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 Blood, 1 October 2006, Vol. 108, No. 7, pp. 2223-2228.
Prepublished online as a Blood First Edition Paper on June 1, 2006; DOI 10.1182/blood-2006-01-009613.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Reversible inhibition of the platelet procoagulant response through manipulation of the Gardos channel

Jef L. Wolfs, Simone J. Wielders, Paul Comfurius, Theo Lindhout, John C. Giddings, Robert F. Zwaal, and Edouard M. Bevers

From the Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands; and the Department of Haematology, Welsh National School of Medicine, Heath Park, Cardiff, United Kingdom.

The platelet procoagulant response requires a sustained elevation of the intracellular Ca2+ concentration, [Ca2+]i, causing exposure of phosphatidylserine (PS) at the outer surface of the plasma membrane. An increased [Ca2+]i also activates Ca2+-dependent K+ channels. Here, we investigated the contribution of the efflux of K+ ions on the platelet procoagulant response in collagen-thrombin–activated platelets using selective K+ channel blockers. The Gardos channel blockers clotrimazol, charybdotoxin, and quinine caused a similar decrease in prothrombinase activity as well as in the number of PS-exposing platelets detected by fluorescence-conjugated annexin A5. Apamin and iberiotoxin, inhibitors of other K+ channels, were without effect. Only clotrimazol showed a significant inhibition of the collagen-plus-thrombin–induced intracellular calcium response. Clotrimazol and charybdotoxin did not inhibit aggregation and release under the conditions used. Inhibition by Gardos channel blockers was reversed by valinomycin, a selective K+ ionophore. The impaired procoagulant response of platelets from a patient with Scott syndrome was partially restored by pretreatment with valinomycin, suggesting a possible defect of the Gardos channel in this syndrome. Collectively, these results provide evidence for the involvement of efflux of K+ ions through Ca2+-activated K+ channels in the procoagulant response of platelets, opening potential strategies for therapeutic interventions.


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