Creatine Kinase is Associated with Bleeding after Myocardial Infarction

Abstract

Background: Highly elevated plasma activity of the ADP scavenging enzyme creatine kinase (CK) might reduce ADP and ADP-dependent platelet activation. Therefore, we studied, whether high CK after myocardial infarction (MI) is associated with bleeding. Method: Data 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. Results: The included patients (N=3339, 82% men, 88% white, mean age 57 y, SE 0.2), had a history of angina pectoris (55%), hypertension (38%), and/or diabetes mellitus (13%). CKmax ranged between 16 and 55 890 IU/L (mean 2389 IU/L; SE 41), reached within 8 h in 51% of the patients (93% within 24 h). 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). The adjusted odds ratio 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). Conclusion: Highly elevated plasma CK after MI might be a hitherto overlooked independent indicator of bleeding and hemorrhagic death. This biologically plausible association warrants prospective study of the potential role of CK in hemorrhagic diathesis, and the risk of severe, potentially fatal bleeding with antithrombotic or thrombolytic therapy in the presence of high plasma CK.

Creatine Kinase during Non-ST-Segment Elevation Acute Coronary Syndromes is Associated with Major Bleeding

“…5-8 During myocardial ischemia 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, catalyzing the reaction: 6-8 …”

“…1-5 Creatine kinase (CK) was recently proposed to be an essential part of the counterregulatory mechanism of endothelial thromboresistance that limit platelet activation. 6,7 After plaque rupture 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) synthesized from arachidonic acid (AA) through prostaglandin (PG) catalyzed by (COX1).…”

“…Activation of P2Y12 receptor results in the activation of glycoprotein receptors IIb/IIIa (integrin (I)-αIIbβ3) and firm platelet aggregation. 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 and fibrinolytic drugs that act on Factor Xa, Thrombin, PAR, COX1, P2Y12, I-αIIbβ3, plasminogen or other factors 1,2 to increase bleeding risk in ACS.…”

“…7,8 The enzyme might act in synergy with antithrombotic and fibrinolytic drugs that act on 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, 2019). 6…”

“…In line with this, it was recently reported that peak plasma CK (CKmax) during admission is strongly and independently associated with bleeding after ST-elevation myocardial infarction (STEMI), with an adjusted odds ratio (OR) per log CK increase of 2.6 [95% CI, 1.8 to 3.7] for fatal/non-fatal bleeding, and 3.1 [2.2 to 4.4] for bleeding/all-cause mortality. 6 As the effect of CK on ADP-dependent platelet aggregation is thought to act in synergy with antithrombotic and thrombolytic therapy, 6 lower levels of CK might also be associated with bleeding. Therefore, it is studied whether moderately elevated CK during NSTE-ACS is independently predictive of major bleeding.…”