Temporal Profile of Thrombogenesis in the Cerebral Microcirculation after Traumatic Brain Injury in Mice

Abstract

Traumatic brain injury (TBI) is associated with an almost immediate reduction in cerebral blood flow (CBF). Because cerebral perfusion pressure is often normal under these circumstances it was hypothesized that the reduction of post-traumatic CBF has to occur at the level of the microcirculation. The aim of the current study was to investigate whether cerebral microvessels are involved in the development of blood flow disturbances following experimental TBI. C57/BL6 mice (n = 12) were intubated and ventilated under control of end-tidal Pco(2) ((ET)P(CO2)). After preparation of a cranial window and baseline recordings, the animals were subjected to experimental TBI by controlled cortical impact (CCI; 6 m/sec, 0.5 mm). Vessel lumina and intravascular cells were visualized by in vivo fluorescence microscopy (IVM) using the fluorescent dyes FITC-dextran and rhodamine 6G, respectively. Vessel diameter, cell-endothelial interactions, and thrombus formation were quantified within the traumatic penumbra by IVM up to 2 h after CCI. Arteriolar diameters increased after CCI by 26.2 +/- 2.5% (mean +/- SEM, p < 0.01 versus baseline), and remained at this level until the end of the observation period. Rolling of leukocytes on the cerebrovascular endothelium was observed both in arterioles and venules, while leukocyte-platelet aggregates were found only in venules. Microthrombi occluded up to 70% of venules and 33% of arterioles. The current data suggest that the immediate post-traumatic decrease in peri-contusional blood flow is not caused by arteriolar vasoconstriction, but by platelet activation and the subsequent formation of thrombi in the cerebral microcirculation.

Targeting coagulation factor XII as a novel therapeutic option in brain trauma

“…This may contribute to secondary brain damage, as reported previously both in humans9, 39, 40 and in experimental TBI 5, 6, 7, 10, 29, 41, 42, 43. Low post‐traumatic cerebral blood flow is a known predictor of worse outcome in pediatric severe TBI44 and in adult diffuse TBI 45.…”

The Formation of Microthrombi in Parenchymal Microvessels after Traumatic Brain Injury Is Independent of Coagulation Factor XI

“…15,34,35 Following controlled cortical impact (CCI; n = 8) or the sham procedure (n = 6; see below), the animals were anesthetized with an intraperitoneal injection of a cocktail containing medetomidine (0.5 mg/kg body weight; Domitor Ò ; Dr. E. Graeub AG, Basel, Switzerland), fentanyl (0.05 mg/kg body weight. ; JanssenCilag, Neuss, Germany), and midazolam (5 mg/kg body weight; Dormicum Ò ; Roche, Basel, Switzerland).…”

“…15,34,35 Special care was applied in order to leave the dura mater intact. The location of the window was placed 1 mm laterally to the sagittal suture and 1 mm frontally to the coronal suture, thereby enabling us to view the region 1.5-3.5 mm frontal to the primary contusion (i.e., in the region where we expected maximum microthrombus formation to occur; Fig.…”

“…[3][4][5][6][7] Various mechanisms, such as vasoconstriction and microthrombosis, were discussed as being responsible for post-trauma ischemia. [8][9][10][11][12][13][14][15] Since large extraparenchymal cerebral vessels seem to be neither spastic nor functionally impaired, the reason of post-trauma ischemia was increasingly believed to be located on the level of the cerebral microcirculation.…”

“…The formation of microthrombi after TBI was reported in patients 11,16,17 and by histology in animal studies. [8][9][10]14,[17][18][19][20][21] However, investigations of thrombus formation after TBI in vivo were, so far, limited to the pial microcirculation, 15,22 which is part of the cerebral microcirculation but does not provide nutritive perfusion to the brain parenchyma. Accordingly, the dynamics and mechanisms of post-trauma thrombus formation in the parenchymal microcirculation, which ultimately determines the fate of injured tissue, remain poorly understood.…”