Molecular Genetics of Blood Coagulation 
of great significance in the study of the fibrino- 
lytic system and its role in a number of important 
diseases. 
We have established a system for directing bac- 
teria to make synthetic PAI-1 in the test tube. This 
recombinant PAI-1 has all of the important prop- 
erties of the natural protein. We have made over 
170 variants of PAI-1 in which a small part of the 
molecule has been changed. Studying the effects 
of these small changes, which can vary consider- 
ably in their ability to regulate the different types 
of plasminogen activators, has advanced our un- 
derstanding of how PAI-1 functions and how it 
interacts with other parts of the blood clotting 
system. These observations might eventually aid 
in the design of new drugs for the treatment of 
bleeding and clotting diseases. This work has 
been funded in part by a grant from the National 
Institutes of Health. 
We have recently identified the molecular de- 
fect in our first patient with complete deficiency 
of PAI-1 . This nine-year-old girl has a moderately 
severe bleeding disorder. Studies of her DNA dem- 
onstrated complete inactivation of the gene, ac- 
counting for the total absence of PAI-1 in her 
blood. These observations have provided impor- 
tant insights into the true function of PAI- 1 and 
the fibrinolytic system in the body. Further stud- 
ies will provide valuable information for the fu- 
ture treatment of this and other patients with 
PAI- 1 deficiency and for studying how PAI- 1 actu- 
ally works inside the body. We are currently at- 
tempting to disrupt the PAI-1 gene in mice to 
create an animal model for this human disease. 
Bone Marrow Transplantation 
Bone marrow transplantation is being used 
with increasing frequency to treat a variety of dis- 
eases, including several types of leukemia and a 
number of other cancers. In this procedure, doses 
of radiation and chemotherapy are given that are 
designed to destroy the patient's diseased bone 
marrow. As this would ordinarily prove fatal, the 
patient is then "rescued" by the transplantation 
of marrow from a healthy donor. Our laboratory 
has had a long-standing interest in bone marrow 
transplantation and has developed techniques to 
monitor what happens to the blood — to the pa- 
tient's own blood cells and those received from 
the donor — following the procedure. 
Currently the major obstacle to the more wide- 
spread use of bone marrow transplantation is an 
often-fatal complication called graft-versus-host 
disease (GVHD). This is caused by small differ- 
ences between the genes of patient and donor 
that cannot yet be detected. We have begun a new 
research effort to identify the gene or genes re- 
sponsible for GVHD. If this effort is successful, 
the process of matching patients and donors will 
be much improved and bone marrow transplanta- 
tion may become considerably safer and more 
widely applied. 
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