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Published on: April 6, 2017
Creatine kinase inhibits ADP-induced platelet aggregation
D L Horjus1, R Nieuwland2, K B Boateng1
1Dept. of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Insights
Plasma creatine kinase levels influence bleeding risk by inhibiting platelet activation. Higher enzyme levels reduce platelet aggregation, potentially increasing bleeding, especially with antiplatelet drugs targeting ADP receptors.
Area of Science:
- Biochemistry
- Hematology
- Pharmacology
Background:
- Bleeding risk associated with antiplatelet therapy presents a significant clinical challenge.
- Inter-individual variability in bleeding risk is not well understood.
- Platelet activation, particularly via adenosine diphosphate (ADP), is a key factor in thrombosis and bleeding.
Purpose of the Study:
- To investigate whether plasma creatine kinase levels modulate bleeding risk.
- To determine if creatine kinase inhibits ADP-induced platelet activation in a dose-dependent manner.
Main Methods:
- In vitro experiments adding exogenous creatine kinase to human plasma.
- Measurement of ADP-induced platelet aggregation.
- In vivo study of endogenous plasma creatine kinase levels and platelet aggregation in healthy men, including post-exercise assessment.
Main Results:
- Exogenous creatine kinase dose-dependently inhibited ADP-induced platelet aggregation in human plasma.
- Endogenous plasma creatine kinase levels in healthy men correlated inversely with ADP-induced platelet aggregation.
- Significantly reduced platelet aggregation was observed at very high creatine kinase levels post-exercise, normalizing as levels decreased.
Conclusions:
- Creatine kinase reduces ADP-induced platelet activation.
- This enzymatic activity may contribute to bleeding risk, particularly in patients using P2Y12 receptor inhibitors.
Abstract:
Bleeding risk with antiplatelet therapy is an increasing clinical challenge. However, the inter-individual variation in this risk is poorly understood. We assessed whether the level of plasma creatine kinase, the enzyme that utilizes ADP and phosphocreatine to rapidly regenerate ATP, may modulate bleeding risk through a dose-dependent inhibition of ADP-induced platelet activation. Exogenous creatine kinase (500 to 4000 IU/L, phosphocreatine 5 mM) added to human plasma induced a dose-dependent reduction to complete inhibition of ADP-induced platelet aggregation. Accordingly, endogenous plasma creatine kinase, studied in 9 healthy men (mean age 27.9 y, SE 3.3; creatine kinase 115 to 859 IU/L, median 358), was associated with reduced ADP-induced platelet aggregation (Spearman's rank correlation coefficient, -0.6; p < 0.05). After exercise, at an endogenous creatine kinase level of 4664, ADP-induced platelet aggregation was undetectable, normalizing after rest, with a concomitant reduction of creatine kinase to normal values. Thus, creatine kinase reduces ADP-induced platelet activation. This may promote bleeding, in particular when patients use platelet P2Y12 ADP receptor inhibitors.
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