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

Abstract

Microthrombus formation and bleeding worsen the outcome after traumatic brain injury (TBI). The aim of the current study was to characterize these processes in the brain parenchyma after experimental TBI and to determine the involvement of coagulation factor XI (FXI). C57BL/6 mice (n = 101) and FXI-deficient mice (n = 15) were subjected to controlled cortical impact (CCI). Wild-type mice received an inhibitory antibody against FXI (14E11) or control immunoglobulin G 24 h before or 30 or 120 min after CCI. Cerebral microcirculation was visualized in vivo by 2-photon microscopy 2-3 h post-trauma and histopathological outcome was assessed after 24 h. TBI induced hemorrhage and microthrombus formation in the brain parenchyma ( p < 0.001). Inhibition of FXI activation or FXI deficiency did not reduce cerebral thrombogenesis, lesion volume, or hemispheric swelling. However, it also did not increase intracranial hemorrhage. Formation of microthrombosis in the brain parenchyma after TBI is independent of the intrinsic coagulation cascade since it was not reduced by inhibition of FXI. However, since targeting FXI has well-established antithrombotic effects in humans and experimental animals, inhibition of FXI could represent a reasonable strategy for the prevention of deep venous thrombosis in immobilized patients with TBI.

Cerebral Microvascular Injury: A Potentially Treatable Endophenotype of Traumatic Brain Injury-Induced Neurodegeneration

“…Injury-induced decreases in CBF and microvascular circulation can result in microthrombus formation (Schwarzmaier et al, 2016) and tissue hypoxia (Bragin et al, 2016). Compared with sham animals, animals exposed to CCI had a greater incidence of stationary leukocyte-platelet aggregates in parenchymal capillaries (Schwarzmaier et al, 2016). Microthrombus aggregation can lead to secondary injuries, including hematoma formation and edema.…”

Pediatric severe factor XI deficiency: A multicenter study

“…Interestingly, in a study evaluating traumatic brain injury in FXI‐deficient mice, cerebral thrombogenesis was not reduced by FXI deficiency 29 . The same study also reported that reduced FXI levels were not associated with increased risk of ICH in mice 29 …”

“…Regarding the patient whose head injury was complicated by cranial sinus vein thrombosis, it is an increasingly reported complication of traumatic head injury 28 . Interestingly, in a study evaluating traumatic brain injury in FXI‐deficient mice, cerebral thrombogenesis was not reduced by FXI deficiency 29 . The same study also reported that reduced FXI levels were not associated with increased risk of ICH in mice 29 …”

Microenvironmental Variations After Blood-Brain Barrier Breakdown in Traumatic Brain Injury

“…By using two-photon microscopy, tissue oxygenation, the diameters of single arterioles and capillaries at different depths in the brain cortex are measured (Tiana et al, 2010;Devor et al, 2011;Kasischke et al, 2011;Schwarzmaier et al, 2016). As for calcium flux, the astrocytes play a key role, when oxygen is limited after BBB breakdown, the astrocyte glycolysis and lactate release are maximized.…”