Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A.
High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.
Hrachovinová
Ingrid
I
The Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115 USA.
Cambien
Beatrice
B
Hafezi-Moghadam
Ali
A
Kappelmayer
János
J
Camphausen
Raymond T
RT
Widom
Angela
A
Xia
Lijun
L
Kazazian
Haig H
HH
Schaub
Robert G
RG
McEver
Rodger P
RP
Wagner
Denisa D
DD
D000328:Adult; D000818:Animals; D001777:Blood Coagulation / Q000502:physiology; D004195:Disease Models, Animal; D005169:Factor VIII / Q000378:metabolism; D006467:Hemophilia A / Q000378:metabolism / Q000628:therapy*; D006487:Hemostasis / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011993:Recombinant Fusion Proteins; D005169:Factor VIII