Editors' ChoiceStroke

A Sweet Spot for Kallikrein in Intracerebral Hemorrhage

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Science Translational Medicine  02 Mar 2011:
Vol. 3, Issue 72, pp. 72ec27
DOI: 10.1126/scitranslmed.3002293

The odds of surviving a bleeding stroke [intracerebral hemorrhage (ICH)] are poor; the mortality rate approaches 60% one year after the event. With little in the way of effective therapy, those that do survive are often left neurologically impaired. Diabetes and hyperglycemia are independent risk factors for death after an ICH event, but the mechanisms underlying this association have been unclear. Now, in a recent Nature Medicine article, Liu and colleagues suggest that plasma kallikrein and hyperglycemia synergize to inhibit the hemostasis that curtails a hemorrhagic stroke and worsen cerebral bleeding. Plasma kallikrein, a circulating serine protease, plays a pivotal role in the intrinsic coagulation cascade as well as in other processes, such as regulation of blood pressure, angiogenesis, and inflammation.

Using an experimental mouse model of ICH, the researchers delivered autologous infusions of whole blood from diabetic mice directly to the site of brain injury. Hyperglycemic blood from streptozotocin-treated and Akita diabetic mice promoted expansion of the hematoma. Bleeding in these diabetic animals was attenuated when hyperglycemic blood was co-administered with small-molecule inhibitors or neutralizing antibodies against plasma kallikrein, whereas hemorrhage was worsened after administration of purified kallikrein. Kallikrein inhibited collagen-stimulated platelet aggregation—an outcome that was enhanced by hyperglycemia. The authors performed a crucial control to determine whether hyperosmolality could substitute for hyperglycemia and found that hyperosmolar mannitol in nondiabetic rats mimicked the effects of elevated blood glucose. Taken together, these data show that hyperglycemia worsens cerebral hemorrhage through osmotic-sensitive induction of plasma kallikrein activity, which decreases hemostasis by inhibiting platelet aggregation.

The model proposed by Liu et al. has translational significance on several levels. First, these results highlight the importance of continued clinical trials aimed at defining optimal levels of blood glucose after ICH. The sensitivity of cerebral bleeding to blood osmotic pressure suggests that the mannitol commonly used after ICH to decrease intracerebral pressure may be harmful. This possibility merits careful follow-up in human studies. Lastly, the implication of kallikrein in the pathophysiology of ICH suggests a new druggable target for an old disease.

J. Liu et al., Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Nat. Med. 17, 206–210 (2011). [Abstract]

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