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A Case of Pulmonary Hemorrhage Due to Drug-Induced Pneumonitis Secondary to Ticagrelor TherapyTicagrelor-Induced Pulmonary Hemorrhage FREE TO VIEW

Timothy J. Whitmore, MBBS (Hons); John P. O’Shea, MBBS; Diana Starac, MBBS; Mark G. Edwards, MBBS; Grant W. Waterer, MBBS
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From the Respiratory Medicine Department (Dr Whitmore), and Department of Cardiothoracic Surgery (Dr Edwards), Royal Perth Hospital, Perth; the Department of Cardiovascular Medicine (Dr O’Shea), Fremantle Hospital, Fremantle; Western Diagnostic Pathology (Dr Starac), Myaree; and the School of Medicine & Pharmacology (Dr Waterer), University of Western Australia, Perth, WA, Australia.

Correspondence to: Timothy J. Whitmore, MBBS (Hons), Respiratory Medicine, Royal Perth Hospital, GPO Box X2213, Perth, WA, Australia 6001; e-mail: timothy.whitmore@health.wa.gov.au


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(3):639-641. doi:10.1378/chest.13-1502
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We report a case of significant pulmonary hemorrhage developing shortly after commencing ticagrelor and aspirin therapy and requiring coronary artery bypass grafting to safely cease the antiplatelet therapy. Lung biopsy findings were consistent with drug-induced lung injury. Clinicians should be aware of this significant adverse event with this drug class.

Figures in this Article

Ticagrelor is a reversibly binding platelet P2Y12 receptor antagonist used clinically in the setting of acute coronary syndrome and percutaneous coronary artery stenting. Here, we report a case of significant pulmonary hemorrhage due to drug-induced pneumonitis with ticagrelor and aspirin.

A 56-year-old man was admitted following his second presentation with 100 to 200 mL of hemoptysis over a 48-h period. Ticagrelor 90 mg bid and aspirin 100 mg daily had been commenced 10 days previously following stenting of his proximal segment of the dominant left circumflex coronary artery. The patient had no shortness of breath, chest pain, fever, or infection symptoms. He had no other bleeding history. His other medications were diltiazem, rosuvastatin, fluticasone, and salmeterol inhaler. He was an ex-smoker but had no other significant exposure history.

On examination, the patient was afebrile and resting comfortably. His pulse rate was 80 beats/min; BP, 132/91 mm Hg; respiratory rate, 24 breaths/min; and oxygen saturation level, 90% on room air. He had coarse crackles bilaterally throughout his lower lung fields. He had no mucosal ulceration, conjunctival pallor, or melena on rectal examination.

The following laboratory findings were all normal: hemoglobin level, 137 g/L; WBC count, 9.07 × 109/L; platelet count, 392 × 109/L; C-reactive protein level < 1.0 mg/L; coagulation indicators (international normalized ratio, 1.1; activated partial thromboplastin time, 27.8 s; fibrinogen level, 4.3 g/L); and indicators of renal and hepatic function. Urinalysis showed no blood or protein, and vasculitis screen results (levels of antineutrophil cytoplasmic antibody, antinuclear antibody, antiglomerular basement membrane antibodies, and complement) were normal. CT imaging of the chest demonstrated bilateral ground-glass opacities consistent with peribronchovascular pulmonary hemorrhages (Fig 1). Diffusing capacity was elevated, consistent with fresh hemorrhage.

Figure Jump LinkFigure 1. CT image of the chest with extensive peribronchovascular opacities extending through the bilateral lower lobes.Grahic Jump Location

Ticagrelor therapy was temporarily stopped, and the patient proceeded to bronchoscopy 1 day after admission, which demonstrated edematous airways and frank blood within both lower lobes. Transbronchial biopsy was not undertaken secondary to ongoing bleeding. BAL demonstrated frank blood with no pathogens identified.

Hemoptysis recurred with recommencement of ticagrelor. The patient’s treatment was changed to clopidogrel given the high risk of in-stent thrombosis,1 but he had ongoing hemoptysis. Twenty-five days after initially starting ticagrelor, he proceeded to undergo open lung biopsy and elective coronary artery bypass grafting (saphenous vein to obtuse marginal artery) to allow safe cessation of clopidogrel.

A typical histologic section is shown in Figure 2, with wedge-shaped lesions in the lung tissue with intervening areas of preserved architecture. Within the areas of lung injury, the alveolar septal walls show variable fibrous thickening and contain a very mild, chronic inflammatory-cell infiltrate. There was no tissue eosinophilia, and dense collections of intraalveolar macrophages were not seen. There was both early and established fibrosis, as well as patchy bronchiolization of the airways (Fig 3). While there was some congestion of the vasculature, no intraalveolar hemorrhage was seen, and there was no evidence of vasculitis. Although nonspecific, in the clinical context, the pathology was most in keeping with drug-induced lung injury.

