Creatine kinase inhibits ADP-induced platelet aggregation

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.

The acute effect of beta‐guanidinopropionic acid versus creatine or placebo in healthy men (ABC‐Trial): A randomized controlled first‐in‐human trial

“…Secondary outcomes included the comparison of tolerability with creatine, and the effect of 1 week of oral GPA on haemodynamic parameters, including peripheral and central blood pressure, and cardiac contractility as compared to creatine and placebo. The tertiary outcome was the effect of GPA on biochemical parameters, including ADP‐induced platelet aggregation , compared to creatine and placebo.…”

“…The tertiary outcome was the effect of GPA on biochemical parameters, including ADP-induced platelet aggregation [19], compared to creatine and placebo.…”

A Multivariate Metabolomics Method for Estimating Platelet Mitochondrial Oxygen Consumption Rates in Patients with Sepsis

“…In regard to specific metabolites and pathways, it is worth noting that both of the platelet models included ADP, which highlights the importance of this molecule in sepsis. ADP and creatine are both substrates of ATP synthesis, but ADP is also maintained in high concentrations within the dense granules of platelets as they utilize the compound to activate aggregation [22][23][24]. Platelet aggregation is also strongly influenced by choline, which is a precursor to platelet activating factor [25].…”

“…Indeed, the appearance of associations between the WB and platelet metabolomes in the subjects with sepsis emphasizes the prolific metabolic response that sepsis provokes. Platelets release metabolites into the blood upon activation, which offers a potential mechanistic explanation for this observation [22][23][24]. Albeit, there were fewer control subjects than in the sepsis group, so this may affect the lack of associations between the platelet and WB metabolites in this group.…”

Creatine kinase: how an obsolete test for skeletal muscle disease became a risk factor for hypertension

“…These misconceptions are likely to impede advance care plan discussions in patients with terminal cancer. 3 There is an urgent need for these misconceptions to be addressed through education.…”