Hemostasis, Thrombosis, and Vascular Biology in Psychiatric Disorders

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.

Conflict of Interest

None declared.

Acknowledgment

The co-guest editors wish to acknowledge with thanks the assistance of Sonia Kamenetsky in the preparing of this volume.

• References

• 1 Devraj K, Kulkarni O, Liebner S. Regulation of the blood-brain barrier function by peripheral cues in health and disease. Metab Brain Dis 2024; 40 (01) 61
• 2 Nagata S, Yamasaki R. The involvement of glial cells in blood-brain barrier damage in neuroimmune diseases. Int J Mol Sci 2024; 25 (22) 12323
• 3 Murat CB, García-Cáceres C. Astrocyte gliotransmission in the regulation of systemic metabolism. Metabolites 2021; 11 (11) 732
• 4 Hage Z, Madeira MM, Koliatsis D, Tsirka SE. Convergence of endothelial dysfunction, inflammation and glucocorticoid resistance in depression-related cardiovascular diseases. BMC Immunol 2024; 25 (01) 61
• 5 Von Känel R. Stress-induced hypercoagulability: insights from epidemiological and mechanistic studies, and clinical integration. Semin Thromb Hemost 2025; 51 (04) 381-400
• 6 Valsamakis G, Chrousos G, Mastorakos G. Stress, female reproduction and pregnancy. Psychoneuroendocrinology 2019; 100: 48-57
• 7 Hoirisch-Clapauch S. The impact of emotional responses on female reproduction: fibrinolysis in the spotlight. Semin Thromb Hemost 2025; 51 (04) 401-411
• 8 Miodownik S, Sheiner A. Stress and pregnancy outcomes: a review of the literature. Semin Thromb Hemost 2025; 51 (04) 412-422
• 9 Habib M, Aronson D. Thromboembolic complications in Takotsubo cardiomyopathy. Semin Thromb Hemost 2025; 51 (04) 426-432
• 10 Ward J, Le NQ, Suryakant S. et al. Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism. Blood Adv 2023; 7 (18) 5341-5350
• 11 Zöller B, Sundquist J, Sundquist K, Ohlsson H. The risk of psychiatric disorders in offspring from thrombosis-prone pedigrees in Sweden: a nationwide family study. Res Pract Thromb Haemost 2025; Jan 28; 9 (01) 102692
• 12 Jacob G, Ocytil Y, Brenner B. The overlooked risk of venous thromboembolism in psychiatric patients: epidemiology, pathophysiology and implications for clinical care. Semin Thromb Hemost 2025; 51 (04) 433-440
• 13 Papadakis E, Gavriilaki E, Kotsiou N, Tufano A, Brenner B. Fright of Long-Haul Flights: Focus on Travel-associated Thrombosis. Semin Thromb Hemost 2025; 51 (04) 441-450
• 14 Gris JC, Chéa M, Bouvier B, Pereira FR. Antiphospholipid antibodies in mental disorders. Semin Thromb Hemost 2025; 51 (04) 451-459
• 15 Conejero I, Chea M, Courted P, Bouvier S, Pereira F. Alterations in the blood-brain barrier in mood disorders and neurodegenerative diseases. Semin Thromb Hemost 2025; 51 (04) 460-467
• 16 Khoury R, Chapman J. Inflammation and coagulation in neurologic and psychiatric disorders. Semin Thromb Hemost 2025; 51 (04) 468-473
• 17 Lippi G, Favaloro EJ. Heparin and post-traumatic stress disorder (PTSD). Semin Thromb Hemost 2025; 51 (04) 423-425

Publication History

Article published online:
14 May 2025