Aspirin induces platelet receptor shedding via ADAM17 (TACE)

Area of Science:

• Biochemistry
• Pharmacology
• Hematology

Background:

• Aspirin (acetylsalicylic acid) is a cornerstone in cardiovascular disease therapy due to its irreversible inhibition of cyclooxygenase 1 (COX-1) in platelets.
• The increased bleeding tendency observed with aspirin, unlike other COX inhibitors, suggests additional mechanisms of action.
• Recent findings indicate aspirin induces L-selectin shedding in neutrophils via metalloproteinases, prompting investigation into its effects on other platelet surface proteins.

Purpose of the Study:

• To investigate the effect of aspirin on the von Willebrand Factor (vWF) receptor complex, glycoprotein (GP) Ib-V-IX.
• To determine if aspirin induces shedding of platelet glycoproteins and elucidate the underlying mechanism.

Main Methods:

• Fluorescence-activated cell sorting (FACS) analysis of whole blood to quantify glycoprotein shedding.
• Immunoprecipitation and Western blot analysis to detect shed fragments and assess surface protein levels.
• Experiments using COX-1 deficient murine platelets, metalloproteinase inhibitors, and ADAM17-inactive platelets to dissect the mechanism.

Main Results:

• Aspirin, but not salicylic acid, induced dose-dependent shedding of GPIbalpha and GPV from human and murine platelets.
• This shedding was independent of COX-1 activity but was blocked by metalloproteinase inhibitors and an inactive form of ADAM17.
• Elevated levels of shed GPIbalpha and GPV fragments were observed in the plasma of aspirin-injected mice.

Conclusions:

• High-dose aspirin induces shedding of platelet glycoproteins GPIbalpha and GPV through an ADAM17-dependent mechanism.
• This novel mechanism, independent of COX-1 inhibition, may contribute to the hemostatic effects of aspirin.
• The findings highlight a new pathway by which aspirin can influence platelet function and potentially bleeding risk.