Viewpoint: Reversible nature of platelet binding causing transfusion-related acute lung injury (TRALI) syndrome may explain dyspnea after ticagrelor and elinogrel

 

 Buy Article Permissions and Reprints

Summary

There may be a universal mechanism explaining dyspnea after ticagrelor and elinogrel, namely, transfusion-related acute lung injury (TRALI). Indeed, recent clinical trials with ticagrelor (DISPERSE, DISPERSE-II, and PLATO), and elinogrel (INNOVATE PCI) revealed double-digit rates of dyspnea after novel reversible antiplatelet agents. In contrast, dyspnea is not associated with conventional non-reversible agents such as aspirin, or thienopyridines (ticlopidine, clopidogrel, or prasugrel) suggesting distinct mechanism of shortness of breath after ticagrelor and elinogrel. The adenosine hypothesis has been offered to explain such adverse association. However, despite obvious similarity between ticagrelor and adenosine molecules, the chemical structure of elinogrel is entirely different. In fact, ticagrelor is a cyclopentyl-triazolo-pyrimidine, while elinogrel is a quinazolinedione. Since both agents cause dyspnea, the adenosine hypothesis is no longer valid. In contrast, the reversible nature of platelet inhibition attributable to both ticagrelor and elinogrel causing premature cell ageing, apoptosis, impaired turnover due to sequestration of overloaded, exhausted platelets in the pulmonary circulation are among potential autoimmune mechanism(s) resulting in the development of a TRALI-like reaction, and frequent dyspnea. Despite expected benefit for better bleeding control, further development of reversible antithrombins is severely limited due to the existence of a potentially universal serious adverse event, such as TRALI-syndrome with dyspnea as a predominant clinical manifestation. Since TRALI is an established number one contributor to mortality after blood transfusions, ticagrelor death “benefit”in PLATO is challenged further.

