Protein Binding Controls Formation of Blood Clots

This study, which adds important information as to how blood clots form, was published in the May 28, 2002, issue of the Proceedings of the National Academy of Sciences.

"Laser tweezers use the force of a focused laser beam to trap and move particles. In this case, we used the tweezers to play tug-of-war with a platelet-bound integrin molecule on one side and a fibrinogen molecule mounted on a tiny latex bead on the other,” explained Dr. John W. Weisel, of the University of Pennsylvania (Philadelphia, USA) and one of the authors. "We were able to measure the force that keeps blood clots together. We can also determine the regulation of forces between individual ligand-receptor pairs and the effects of anticlotting drugs, at the single molecule level.”

Platelets are activated and change shape after receiving chemical signals from damaged blood vessel cells. The platelets change shape and expose approximately 80,000 copies of the alpha IIb beta 3 integrin protein. Each of these copies binds to fibrinogen, a fibrous protein that binds the platelets together to form a clot. Clotting is vitally important to control bleeding, but inappropriate formation of a clot can lead to heart attack or stroke.

The investigators developed a new model system using tiny pedestals and beads that could be trapped and moved in order to use laser tweezers to measure the strength of a single bond between protein molecules. They attached fibrinogen to microscopic plastic beads and exposed them to integrin that was either attached to pedestals or in situ on the surface of living, reactive platelet cells. Measurements showed that the rupture forces of individual fibrinogen molecules and purified integrin on the surface of living platelets were 60 to 150 pN (picoNewtons) with peak yield strength of 80-100 pN.

"Platelets are like multiple-watt lightbulbs: they can be turned on to different degrees of activation,” said Dr. Weisel. "Interestingly, our findings suggest that no matter which setting you turn a platelet to, integrin binds to fibrinogen with the same affinity.”



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