14 September 2024: Articles
Life-Threatening tPA-Associated Angioedema: A Rare Case Report and Critical Review
Unusual or unexpected effect of treatment, Diagnostic / therapeutic accidents, Rare disease, Adverse events of drug therapy, Educational Purpose (only if useful for a systematic review or synthesis)
Mohamad El Labban 1AEF*, Roba El Zibaoui2EF, Alpha C. Amadi3EF, Tashfia Zareen4EF, Syed Anjum Khan5ADEDOI: 10.12659/AJCR.944221
Am J Case Rep 2024; 25:e944221
Abstract
BACKGROUND: Angioedema is characterized by localized self-limiting edema of the deep dermis, subcutaneous, and submucosal tissues. Acute episodes often involve the skin of the face, lips, tongue, limbs, and genitals, as well as internal areas of the body and respiratory and gastrointestinal mucosa, which could be life-threatening. Histamine and bradykinin are the most recognized vasoactive mediators in the pathophysiology of angioedema. Tissue plasminogen activator (tPA) is a fibrinolytic that is commonly used for the treatment of cerebrovascular accidents. Angioedema is a rare adverse effect of tPA, with an estimated incidence of 0.02% in patients with myocardial infarction or pulmonary embolism and 0.2% to 5.1% in patients with stroke. We report a unique case of tPA-associated angioedema with 24-h management.
CASE REPORT: A 79-year-old male patient presented to the Emergency Department with acute onset right-sided weakness, right-sided facial droop, and speech difficulties. Following the initial evaluation, it was determined that he was a candidate for receiving tPA therapy. On arrival at the Intensive Care Unit, he was noted to have right upper and then lower lip swelling. The patient was asymptomatic and did not show any signs concerning airway compromise. Treatment included systemic corticosteroids and antihistamines. The progression of the angioedema was further described with sequential images. The angioedema was completely resolved with treatment.
CONCLUSIONS: Angioedema is a rare but potentially life-threatening adverse effect of tPA. Although it generally has a mild self-limiting course, it can cause life-threatening airway compromise.
Keywords: ischemic stroke, Tissue Plasminogen Activator, Acquired Angioedema
Introduction
Angioedema is characterized by localized self-limiting edema of the deep dermis and subcutaneous and submucosal tissues [1]. It occurs due to a temporary increase in vascular permeability caused by the release of vasoactive mediators [1]. Histamine and bradykinin are the most recognized vasoactive mediators in the pathophysiology of angioedema. Acute episodes often involve the skin of the face, lips, tongue, limbs, and genitals, as well as internal areas of the body and respiratory and gastrointestinal mucosa, which could result in life-threatening angioedema [1]. Angioedema can be classified as mast cell-mediated or bradykinin-mediated [2]. Mast cell-mediated angioedema includes causes related to food, drugs (non-steroidal anti-inflammatory drugs), latex, exercise, or allergens. It is typically associated with pruritus or urticaria. Bradykinin-mediated angioedema includes causes related to angiotensin converting enzyme inhibitor (ACEi), dipeptidyl peptidase 4 inhibitors such as sitagliptin, hereditary and acquired C1 inhibitor deficiency, or hereditary angioedema with normal C1 inhibitor [2]. Tissue plasminogen activator (tPA) is a fibrinolytic that is commonly used for the treatment of cerebrovascular accidents. The most common complication of tPA use is intracerebral hemorrhage, among other types of bleeding, but angioedema is uncommon. The reported incidence of tPA-induced angioedema ranges from 1% to 5% [3]. We report a rare case of acquired angioedema associated with tPA administration.
