Background: Venous thromboembolism (VTE) complicates ∼1.2 of every 1000 deliveries. Despite these low absolute risks, pregnancy-associated VTE is a leading cause of maternal morbidity and mortality.
...Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and others in decisions about the prevention and management of pregnancy-associated VTE.
Methods: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.
Results: The panel agreed on 31 recommendations related to the treatment of VTE and superficial vein thrombosis, diagnosis of VTE, and thrombosis prophylaxis.
Conclusions: There was a strong recommendation for low-molecular-weight heparin (LWMH) over unfractionated heparin for acute VTE. Most recommendations were conditional, including those for either twice-per-day or once-per-day LMWH dosing for the treatment of acute VTE and initial outpatient therapy over hospital admission with low-risk acute VTE, as well as against routine anti-factor Xa (FXa) monitoring to guide dosing with LMWH for VTE treatment. There was a strong recommendation (low certainty in evidence) for antepartum anticoagulant prophylaxis with a history of unprovoked or hormonally associated VTE and a conditional recommendation against antepartum anticoagulant prophylaxis with prior VTE associated with a resolved nonhormonal provoking risk factor.
Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and ...well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy – however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.
Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms ...driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.
Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress ...response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell-cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1β, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.
Mild traumatic brain injury (mTBI) leads to diverse symptoms including mood disorders, cognitive decline, and behavioral changes. In some individuals, these symptoms become chronic and persist in the ...long-term and can confer an increased risk of neurodegenerative disease and dementia diagnosis later in life. Despite the severity of its consequences, the pathophysiological mechanism of mTBI remains unknown. In this post-mortem case series, we assessed DNA damage-induced cellular senescence pathways in 38 professional athletes with a history of repeated mTBI and ten controls with no mTBI history. We assessed clinical presentation, neuropathological changes, load of DNA damage, morphological markers of cellular senescence, and expression of genes involved in DNA damage signaling, DNA repair, and cellular senescence including the senescence-associated secretory phenotype (SASP). Twenty-eight brains with past history of repeated mTBI history had DNA damage within ependymal cells, astrocytes, and oligodendrocytes. DNA damage burden was increased in brains with proteinopathy compared to those without. Cases also showed hallmark features of cellular senescence in glial cells including astrocytic swelling, beading of glial cell processes, loss of H3K27Me3 (trimethylation at lysine 27 of histone H3) and lamin B1 expression, and increased expression of cellular senescence and SASP pathways. Neurons showed a spectrum of changes including loss of emerin nuclear membrane expression, loss of Brahma-related gene-1 (BRG1 or SMARCA4) expression, loss of myelin basic protein (MBP) axonal expression, and translocation of intranuclear tau to the cytoplasm. Expression of DNA repair proteins was decreased in mTBI brains. mTBI brains showed substantial evidence of DNA damage and cellular senescence. Decreased expression of DNA repair genes suggests inefficient DNA repair pathways in this cohort, conferring susceptibly to cellular senescence and subsequent brain dysfunction after mTBI. We therefore suggest that brains of contact-sports athletes are characterized by deficient DNA repair and DNA damage-induced cellular senescence and propose that this may affect neurons and be the driver of brain dysfunction in mTBI, predisposing the progression to neurodegenerative diseases. This study provides novel targets for diagnostic and prognostic biomarkers, and represents viable targets for future treatments.
Emerging evidence suggests cellular senescence, as a consequence of excess DNA damage and deficient repair, to be a driver of brain dysfunction following repeated mild traumatic brain injury (rmTBI). ...This study aimed to further investigate the role of deficient DNA repair, specifically BRCA1-related repair, on DNA damage-induced senescence. BRCA1, a repair protein involved in maintaining genomic integrity with multiple roles in the central nervous system, was previously reported to be significantly downregulated in post-mortem brains with a history of rmTBI. Here we examined the effects of impaired BRCA1-related repair on DNA damage-induced senescence and outcomes 1-week post-rmTBI using mice with a heterozygous knockout for BRCA1 in a sex-segregated manner. Altered BRCA1 repair with rmTBI resulted in altered anxiety-related behaviours in males and females using elevated zero maze and contextual fear conditioning. Evaluating molecular markers associated with DNA damage signalling and senescence-related pathways revealed sex-specific differences attributed to BRCA1, where females exhibited elevated DNA damage, impaired DNA damage signalling, and dampened senescence onset compared to males. Overall, the results from this study highlight sex-specific consequences of aberrant DNA repair on outcomes post-injury, and further support a need to develop sex-specific treatments following rmTBI.
