Grant: Operating Grant

Normally, platelets help clot formation by sticking at sites of blood vessel injury and releasing substances that protect clots from being dissolved too rapidly. We are studying an inherited illness, called the Quebec Platelet Disorder (QPD), that causes excessive bleeding. Individuals with this condition have increased levels of a "clot busting" enzyme activator called urokinase (uPA) in their platelets; this enzyme is found in trace amounts in normal platelets. uPA is a potent activator of the clot dissolving pathway in blood. In the QPD, changes in uPA convert platelets from "clot formers" into "clot busters". The result is a high risk of bleeding. We have been looking at normal and QPD cells to understand how normal clot-protective platelets are produced and how platelets and some other types of blood cells are changed into "clot busters" in the Quebec Platelet Disorder. We now know that the QPD increases uPA as stem cells mature to make platelets and white blood cells (cells that fight infection and normally make uPA to help break down clots). We have identified that patients with QPD have a duplicated copy of the uPA gene, and we have developed tests to detect this extra copy to help diagnose individuals with bleeding problems. We now want to determine how and why this extra copy of the uPA gene changes platelets, and some white blood cells, into "clot busters". This will help us work on designing better treatments for this serious bleeding disorder.