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Review
. 2022 Oct 20;23(20):12575.
doi: 10.3390/ijms232012575.

Dysregulated Hemostasis and Immunothrombosis in Cerebral Cavernous Malformations

Maria Ascencion Globisch  1 , Favour Chinyere Onyeogaziri  1 , Ross Osborne Smith  1 , Maximiliano Arce  1 , Peetra Ulrica Magnusson  1
Affiliations
Review

Dysregulated Hemostasis and Immunothrombosis in Cerebral Cavernous Malformations

Maria Ascencion Globisch et al. Int J Mol Sci. .

Abstract

Cerebral cavernous malformation (CCM) is a neurovascular disease that affects 0.5% of the general population. For a long time, CCM research focused on genetic mutations, endothelial junctions and proliferation, but recently, transcriptome and proteome studies have revealed that the hemostatic system and neuroinflammation play a crucial role in the development and severity of cavernomas, with some of these publications coming from our group. The aim of this review is to give an overview of the latest molecular insights into the interaction between CCM-deficient endothelial cells with blood components and the neurovascular unit. Specifically, we underscore how endothelial dysfunction can result in dysregulated hemostasis, bleeding, hypoxia and neurological symptoms. We conducted a thorough review of the literature and found a field that is increasingly poised to regard CCM as a hemostatic disease, which may have implications for therapy.

Keywords: BBB; CCM; NETosis; bleeding; coagulation; endothelium; hemostasis; hypoxia; immunothrombosis; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hemodynamics in CCM. A schematic representation of blood flow in a cavernoma. Normal blood flow (solid white arrows) results in high shear stress on endothelial cells while disturbed blood flow (diffused white arrows) results in low shear stress on endothelial cells. A blood clot (dark purple) may further disturb the already reduced blood flow in the cavernoma. In addition, a blood clot may also obstruct nearby blood vessels and further reduce blood flow. The figure was assembled with Adobe Illustrator and BioRender (agreement number QG24D9MLOD).
Figure 2
Figure 2
The CCM microenvironment. A schematic representation of the CCM microenvironment of procoagulant (red) and anticoagulant (blue) regions, where endothelial cells are the key regulators of hemostasis, neuroinflammation and bleeding. Endothelial cells interact with blood cells and glycoproteins to regulate coagulation and anticoagulation. CCM-deficient endothelial cells cannot maintain a hemostatic balance and this results in neuroinflammation and hypoxia in the brain parenchyma (light purple). Neuroinflammation, hypoxia and bleeding are all hallmarks of CCM. A simplified version of the coagulation cascade is shown in the lumen and clinical aspects of cavernomas are written in dark blue. Tissue Factor (TF); Urokinase plasminogen activator (uPA); Tissue plasminogen activator (tPA); Neutrophil extracellular traps (NETs); Blood-brain barrier (BBB). The figure was assembled with Adobe Illustrator and BioRender (agreement number QG24D9MLOD).
See this image and copyright information in PMC

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