Article
Perihematomal thrombin expression is initiated in the early phase after intracerebral hemorrhage and correlates with worse neurological outcome in patients with ICH
Perihematomal thrombin expression is initiated in the early phase after intracerebral hemorrhage and correlates with worse neurological outcome in patients with ICH
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Published: | June 26, 2020 |
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Objective: Spontaneous intracerebral hemorrhage (ICH) is a leading cause of disability and mortality. Thrombin induces brain edema and neuronal death. However, whether the perihematomal thrombin is generated by a local cerebral thrombin system or washed in from circulation, is still unknown. In our study, we utilize a unique mouse model (1) as well as cerebrospinal fluid (CSF) samples of patients with ICH (2).
Methods:
- 1.
- Prothrombin expression was analyzed using quantitative RT-PCR 4h and 24h after ICH in our mouse model. Further, perihematomal thrombin concentration 24h after ictus was measured using immunohistology. The neurological outcome was assed using the Rotarod performance test.
- 2.
- Blood and CSF samples were obtained from 12 patients with ICH (7 male, 5 females; mean age 65+-2 years) and 2 controls (both male) on days 1 and 3. Factor IIa was analyzed using enzyme-linked immunosorbent assay. Clot volumes were determined based on computed tomography and neurological outcome was determined 6 weeks after ICH onset using the modified Rankin Scale.
Results:
- 1.
- Animals receiving blood injections showed a 4.24+-.0.5 (P < 0.05) fold increase in thrombin concentrations 24h after ICH. Prothrombin transcription was increased 4h after ICH and decreased of the course of 24h (4.7+-1.6 fold; P < 0.05). Elevated thrombin concentrations correlate with detrimental neurological outcome (sham: 72+-.8.85sec, blood: 3.5+-.95).
- 2.
- CSF thrombin concentrations are likewise elevated after ICH (P < 0.05) compared to controls. The thrombin concentration does not correlate with the initial clot size (r2 = 0.21, p = 0.15) or the presence of intraventricular hemorrhage. However, increasing thrombin concentration in CSF correlate with a detrimental neurological outcome 6 weeks after onset of ICH (r2 = 0.5, p < .05).
Conclusion: Our study strengthens the importance of thrombin as contributor to secondary injury after ICH and as potential target for future pharmacotherapy.