Calcium for strong clotting

Calcium fluctuations in the bottom layer of a platelet mass are propagated upwards to determine the size of a blood clot, or thrombus, according to results from Nesbitt et al. presented on page 1151.Platelets adhere to substrates in the vessel wall through receptors such as GPIb and certain integrins. Initial receptor engagement stimulates Ca²⁺ spikes in the platelets that lead to firm, permanent adhesion between the vessel wall and the primary layer of platelets. Now, Nesbitt et al. show that Ca²⁺ signals in this bottom layer are propagated among cells to promote platelet aggregation.

The group visualized cytosolic Ca²⁺ concentrations in platelets and found that cells with strong Ca²⁺ oscillations efficiently nucleated platelet aggregates. Flowing platelets that contacted an anchored platelet at the peak of its Ca²⁺ fluctuation adhered and initiated their own Ca²⁺ oscillations. Propagation of the Ca²⁺ signals, which the authors call intercellular calcium communication, requires integrin α_IIbβ₃ and ADP, as well as the ADP receptor, P2Y₁₂. The group proposes that integrin activation tethers neighboring platelets, initiates Ca²⁺ spikes through release of stores in the newly adherent platelet, and stimulates local release of ADP. ADP activation of P2Y₁₂ signaling in nearby cells amplifies the Ca²⁺ flux in the nearby cells and sustains integrin-driven aggregation.

The results provide a model to explain how the vessel substrate collagen, which only contacts the first layer of adhering platelets, is nonetheless particularly effective at promoting thrombus growth. The group shows that compared with von Willebrand factor (vWf), another vessel substrate, collagen induced both stronger and more widespread Ca²⁺ oscillations in the primary layer of adhering platelets. As a result, collagen-based thrombi were over five times larger than those that formed on vWf. ▪