Why aspirin doesn't always stop blood clots
27 June 2007
Aspirin's blood-thinning properties are well known, making it the drug of choice for protection against blood clots in heart disease. But it doesn't work for everyone: some people are aspirin resistant and continue to develop clots. Now, Spanish cardiovascular researchers led by Carlos Macaya at Madrid's San Carlos Hospital Clinic have linked aspirin resistance to a protein that binds vitamin D.
Aspirin, acetylsalicylic acid, thins blood because it stops platelets - the cells involved in blood-clot formation - from aggregating. The drug blocks the synthesis of thromboxane A2 (an eicosanoid related to the prostaglandin family of lipids), which activates the formation of platelets, making them stick together. Thromboxane A2 synthesis is blocked by irreversibly inhibiting the action of an enzyme called cyclooxygenase-1 (COX-1).
Normally aspirin stops the production of thromboxane-A2 (above) by inhibiting the enzyme COX-1. In aspirin-resistant patients, vitamin D binding protein prevents aspirin from working
COX-1 activity is not blocked in aspirin-resistant patients, but reasons for this had remained unclear. It was thought that resistant patients might carry aspirin-resistant COX-1 gene mutations, or that the patients' vascular systems and how their platelets interact with other cells in blood plasma might have been modified.
The Spanish team conducted a trial with 19 aspirin-sensitive and 19 aspirin-resistant patients who had experienced recent acute coronary ischemic events. They used proteomics techniques to look at different blood-serum proteins expressed by the two patient groups.
Two-dimensional gel electrophoresis was used to separate and identify the proteins. The protein mix was first separated according to charge, then the gel was rotated through 90o and the proteins separated by mass.
Macaya's team found that aspirin-resistant patients' serum contained raised levels of a vitamin D-binding protein (DBP) in three fully functional versions. When this protein was incubated with blood from healthy volunteers, it significantly reduced aspirin's inhibitory effect on platelet thromboxane A2 production.
The Spanish team says this suggests a completely new mechanism for aspirin resistance. 'DBP might directly reduce aspirin's ability to acetylate COX-1's active site,' said Macaya. 'Or DBP might bind platelet cytoskeleton proteins that change COX-1's structure, making its active site less accessible to aspirin.'
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ReferencesA J López-Farré, J. Proteome Res., 2007, DOI: 10.1021/pr060600i
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