Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells.

Nonpancreatic secretory phospholipase A2 (sPLA2) displays proinflammatory properties; however, its physiological substrate is not identified. Although inactive toward intact cells, sPLA2 hydrolyzed phospholipids in membrane microvesicles shed from Ca(2+)-loaded erythrocytes as well as from platelets and from whole blood cells challenged with inflammatory stimuli. sPLA2 was stimulated upon degradation of sphingomyelin (SPH) and produced lysophosphatidic acid (LPA), which induced platelet aggregation. Finally, lysophospholipid-containing vesicles and sPLA2 were detected in inflammatory fluids in relative proportions identical to those used in vitro. We conclude that upon loss of phospholipid asymmetry, cell-derived microvesicles provide a preferential substrate for sPLA2. SPH hydrolysis, which is provoked by various cytokines, regulates sPLA2 activity, and the novel lipid mediator LPA can be generated by this pathway.

Comparative effects of small and large aprotinin doses on bleeding during orthotopic liver transplantation.

Large prophylactic doses of aprotinin efficiently reduce blood loss during orthotopic liver transplantation (OLT). Small doses of aprotinin are usually used to treat fibrinolysis. However, no studies have investigated the benefit of prophylactic administration of a smaller dose of aprotinin during liver transplantation. We compared two methods of aprotinin therapy on transfusion outcome in liver transplant patients in a prospective study of 199 patients undergoing OLT who were randomized to large or small prophylactic doses of aprotinin during the transplant procedure. In the large-dose group (n = 94) an initial dose of 2,000,000 kallikrein inactivation units (KIU) was followed by infusion of 500,000 KIU/h until the patient's return to the intensive care unit. In the small-dose group (n = 95), an initial dose of 500,000 KIU was followed by an infusion of 150,000 KIU/h. Outcome measurements included intraoperative transfusion requirements (packed red blood cells, fresh frozen plasma, platelets, intraoperative salvage) and postoperative hematologic values. There were no differences in transfusion requirements in the two groups of patients. Patients treated with low-dose aprotinin had slightly higher postoperative fibrinogen concentrations. Large-dose aprotinin therapy does not appear to offer additional benefit compared to low-dose aprotinin administration.