Endothelial Cells are the Source of Factor VIII
The endothelial cells are the source of factor VIII (option d), as confirmed by multiple high-quality studies showing that factor VIII is synthesized in endothelial cells, packaged in Weibel-Palade bodies, and secreted bound to von Willebrand factor strings 1, 2.
Evidence for Factor VIII Production in Endothelial Cells
- Factor VIII (FVIII) is encoded by the F8 gene and is primarily produced by liver sinusoidal endothelial cells 1
- Direct evidence shows FVIII synthesis in primary human endothelial cells, specifically:
- Glomerular microvascular endothelial cells (GMVECs)
- Human umbilical vein endothelial cells (HUVECs) 2
- FVIII protein has been detected by fluorescent microscopy in Weibel-Palade bodies within endothelial cells 2
- Endothelial cells express the AVPR2 gene (vasopressin V2 receptor) which is involved in the secretion of FVIII 2
Production Sites of Other Coagulation Factors
- Factor II (prothrombin) - Synthesized primarily in the liver, not in endothelial cells 3
- Factor V - Primarily synthesized in the liver, with some evidence of endothelial cell production, but not as its main source 1, 4
- Factor VII - Primarily synthesized in the liver, initiated by tissue factor which can be expressed by endothelial cells under certain conditions, but not produced by them 1, 5
- Factor X - Primarily synthesized in the liver, not in endothelial cells 1, 3
Role of Endothelial Cells in Coagulation
Endothelial cells play multiple roles in coagulation beyond just producing factor VIII:
- They express thrombomodulin on their surface, which acts as a cofactor for thrombin-catalyzed activation of protein C 1
- They synthesize and store von Willebrand factor (VWF) in Weibel-Palade bodies 1
- FVIII stability and half-life depend on non-covalent complex formation with VWF to avoid proteolysis and clearance 2
- Under certain pathological conditions (like inflammation), endothelial cells can express tissue factor, which promotes factor VIIa-mediated activation of factors IX and X 6, 5
Clinical Significance
- Hemophilia A results from deficiency of factor VIII, which is encoded by the F8 gene 1
- Gene therapy approaches for hemophilia A target hepatocytes rather than endothelial cells (the natural site of FVIII synthesis) because expression of FVIII in hepatocytes still results in functional protein 1
- Understanding the source of factor VIII is crucial for developing effective treatments for hemophilia A and other coagulation disorders 1, 2
The evidence clearly demonstrates that among the options presented, only factor VIII is primarily produced by endothelial cells, making option (d) the correct answer.