Optimizing DCD Liver Grafts With Prolonged Warm Ischemic Time Using Stabilized Plasmin in a Static Cold Storage Orthotopic Rat Liver Transplant Model.

Background: The clinical success of liver transplantation has led to increased demand, requiring further expansion of the donor pool. Therapeutic interventions to optimize organs from donation after circulatory death (DCD) have significant potential to mitigate the organ shortage. Dysfunction in DCD liver grafts is mediated by microvascular thrombosis during the warm ischemic period, and strategies that reduce this thrombotic burden may improve graft function.

Direct microscopic monitoring of initial and dynamic clot lysis using plasmin or rt-PA in an in vitro flow system.

Introduction: Plasmin is a direct-acting thrombolytic agent with a favorable safety profile upon intra-arterial delivery in pre-clinical and phase I studies. However, the thrombolytic efficacy of plasmin, relative to that of rt-PA, remains to be established. We have compared the dynamics of clot lysis with plasmin or rt-PA in an in vitro perfusion system, in which thrombolytic agent is administered locally, allowed to induce lysis for short intervals, then washed with plasma in a re-circulation circuit.

Comparison of local thrombolytic efficacy of plasmin and rt-PA in an in-vitro flow system; a pilot study.

Plasmin, a directly acting thrombolytic agent, demonstrated a very favorable safety profile upon intra-arterial delivery to the clot site; however, its thrombolytic efficacy remains to be further assessed. In this study, differences in thrombolysis between clots exposed to equimolar concentrations of plasmin and recombinant tissue-type plasminogen activator (rt-PA) after partial vessel recanalization were tested in a model system. Model blood clots were prepared in glass chambers enabling direct observation by dynamic optical microscopy.

Safety evaluation of a recombinant plasmin derivative lacking kringles 2-5 and rt-PA in a rat model of transient ischemic stroke.

Background: Tissue type plasminogen activator is the only approved thrombolytic agent for the treatment of ischemic stroke. However, it carries the disadvantage of a 10-fold increase in symptomatic and asymptomatic intracranial hemorrhage. A safer thrombolytic agent may improve patient prognosis and increase patient participation in thrombolytic treatment.

Haemostatic safety of a unique recombinant plasmin molecule lacking kringles 2-5.

We previously demonstrated a significant margin of haemostatic safety for full-length plasmin in comparison with tissue plasminogen activator (t-PA). We now report studies that compare haemostatic safety of full-length plasmin with a novel recombinant plasmin derivative, (Δ K2-5) plasmin, consisting of kringle 1 linked to the serine protease domain of plasmin. Agent was administered intravenously in a randomised, blinded manner in a rabbit model of fibrinolytic haemorrhage.