For a long time, psychiatric diseases, as opposed to neurological diseases, were defined
by the absence of brain lesions. Recent advances in imaging show that this is not
quite that simple. This conceptual shift has been made possible largely due to two
major complementary technological developments. Magnetic resonance imaging, both anatomical
and functional, sheds light on the volumes of gray matter and the microstructure of
the white matter; in other words, on the architecture of the brain and its overall
functioning. Positron emission tomography provides information on brain biochemistry
by marking a neurotransmitter with a radioactive agent, which enables tissue visualization.
The considerable progress made in brain imaging over the last 10 years reshuffles
the cards: psychiatric illnesses may have an organic basis. However, whereas brain
lesions are visible to the naked eye in neurological patients, the detection of brain
changes in psychiatric patients requires computer and statistical analysis of the
images.
The brain does not function independently of general physiology. Its cellular activity
depends on the systemic vascular circulation and on the performance of the blood–brain
barrier (BBB) that is crucial for neuronal[1] and glial cell[2] functions. The brain also affects and modulates general physiology through the neuroendocrine
system that involves interactions between the hypothalamus, pituitary gland, and endocrine
glands, where hormones are produced and released into the bloodstream to regulate
various bodily functions.[3]
[4]
Due to this increasingly crucial interface, it is becoming promising to explore the
consequences of vascular and hemostatic abnormalities for brain functioning in the
context of psychiatric diseases and their underlying neurobiological abnormalities.
Stress is a reaction of the body to a fearsome situation, increasingly reported as
a risk factor for a wide range of health problems, including vascular thrombotic events.
In that context, von Känel has reviewed the available evidence on stress-induced hypercoagulability,[5] integrating extensive findings from comprehensive reviews, meta-analyses, and cutting-edge
genetic studies. Cohort studies demonstrate an association between stress and a hypercoagulable
state in atherothrombosis and venous thromboembolism (VTE). Mendelian randomization
studies suggest that these associations are partially causal. The activation of the
sympathetic nervous system and the hypothalamic–pituitary–adrenal axis, along with
vagal withdrawal, and the effects of catecholamines, cortisol, and vasopressin, are
the central mechanisms involved. However, a causal link between chronic stress and
hypercoagulability as well as its practical implications for thromboprophylaxis in
exposed individuals still needs to be proven.
Stress is one of the most common, albeit underappreciated, causes of reproductive
frailty in women. Both acute and chronic stress impairs reproduction. Stressful events
occurring during pregnancy modify epigenetic components of the fetal hypothalamic–pituitary–adrenal
axis.[6] Hoirisch-Clapauch puts fibrinolysis in the spotlight of the impact of emotional
responses on female reproduction.[7] Hypercortisolism and inflammatory cytokines associated with chronic anxiety and
fear stimulate the production of PAI-1, the main endovascular inhibitor of plasminogen
activation. Randomized controlled trials are warranted to test the effect of lifestyle
interventions on the fibrinolytic system and reproductive prognosis.
An overall association between stress and pregnancy outcomes is extensively reviewed
by Miodownik and Sheiner,[8] highlighting the links and identifying research gaps. Stressful stimuli have been
related to several adverse pregnancy outcomes. Establishing the factors that put women
at risk for adverse pregnancy outcomes can aid in identifying the vulnerable population
who could benefit from early stress-reducing interventions.
Psychiatric disorders, particularly anxiety and depression, are frequently associated
with apical ballooning syndrome, a distinct cardiomyopathy often resembling acute
myocardial infarction in presentation, commonly known as Takotsubo syndrome (TTS).
This suggests a role of chronic stress in disease susceptibility. Habib and Aronson[9] review the current understanding, challenges in diagnosis and management strategies
for TTS, discuss the association with psychiatric disorders, and show its thrombogenic
capacity.
