RGD Reference Report - Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. - Rat Genome Database

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

Authors: Hijazi, N  Abu Fanne, R  Abramovitch, R  Yarovoi, S  Higazi, M  Abdeen, S  Basheer, M  Maraga, E  Cines, DB  Higazi, AA 
Citation: Hijazi N, etal., Blood. 2015 Apr 16;125(16):2558-67. doi: 10.1182/blood-2014-08-588442. Epub 2015 Feb 11.
RGD ID: 11541064
Pubmed: PMID:25673638   (View Abstract at PubMed)
PMCID: PMC4400292   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2014-08-588442   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Cerebral Hemorrhage severityISOPlat (Mus musculus)11541064; 11541064associated with Brain InjuriesRGD 
Cerebral Hemorrhage severityIMP 11541064associated with Brain InjuriesRGD 

Objects Annotated

Genes (Rattus norvegicus)
Plat  (plasminogen activator, tissue type)

Genes (Mus musculus)
Plat  (plasminogen activator, tissue)

Genes (Homo sapiens)
PLAT  (plasminogen activator, tissue type)


Additional Information