Diabetes is associated with a 2 to 6-fold increased risk of stroke, which is a leading cause of mortality and adult disability. Stroke is often associated with intracerebral hemorrhage (ICH), which occurs as the primary event in hemorrhagic stroke and can also occur spontaneously following an initial ischemia event, especially during thrombolytic intervention. Both diabetes and hyperglycemia are associated with worse clinical outcomes following ICH, including increased early and long-term mortality, occurrence of symptomatic ICH in stroke patients treated with intravenous tissue plasminogen activator (tPA), and increased hematoma volume and expansion, which are significant and independent determinants of poor clinical outcomes. Although a large amount of clinical data has associated diabetes and hyperglycemia with poor clinical outcomes, and nearly 50% of all acute stroke patients have hyperglycemia upon admission, the effects of glucose and its related mechanisms on ICH are poorly understood. Moreover, information on the clinical benefit of glucose lowering in ICH is limited and controversial, and the potential therapeutic window for glucose lowering is unknown. Recently we have reported that hyperglycemia increases hematoma formation in rodent models of ICH and that this response is mediated by plasma kallikrein. The mechanisms for this response involved a glucose sensitive plasma kallikrein-mediated inhibition of platelet activation, which interfered with collagen-induced GPVI receptor activation. These studies have revealed a novel function of plasma kallikrein in the inhibition of platelet aggregation, which is an early event in establishing hemostasis following cerebral vascular injury. In preliminary studies, we have demonstrated that hyperglycemia also increases hematoma area in both tPA and in hypertension-induced models of spontaneous ICH, and we have begun to map the functional domain on plasma kallikrein that is responsible for its inhibitory effects of platelet activation. These exciting findings have suggested that plasma kallikrein actions are glucose sensitive and that this enzyme has previously unrecognized effects in the coagulation system. This grant will examine the potential therapeutic opportunities using glucose control and new strategies to inhibit PK to reduce ICH in a series of preclinical studies to develop and characterize findings using multiple experimental models and molecular interventions. The mechanisms that mediate the effects of plasma kallikrein will be characterized by identifying the structural domain on this protein that mediates this anti-platelet effect, which we have shown does not require plasma kallikrein's catalytic activity. Since a major complication associated with ICH is its effects on edema, we will examine the effects of insulin and plasma kallikrein inhibition on the prevention and reversal of ICH-induced edema. This grant will examine the hypothesis that the direct effects of plasma kallikrein on hemostasis and peri-hematomal edema contribute to the poor ICH outcomes in diabetes and hyperglycemia.

Public Health Relevance

Diabetes and high blood glucose levels are associated with increased bleeding during hemorrhagic stroke, resulting in worse clinical outcomes. Recent studies have revealed that an enzyme named plasma kallikrein contributes an impairment to control cerebral bleeding in animal models with diabetes. This grant will perform mechanistic studies to characterize this newly identified function of plasma kallikrein and preclinical studies to examine potential therapeutic opportunities in reducing cerebral bleeding by controlling blood glucose and inhibiting plasma kallikrein.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Joslin Diabetes Center
United States
Zip Code
Simão, Fabrício; Feener, Edward P (2017) The Effects of the Contact Activation System on Hemorrhage. Front Med (Lausanne) 4:121
Simão, Fabrício; Ustunkaya, Tuna; Clermont, Allen C et al. (2017) Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke. Blood 129:2280-2290
Kokoye, Yasin; Ivanov, Ivan; Cheng, Qiufang et al. (2016) A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation. Thromb Res 140:118-124
Feener, E P; Zhou, Q; Fickweiler, W (2013) Role of plasma kallikrein in diabetes and metabolism. Thromb Haemost 110:434-41