• References

• 1 Frese T, Sobeck C, Herrmann K. et al. Dyspnea as the reason for encounter in general practice. J Clin Med Res 2011; 3: 239-246.
  PubMedGoogle Scholar
• 2 Bonafede M, Jing Y, Gdovin Bergeson J. et al. Impact of dyspnea on medical utilization and affiliated costs in patients with acute coronary syndrome. Hosp Pract (Minneap) 2011; 39: 16-22.
  CrossrefPubMedGoogle Scholar
• 3 Serebruany VL, Stebbing J, Atar D. Dyspnea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract 2007; 61: 529-533.
  CrossrefPubMedGoogle Scholar
• 4 Serebruany VL. Dyspnea after AZD 6140:safety first?. Eur Heart J 2006; 27: 1505.
  PubMedGoogle Scholar
• 5 Cannon CP, Husted S, Harrington RA. et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results ofthe DISPERSE-2 trial. J Am Coll Cardiol 2007; 50: 1844-1851.
  CrossrefPubMedGoogle Scholar
• 6 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1045-1057.
  CrossrefPubMedGoogle Scholar
• 7 A Phase 2 Safety and Efficacy Study of PRT060128, a Novel Intravenous and Oral P2Y12 Inhibitor, in Non-Urgent PCI (INNOVATE-PCI). Available at: http://clinicaltrials.gov/ct2/show/NCT00751231?term=elinogrel&rank=2 Accessed June 18, 2012
  PubMedGoogle Scholar
• 8 Bhatt DL, Lincoff AM, Gibson CM. et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
  CrossrefPubMedGoogle Scholar
• 9 Rao S. for the INNOVATE PCI investigators. A randomized, double-blind, active controlled trial to evaluate intravenous and oral PRT060128 (elinogrel), a selective and reversible P2Y12 receptor inhibitor vs clopidogrel as a novel antiplatelet therapy in patients undergoing non-urgent percutaneous coronary interventions. European Society of Cardiology 2010 Congress;August 30, 2010;Stockholm, Sweden. Heart J 2010; 31 (Suppl. 01) 132.
  PubMedGoogle Scholar
• 10 Angiolillo DJ, Firstenberg MS, Price MJ. et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. J Am Med Assoc 2012; 307: 265-274.
  PubMedGoogle Scholar
• 11 Husted S, Emanuelsson H, Heptinstall S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
  CrossrefPubMedGoogle Scholar
• 12 Serebruany VL. Adenosine release: a potential explanation for the benefits of ticagrelor in the PLATelet inhibition and clinical outcomes trial?. Am Heart J 2011; 161: 1-4.
  CrossrefPubMedGoogle Scholar
• 13 Deeks ED. Ticagrelor: areviewof its use in the management of acute coronary syndromes. Drugs 2011; 71: 909-933.
  CrossrefPubMedGoogle Scholar
• 14 Josefsson EC, White MJ, Dowling MR. et al. Platelet life span and apoptosis. Methods Mol Biol 2012; 788: 59-71.
  PubMedGoogle Scholar
• 15 Mason KD, Carpinelli MR, Fletcher JI. et al. Programmed anuclear cell death delimits platelet life span. Cell 2007; 128: 1173-1186.
  CrossrefPubMedGoogle Scholar
• 16 Li G, Kojicic M, Reriani MK. et al. Long-term survival and quality of life after transfusion-associated pulmonary edema in critically ill medical patients. Chest 2010; 137: 783-789.
  CrossrefPubMedGoogle Scholar
• 17 Holness L, Knippen MA, Simmons L. et al. Fatalities caused by TRALI. Transfus Med Rev 2004; 18: 184-188.
  CrossrefPubMedGoogle Scholar
• 18 Toy P, Gajic O, Bacchetti P. et al. , for theTRALIStudy Group. Transfusion-related acute lung injury: incidence and risk factors. Blood 2012; 119: 1757-1767.
  CrossrefPubMedGoogle Scholar
• 19 Khan SY, Kelher MR, Heal JM. et al. Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 2006; 108: 2455-2462.
  CrossrefPubMedGoogle Scholar
• 20 Fouad HH, Al-Dera H, Bakhoum SW. et al. Levels of sCD40 ligandin chronic and acutecoronarysyndromes and its relation to angiographic extent of coronaryarterial narrowing. Angiology 2010; 61: 567-573.
  CrossrefPubMedGoogle Scholar
• 21 Antoniades C, Bakogiannis C, Tousoulis D. et al. TheCD40/CD40 ligandsystem: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009; 54: 669-677.
  CrossrefPubMedGoogle Scholar
• 22 Vlaar AP, Straat M, Juffermans NP. The relation between aged blood products and onset of transfusion-related acute lung injury. A review of pre-clinical data. Clin Lab 2011; 57: 267-272.
  PubMedGoogle Scholar
• 23 Silliman CC, Bjornsen AJ, Wyman TH. et al. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion 2003; 43: 633-640.
  CrossrefPubMedGoogle Scholar
• 24 Cherry T, Steciuk M, Reddy VV. et al. Transfusion-related acute lung injury: past, present, and future. Am J Clin Pathol 2008; 129: 287-297.
  CrossrefPubMedGoogle Scholar
• 25 Looney MR, Gilliss BM, Matthay MA. Pathophysiology of transfusion-related acute lung injury. Curr Opin Hematol 2010; 17: 418-423.
  CrossrefPubMedGoogle Scholar
• 26 Povsic TJ, Cohen MG, Chan MY. et al. Dose selection for a direct and selective factor IXa inhibitor and its complementary reversal agent: translating pharmacokinetic and pharmacodynamic properties of the REG1 system to clinical trial design. J Thromb Thrombolysis 2011; 32: 21-31.
  CrossrefPubMedGoogle Scholar
• 27 Serebruany VL. Viewpoint: paradoxical excess mortality in the PLATO trial should be independently verified. Thromb Haemost 2011; 105: 752-759.
  Article in Thieme ConnectPubMedGoogle Scholar
• 28 Wallentin L, Becker RC, James SK. et al. The PLATO trial reveals further opportunities to improve outcomes in patients with acute coronary syndrome. Thromb Haemost 2011; 105: 760-762.
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Ohman EM, Roe MT. Explaining the unexpected: insights from the PLATelet inhibition and clinical Outcomes (PLATO) trial comparing ticagrelor and clopidogrel. Thromb Haemost 2011; 105: 763-765.
  Article in Thieme ConnectPubMedGoogle Scholar