Extracellular creatine kinase may modulate purinergic signalling

2020

Open Heart

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BackgroundIt was recently reported that highly elevated plasma activity of the ADP-scavenging enzyme creatine kinase (CK), to >10 times the upper reference limit (URL), is independently associated with fatal or non-fatal bleeding during treatment for ST-segment elevation myocardial infarction (OR 2.6 (95% CI, 1.8 to 2.7)/log CK increase). Evidence indicates that CK attenuates ADP-dependent platelet aggregation. This study investigates whether moderately elevated CK in non-ST-segment elevation acute coronary syndrome (NSTE-ACS) is associated with major bleeding.MethodsThe Thrombolysis In Myocardial Ischemia (TIMI) 3B trial compared recombinant tissue-type plasminogen activator (rt-PA) (35–80 mg) with placebo and early catheterisation with conservative management in patients with NSTE-ACS. Main outcomes of the current study are the independent association of peak plasma CK (CKmax) with adjudicated fatal or non-fatal major bleeding (primary) and with combined major bleeding, stroke and hospital death (secondary), with covariables including age, sex, body mass index, systolic blood pressure, creatinine and assignment to add-on rt-PA versus placebo. Discrimination was assessed with C-statistics.ResultsThe study included 1473 patients (66% men, 80% white, mean age 59 years, SE 0.3). CKmax ranged between 15 and 19 045 IU/L (mean (SE), 450 (24) IU/L; two times URL). Major bleeding occurred in 2.0% (mean age 65 (1.3) years; mean CKmax 1015 (319) IU/L; six times URL), and the combined outcome in 4.3% of the patients, adjusted OR per log CK increase, respectively, 3.1 (1.6 to 5.9) for major bleeding and 3.9 (2.5 to 6.1) for the combined outcome; C-index 0.8 for both outcomes. The association between CK and bleeding was independent of the use of thrombolytic therapy.DiscussionThe presented data add to the existing evidence that proportionate to its plasma activity, the ADP-binding enzyme CK is strongly and independently associated with non-fatal and fatal major bleeding during treatment for NSTE-ACS. CK might increase the accuracy of prediction models for major bleeding in patients with NSTE-ACS.Trial registration numberNCT00000472.

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

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

Brewster¹,

2020

Open Heart

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“… 22 Importantly, vascular endothelium and blood cells are known to contribute to the interconversion of extracellular adenine nucleotides via ecto-nucleoside triphosphate diphosphohydrolases, ecto-nucleotide pyrophosphatase/phosphodiesterases, ecto-5'-nucleotidase and alkaline phosphatases. 23 24 Thus, the effect of highly elevated extracellular and circulating CK on platelet activation is thought to be mainly through ADP reduction, but the role of ATP, and the potential interaction between CK and ectoenzymes that convert ATP and ADP needs further exploration.…”

Section: Discussionmentioning

confidence: 99%

Creatine kinase is associated with bleeding after myocardial infarction

Brewster¹,

2020

Open Heart

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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.

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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. 6 (Modified after Brewster and Fernand, 2019).…”

Section: Introductionmentioning

confidence: 99%

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

Brewster¹,

2020

Preprint

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Background It was recently reported that highly elevated plasma activity of the ADP-scavenging enzyme creatine kinase (CK), to >10 times the upper reference limit (URL), is independently associated with fatal or non-fatal bleeding during treatment for ST-segment elevation myocardial infarction (OR 2.6 [95% CI, 1.8 to 2.7]/log CK increase). Evidence indicates that CK attenuates ADP-dependent platelet aggregation. This study investigates whether moderately elevated CK in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) is associated with major bleeding. Methods The Thrombolysis In Myocardial Ischemia (TIMI) 3B trial compared rt-PA (35 to 80 mg) with placebo, and early catheterization with conservative management in patients with NSTE-ACS. Main outcomes of the current study are the independent association of peak plasma CK (CKmax) with adjudicated fatal or non-fatal major bleeding (primary), and with combined major bleeding, stroke, and all-cause mortality (secondary) in multivariable binomial logistic regression analysis, with co-variables including age, sex, BMI, SBP, creatinine, and treatment assignment. Discrimination was assessed with C-statistics. Results The study included 1473 patients (66% men, 80% white, mean age 59 y, SE 0.3). CKmax ranged between 15 and 19045 IU/L (mean (SE), 450(24) IU/L; i.e. 2 times URL). Major bleeding occurred in 2.0% (mean age 65(1.3) y; mean CKmax 1015(318) IU/L; 6 times URL), and the combined outcome in 4.3% of the patients, adjusted OR per log CK increase respectively 3.1 [1.6 to 5.8] for major bleeding, and 3.9 [2.5 to 6.1] for the combined outcome; C-index 0.8 for both outcomes. Discussion The presented data add to the existing evidence that proportionate to its plasma activity, the ADP-binding enzyme CK is strongly and independently associated with non-fatal and fatal major bleeding during ACS treatment. CK might increase the accuracy of prediction models for major bleeding in patients treated with antithrombotic or thrombolytic drugs for ACS.