Perioperative platelet activation and the inhibitory effect of milrinone.

SURGERY activates the circulating pool of blood platelets. This process is most intense at sites of vascular injury, where platelets adhere and aggregate to plug vascular holes and provide the phospholipid surface necessary for coagulation proteins to assemble and generate fibrin. However, activated platelets can also be detected in blood remote from sites of surgical trauma. These less intensively activated circulating platelets may contribute to the postsurgical prothrombotic state by responding more vigorously to subsequent activating stimuli or by inducing procoagulant behavior in other cells, primarily leukocytes and endothelial cells. In this issue of ANESTHESIOLOGY, Beppu et al. extend previous observations by characterizing perioperative activation of platelet intracellular activation pathways, monocyte tissue factor expression, and the ability of milrinone to inhibit these prothrombotic activation events. Platelets circulate in the blood in a quiescent state and can be rapidly activated by a variety of chemical (e.g., collagen, thrombin, adenosine diphosphate, epinephrine) and physical (shear stress) stimuli. Recognition of these extracellular stimuli by specific platelet surface receptors leads to activation of intracellular activation pathways, which in turn increases the surface expression of platelet adhesive molecules, such as the fibrinogen receptor (integrin IIb 3) and P-selectin. The expression of a conformationally active fibrinogen receptor transforms platelets from a quiescent to an active state capable of binding soluble fibrinogen and aggregating. This activation step is critical to clinical hemostasis and is the target of glycoprotein IIb–IIIa antagonists in current therapeutic use for prevention of coronary thrombosis. The expression of P-selectin allows platelets to bind to a constitutively expressed receptor on monocytes and neutrophils termed P-selectin glycoprotein ligand 1. The clinical relevance of these platelet–leukocyte interactions is not entirely clear; however, greater numbers of circulating platelet–leukocyte aggregates are associated with increased risk of recurrent myocardial ischemia in patients with acute coronary syndromes. In laboratory models, the interaction between platelet Pselectin and leukocyte P-selectin glycoprotein ligand 1 promotes tissue factor expression on monocytes and formation of circulating tissue factor–bearing microparticles, which contribute to thrombus formation in vivo. In their report, Beppu et al. confirm previous observations by demonstrating increased platelet aggregability and expression of conformationally active fibrinogen receptors (identified by PAC1 binding) on circulating platelets remote from the site of surgery. They demonstrate an increase in platelet P-selectin expression and platelet–leukocyte aggregate formation in the perioperative period, consistent with in vivo platelet activation. The authors also observe increased activation (phosphorylation) of several intracellular platelet pathways. Specifically, they note postoperative increases in phosphorylation of the mitogen-activated protein kinases (MAPKs), p38 MAPK and extracellular signal–regulated kinase 1/2, and of Akt, which is dependent on phosphotidylinositol 3-kinase for activation. The reported observations on MAPK pathways are of particular interest because the role of these kinases in platelet function is incompletely understood and has not been previously characterized in surgical patients. Also of great interest is the authors’ observation that monocyte tissue factor expression increases postoperatively, paralleling results of platelet–leukocyte aggregate formation. The reported increase in plasma fibrin monomer is consistent with activation of platelets and monocytes, although these events are not definitively linked by the studies performed. The authors examined the effect of milrinone infusion on platelet and monocyte function and fibrin formation in vivo in a randomized clinical trial of knee arthroplasty patients. Compared with placebo, a 24-h infusion of milrinone reduced the postoperative increase in platelet aggregability, PAC1 and P-selectin expression, phosphorylation of platelet p38 MAPK, extracellular signal–regulated kinase 1/2 and Akt, platelet–leukocyte aggregate formation, monocyte tissue factor expression, and fibrin monomer formation. Milrinone is a phosphodiesterase inhibitor with relative specificity for the phosphodiesterase 3 (PDE3) isoform, and milrinone infusion increases cyclic adenosine monophosphate levels in platelets and other PDE3-expressing cells. Cyclic adenosine monophosphate is a second messenger regulating platelet calcium metabolism, which is critical to the activation state of platelets. An increase in cyclic adenosine monophosphate reduces platelet calcium concentration, suppressing platelet activation caused by a variety of stimuli. Although milrinone infusion is approved by the U.S. Food and Drug Administration for use in congestive heart failure, its antiplatelet effects are well known, and, indeed, another PDE3 inhibitor, cilostazol, is approved for treatment of intermittent claudication (in the United This Editorial View accompanies the following article: Beppu S, Nakajima Y, Shibasaki M, Kageyama K, Mizobe T, Shime N, Matsuda N: Phosphodiesterase 3 inhibition reduces platelet activation and monocyte tissue factor expression in knee arthroplasty patients. ANESTHESIOLOGY 2009; 111:1227–37.