Molecular Genetics of Blood Coagulation 
David Ginsburg, M.D. — Associate Investigator 
Dr. Ginsburg is also Associate Professor in the Departments of Internal Medicine and Human Genetics at 
the University of Michigan Medical School. He received his B.A. degree in molecular biophysics and bio- 
chemistry from Yale University and his M.D. degree from Duke University School of Medicine. His post- 
doctoral research training was done in the laboratory of Stuart Orkin at the Children's Hospital, Harvard 
Medical School. While in Boston, Dr. Ginsburg was also Instructor in Medicine at the Brigham and 
Women 's Hospital, Harvard Medical School. 
THE major research activities of my laboratory 
are centered around the study of two impor- 
tant blood clotting proteins, von Willebrand fac- 
tor and plasminogen activator inhibitor- 1, and 
their associated human diseases. In addition, we 
are applying molecular tools to the study of bone 
marrow transplantation. 
von Willebrand Factor 
One major function of von Willebrand factor, 
which is an important part of the body's blood 
clotting system, is to serve as a bridge connecting 
blood platelets to the wall of injured blood ves- 
sels, thereby helping to control bleeding, von 
Willebrand factor also serves as the carrier for 
factor VIII, the substance missing in patients with 
hemophilia. Abnormalities in von Willebrand 
factor result in von Willebrand disease, the most 
common human inherited bleeding disorder, oc- 
curring in 1-3 percent of the general population. 
Although more than 20 different subtypes of this 
disease have been described, the molecular basis 
for this variation is unclear. 
In previous work, we cloned and characterized 
a major portion of the gene for human von Wille- 
brand factor. Presently we are applying these mo- 
lecular tools to increase our understanding of the 
function of von Willebrand factor and the molec- 
ular basis for von Willebrand disease, von Wille- 
brand factor is a large molecule with multiple 
discrete functions. We are conducting experi- 
ments to localize the various functions of von 
Willebrand factor to precise regions within the 
molecule. The specific segment involved in bind- 
ing to factor VIII has been localized, and we are 
characterizing the regions required for von Wil- 
lebrand factor interaction with the platelet sur- 
face and the blood vessel wall. 
We are also focusing on the molecular basis of 
human von Willebrand disease. The defect in 
some patients with type III von Willebrand dis- 
ease (the most severe form) is an inability to copy 
the von Willebrand factor gene into normal mes- 
senger RNA. Most of the patients with type IIB 
von Willebrand disease appeared to have one of 
four defects, all clustered within a small region of 
the von Willebrand factor gene thought to be crit- 
ical for its interaction with blood platelets. By 
introducing one of these defects into the DNA of 
tissue culture cells, we have shown that this sin- 
gle change is responsible for the type IIB variant. 
In similar studies of type IIA von Willebrand dis- 
ease, we identified a separate set of defects clus- 
tered in a different region of the von Willebrand 
factor gene. By introducing these defects into tis- 
sue culture cells, we have shown that type IIA 
may be due to abnormalities in the process 
whereby von Willebrand factor is manufactured 
inside the cell. Finally, in studies of a patient 
whose von Willebrand factor is unable to bind 
factor VIII, we identified a single change in the 
gene that has helped to pinpoint the region of 
von Willebrand factor responsible for carrying 
factor VIII. 
Through these studies, we hope to expand our 
understanding of von Willebrand factor, to ad- 
vance our ability to diagnose and classify von 
Willebrand disease accurately, and to improve 
the medical treatment for this common human 
disorder. 
Plasminogen Activator Inhibitor- 1 
The fibrinolytic system is the body's mecha- 
nism for breaking down blood clots. This system 
is delicately balanced with the system that forms 
blood clots. A precise balance between these two 
systems is vital. Overactivity of either system 
could result in uncontrolled bleeding or uncon- 
trolled blood clotting. Plasminogen activator is 
the protein that turns on the fibrinolytic system. 
Its activity is controlled by the regulator protein 
— plasminogen activator inhibitor- 1 . 
Synthetic plasminogen activators are now used 
in patients to dissolve blood clots, particularly in 
the early stages of a heart attack when a major 
blood vessel to the heart has suddenly become 
blocked. There is also increasing evidence that 
patients with abnormally high blood levels of 
plasminogen activator inhibitor- 1 (blocking the 
normal blood clot-dissolving activity of natural 
plasminogen activator) are at particularly high 
risk for heart attacks and other diseases due to 
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