VTE is an under-recognized yet critical contributor to morbidity and mortality in
psychiatric patients. An increasing number of studies report an association between
different psychiatric disorders and VTE. A Mendelian randomization study has suggested
that depression is causally related to VTE and that genetic factors contribute to
the association between depression and VTE.[10] A nationwide study has shown that offspring of pedigrees with a high density of
VTE, especially females, are slightly more prone to several psychiatric disorders.[11] Jacob et al review the available evidence,[12] which is generally attributed to a hypercoagulable–hypofibrinolytic state influenced
by a significant number of cofactors, from metabolic abnormalities to inflammatory
reactions, psychiatric treatments, and genetic factors. The authors explore the epidemiology,
pathophysiology, and underpinning mechanisms and call for effective risk assessment
and management of thromboembolism in psychiatric patients.
Among VTE events associated with a transient risk factor is travel-related thrombosis
(TRT). Papadakis et al[13] reviews the current knowledge on this yet incompletely understood complex issue,
with a specific development on psychological aspects. The authors recommend addressing
both psychological and physical health in at-risk travelers. They review both the
risk assessment methodology and the available guidelines in that setting and describe
some clinical vignettes enabling the reader to familiarize with the practice of TRT
assessment, prevention, and management.
Neuropsychiatric manifestations are increasingly described in patients with persistently
positive antiphospholipid antibodies. Gris et al review relevant animal models, human
case reports, systematic human clinical association studies, and laboratory data regarding
the effects of antiphospholipid antibodies on brain cells.[14] Clusters of arguments make the association between psychiatric diseases and antiphospholipid
antibodies increasingly plausible but large-scale prospective clinical research initiatives
are still lacking. It remains unknown if the overall thrombotic risk can modulate
brain functions and generate brain-specific diseases. Likewise, the therapeutic management
of this association remains unresolved.
Modifications of brain microvasculature and specifically alterations of the BBB have
been suggested to contribute to the vulnerability to psychiatric diseases. The evidence
linking BBB impairments with mood disorders and suicide is presented by Conejero et
al.[15] The implication of multiple dysfunctions of the BBB is highlighted, including altered
expression of endothelial cell junction proteins, involvement of extracellular matrix
receptors and angiogenic factors, as well as changes in perivascular astrocytes. Furthermore,
local and systematic inflammation and coagulation can interact with the BBB, thus
contributing to neurodegenerative processes. These models open avenues for innovative
therapeutic developments.
A specific focus on the coagulation system and its direct effects on the brain is
proposed by Khury and Chapman.[16] Coagulation factors are expressed in various brain cells, including astrocytes and
microglia. Cellular effects of coagulation are mediated mainly by protease-activated
receptors. Molecular links between players of the hemostatic system and multiple sclerosis,
ischemic stroke, Alzheimer's disease, major depressive disorders/suicidality, and
even schizophrenia are reviewed. Given that the crosstalk between coagulation factors
and the inflammatory system in the brain seems crucial for the development of many
central nervous system diseases, including psychiatric disorders, the potential impact
of anti-inflammatory and anticoagulation interventions warrants further investigation.
Finally, a commentary by Lippi and Favaloro focuses on posttraumatic stress disorder.[17] Between 5 and 10% of the general population may be affected by this condition during
their life. Searching for treatment options is thus a public health issue. Available
data and preliminary results on heparin-based treatments are commented on. A possible
clinical efficacy seems to emerge and needs confirmation.
We hope that the current issue of Seminars on Thrombosis and Hemostasis will encourage
the readers to delve into an area that has not yet been fully explored, namely, the
anticipated bijective relationship between psychiatric diseases and thrombotic risk.
The last two lines of William Ernest Henley's poem Invictus, “I am the master of my fate, I am the captain of my soul,” suggest a dream of total
control. However, a deeper understanding of the role of the gut microbiota has led
to the description of a gut–brain axis, that is, modulation of mood and cognition
by peripheral biological signals that we do not instinctively master. Circulating
mediators generated by the abnormal variations of vessel biology could act in the
same way. Circulating mediators generated by a diseased brain could favor thrombotic
diseases. The Latin quote “mens sana in corpore sano” is more relevant than ever.
