica FR, Kwong SL, Padua FR. Adverse events of
intravenous immunoglobulin infusions: a ten-year retro-
spective study. Asia Pac Allergy. 2013;3:249–256.
10. Huang L, Kanellis J, Mulley W. Slow and steady. Reduc-
ing thrombotic events in renal transplant recipients trea-
ted with IVIG for antibody-mediated rejection.
Nephrology (Carlton). 2011;16:239–242.
11. Tan S, Tambar S, Chohan S, et al. Acute myocardial
infarction after treatment of thrombocytopenia in
a young woman with systemic lupus erythematous. J Clin
Rheumatol. 2008;14:350–352.
12. Elkayam O, Paran D, Milo R, et al. Acute myocardial
infarction associated with high dose intravenous immu-
noglobulin infusion for autoimmune disorders. A study
of four cases. Ann Rheum Dis. 2000;59:77–80.
13. Fagbemi AO, Torrente F, Hilson AJW, et al. Massive
gastrointestinal haemorrhage in isolated intestinal
Henoch-Schonlein purpura with response to intravenous
immunoglobulin infusion. Eur J Pediatr. 2007;166:915–919.
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