Creatine kinase is associated with bleeding after myocardial infarction

Abstract

BackgroundThe ADP-scavenging enzyme creatine kinase (CK) is reported to reduce ADP-dependent platelet activation. Therefore, we studied whether highly elevated CK after ST-elevation myocardial infarction (STEMI) is associated with bleeding.MethodsData of the Thrombolysis in Myocardial Infarction Study Group phase II trial on the efficacy of angioplasty, following intravenous recombinant tissue-type plasminogen activator (rt-PA), are used to assess whether peak plasma CK (CKmax) is independently associated with adjudicated fatal or non-fatal bleeding (primary) and combined bleeding/all-cause mortality (secondary) in multivariable binomial logistic regression analysis, adjusting for baseline and treatment allocation covariates.ResultsThe included patients (n=3339, 82% men, 88% white, mean age 57 years, SE 0.2) had a history of angina pectoris (55%), hypertension (38%) and/or diabetes mellitus (13%). CKmax ranged from 16 to 55 890 IU/L (mean 2389 IU/L, SE 41), reached within 8 hours in 51% of the patients (93% within 24 hours). Adjudicated fatal/non-fatal bleeding occurred in 30% of the patients (respectively 26% in the low vs 34% in the high CK tertile), and bleeding/all-cause mortality in 35% (29% in the low vs 40% in the high CK tertile). In multivariable regression analysis, the adjusted OR for fatal/non-fatal bleeding (vs not bleeding and survival) was 2.6 (95% CI 1.8 to 3.7)/log CKmax increase, and 3.1 (2.2 to 4.4) for bleeding/all-cause mortality.ConclusionHighly elevated plasma CK after myocardial infarction might be an independent predictor of bleeding and haemorrhagic death. This biologically plausible association warrants further prospective study of the potential role of extracellular CK in ADP-dependent platelet activation and bleeding.

Creatine kinase during non-ST-segment elevation acute coronary syndromes is associated with major bleeding

“…Age was another independent risk factor for major bleeding as previously noted. 3 The biological plausibility regarding ADP binding (figure 1), the observed strong, consistent, independent association with bleeding in large multicentre clinical studies, the temporal precedence, dose-effect relationship and the experimental evidence on inhibition of platelet aggregation [6][7][8] substantiate the hypothesis that CK may increase bleeding risk.…”

“…7 8 The enzyme might act in synergy with antithrombotic or fibrinolytic drugs that target factor Xa, thrombin, PAR, COX1, P2Y12, I-αIIbβ3, plasminogen or other factors 1 2 to increase bleeding risk in ACS 6 (modified after Brewster and Fernand, 2020). 6 on December 6, 2020 by guest. Protected by copyright.…”

“… 5–8 During myocardial ischaemia and infarction, CK and other cell constituents such as myoglobin and troponin enter plasma along with smaller molecules including phosphocreatine. 6–8 Extracellular CK is thought to reduce ADP and ADP-dependent platelet activation through its scavenging action on ADP or through conversion into ATP, catalysing the reaction 6–8 :…”

“… 1–5 CK was recently proposed to be an essential part of the counterregulatory mechanism of endothelial thromboresistance that limits platelet activation. 6 7 After plaque ruptures, platelets adhere to the injured vessel wall and undergo activation through collagen and von Willebrand factor (vWF). Activated platelets release substances including ADP and thromboxane A2 (TXA2) synthesised from arachidonic acid (AA) through prostaglandin (PG) catalysed by COX1.…”

“… 5 6 CK strongly binds ADP and reduces platelet aggregation in the presence of phosphocreatine (CrP). 7 8 The enzyme might act in synergy with antithrombotic or fibrinolytic drugs that target factor Xa, thrombin, PAR, COX1, P2Y12, I-αIIbβ3, plasminogen or other factors 1 2 to increase bleeding risk in ACS 6 (modified after Brewster and Fernand, 2020). 6 …”