Angioedema is a swelling of the deep layers of the skin and subcutaneous (SC) tissue, submucous, and mucous membranes. It occurs secondary to localized vasomotor changes induced primarily by bradykinin and histamine leading to vasodilatation and increased vascular permeability. It may occur anywhere in the body, but it commonly involves the face, lips, oral cavity, and upper airways. In general, angioedema (particularly the orolingual subtype) is a rare but recognized side effect of thrombolytic treatment of acute stroke. It developed in 0.2%–5.1% of stroke patients during or after treatment with alteplase, whereas the incidence was much lower when alteplase was used for other indications, such as myocardial infarction (MI), 0.02%. Although angioedema was reported with alteplase and tenecteplase in the treatment of acute stroke, to the best of our knowledge, it has not been reported before with either of them following treatment of acute MI. However, there are few reports that confirmed the incidence of angioedema with streptokinase treatment in patients who presented with acute MI. In this case report, we present a patient who developed facial and oropharyngeal angioedema and localized urticarial rash shortly after treatment of acute MI with tenecteplase.
A 68-year-old male patient with a background history of type 2 diabetes mellitus, hypertension, and valvular heart disease presented to the emergency department at Benghazi Medical Center, Libya, with a history of central crushing chest pain started 6 h ago. The pain radiated to the shoulders, associated with nausea, vomiting, and profuse sweating, and not improved with sublingual glyceryl trinitrate given in the emergency department. His regular medications are metformin 850 mg po bd, glimepiride 4 mg po od, and amlodipine 5 mg po od. He has no previous history of known drug allergy. On initial assessment, his blood pressure (BP) was 220/100 mmHg and pulse rate was regular and 80 beats per min. He was conscious and oriented but in real discomfort because of pain. The cardiac examination revealed normal heart sounds with ejection systolic murmur Grade 3/6 best heard at the aortic area. His jugular venous pressure was not raised, and the chest examination was clear. The electrocardiogram (ECG) showed ST-segment elevation in leads V1 to V6 [Figure 1]. As the patient satisfied the clinical and ECG criteria for the diagnosis of ST-elevation MI (STEMI), and because percutaneous coronary intervention (PCI) was not available within 120 min after hospital admission, the decision was made to thrombolyse the patient. However, because the BP exceeded the limit of the thrombolytics, oral captopril 25 mg was given to lower the BP. After 90 min, the BP dropped to 160/70 mmHg, and at the time, 10,000 international units of tenecteplase was given as a rapid bolus. After 15 min, the patient complained of throat discomfort. 30 min later, he started complaining of difficulty in breathing and itching around the cannula site. On examination, there were few hives bilaterally on the upper extremities (five around the cannula site and two on the other limb), the throat looked hyperemic, the uvula was swollen and edematous with normal lips and tongue, and the eyes appeared congested with facial and periorbital swelling. Apart from mild tachycardia, the patient was vitally stable. There was no wheeze or stridor. The cannula was removed immediately and the patient was treated with antihistamine, 100 mg intravenous (IV) hydrocortisone, through a new IV cannula, and 0.5 mg subcutaneous adrenaline, and no airway management or intubation were required. The patient's condition has improved dramatically, the urticarial rash has disappeared after 30 min, and the swelling has resolved completely within 4 h. Coronary angiography was performed before hospital discharge which revealed 80% stenosis in the distal segment of the left circumflex artery.
The fibrinolytic drugs convert plasminogen to plasmin which activates kinin–kallikrein system. This leads to an increased level of bradykinin which is the main mediator responsible for the pathophysiology of angioedema. Moreover, plasmin directly activates the coagulation cascade which leads to the release of anaphylatoxin such as C3a which causes mast cell degranulation with increasing release of histamine to the circulation. This explains why Type I allergic and anaphylactoid reactions are recognized side effects of fibrinolytic drugs. In fact, bradykinin is degraded into inactive metabolites by angiotensin-converting enzyme. Therefore, concurrent use of angiotensin-converting enzyme inhibitors (ACEIs) and fibrinolytics increases the risk of angioedema. Although our patient was not on ACEIs before and it was only given before thrombolytics, our findings are consistent with Correia et al. and Khurana et al. who reported four patients developed angioedema after alteplase treatment of stroke preceded by giving ACEIs for the first time to lower the BP. Hurford et al. concluded that prior use of ACEIs was a significant independent predictor factor (odds ratio: 2.3) for the development of angioedema following treatment of stroke. The difference between the incidence of angioedema associated with thrombolytic treatment between ACEI- and non-ACEI-treated patients was statistically significant. Therefore, extra caution is required during thrombolytic treatment for patients who are already on ACEIs by providing more close observation and frequent examination of the face and oral cavity following the treatment. Having said that, alternative antihypertensive medications should be considered to lower BP before thrombolytic treatment to decrease the risk of development of postthrombolytic angioedema.
