enged nitric oxide production. Previous studies (Valeri et al., 1998) have suggested that the nitric oxide-mediated platelet dysfunction occurs as a result of hemodilution and the lack of availability of adequate red blood cells to scavenge nitric oxide by oxidation or by binding of nitric oxide to the hemoglobin molecule. In addition, red blood cell scavenging of nitric oxide activates platelets to produce thromboxane A2 and serotonin and stimulates endothelium-derived endothelin production in an effort to restore and maintain microcirculatory hemostasis (C. R. Valeri, personal communication). Anemia-related platelet dysfunction has been described by several laboratories (Blajchman et al., 1994; Duke, 1910; Hellem et al., 1961; Marcus, 1990), and altered bleeding times have been correlated with peripheral hemoglobin and hematocrit contents. The altered bleeding associated with a reduced circulating red blood cell content has been attributed, in part, to the decrease in blood viscosity and increased sheer stress at the levels of the endothelium.

More recently, studies from the Naval Blood Research Laboratory have shown that the hematocrit level and the oxygen state of red blood cells have a greater effect on bleeding time than does the concentration of either platelets or clotting proteins. In correcting the effects of hemodilution on bleeding time, the transfusion of platelets produces only a transient rise in total platelet count related, in part, to the short half-life of this cell type. Transfusion and an increase in the level of circulating red blood cells after aggressive fluid resuscitation from hemorrhagic shock have been shown to have a beneficial effect on platelet function. Red blood cells disperse platelets from the center of the blood vessel, concentrating this cell population near endothelial cells of the vessel walls (Turitto and Weiss, 1980). The ability of red blood cells to stimulate platelet synthesis of thromboxane A2 has important effects on vasoconstriction and platelet aggregation in the presence of continuing blood loss. Anemia and subsequent platelet dysfunction diminish the level of production of thromboxane A2, contributing to continued blood loss. These data raise additional concerns regarding large-volume lactated Ringer's solution resuscitation in a subject with continuing blood loss. Dilution of clotting proteins and increased bleeding time would exacerbate hemorrhage-related blood loss as well as microcapillary oozing. Aggressive fluid resuscitation from hemorrhage and the resulting anemia increase the blood flow but also increase the shear stress on vascular endothelial cells, promoting the release of endothelium-derived nitric oxide (Duke and Abelmann, 1969; Griffith, 1987; Ignarro, 1987; Loscalzo, 1995; Palmer et al., 1987). Shear stress on the endothelium is related to both shear rate and whole-blood viscosity. With hemodilution, blood viscosity falls, but the shear rate increases and the net result is increased shear stress. Finally, hemodilution-related increases in shear stress can promote the release of adenosine diphosphate (ADP) from red blood cells, potentiating shear-related platelet aggregation (Alkhamis, 1988; Alkhamis et al., 1990; Bell et al., 1990; Luthje, 1989; Saniabadi et al., 1987; Santos et al., 1991; Valles et al., 1991). Although increased shear stress on endothelial cells enhances nitric oxide production, the subsequent rise in platelet cyclic guanosine monophosphate (cGMP) levels further inhibits platelet function (Azuma et



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