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 biochemistry from Yale University and his M.D. degree from Duke University School of Medicine. 
His postdoctoral 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 Brigham and Women 's Hospital, Harvard Medical School. 
THE major research activities of my laboratory 
concern two important blood clotting pro- 
teins, von Willebrand factor and plasminogen 
activator inhibitor- 1, and their associated hu- 
man diseases. In addition, we are applying mo- 
lecular tools to the study of bone marrow 
transplantation. 
von Willebrand Factor 
One major function of von Willebrand factor 
(vWF) , which is an important part of the body's 
blood clotting system, is to serve as a bridge be- 
tween blood platelets and the wall of an injured 
blood vessel, thereby helping to control bleed- 
ing. vWF is also the carrier for factor VIII, the 
missing substance in patients with hemophilia. 
Abnormalities in vWF result in von Willebrand 
disease (vWD), the most common inherited 
bleeding disorder, occurring in 1-3 percent of 
the general population. Over 20 different types 
of vWD have been described. 
Our aim is to understand how the various parts 
of the vWF protein work in the body and how 
they interact with other factors in the blood clot- 
ting system. Recently we have made considerable 
progress in identifying the defects within the 
vWF gene that are responsible for vWD. In addi- 
tion to aiding in the diagnosis and management of 
vWD, this information has provided important in- 
sights into the function of vWF. 
Over 90 percent of patients with type IIB vWD 
have one of four specific defects, all within a 
small region of the vWF gene critical for its inter- 
action with blood platelets. By introducing one 
of these defects into the DNA of tissue culture 
cells, we have shown that this single change is 
responsible for the type IIB variant. In similar 
studies of type IIA vWD, we have identified an- 
other set of defects clustered in a different region 
of the vWF gene. We have introduced these de- 
fects into cultured cells and have shown that type 
IIA vWD may be due to abnormalities in the pro- 
cess whereby vWF is manufactured inside the 
cell. In studies of a patient whose vWF is unable 
to bind factor VIII, we identified a single change 
in the gene that has helped to pinpoint the region 
of vWF responsible for factor VIII transport. 
We have also identified in some patients with 
type III vWD (the most severe form) a defect in 
the ability to copy the vWF gene into normal mes- 
senger RNA. 
Despite considerable progress, type I vWD, the 
most common variant, remains a mystery. We 
have recently begun a new project to study the 
molecular basis for a disease in mice that closely 
resembles type I vWD of humans. Surprisingly, it 
appears that the defect in the mouse may be in a 
gene other than vWF. If we are successful in iden- 
tifying the mutant gene in the mouse, our find- 
ings should be directly transferable to the study 
of human type I vWD. Through these studies, we 
hope to expand our understanding of vWF, to ad- 
vance our ability to diagnose and classify vWD, 
and eventually to improve the medical treatment 
for this common human disorder. The work on 
von Willebrand factor has been funded in part by 
a grant from the National Institutes of Health. 
Plasminogen Activator Inhibitor-1 
The fibrinolytic system is the body's mecha- 
nism for breaking down blood clots. This system 
must be precisely balanced with the clot-forming 
system, since an imbalance can result in un- 
wanted blood clotting or uncontrolled bleeding. 
The protein that turns on the fibrinolytic system 
is plasminogen activator. Its activity is controlled 
by a regulator protein, plasminogen activator in- 
hibitor! (PAI-1). 
Synthetic plasminogen activators, such as re- 
combinant tissue-type plasminogen activator 
(t-PA) and urokinase, 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 muscle has become blocked. There is 
also increasing evidence that patients with abnor- 
mally high blood levels of PAI-1 (disrupting the 
normal clot-dissolving activity of natural plas- 
minogen activator) are at particularly high risk 
for heart attacks and other diseases due to in- 
creased blood clot formation. Thus an under- 
standing of the structure and function of PAI-1 
and its interaction with plasminogen activators is 
161 
