期刊
BLOOD
卷 102, 期 7, 页码 2472-2481出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2003-03-0734
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- NHLBI NIH HHS [HL70683] Funding Source: Medline
Prothrombinase activity was tested on thrombin- and SFLLRN-activated platelets treated with RO318220, a potent inhibitor of protein kinase C. RO318220 completely inhibited platelet dense and alpha-granule secretion at a concentration of 20 muM but had no effect on prothrombinase activity in the presence of excess factor Va (20 nM). This indicates that protein kinase C activity and agonist-initiated secretion are not necessary for the development of a procoagulant surface. Treatment with 75 to 150 muM RO318220 potentiated platelet-supported thrombin generation up to 280% of control platelets with no change in K-d (appFxa). Treated with increasing concentrations of RO318220, an increasing proportion of thrombin-stimulated platelets bound annexin V with decreasing binding sites per platelet. A lower mean forward scatter (FSC-H) of platelets treated with RO318220 suggested platelet vesiculation as a result of RO318220 treatment; however, 100 muM calpeptin pretreatment eliminated the decrease in FSC-H without affecting either the increase in platelets positive for annexin V binding, the decrease in binding sites per platelet, or the 3-fold increase in prothrombinase activity. Thus, RO318220 appears to increase prothrombinase activity by increasing platelet responsiveness to thrombin rather than by inducing platelet vesiculation. This suggests that RO318220 inhibits a signaling molecule within a negative regulatory pathway that governs platelet procoagulant surface changes. (C) 2003 by The American Society of Hematology.
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