Severe Orolingual and Laryngeal Angioedema after Thrombolysis with Alteplase: Angiotensin II Receptor Blockers Should Not Be Underestimated

Introduction: Alteplase is a recombinant tissue plasminogen activator (rt-PA), used for intravenous thrombolysis in ischaemic strokes. Orolingual angioedema is a rare but potentially lifethreatening complication of alteplase. Concomitant treatment with angiotensin-converting enzyme (ACE) inhibitors has been identified as a primary risk factor. Angiotensin II receptor blockers (ARBs) have been rarely related to angioedema. Case Presentation: A 72-year-old woman with a personal history of type 1 diabetes mellitus, dyslipidemia, stage 3 CKD, and arterial hypertension, in treatment with valsartan/amlodipine, atorvastatin, acetylsalicylic acid, and metformin, visited the emergency room with a diagnosis of an ischemic stroke, affecting the right middle cerebral artery territory. Intravenous alteplase (Actilyse™) was administered for thrombolysis. Twenty minutes later, the patient developed progressive lingual angioedema. She was initially treated with methylprednisolone, hydrocortisone, and intramuscular adrenaline. Her angioedema worsened, leading to an acute hypoxemic respiratory failure. A C1 esterase inhibitor (Berinert™) was administered with no improvement. Sedation and orotracheal intubation were finally necessary. No other symptoms were associated. Due to the suspicion of an interaction between alteplase and valsartan, the ARB was discontinued. No history of previous episodes of angioedema was mentioned. After 3 days, extubation failed due to respiratory distress and severe stridor, probably secondary to laryngeal edema. Successful extubation was achieved 7 days later, and the patient was discharged from the ICU after 9 days of admission. She was later referred, and an allergy workup was carried out. A blood analysis with a basal tryptase, an ACE, a total immunoglobulin E (IgE) profile, and complement proteins (C3, C4, C1q, C1 inhibitor) showed normal serum levels. Skin prick and intradermal tests with alteplase were performed, which showed negative results. The increased production of bradykinin due to alteplase and the decreased degradation of bradykinin due to ACE inhibition explained the development of angioedema. ARBs, such as valsartan, have a different pathway. They directly block the angiotensin II receptors (AT1 receptors), preventing angiotensin II (ATII) from exerting its vasoconstrictive effect. By blocking the effect of ATII, the negative feedback that normally regulates bradykinin is deactivated, potentially leading to higher concentrations of bradykinin. The main suspicion in our patient was a solitary rt-PA-induced bradykininmediated angioedema, secondary to an increase of bradykinin promoted by alteplase and likely amplified by valsartan. Conclusion: We have presented the case of a patient with severe and life-threatening nonimmunologic angioedema secondary to a combination of IV alteplase and valsartan. We emphasize the importance of being aware of this potentially severe complication in patients with ischaemic stroke treated with an rt-PA and in patients on treatment with ACEi and ARB. Alteplase and tenecteplase are recombinant tPA, with a potential risk of producing angioedema. There are no solid treatment recommendations for angioedema caused by rt-PA. Still, an early treatment with icatibant seems to be a consistent option in a bradykinin-mediated angioedema independent of the pathway responsible for bradykinin formation. Specific and revised protocols to manage this solitary angioedema based on severity are crucial and urgent. Finding an alternative IV thrombolytic treatment to improve the patients’ safety should become an objective of research.