Figure Jump LinkFigure 2. Low-power view showing an approximately wedge-shaped lesion in the lung, reminiscent of a usual interstitial pneumonia pattern of lung injury. The pleural surface is on the right. On either side of the lesion, the lung parenchyma is relatively spared (hematoxylin and eosin, original magnification × 16).Grahic Jump Location
Figure Jump LinkFigure 3. At higher power, the same area shows heterogeneous alveolar septal fibrosis, which is more established toward the center of the image. However, there is also early fibrosis, as evidenced by formation of fibroblastic foci, indicated by the star. The double arrow shows bronchiolization of airways, commonly seen secondary to lung injury (hematoxylin and eosin, original magnification × 50).Grahic Jump Location

Following this, the patient’s hemoptysis ceased, and he was discharged on aspirin monotherapy. Six weeks postoperatively, he had experienced no further hemoptysis, and imaging of his chest was repeated and showed marked improvement.

Ticagrelor, a P2Y12 receptor antagonist, acts by binding to adenosine diphosphate noncompetitively, inhibiting the prothrombotic effects of platelet adenosine diphosphate binding.2 It has more rapid onset and more pronounced inhibition than clopidogrel and is associated with reduced operative bleeding risk, due to more rapid loss of platelet inhibition following cessation.3

Although dyspnea is often reported as a side effect of ticagrelor therapy, to our knowledge pulmonary hemorrhage has not previously been reported in the literature.4,5 Other reported adverse events include elevations in serum creatinine level, minor bleeding, transient bradycardia, and dyspnea.5,6 Following the DISPERSE (Dose Confirmation Study Assessing Antiplatelet Effects of AZD6140 vs Clopidogrel in Non-ST-segment Elevation Myocardial Infarction), DISPERSE-II, and PLATO (Study of Platelet Inhibition and Patient Outcomes) trials demonstrating statistically significant mortality reduction, it is used clinically in combination with aspirin in the setting of acute coronary syndrome and coronary artery stenting.3,7,8

Use of dual antiplatelet agents is associated with minor bleeding complications in up to 32.4% of patients, with major bleeding rates between 0.9% and 5.7%.9,10 Earlier antiplatelet agents have been implicated in pulmonary hemorrhage—most classically, the glycoprotein IIb/IIIa inhibitors, but additionally P2Y12 antagonists such as clopidogrel and ticlopidine, with significant associated morbidity and mortality.11-13 These have been reported in the setting of acute ST-elevation acute coronary syndrome, and management has been supportive only due to the high risk of acute in-stent thrombosis with cessation of antiplatelet therapy.1

The rapid onset of hemoptysis and alveolar hemorrhage within 14 days following introduction of ticagrelor, with associated relief in symptoms with cessation of ticagrelor and recurrence when the drug was restarted, are strong factors in the argument that it was the causative agent in this patient. The histopathologic evidence of a lung injury pattern consistent with drug-induced injury and resolution of changes on CT scan at follow-up effectively ruled out other potential diseases causing pulmonary hemorrhage.

The mechanism by which ticagrelor induced lung injury in this patient is unclear. It has been hypothesized that the reversible nature of platelet inhibition with ticagrelor could lead to sequestration of overloaded, exhausted platelets in the pulmonary circulation, with subsequent disruption of endothelial function.14 However, this remains unproven. As this side effect is obviously rare, it suggests some unusual genetic factor related to the binding or action of ticagrelor is likely to be a contributing factor. If more reports of pulmonary hemorrhage emerge with ticagrelor therapy, then a clearer pattern of risk profile may emerge. To our knowledge, this is the first report of pulmonary hemorrhage as a result of dual antiplatelet therapy involving ticagrelor.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents. N Engl J Med. 2013;368(3):254-265. [CrossRef] [PubMed]
 
Juneja S, Gupta K, Kaushal S. Ticagrelor: an emerging oral antiplatelet agent. J Pharmacol Pharmacother. 2013;4(1):78-80. [CrossRef] [PubMed]
 
Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. [CrossRef] [PubMed]
 
Camus PH, Foucher P, Bonniaud PH, Ask K. Drug-induced infiltrative lung disease. Eur Respir J Suppl. 2001;32:93s-100s. [PubMed]
 
Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32(23):2945-2953. [CrossRef] [PubMed]
 
Storey RF, Bliden KP, Patil SB, et al; ONSET/OFFSET Investigators. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193. [CrossRef] [PubMed]
 
