title: Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice.
abstract: Persistent intracerebral hemorrhage (ICH) is a major cause of death and disability after traumatic brain injury (TBI) for which no medical treatment is available. Delayed bleeding is often ascribed to consumptive coagulopathy initiated by exposed brain tissue factor. We examined an alternative hypothesis, namely, that marked release of tissue-type plasminogen activator (tPA) followed by delayed synthesis and release of urokinase plasminogen activator (uPA) from injured brain leads to posttraumatic bleeding by causing premature clot lysis. Using a murine model of severe TBI, we found that ICH is reduced in tPA(-/-) and uPA(-/-) mice but increased in PAI-1(-/-) mice compared with wild-type (WT) mice. tPA(-/-), but not uPA(-/-), mice developed a systemic coagulopathy post-TBI. Tranexamic acid inhibited ICH expansion in uPA(-/-)mice but not in tPA(-/-) mice. Catalytically inactive tPA-S(481)A inhibited plasminogen activation by tPA and uPA, attenuated ICH, lowered plasma d-dimers, lessened thrombocytopenia, and improved neurologic outcome in WT, tPA(-/-), and uPA(-/-) mice. ICH expansion was also inhibited by tPA-S(481)A in WT mice anticoagulated with warfarin. These data demonstrate that protracted endogenous fibrinolysis induced by TBI is primarily responsible for persistent ICH and post-TBI coagulopathy in this model and offer a novel approach to interrupt bleeding.
authors: Department of Clinical Biochemistry and.
authors: Nuha
authors: N
authors: Hijazi
authors: Department of Clinical Biochemistry and.
authors: Rami
authors: R
authors: Abu Fanne
authors: MRI/MRS Laboratory of the Human Biology Research Center, Department of Medical Biophysics, Hebrew University-Hadassah Medical Center, Jerusalem, Israel; and.
authors: Rinat
authors: R
authors: Abramovitch
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Serge
authors: S
authors: Yarovoi
authors: Department of Clinical Biochemistry and.
authors: Muhamed
authors: M
authors: Higazi
authors: Department of Clinical Biochemistry and.
authors: Suhair
authors: S
authors: Abdeen
authors: Department of Clinical Biochemistry and.
authors: Maamon
authors: M
authors: Basheer
authors: Department of Clinical Biochemistry and.
authors: Emad
authors: E
authors: Maraga
authors: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Douglas B
authors: DB
authors: Cines
authors: Department of Clinical Biochemistry and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors: Abd Al-Roof
authors: AA
authors: Higazi
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D001930:Brain Injuries / Q000097:blood / Q000150:complications*; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014148:Tranexamic Acid / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D000933:Antifibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D014148:Tranexamic Acid; D005337:Fibrin; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator