A neurovascular condition called cerebral cavernous malformation (CCM) causes various neurological symptoms. In surgically removed CCM patient biopsies, thrombi have been seen, although their molecular characteristics are yet unknown. For a study, researchers sought to determine how thrombi influence the vasculature and cause cerebral hypoxia in CCM, as well as the kinetics of thrombi production in that tissue.
They examined the transcriptome of endothelial cells with an inducible Ccm3 knockout (Ccm3-iECKO) using RNA sequencing. Comparing wild-type and Ccm3-deficient brain endothelial cells, they discovered that the former expressed more coagulation cascade and hypoxia-related genes. In addition, in Ccm3-iECKO animals and human CCM biopsies, immunofluorescent tests showed important thrombi molecular markers such as fibrin, von Willebrand factor, and activated platelets.
Notably, they discovered and first reported polyhedrocytes in Ccm3-iECKO human CCM biopsies. They also discovered that there is hypoxia in the parenchyma surrounding CCM lesions and that the presence of more thrombi was correlated with greater hypoxia. Finally, using an in vitro model they developed to investigate the pathogenesis of CCM, they discovered that human brain endothelial cells lacking CCM3 produced higher amounts of the plasminogen activator inhibitor-1 and had reorganized von Willebrand factor.
The study provided experimental proof that genes and proteins associated with the coagulation cascade alter the brain vasculature and enhance neurological side effects, including hypoxia in CCMs. It does this using transcriptomics, extensive imaging, and an in vitro CCM preclinical model. The study lent credence to the idea that antithrombotic medication may be advantageous for CCM patients.