The process of blood clotting is a delicate one—the body needs to be able to form a blood clot when injury occurs, but unnecessary clotting can be harmful as well. To better understand this process, researchers from Emory Health Sciences have measured and mapped the key molecular forces on platelets that trigger the process. Their results were published in two separate studies in the Proceedings of the National Academy of Sciences and in Nature Methods.
"We show conclusively that, in order to activate clotting, the cell needs a targeted force of a magnitude of just a few piconewtons—or a force about a billion times less than the weight of a staple," says Khalid Salaita, associate professor in Emory University's Department of Chemistry and the lead author of the studies. "The real surprise we found is that platelets care about the direction of that force and that it has to be lateral. They're very picky.”
The Salaita lab set up an experiment where fibrinogen ligands were anchored to a lipid membrane—the ligands could slip and slide laterally but resisted motion perpendicular to the surface. When platelets were introduced to this surface, they failed to activate and stick together. However, when fibrinogen ligands were unable to move laterally, platelets were rapidly activated.
The theory is that when a platelet encounters struck fibrinogen molecules, the platelet tugs on it to test it. The force generates a potent signal to activate the platelets and grab fibrinogen from the blood, causing clumping. Errors in this biomechanical action may be the cause of abnormal clotting that leads to strokes.
The team was able to make this discovery using a newly created imaging technology that uses DNA molecules as force probes that extend in the direction that a cellular force pulls. Captured images can reveal the orientation of the DNA, which can be used to calculate the orientation of piconewton cell forces.
Image: A scanning electron micrograph shows a red blood cell, an activated platelet (in yellow) and a white blood cell. The ability to map the magnitude and orientation of forces on a cell provides a new tool for investigating not just blood clotting but a range of biomechanical processes. Image courtesy of the National Cancer Institute.