title: Phosphodiesterase 3 inhibition reduces platelet activation and monocyte tissue factor expression in knee arthroplasty patients.
abstract: BACKGROUND
  Tissue damage during surgery activates platelets and provokes a prothrombic state. The current study attempted to determine the impact of phosphodiesterase 3 inhibitors on platelet activation, platelet-leukocyte aggregate formation, and monocyte tissue factor expression during and after total knee arthroplasty.
  
  
  METHODS
  Thirty-four patients undergoing scheduled total knee arthroplasty were randomly assigned to receive either the phosphodiesterase 3 inhibitor milrinone or the same amount of saline perioperatively. The effects of milrinone on platelet and leukocyte function in vitro were then assessed in healthy volunteers.
  
  
  RESULTS
  Perioperative infusion of milrinone significantly attenuated platelet activation; phosphorylation of intraplatelet p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt; and platelet-leukocyte aggregation. Furthermore, perioperative tissue factor expression on monocytes and fibrin monomer complex production were reduced by milrinone infusion in patients undergoing total knee arthroplasty. In vitro studies using adenosine diphosphate- and collagen-stimulated blood samples from healthy volunteers confirmed the antiplatelet effects and reduced monocyte tissue factor expression by milrinone. These studies further showed that platelet aggregation and integrin alpha(IIb)beta(3) activation were modified by intraplatelet phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways, and that P-selectin expression on platelets and platelet-leukocyte aggregation were modulated by intraplatelet p38 mitogen-activated protein kinase pathway.
  
  
  CONCLUSIONS
  Continuous milrinone infusion has the potential to reduce platelet activation and monocyte tissue factor expression during the perioperative period in total knee arthroplasty. These events may be mediated in part by the ability of milrinone to reduce activation of intraplatelet mitogen-activated protein kinases and phosphatidylinositol 3-kinase. The clinical impact of phosphodiesterase 3 inhibition on perioperative hemostasis remains to be elucidated.
authors.affiliation: Department of Anesthesiology and Intensive Care, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Beppu
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kageyama
authors.forename: Toshiki
authors.initials: T
authors.lastname: Mizobe
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shime
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Matsuda
mesh_terms: D000368:Aged; D000768:Anesthesia, General; D019645:Arthroplasty, Replacement, Knee; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D020105:Milrinone / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019007:P-Selectin / Q000096:biosynthesis / Q000097:blood; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects*; D011446:Prospective Studies; D013925:Thromboplastin / Q000096:biosynthesis*
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D019007:P-Selectin; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; C011468:fibrinmonomer; D013925:Thromboplastin; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases; D020105:Milrinone