Review Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis, 2023, Akbulut et al.

[SNT Gatchaman]

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis
Asim Cengiz Akbulut; Ryanne A. Arisz; Constance C. F. M. J. Baaten; Gaukhar Baidildinova; Aarazo Barakzie; Rupert Bauersachs; Jur ten Berg; Wout W. A. van den Broek; H. C. de Boer; Amandine Bonifay; Vanessa Bröker; Richard J. Buka; Hugo ten Cate; Arina J. ten Cate-Hoek; S. Cointe; Ciro De Luca; Ilaria De Simone; Rocio Vacik Diaz; Françoise Dignat-George; Kathleen Freson; Giulia Gazzaniga; Eric C. M. van Gorp; Anxhela Habibi; Yvonne M. C. Henskens; Aaron F. J. Iding; Abdullah Khan; Gijsje H. Koenderink; Akhil Konkoth; Romaric Lacroix; Trisha Lahiri; Wilbur Lam; Rachel E. Lamerton; Roberto Lorusso; Qi Luo; Coen Maas; Owen J. T. McCarty; Paola E. J. van der Meijden; Joost C. M. Meijers; Adarsh K. Mohapatra; Neta Nevo; Alejandro Pallares Robles; Philippe Poncelet; Christoph Reinhardt; Wolfram Ruf; Ronald Saraswat; Claudia Schönichen; Roger Schutgens; Paolo Simioni; Stefano Spada; Henri M. H. Spronk; Karlygash Tazhibayeva; Jecko Thachil; Rocio Vacik Diaz; L. Vallier; Alicia Veninga; Peter Verhamme; Chantal Visser; Steve P. Watson; Philip Wenzel; Ruth A. L. Willems; Anne Willers; Pengyu Zhang; Konstantinos Zifkos; Anton Jan van Zonneveld

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes.

Theme 1: The “coagulome” as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics.

Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding.

Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed.

Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed.

Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk.

Finally, COVID-19-associated coagulopathy is revisited.

Link | PDF (Thrombosis and Haemostasis)

 

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The different effects of antiplatelet and anticoagulant agents on the CNS can be in part due to the existence of a unique and complex interface represented by the neurovascular unit (NVU). [...] During CNS development through a clear contribution of coagulation factors such as tissue factor pathway inhibitor (TFPI), FV, FVII, and FX, the mesenchyma enters the nervous parenchyma. The same happens for the resident immune cells, the microglia, which is a distinct population of myeloid cells, not differentiated from the bone marrow (BM), but originating from the yolk sac. Hence the coagulation factors, as mentioned, do not limit their intervention to vascular repair and exert their function also on the nervous tissue, justifying their emerging role in neurological diseases other than stroke.

This pleiotropy has been demonstrated in various pathologies that have no strict vascular etiology, such as multiple sclerosis (MS), Parkinson’s disease (PD), and Alzheimer’s disease (AD).

As a neurodegenerative disease, AD is characterized by abnormal loss of cholinergic neurons in areas of the brain that are primarily responsible for cognition and memory. The key pathological elements in AD have been proven to be amyloid-β (Aβ) peptides and neurogenic fiber tangles. In animal studies [...] results have shown that coagulation factors are involved in the metabolism of Aβ, which can lead to the activation of FXII, resulting in FXI activation and thrombin generation, ultimately leading to a prothrombotic environment that contributes to the development of AD.

Compared with cognitively healthy people or patients diagnosed with mild cognitive impairment, patients who are diagnosed with AD have significantly increased plasmatic levels of FXI.

The pathogenesis of AD could be particularly sensitive to NVU disruption; fibrin deposition, possibly an end stage product resulting from the long-term dysfunction of the NVU, has been demonstrated in both large vessels and capillaries of AD patients and can have a great impact on metabolic coupling, particularly in the hippocampal region. Parenchymal deposition of fibrin, as the last step of the coagulation cascade, could enhance the inflammatory state and contribute to the loss of integrity of the bloodbrain barrier (BBB).