Mild traumatic brain injuries (mTBIs) are a prevalent form of injury that can result in persistent neurological impairments. Microglial activation has become increasingly recognized as a key process ...regulating the pathology of white matter in a wide range of brain injury and disease contexts. As white matter damage is known to be a major contributor to the impairments that follow mTBI, microglia have rightfully become a common target of investigation for the development of mTBI therapies and biomarkers. Recent work has demonstrated that the efficacy of microglial manipulation as a therapeutic intervention following injury or disease is highly time-sensitive, emphasizing the importance of advancing our understanding of the dynamics of post-mTBI microglial activation from onset to resolution. Current reporting of microglial activation in experimental studies of mTBI is non-standardized, which has limited our ability to identify concrete patterns of post-mTBI microglial activation over time. In this review, we examine preclinical studies of mTBI that report on microglial activation in white matter regions to summarize our current understanding of these patterns. Specifically, we summarize timecourses of post-mTBI microglial activation in white matter regions of the brain, identify factors that influence this activation, examine the temporal relationship between microglial activation and other post-mTBI assessments, and compare the relative sensitivities of various methods for detecting microglial activation. While the lack of replicated experimental conditions has limited the extent of conclusions that can confidently be drawn, we find that microglia are activated over a wide range of timecourses following mTBI and that microglial activation is a long-lasting outcome of mTBI that may resolve after most typical post-mTBI assessments, with the exception of those measuring oligodendrocyte lineage cell integrity. We identify several understudied parameters of post-mTBI microglial activation in white matter, such as the inclusion of female subjects. This review summarizes our current understanding of the progression of microglial activation in white matter structures following experimental mTBI and offers suggestions for important future research directions.
Ethyl glucuronide (EtG), a minor metabolite of ethanol, is used as a marker of alcohol consumption in a variety of clinical and forensic settings. At present there are very few studies of ...UDP-glucuronosyltransferases (UGT), responsible for catalyzing EtG formation, and the possible effect of nutritional components, e.g. flavonoids, which are extensively glucuronidated, on EtG formation has not been addressed at all. The following incubation conditions were optimized with regard to previously published conditions: buffer, substrate concentration, and incubation time. Isolation of EtG from the incubation mixture was also optimized. Recombinant UGT enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 2B10, 2B15) were screened for their activity towards ethanol, and kinetic data were then established for all enzymes. It was decided to study the effect of the flavonoids quercetin and kaempferol on glucuronidation of ethanol. Isolation was by solid-phase extraction (SPE) to minimize matrix effects. Analysis was performed by liquid chromatography–tandem mass spectrometry (LC–MS–MS), with EtG-d
5
as the internal standard. SPE was vital to avoid severe ion suppression after direct injection of the incubation solution. EtG formation was observed for all enzymes under investigation; their kinetics followed the Michaelis–Menten model, meaning the maximum reaction rate achieved at saturating substrate concentrations (
V
max
) and the substrate concentration at which the reaction rate is half of
V
max
(Michaelis–Menten constant,
K
m
) could be calculated. The highest rate of glucuronidation was observed with UGT1A9 and 2B7. After co-incubation with both flavonoids, formation of EtG was significantly reduced for all enzymes except for UGT2B15, whose activity did not seem to be affected. Results reveal that multiple UGT isoforms are capable of catalyzing glucuronidation of ethanol; nevertheless, the effect of UGT polymorphism on glucuronidation of ethanol needs further study. Formation of EtG is inhibited by the flavonoids under investigation. Obviously, nutritional components affect conversion of ethanol to EtG. This observation may serve as a partial explanation of its variable formation in man.
Figure
Dixon Plot for determination of the inhibitory constant Ki for UGT1A9 and quercetin
To determine whether an association exists between career duration or position played and the presence of chronic traumatic encephalopathy (CTE) at autopsy in a series of elite football and hockey ...players.
This retrospective cohort study analyzed postmortem brains of 35 former football or hockey players (29 professional, 6 university varsity/major junior), with the presence of CTE at autopsy as the primary outcome. Position played (highest level), age at retirement (indicator of lifetime exposure to sport), and hockey fighting/penalization histories (surrogate marker for role/style of play) were collected. A blinded neuropathologic evaluation of each participant was performed, providing an assessment for neurodegenerative diseases including CTE, based on the 2015 National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineeringconsensus paper.
In total, 17 of 35 former players (48.6%) showed pathologic evidence of CTE. There was no correlation found between position played and CTE presence, nor between hockey fighting/penalization histories and CTE, in either the football or hockey groups (
> 0.75, Mann-Whitney-Wilcoxon). Similarly, there was no association between age at retirement and CTE presence (
> 0.5, Mann-Whitney-Wilcoxon). In 24 of 35 cases (68.6%), other neuropathologies were present, 13 of 24 (54.2%) of which were coexistent with CTE.
In this cohort of 35 former collision sports athletes, no significant associations were found between career duration, position or role played, and CTE presence at autopsy. Although limited by the small and nonrepresentative sample studied, these findings suggest that nonsport factors may be important to understand differing susceptibilities among athletes to CTE.
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