Vessel-blocking clots (top) are avoided when platelets lack STIM1 (bottom).

On page 1583, Varga-Szabo et al. show that platelets missing a calcium channel opener build puny, feeble clots that may actually save lives.

Platelets require calcium to initiate clotting in response to extracellular cues. When calcium is needed, most cells first deplete their ER stores. This depletion is sensed by an ER protein called STIM1, which sits near enough to the plasma membrane to open up calcium channels on the cell surface. But since platelets have only stunted ER-like tubules, they were thought to rely instead on an activation-induced lipid, which opens surface calcium channels independently of internal stores.

Platelets also have plenty of STIM1, however, which Varga-Szabo et al. now show is needed for slow-but-steady clot formation. Activated STIM1-deficient platelets, the authors found, did not accumulate calcium from external sources.

Internal calcium stores in the mutant platelets were sufficient for rapid clot formation in response to short-lived ligands such as thrombin. But platelets needed STIM1-induced calcium influx to clot in response to collagen on injured vessels, which triggers a slower signaling pathway. In the absence of STIM1, clots were small and disintegrated easily, particularly under conditions that mimicked blood flow. The defective platelets continually broke away from the clots, suggesting that STIM1 helps make platelets stickier.

The results suggest that a quick calcium burst from ER-like tubules might be sufficient to build small clots to patch up a minor tear. The STIM1-driven calcium spike, on the other hand, might be necessary to form larger clots under high shear, as occurs in small or fat-clogged vessels.

Mice lacking STIM1 were protected from injury-induced vessel blockage and strokes, as their feeble clots allowed some blood to flow into injured brain tissues. As the clotting problem didn't prolong bleeding, a small, transient clot might be all that's needed to prevent hemorrhage, with the added bonus of avoiding a complete halt in blood flow.