Lange RA, Hillis LD. The duel between dual antiplatelet therapies. N Engl J Med. 2013;368(14):1356-1357. [CrossRef] [PubMed]
 
Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun. 2012;418(4):754-758. [CrossRef] [PubMed]
 
Roy P, Bonello L, Torguson R, et al. Impact of “nuisance” bleeding on clopidogrel compliance in patients undergoing intracoronary drug-eluting stent implantation. Am J Cardiol. 2008;102(12):1614-1617. [CrossRef] [PubMed]
 
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502. [CrossRef] [PubMed]
 
Ikeda M, Tanaka H, Sadamatsu K. Diffuse alveolar hemorrhage as a complication of dual antiplatelet therapy for acute coronary syndrome. Cardiovasc Revasc Med. 2011;12(6):407-411. [CrossRef] [PubMed]
 
Ishida R, Nomura T, Kojima A, et al. Pulmonary hemorrhage in a middle-aged woman as a complication of treatments for acute myocardial infarction. Journal of Cardiology Cases. 2010;1(1):e37-e41. [CrossRef]
 
Iskandar SB, Kasasbeh ES, Mechleb BK, et al. Alveolar hemorrhage: an underdiagnosed complication of treatment with glycoprotein IIb/IIIa inhibitors. J Interv Cardiol. 2006;19(4):356-363. [CrossRef] [PubMed]
 
Serebruany VL. Viewpoint: reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and elinogrel. Thromb Haemost. 2012;108(6):1024-1027. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. CT image of the chest with extensive peribronchovascular opacities extending through the bilateral lower lobes.Grahic Jump Location
Figure Jump LinkFigure 2. Low-power view showing an approximately wedge-shaped lesion in the lung, reminiscent of a usual interstitial pneumonia pattern of lung injury. The pleural surface is on the right. On either side of the lesion, the lung parenchyma is relatively spared (hematoxylin and eosin, original magnification × 16).Grahic Jump Location
Figure Jump LinkFigure 3. At higher power, the same area shows heterogeneous alveolar septal fibrosis, which is more established toward the center of the image. However, there is also early fibrosis, as evidenced by formation of fibroblastic foci, indicated by the star. The double arrow shows bronchiolization of airways, commonly seen secondary to lung injury (hematoxylin and eosin, original magnification × 50).Grahic Jump Location

Tables

References

Stefanini GG, Holmes DR Jr. Drug-eluting coronary-artery stents. N Engl J Med. 2013;368(3):254-265. [CrossRef] [PubMed]
 
Juneja S, Gupta K, Kaushal S. Ticagrelor: an emerging oral antiplatelet agent. J Pharmacol Pharmacother. 2013;4(1):78-80. [CrossRef] [PubMed]
 
Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. [CrossRef] [PubMed]
 
Camus PH, Foucher P, Bonniaud PH, Ask K. Drug-induced infiltrative lung disease. Eur Respir J Suppl. 2001;32:93s-100s. [PubMed]
 
Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32(23):2945-2953. [CrossRef] [PubMed]
 
Storey RF, Bliden KP, Patil SB, et al; ONSET/OFFSET Investigators. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193. [CrossRef] [PubMed]
 
Lange RA, Hillis LD. The duel between dual antiplatelet therapies. N Engl J Med. 2013;368(14):1356-1357. [CrossRef] [PubMed]
 
Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun. 2012;418(4):754-758. [CrossRef] [PubMed]
 
Roy P, Bonello L, Torguson R, et al. Impact of “nuisance” bleeding on clopidogrel compliance in patients undergoing intracoronary drug-eluting stent implantation. Am J Cardiol. 2008;102(12):1614-1617. [CrossRef] [PubMed]
 
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502. [CrossRef] [PubMed]
 
Ikeda M, Tanaka H, Sadamatsu K. Diffuse alveolar hemorrhage as a complication of dual antiplatelet therapy for acute coronary syndrome. Cardiovasc Revasc Med. 2011;12(6):407-411. [CrossRef] [PubMed]
 
Ishida R, Nomura T, Kojima A, et al. Pulmonary hemorrhage in a middle-aged woman as a complication of treatments for acute myocardial infarction. Journal of Cardiology Cases. 2010;1(1):e37-e41. [CrossRef]
 
Iskandar SB, Kasasbeh ES, Mechleb BK, et al. Alveolar hemorrhage: an underdiagnosed complication of treatment with glycoprotein IIb/IIIa inhibitors. J Interv Cardiol. 2006;19(4):356-363. [CrossRef] [PubMed]
 
Serebruany VL. Viewpoint: reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and elinogrel. Thromb Haemost. 2012;108(6):1024-1027. [CrossRef] [PubMed]
 
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