Case Report
A 79-year-old male patient presented to the Emergency Department with concerns of acute-onset right-sided weakness, right-sided facial droop, and speech difficulties. He first noted right-hand weakness and loss of sensation on the right side, followed by difficulty with word finding. These symptoms started abruptly, precisely 17 min prior to presentation (Figure 1). The review of systems was otherwise negative. His past medical history was significant for primary hypertension, with treatment of lisinopril, and cigarette smoking (30-pack-year smoking history). The vital signs on presentation were as follows: temperature 36.8 °C, heart rate 61 beats/min, blood pressure 154/113 mmHg, respiratory rate 23 breaths/min, and oxygen saturation 93% on room air. The initial National Institutes of Health Stroke Scale (NIHSS) score was 6, with 1 point for each of the following elements: performs 1 out of the 2 tasks of “blink eyes” and “squeeze hands”, partial paralysis (lower face), left leg motor drift without hitting the bed, right leg motor drift without hitting the bed, right arm motor drift without hitting the bed, and mild-moderate dysarthria. Initial evaluation included computed tomography (CT) head-neck angiogram with contrast that did not show evidence of intracranial bleeding or acute abnormality of the head and neck arterial system. The patient received a tenecteplase injection of 18 mg (0.25 mg/kg) 55 min after arrival at the Emergency Department, 72 min after the onset of symptoms. The patient was then transferred to the Intensive Care Unit (ICU) for monitoring after thrombolytic therapy. Upon arrival to the ICU (148 min after the tenecteplase), he was noted to have right upper lip swelling (Figure 2A), which then progressed to involve the right lower lip. The patient did not notice the swelling, as he was asymptomatic. It was brought to his attention by the intensivist. The patient showed no signs of airway obstruction, with oxygen saturation levels above 90% on room air, no difficulty swallowing oral secretions, no signs of aspiration, and no changes in voice or breathing. The patient was treated with 40 mg intravenous methylprednisolone every 6 h for 4 doses and famotidine 20 mg every 12 h for 4 doses. The angioedema started improving after 1 dose of steroids and famotidine (Figure 2B). The NIHSS score the following day was 5, with improvement in dysarthria. Magnetic resonance imaging of the brain without contrast showed a cortical embolic-appearing left MCA infarct, along with some mild asymptomatic hemorrhagic transformation. The angioedema entirely resolved almost 24 h after the first dose of steroids (Figure 2C). The patient was discharged from the hospital on day 5. During his follow-up clinic visit, he reported no recurrence of any swelling and an improvement in his right-side weakness.
Discussion
PATHOPHYSIOLOGY:
tPA is an enzyme that acts as a serum protease. Its function involves breaking down plasminogen into plasmin, which induces the desired fibrinolytic effect following an ischemic event. tPa-associated angioedema is thought to be stimulated via the activation of the kinin pathway and the complement cascade [9]. The kinin pathway is activated by the conversion of factor XII into factor XIIa, which leads to an elevation of bradykinin production [9]. Bradykinin is a potent vasodilator and pro-inflammatory peptide that stimulates vascular bradykinin B2 receptors, contributing to the occurrence of angioedema by increasing vascular permeability. Another hypothesis is that tPA and plasmin directly cleave C1 and C2, initiating the complement cascade [10]. This causes the release of anaphylatoxins such as C3a, C4a, and C5a. These major anaphylatoxins cause vasodilation and increase vascular permeability by inducing the release of basophils and degranulation of mast cells. Furthermore, brain ischemia can independently lead to autonomic dysfunction, the generation of bradykinin, and alterations in vasomotor activity. These factors collectively contribute to an increased vulnerability to angioedema [11].
EPIDEMIOLOGY:
In 2018, Sczepanski et al reported that out of 147 patients, 4 developed severe angioedema due to tPA, resulting in an incidence of 2.72%, out of which 1 patient died. Hill et al reported a study that included 1135 patients, out of which 1.3% (95% CI 0.7%–2.2%) developed angioedema [12].
CLINICAL PRESENTATION:
Angioedema has most commonly been reported to occur acutely while the tPA is still infusing, yet it can also be delayed up to 24 h after tPA administration [9]. The precise onset of our patient’s symptoms following tPA administration remains unclear. Nonetheless, it was established that 148 min after the administration, the patient exhibited lip swelling, which aligns with the referenced time frame. Our conviction in the association was strengthened by this unequivocal temporal correlation between the drug’s administration and the onset of symptoms. The resulting angioedema typically occurs on the contralateral side of the ischemic hemisphere and is often limited to the orolingual area [13]. Mucosal tissue is most affected, although the edema can extend to dermal or subcutaneous tissues. In severe cases, laryngeal involvement can lead to airway collapse and severe respiratory distress, requiring intubation [14]. Case reports of angioedema remain quite scarce, possibly due to underreporting or failure to detect symptoms in the acute phase of tPA administration. Nevertheless, current literature has found that the incidence of tPA-induced angioedema is approximately 5 times greater in patients with a large stroke involving frontal, insular, and peri-insular brain regions [15]. The association of these regions to angioedema is partially thought to be due to proximity to the facial cortex but has been mainly linked to sympathetic hyperactivity and peripheral vasoconstriction [16]. The most widely documented risk factor with a 7-fold odd ratio for developing angioedema post-tPA therapy is using ACEi. Still, a clear causative etiology has not yet been established [17]. Several large-scale studies have reported an increased incidence of angioedema in patients treated with ACEi, due to their inhibition of the kinase inhibitor pathway [18–21]. A study on 120 patients treated with tPA for ischemic stroke found the incidence of angioedema to be 5% greater in patients taking ACEi when compared with the 1% incidence of patients not on medication or using other forms of antihypertensives [17,20]. As a result of these findings, treatment with ACEi has been identified as an independent predictor of angioedema development [15]. Further support for this theory comes from a prospective cohort study of 923 patients who received tPA for ischemic stroke. A higher occurrence of angioedema was found in patients who were concomitantly on ACEi, with an odds ratio of 4 even after stratification of data results [15]. Other less commonly reported risk factors for the development of angioedema include arterial hypertension, diabetes mellitus, and hypercholesterolemia. Yet, the strength of such associations remains unclear, as most of these patients are often on ACEi therapy [15].
