Endogenous platelet factor 4 stimulates activated protein C generation in vivo and improves survival after thrombin or lipopolysaccharide challenge.
Pharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affects APC generation. Mice completely deficient in PF4 (mPF4(-/-)) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C-deficient (PC(+/-)) mice. Transgenic mice overexpressing human PF4 (hPF4(+)) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen in PC(+/-) mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4(+) and PC(+/-)/hPF4(+) mice had improved survival. Further, infusion of hPF4(+) platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting.
Kowalska
M Anna
MA
Division of Hematology, The Children's Hospital of Philadelphia, PA 19104, USA. kowalska@email.chop.edu
Mahmud
Shawn A
SA
Lambert
Michele P
MP
Poncz
Mortimer
M
Slungaard
Arne
A
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001777:Blood Coagulation; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006490:Hemostatics / Q000494:pharmacology*; D006579:Heterozygote; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010978:Platelet Factor 4 / Q000235:genetics / Q000502:physiology*; D011486:Protein C / Q000096:biosynthesis*; D020151:Protein C Deficiency; D015996:Survival Rate; D013917:Thrombin / Q000494:pharmacology*
D000925:Anticoagulants; D006490:Hemostatics; D008070:Lipopolysaccharides; D011486:Protein C; D010978:Platelet Factor 4; D013917:Thrombin