The liver and lungs have something in common—factor VIII (FVIII) is produced in both. A study published in the February 11, 2010, issue of PLoS ONE, the journal of the Public Library of Science, by Claire L. Shovlin, PhD, and colleagues from the Imperial College London (ICL) and the University of Lisbon, provided the proof.
“Some of the novelty of this study is that it was a fairly rigorous examination of the amount and quality of FVIII that could be produced in the lungs,” says Steven Pipe, MD, director of the Division of Pediatric Hematology and Oncology and pediatric medical director for the Hemophilia and Coagulation Disorders Program at the University of Michigan, Ann Arbor. (Pipe was not involved in the study.) Prior studies have shown that FVIII may also be produced in the kidneys and spleen, he says.
The UK researchers evaluated a small number of pulmonary tissue and blood samples, using microscopic and biochemical techniques. They discovered that the site of FVIII synthesis and secretion was endothelial cells lining pulmonary blood vessels. “If you think of the endothelium as the largest organ in the body, having some evidence that it is also a source of where FVIII could be released from shows a tremendous reserve in the body,” Pipe says.
The Lungs and DDAVP
Further, the research team discovered that FVIII and von Willebrand factor (VWF)—the carrier clotting protein with which FVIII circulates in the blood—are housed in the same endothelial cell storage granules in the lungs. When DDAVP, a synthetic hormone used to treat von Willebrand disease and mild hemophilia, is administered in the body, it stimulates the release of FVIII and VWF from storage sites into the plasma. “The fact that the pulmonary endothelium is the source of a DDAVP-releasable pool, which has the largest surface area, means that the lungs could be a significant source of FVIII for the body and maybe one of the key sources of the DDAVP response,” Pipe says. The findings also provide evidence that elevated levels of FVIII and VWF in the lungs contribute to the formation of blood clots called venous thromboemboli.
“Our study suggests that the blood vessels in the lung are playing a crucial role in altering how blood clots form in the body,” says Shovlin, senior lecturer in respiratory medicine at the ICL’s National Heart and Lung Institute. “This means it’s really important for us to understand exactly how the behavior of the lung blood vessels might be affecting diseases where blood clotting is a factor.”
Advancing Liver Disease
The study helped solve at least one other mystery, says Pipe. “With advancing liver disease, FVIII levels actually rise, whereas many other factors go down.” Previously, it was assumed that the diseased liver could not clear the FVIII. Shovlin’s team helped explain this phenomenon. “As the liver gets diseased and the clearance goes down, tissues like the pulmonary endothelium are still producing significant amounts of FVIII,” says Pipe.
Further research on a larger number of samples is needed to verify all of these preliminary findings. Determining how the lungs modify the clotting process of blood could pave the way for new, more effective treatments, the researchers say.
In the meantime, this study has value for the bleeding disorders community. “It shows that the liver is not the sole source of production of FVIII,” Pipe says. “These new insights into normal physiology will be useful in helping us understand what is going on in our patients.”