Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein.
Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.
Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA.
Jia
J
Liu
Ben-Bo
BB
Gao
Allen C
AC
Clermont
Price
P
Blair
Tamie J
TJ
Chilcote
Sukanto
S
Sinha
Robert
R
Flaumenhaft
Edward P
EP
Feener
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D006406:Hematoma / Q000503:physiopathology*; D006943:Hyperglycemia / Q000503:physiopathology*; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D020842:Plasma Kallikrein / Q000494:pharmacology / Q000502:physiology*; D010958:Plasminogen / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D010958:Plasminogen; D020842:Plasma Kallikrein
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