Vascular heterogeneity results in either microbleeds or polyhedrocytes at the vessel wall. (A) Confocal images of Ccm3-iECKO P7 (right) and (B) P8 (left) cerebellums illustrating microbleeds (white arrows) and polyhedral red blood cells (yellow arrows); DAPI (blue) TER-119 (green), and CD31 (red). (C) Scanning electron microscopy images of vessels in Ccm3-iECKO mice. In the right panel a clot near the vessel wall is seen with polyhedrocytes (yellow arrows), fibrin threads (asterisk), and regular red blood cells (red arrowhead). In the right panel, a vessel is seen with multiple polyhedrocytes. (D) Familial CCM patient biopsy stained for LENDRUM; normal red blood cells (yellow), fibrin-coated red blood cells (pink), and collagen IV (green). Different regions highlight the heterogeneity of red blood cells. In the left normal red blood cells are shown, and in the middle panel fibrin-coated red blood cells are highlighted. The region highlighted in a white box is magnified to the right. (E) Familial CCM patient biopsy stained for thrombomodulin. Patient #4 shows lesions with a high expression of thrombomodulin, and patient #5 shows a lesion with no thrombomodulin. White arrow shows hemosiderin, which is an indication of a previous hemorrhage. (F) Pie chart showing the quantification of the heterogeneous expression of thrombomodulin relative to red blood cell (RBC) composition. THBD, thrombomodulin; RBC, red blood cells.