Inhibition of fibrin formation reduces neuroinflammation and improves long-term outcome after intracerebral hemorrhage

Background: Intracerebral hemorrhage (ICH) is a severe type of stroke without effective treatment. The coagulation cascade is activated after blood flows into the brain parenchyma. The conversion of fibrinogen to fibrin is an essential step of coagulation processes, but its influences on neuroinflammation and long-term outcome after ICH have not been adequately studied. Hirudin binds to thrombin and inhibits the conversion of fibrinogen to fibrin. We therefore investigated the impact of hirudin treatment on brain inflammation and long-term outcome of ICH in mice. Methods: Fibrinogen levels were measured in plasma samples from patients with ICH. In mice subjected to collagenase injection, fibrinogen levels were measured in the plasma and brain. The impact of hirudin on neuroinflammation and long-term neurological outcome was determined in ICH mice. Results: Circulating fibrinogen level was increased in patients with ICH at day 1 and day 4 after onset. In ICH mice, fibrinogen levels in the blood and brain were increased at day 7. Delayed daily administration of hirudin from day 7 to day 28 significantly improved long-term outcome in ICH mice. Hirudin treatment reduced leukocyte accumulation in the brain and shifted microglia toward an anti-inflammatory phenotype. In addition, depletion of microglia in ICH mice diminished the benefit of hirudin in ICH mice. Conclusions: These results suggest that inhibition of fibrin formation alleviates brain inflammation and improves long-term outcome after ICH.