Novel treatment for DIC

Project Summary
Several diseasesincluding endotoxemiaand sepsis can cause disseminated intravascular
coagulationDICDIC can induce the formation of microvascular thrombicausing organ
failure and death in the absence of the appropriate treatmentTo datethere are no drugs to
treat DICand several reagents have been tested buttheir strong doses can lead to severe
bleedingsignificantly diminishing their benefitsA severe insult like systemic inflammation
activates both endothelium and coagulation systemThis is characterized by the increment of
a widespread of fibrin deposition that is a hallmark in DICOur candidate drugthe Aprotein
binds to fibrinIn vitrothe Aprotein delayed fibrin formation and blocked platelet adhesion to
fibrin ogenunder high shear stressImportantlythe Aprotein efficiently reduced the
formation of microvascular thrombosis in two different animal species and models for DICa murine model for endotoxemia induced DICanda pig model for bacteria induced DICNote that the Aprotein was given to the micehours after the insult with endotoxinwhile
the Aprotein was administered to the pigshours after the intravenous inoculation of
bacteriaFurthermorein the murine model the Aprotein prevented organ failureand
markedly improved the survival of the treated miceNotablythe Aprotein had no effect on
platelet aggregation in vitro nor affected the tail bleeding time in miceThe Aims for this STTR
areAimTo determine the pharmacological benefit of the Aprotein on reducing
microvascular thrombosis in a porcine model of bacteria induced sepsisThis aim will
demonstrate that the Aprotein is effective in reducing microvascular thrombosis and proinflammatory markers using a gram positive or gram negative bacteria induced DIC modelAimTo determine the safety of the Aprotein for hemostasisThis aim will investigate the
effect of the Aprotein on hemostasis using large animal modelsIn Phase IIwe will optimize
the production of the candidate productand will perform pharmacokineticpharmacologicaland toxicological studiesFinallywe will perform time window studies using larger animals Narrative
This project will further investigate the beneficial effect of Aprotein in treating
disseminated microvascular thromboses such as disseminated intravascular
coagulationDICas seen in conditions like sepsisDifferent primary disordersincluding sepsisendotoxemiacancerand malariacan cause DIC and currentlythe
management of DIC is restricted to treat the underlying conditionand use of antibiotics
in sepsisThe development of the candidate drug addresses this unmet medical need
by providing a safe and effective novel therapeutic approach