Case Studies in Toxicology: Angioedema Post-tPA: Hemorrhage Is Not the Only Risk Factor
Case
A 49-year-old man with a history of hypertension, for which he was taking aspirin, carvedilol, hydralazine, and nifedipine, presented to the ED with complaints of left-sided weakness that started 3 hours before he came to the ED. Initial vital signs were: blood pressure, 158/90 mm Hg; heart rate, 74 beats/min; respiratory rate, 18 breaths/min; and temperature, 98°F. Oxygen saturation was 100% on room air, and a finger-stick glucose test was 106 mg/dL.
Physical examination revealed slowed speech with mild dysarthria, mild left facial droop, 2/5 strength in all muscle groups in the left upper and lower extremities, and decreased sensation to light touch on the left side. The patient also had left-sided sensory neglect and an abnormal gait, and dragged his left foot on the floor when walking. The rest of his examination was normal.
The stroke team was activated, and the patient was immediately transferred to the ED radiology department for imaging studies. A noncontrast head computed tomography (CT) was negative for any acute intracranial hemorrhage or cerebral edema. A CT angiogram (CTA) also was performed, which revealed atherosclerosis but no arterial occlusion. Based on these findings and the existing protocol, the patient received an intravenous (IV) bolus of tissue plasminogen activator (tPA). Approximately 17 minutes after tPA administration, the patient developed left-sided upper and lower lip swelling. There was no voice change, tongue swelling, or uvular deviation.
What is the differential diagnosis of swelling of the lip?
The differential diagnoses for lip swelling includes trauma, allergic reaction, and angioedema (hereditary, or angiotensin converting enzyme inhibitor [ACEI]-induced). The patient in this case denied any trauma to the lip, and no bleeding was noted from the lip; however, his entire left lip (upper and lower) was swollen. He was not taking any ACEIs or angiotensin-receptor blockers (ARBs). He also denied a family history of angioedema or any prior similar episodes. The patient further denied exposure to any new medications, foods, or other substances and had no respiratory distress, urticaria, or other findings consistent with an allergy.
What are the common adverse effects of tPA?
The only US Food and Drug-approved pharmacological treatment for ischemic stroke is tPA (also known as IV rtPA). Tissue plasminogen activator hydrolyzes plasminogen to plasmin, which exerts a fibrinolytic effect. Based on the ability of tPA to lyse thrombus, it is also a standard therapy for hemodynamically unstable patients with confirmed pulmonary embolism, as well as for patients with myocardial infarction in whom percutaneous intervention is contraindicated or unavailable. Despite the beneficial effects of tPA, significant adverse effects are associated with the drug. For example, thrombolysis may result in conversion of an ischemic stroke into a hemorrhagic event, resulting in generalized bleeding from mucosal surfaces.
The increase in plasmin may play a role in the development of angioedema by activating the kinin pathway, leading to the formation of the vasodilator bradykinin (Figure). Plasmin also activates the complement system and leads to the production of anaphylatoxins C3a, C4a, and C5a, which also cause mast cell degranulation and histamine release.1
When does post-tPA angioedema occur?
In the few published case reports available, tPA-induced angioedema was shown to typically occur in the stroke distribution (which was attributed to the left-sided swelling in this patient).2 Following tPA administration, the onset of angioedema reportedly varies from as early as 10 to 15 minutes from initiation until about 1 hour postinfusion. The short half-life of tPA (approximately 7 minutes)2 limits the outer- time window for the initial development of angioedema, but progression can continue well beyond this timeframe.
What is the treatment for tPA-induced angioedema?
The first priority of acute management of angioedema is discontinuation of the inciting substance, if possible—in this case, the tPA infusion.3 Assessment and maintenance of a patent airway are of utmost concern. Patients with posterior oropharyngeal effects or who are progressing should be admitted to an intensive care unit (ICU) for observation.4-6