MANAGEMENT AND OUTCOMES:
Currently, there are no recommended treatment guidelines for tPA-induced angioedema in patients with ischemic stroke [16]. In most cases, supportive therapy through airway protection, discontinuing the tPA infusion, and withholding ACEi is advised. Medical management is often conservative and includes a combination of steroids, antihistamines, and epinephrine. However, bradykinin-induced angioedema cannot always be treated by the aforementioned drugs since its development is based on different biochemical pathways [22]. Therefore, escalation of therapy with complement (C1)-esterase inhibitors and bradykinin inhibitors in cases of refractory angioedema may be necessary. In addition, emergent intubation may be required in cases of severe airway compromise due to the rapid progression and involvement of the larynx and hypopharynx [16]. In a recent report of 489 patients who received tPA for ischemic stroke, 2 patients with no known allergies or hereditary angioedema developed bradykinin-induced angioedema refractory to classic therapy [23]. However, both patients were concomitantly treated with ACEi [23]. One patient required intubation, while the symptoms of the second patient resolved with the use of (C1)-esterase inhibitors [23]. Studies comparing the 3-month outcomes of stroke patients treated with tPA who developed angioedema with those who did not found no significant difference in regards to patient functional scores, the evolution of systolic blood pressure, or overall mortality [15].
Our report has some limitations. First, we could not accurately specify when the angioedema started after tPA administration. Since the patient was completely asymptomatic, the swelling was noted when the patient arrived to the ICU for post-tPA monitoring. We make up for this limitation by otherwise providing a detailed timeline of events (Figure 1). Second, although ACEi use is a strong risk factor for development of tPA-induced angioedema, we cannot conclusively rule it out as the sole contributor in this case.
Conclusions
This report of a 79-year-old patient with tPA-associated angioedema offers several valuable lessons. First, the use of tPA in patients with ischemic stroke has been increasing over the last decade; therefore, healthcare workers must be aware of all the possible complications associated with it. Second, despite being uncommon, angioedema has been established as a possible life-threatening adverse effect of tPA. Third, the use of ACE inhibitors is the most important independent risk factor for the development of tPA-associated angioedema. Fourth, tPA-induced angioedema commonly has a mild self-limiting course; however, life-threatening airway compromise can happen.
References:
1.. Cicardi M, Aberer W, Banerji A, Classification, diagnosis, and approach to treatment for angioedema: Consensus report from the Hereditary Angioedema International Working Group: Allergy, 2014; 69(5); 602-16
2.. Hahn J, Hoffmann TK, Bock B, Angioedema: Dtsch Arztebl Int, 2017; 114(29–30); 489-96
3.. Shirazy M, Chaari A, Hakim K, A case of oropharyngeal angioedema following intravenous recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy.: Drug Saf Case Rep., 2019; 6(1); 10
4.. Tsivgoulis G, Katsanos AH, Sandset EC, Thrombolysis for acute ischaemic stroke: Current status and future perspectives.: Lancet Neurol, 2023; 22(5); 418-29
5.. Jilani TN, Siddiqui AH, Tissue plasminogen activator.: StatPearls [Internet]., 2024, Treasure Island (FL), StatPearls Publishing [Updated 2023 Feb 20].
