Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice

Blood. 2015 Apr 16;125(16):2558-67. doi: 10.1182/blood-2014-08-588442. Epub 2015 Feb 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifibrinolytic Agents / pharmacology
  • Brain / blood supply
  • Brain / metabolism
  • Brain Injuries / blood
  • Brain Injuries / complications*
  • Cerebral Hemorrhage / etiology
  • Cerebral Hemorrhage / genetics
  • Cerebral Hemorrhage / metabolism*
  • Fibrin / metabolism
  • Fibrinolysis / drug effects
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Plasminogen / metabolism
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / metabolism
  • Protein Binding
  • Time Factors
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*
  • Tranexamic Acid / pharmacology
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism*

Substances

  • Antifibrinolytic Agents
  • Plasminogen Activator Inhibitor 1
  • Tranexamic Acid
  • Fibrin
  • Plasminogen
  • Tissue Plasminogen Activator
  • Urokinase-Type Plasminogen Activator