Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice

Abstract

Background and Purpose-Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke. Methods-TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated. Results-Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant. Conclusions-Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy.

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

“…To dissect out the contribution of PAI-1 inhibition and TAFI inhibition during ischaemic stroke, Denorme et al used monoclonal antibodies to identify the effect of inhibiting each of these antifibrinolytic factors. In a mouse model of transient middle cerebral artery occlusion, inhibition of TAFI or PAI-1 significantly decreased fibrin(ogen) deposition in the ischaemic brain, thereby improving reperfusion, but the combined inhibition had an additive beneficial effect [158]. PAI-1 inhibition is also possible with nanobodies, which was demonstrated by Zhou et al who used nanobodies against PAI-1 to inhibit profibrinolytic activity in an in vitro clot lysis assay [159].…”

The Role of PAI-1 4G/5G Promoter Polymorphism and Its Levels in the Development of Ischemic Stroke in Young Indian Population

“…While in our study, we have tried to overcome such limitations to arrive at conclusive results. However, a recent study by Denorme et al, 32,33 on murine acute IS model demonstrated that targeting PAI-1 inhibition through a monoclonal antibody helps to attenuate fibrin deposition and improves reperfusion while the bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding. 31 Genetic variations are quite determining in influencing PAI-1 levels, and the most studied genetic variant, impacting PAI-1 levels, is the 4G/5G promoter polymorphism.…”

Impaired thrombolytic status predicts adverse cardiac events in patients undergoing primary percutaneous coronary intervention

“…Furthermore, when intracoronary thrombi aspirated during PPCI were examined, increased von Willebrand factor, P-selectin and fibrin content were related to unfavourable thrombus characteristics rendering the thrombus resistant to lytic therapy (33) and denser plasma fibrin clots were independently associated with high fibrin content (34). Recently, a crucial role of fibrinolysis 18 in determining infarct outcome was shown by combined inhibition of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1, prior to transient cerebral artery occlusion in mice, which reduced cerebral infarct size by 50% (35).…”