A unique molecular defect in an unusual blood disorder first identified and described at Johns Hopkins by the late Sir William Osler almost a century ago has now been discovered by a team of his professional descendants.
The molecular defect that may be responsible for polycythemia vera was reported by the Hopkins team recently in The New England Journal of Medicine. The finding could eventually serve as a definitive test for the disorder, which can be frustratingly difficult to diagnose. It also could be used as a model for identifying the origins of malignant disease.
"Polycythemia vera mimics other cancerous and non-cancerous blood diseases," says Jerry L. Spivak, M.D., professor of medicine and oncology at Hopkins and senior author of the research report. "We now have a diagnostic tool that we hope will identify patients earlier, perhaps increasing their lifespan."
The Hopkins research, supported by the National Institutes of Health, found that patients with polycythemia vera express a defective form of the receptor for thrombopoietin, an essential growth factor that regulates the growth of bone marrow stem cells. It also regulates the production of platelets, disc-shaped structures in the blood that promote clotting.
This receptor, when located on platelets, normally triggers the chemical reactions that sustain platelet function. But in polycythemia vera platelets, the correct signals are not sent. This reduced activity was observed in all patients with polycythemia vera, helping distinguish it from all other blood diseases with which it can be confused. A similar reduction was noticed in patients with idiopathic myelofibrosis, a condition closely related to polycythemia vera in which blood production occurs outside of the bone marrow in the spleen and liver.
Polycythemia vera is marked by a great increase in the number of red cells in the blood, resulting in headaches and potentially fatal blood clots. It is usually treated by a modern form of bloodletting, although more severe cases may require chemotherapy.
In 1903, Sir William Osler, Hopkins' first physician-in-chief and chair of the Department of Medicine, was the first to recognize polycythemia vera as a unique entity and relate its symptoms to the increase in the number of red blood cells. The disorder, which can be malignant, affects five to 10 of every 100,000 people and is now being recognized more frequently in young women of reproductive age.
Hopkins researchers compared platelets and bone marrow samples from 34 people with polycythemia vera to a control group of 44 people who either were normal or had disorders similar to polycythemia vera. Platelets were exposed to either thrombopoietin or thrombin, another platelet activating factor, and then analyzed for the expected responses and protein expression.
Platelets from normal subjects, when exposed to thrombopoietin, produced the correct signals and expressed a normal thrombopoietin receptor. By contrast, platelets from polycythemia vera patients were much less active or showed no signaling at all to thrombopoietin in contrast to thrombin. The response to thrombopoietin was found to be due to the presence of an abnormality in the thrombopoietin receptor. A similar abnormality was observed in the megakaryocytes, the bone marrow cells that produce platelets.
The study's other authors were Alison R. Moliterno, M.D., and W. David Hankins, Ph.D.
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Journal
New England Journal of Medicine