There are few factors that explain why orolingual angioedema is more commonly reported with alteplase as well as with tenecteplase after treatment of stroke than with other indications. Occlusion of territories was replaced with branches to make the meaning clearer. Total infarction of the insular cortex leads to autonomic dysregulation which causes vasomotor changes in the hemiparetic side of the body. This explains the unilateral distribution (which is contralateral to the infarction site) of the orolingual angioedema associated with thrombolytic treatment of stroke. The brain damage induced by ischemia increases the release of bradykinin to the circulation. The same result has been detected in a rat with ischemic heart, and there was a greater increase in bradykinin level when the rat was treated with ramipril. In one study, the incidence of orolingual angioedema following thrombolytic treatment of stroke increased from 1:50 to 1:10 in total insular infarction and from 1:50 to 1:6 with the combined use of thrombolytics and ACEIs. Interestingly, the unique feature in our case is the development of angioedema after tenecteplase treatment of MI which is the first reported case to the best of our knowledge. Furthermore, the distribution of angioedema in our patient which spared the lips and tongue is unique compared with the commonly reported orolingual distribution. It seems that the lack of autonomic dysregulation and the subsequent vasomotor changes in patients with MI could explain the lower reported incidence of angioedema with thrombolytic treatment of MI compared with stroke. The other possible explanation is the rate of using thrombolytic drugs in the treatment of MI has declined as PCI is the first-line treatment when available, whereas in stroke, thrombolytic drugs are still the mainstay of management.
Type I allergic reactions, ranging from urticarial skin rash to severe anaphylaxis, are more commonly reported with streptokinase than with alteplase, and they are rare with tenecteplase. Tenecteplase was associated with hypotension in a patient who presented with severe chest pain and was diagnosed with MI. The BP dropped following the administration of tenecteplase. It improved to the normal baseline following treatment with isotonic saline and vasopressor. In contrast, our patient was hemodynamically stable, and the urticarial skin rash responded dramatically to the anti-allergic treatment. In fact, allergic and anaphylactic reactions are rare with tenecteplase, and we believe that this is the first case report which documented allergic reactions following tenecteplase treatment of MI.
This case report highlights the importance for the physician to be aware that angioedema and allergic reaction can occur not only following thrombolytic treatment of stroke but also with MI. More precautious measures should be followed when treating patients who are on ACEIs with thrombolytics as this increases the risk of not only angioedema but also increases the risk of anaphylaxis.
The patient has provided written consent to present his clinical details in this.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Correia AS, Matias G, Calado S, Lourenço A, Viana-Baptista M. Orolingual angiodema associated with alteplase treatment of acute stroke: A reappraisal J Stroke Cerebrovasc Dis. 2015;24:31–40
2. Hurford R, Rezvani S, Kreimei M, Herbert A, Vail A, Parry-Jones AR, et al Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke J Neurol Neurosurg Psychiatry. 2015;86:520–3
3. Duangmee K, Boonmuang P, Santimaleeworagun W, Prasitdumrong H. Urticaria, angioedema, and type I hypersensitivity reactions associated with fibrinolytic agents Asian Pac J Allergy Immunol. 2019 ahead of print
4. Myslimi F, Caparros F, Dequatre-Ponchelle N, Moulin S, Gautier S, Girardie P, et al Orolingual angioedema during or after thrombolysis for cerebral ischemia Stroke. 2016;47:1825–30
5. Khurana D, Sharma M, Prabhakar S. Hemi orolingual angioedema Ann Indian Acad Neurol. 2008;11:199
6. Haley EC Jr, Lyden PD, Johnston KC, Hemmen TMTNK in Stroke Investigators. . A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke Stroke. 2005;36:607–12
7. Oliveira DC, Coelho OR, Paraschin K, Ferraroni NR, Zolner Rde L. Angioedema related to the use of streptokinase Arq Bras Cardiol. 2005;85:131–4
8. Cooper JP, Quarry DP, Beale DJ, Chappell AG. Life-threatening, localized angio-oedema associated with streptokinase Postgrad Med J. 1994;70:592–3
9. Hill MD, Barber PA, Takahashi J, Demchuk AM, Feasby TE, Buchan AM. Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke CMAJ. 2000;162:1281–4
10. Baxter GF, Ebrahim Z. Role of bradykinin in preconditioning and protection of the ischaemic myocardium Br J Pharmacol. 2002;135:843–54
11. Wang YX, Li YQ, Chen Y, Zhang CH, Dong Z, Wang Z, et al Analysis of related factors of orolingual angioedema after rt-PA intravenous thrombolytic therapy Eur Rev Med Pharmacol Sci. 2018;22:1478–84
12. Fugate JE, Kalimullah EA, Wijdicks EF. Angioedema after tPA: What neurointensivists should know Neurocrit Care. 2012;16:440–3
13. Gröger M, Lebesgue D, Pruneau D, Relton J, Kim SW, Nussberger J, et al Release of bradykinin and expression of kinin B2 receptors in the brain: Role for cell death and brain edema formation after focal cerebral ischemia in mice J Cereb Blood Flow Metab. 2005;25:978–89
14. Zarar A, Khan AA, Adil MM, Qureshi AI. Anaphylactic shock associated with intravenous thrombolytics Am J Emerg Med. 2014;32:113e3–5
15. Dunn C, Goa K. Tenecteplase Am J Cardiovasc Drugs. 2001;1:51–66
16. Foster-Goldman A, McCarthy D. Angioedema from recombinant TPA administration: Case report and pathophysiology review Am J Ther. 2013;20:691–3