Page 27 - Haematologica Vol. 109 - July 2024

SPOTLIGHT REVIEW ARTICLE
Hemostasis and endothelial functionality: the double face of coagulation factors
Cristina Olgasi,1* Simone Assanelli,2* Alessia Cucci2* and Antonia Follenzi2,3
1Department of Translational Medicine, Università del Piemonte Orientale, Novara; 2Department of Health Sciences, Università del Piemonte Orientale, Novara and 3Dipartimento Attività Integrate Ricerca Innovazione, Azienda Ospedaliero-Universitaria SS. Antonio e Biagio e C. Arrigo, Alessandria, Italy
*CO, SA and AC contributed equally as first authors.
Abstract
Hemostasis is a sophisticated sequence of events aimed at repairing vessel injury. This process occurs in combination with angiogenesis, which leads to new blood vessel formation, helping in wound repair and facilitating tissue healing. The fine mechanisms that regulate hemostasis and angiogenesis are well described, but for a long time, coagulation factors (CF) have been considered merely players in the coagulation cascade. However, evidence from several experiments highlights the crucial functions of these CF in regulating endothelial functionality, especially in the angiogenic process. Some of these CF (e.g., thrombin and tissue factor) have been widely investigated and have been described as triggering intracellular sig- naling related to endothelial cell (EC) functionality. For others (e.g., factor VIII and thrombomodulin), potential receptors and molecular mechanisms have not been fully elucidated but some data show their potential to induce EC response. This review focuses on the emerging roles of selected CF in regulating EC functions, highlighting in particular their ability to activate signaling pathways involved in angiogenesis, migration, proliferation and endothelial barrier stability.
Introduction
Coagulation factors (CF) are a well-known class of proteins essential for hemostasis. They can be divided into pro- and anti-CF according to their function in promoting or arresting coagulation, respectively. Pro-CF work together in a cascading sequence, initiating a series of enzymatic reactions that lead to the formation of a blood clot; this process is counterbalanced by anti-CF for a correct ho- meostasis. CF participate in the regulation of the clotting process by interacting with platelets, vessel walls, and other proteins to form a stable clot, thus preventing ex- cessive bleeding when blood vessels are injured.1
Beyond hemostasis, angiogenesis is a physiological mech- anism involved in the repair of vessel injury. The vascular sprouting and the new blood vessel formation are required for wound closure and co-operate with the hemostatic system maintaining blood flow and regulating platelet adherence and fibrin deposition. During vascular injury, initial vessel constriction occurs to control blood flow and to reduce hemorrhage, followed by sub-endothelial matrix exposure where platelets can adhere.2 Vascular endothelial
cells are first required to bind and anchor the clot and then, from the clot margins, they invade the fibrin struc- ture to form a new vessel wall. Many proteins released by endothelial cells (EC) and present in the blood are required to finely control this process. Indeed, by adhering to EC, platelets regulate angiogenesis releasing pro-angiogenic molecules, like vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), angiopoietin-1 (Ang1), insulin-like growth factor-1 and -2 (IGF-1 and IGF-2), platelet-derived growth factor (PDGF), and sphingosine 1-phosphate. On the other hand, platelets can also release proteins that inhibit vessel formation, such as endostatin, thrombospondin-1 (TSP-1), plasminogen activator inhibitor-1 (PAI-1), and angiostatin.3 Recent evidence supports the notion that angiogenesis and broader EC functions can be influenced by some specific CF. These factors have been shown to have a variety of roles, encompassing both pro- and anti-angiogenic fea- tures, and influencing EC permeability. Their multifaceted action extends beyond simple hemostatic roles, contrib- uting to the intricate modulation of angiogenic processes and the regulation of EC barrier function.2
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Correspondence: A. Follenzi antonia.follenzi@med.uniupo.it
Received: Accepted: Early view:
October 2, 2023. February 15, 2024. February 29, 2024.
https://doi.org/10.3324/haematol.2022.282272
©2024 Ferrata Storti Foundation Published under a CC BY-NC license