Nota Bene: Weathering the Big Chill

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Science  24 Jan 2003:
Vol. 299, Issue 5606, pp. 530
DOI: 10.1126/science.299.5606.530

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P latelets are tiny disc-shaped cells devoid of a nucleus that are produced by the bone marrow. At sites of injury, platelets bind to von Willebrand factor (vWF) on the surface of endothelial cells, become activated by thrombin, and interact with plasma fibrin to form clots. For more than 50 years, platelet transfusions have prevented life-threatening blood loss in trauma, surgery, and bone marrow transplant patients. However, unlike red blood cells, which are amenable to cold storage, refrigerated platelets are cleared rapidly from the patient's circulation after transfusion. Unfortunately, the shelf life of platelets at room temperature is only 5 days, resulting in an acute shortage of platelets for transfusion. In a recent issue of Cell, Hoffmeister and colleagues (1) reveal why chilled, transfused platelets disappear rapidly from the circulation and propose a strategy to block this clearance.

The rapid disappearance of chilled, transfused platelets has been attributed to the cold-induced loss of their normal discoid shape, presumably leading to the ensnaring of deformed platelets in capillaries. Not so, say Hoffmeister et al., who show that even preserving the disc shape of chilled mouse platelets with drugs does not prevent their rapid clearance after transfusion into mice. The researchers next demonstrated that clearance of chilled platelets is due to their ingestion (phagocytosis) by liver macrophages called Kupffer cells.

Phagocytosis of platelets depends on their binding to an integrin called CR3 on the Kupffer cell surface. When chilled mouse platelets are transfused into mice lacking CR3, they circulate with the same kinetics as transfused platelets kept at room temperature. Seeking the platelet counter-receptor that interacts with CR3, the researchers first investigated GP1ba, the platelet surface glycoprotein that binds to vWF. They found that enzymatically cleaving the extracellular portion of GP1ba from chilled mouse platelets boosted platelet survival after transfusion. Furthermore, in an in vitro assay, enzyme-treated chilled human platelets were not ingested by macrophages, implying that GP1ba is the platelet counter-receptor for CR3.

Electron microscopy revealed that refrigeration induced the rearrangement of both mouse and human platelet GP1ba from neat, linear rows into clusters. This redistribution of GP1ba did not affect normal platelet behavior, because chilled platelets circulating in CR3-deficient mice were still able to bind to vWF, respond to thrombin and other mediators, and promote clot formation. If cold-induced platelet clearance could be blocked, then platelets could be stored in the cold and their shelf life dramatically extended. At a recent meeting, Hoffmeister and co-workers (2) presented a strategy to attain this goal. By using galactose sugar residues to shield the sugar molecules on GP1ba that bind to CR3, they prevented the clearance of chilled, transfused mouse platelets. Chilled platelets with sugar-modified GP1ba circulated with a normal life-span in transfused mice and fulfilled their normal functions. The Hoffmeister et al. work is a big step toward making platelet refrigeration a reality and alleviating the acute shortage of platelets for transfusion.