6.. Miller DJ, Simpson JR, Silver B, Safety of thrombolysis in acute ischemic stroke: A review of complications, risk factors, and newer technologies: Neurohospitalist, 2011; 1(3); 138-47
7.. Kim C, Hladik A, Angioedema aecondary to tPA use in acute ischemic stroke patient with hypertension: A case report: Clin Pract Cases Emerg Med, 2021; 5(2); 159-62
8.. Chaucer B, Whelan D, Veys C, Upadhyaya M, Angioedema secondary to IV tissue plasminogen activator administration for treatment of acute ischemic stroke.: Case Rep Crit Care., 2018; 2018; 3257215
9.. Sczepanski M, Bozyk P, Institutional incidence of severe tPA-induced angioedema in ischemic cerebral vascular accidents.: Crit Care Res Pract., 2018; 2018; 9360918
10.. Hill MD, Barber PA, Takahashi J, Anaphylactoid reactions and angioedema during alteplase treatment of acute ischemic stroke.: CMAJ, 2000; 162(9); 1281-84
11.. Groger M, Lebesgue D, Pruneau D, 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(8); 978-89
12.. Hill MD, Buchan AM, Thrombolysis for acute ischemic stroke: Results of the Canadian Alteplase for Stroke Effectiveness Study: CMAJ, 2005; 172(10); 1307-12
13.. Krishnaiah B, McLaughlin D, Lee J, Good D, Double trouble: tPA-induced angioedema.: Postgrad Med J Feb, 2017; 93(1096); 103-4
14.. Rathbun KM, Angioedema after thrombolysis with tissue plasminogen activator: An airway emergency: Oxf Med Case Reports, 2019; 2019(1) omy112
15.. Myslimi F, Caparros F, Dequatre-Ponchelle N, Orolingual angioedema during or after thrombolysis for cerebral ischemia.: Stroke, 2016; 47(7); 1825-30
16.. Pahs L, Droege C, Kneale H, Pancioli A, A novel approach to the treatment of orolingual angioedema after tissue plasminogen activator administration: Ann Emerg Med, 2016; 68(3); 345-48
17.. Burd M, McPheeters C, Scherrer LA, Orolingual angioedema after tissue plasminogen activator administration in patients taking angiotensin-converting enzyme inhibitors: Adv Emerg Nurs J, 2019; 41(3); 204-14
18.. Hurford R, Rezvani S, Kreimei M, Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke: J Neurol Neurosurg Psychiatry, 2015; 86(5); 520-23
19.. Rudolf J, Grond M, Schmulling S, Orolingual angioneurotic edema following therapy of acute ischemic stroke with alteplase: Neurology, 2000; 55(4); 599-600
20.. Engelter ST, Fluri F, Buitrago-Tellez C, Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke: J Neurol, 2005; 252(10); 1167-70
21.. Hill MD, Lye T, Moss H, Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke: Neurology, 2003; 60(9); 1525-27
22.. Hebert J, Boursiquot JN, Chapdelaine H, Bradykinin-induced angioedema in the emergency department: Int J Emerg Med, 2022; 15(1); 15
23.. Špatenková V, Šímová D, Beneš Rd V, Jedlička J, [Orolingual bradykinin angioedema after tissue plasminogen activator in acute stroke-treatment with or without C1-esterase inhibitor.]: Česká a Slovenská Neurologie a Neurochirurgie., 2018; 81(4); 478-80 [in Czech]
In Press
Case report
Iron-Related Pseudomelanosis Duodeni in a Patient with Gastrointestinal Bleeding: A Case ReportAm J Case Rep In Press; DOI: 10.12659/AJCR.945238
Case report
Aortic Homografts in Surgical Management of Prosthetic Valve Endocarditis: A Case Series from GreeceAm J Case Rep In Press; DOI: 10.12659/AJCR.945030
Case report
Retrograde Colonic Intussusception After Colonoscopy without Organic Pathology: A Case ReportAm J Case Rep In Press; DOI: 10.12659/AJCR.945423
Case report
Dual Hepatic Injury from Refeeding Syndrome and Starvation in a Malnourished Woman After Bariatric Surgery:...Am J Case Rep In Press; DOI: 10.12659/AJCR.944088
Most Viewed Current Articles
21 Jun 2024 : Case report 58,089
Intracranial Parasitic Fetus in a Living Infant: A Case Study with Surgical Intervention and Prognosis Anal...DOI :10.12659/AJCR.944371
Am J Case Rep 2024; 25:e944371
07 Mar 2024 : Case report 42,685
Neurocysticercosis Presenting as Migraine in the United StatesDOI :10.12659/AJCR.943133
Am J Case Rep 2024; 25:e943133
10 Jan 2022 : Case report 32,469
A Report on the First 7 Sequential Patients Treated Within the C-Reactive Protein Apheresis in COVID (CACOV...DOI :10.12659/AJCR.935263
Am J Case Rep 2022; 23:e935263
23 Feb 2022 : Case report 19,983
Penile Necrosis Associated with Local Intravenous Injection of CocaineDOI :10.12659/AJCR.935250
Am J Case Rep 2022; 23:e935250