ORIGINAL ARTICLE

Plasminogen activator inhibitor type 1 deciency

R. MEHTA* and A. D. SHAPIRO
*Department of Clinical Medicine, Section of Hematology/Oncology, Indiana University School of Medicine; and Indiana
Hemophilia and Thrombosis Center, Indianapolis, IN, and Department of Pediatrics, Michigan State University, East
Lansing, MI, USA
Summary. Plasminogen activator inhibitor type 1
(PAI-1) is an important component of the coagula-
tion system that down-regulates brinolysis in the
circulation. Reduced PAI-1 levels may result in
increased brinolysis and an associated bleeding
diathesis. Clear documentation of PAI-1 deciency
as a cause of a bleeding disorder has been rare. PAI-1
was initially identied in the 1980s, and the rst
reported case of PAI-1 deciency appeared in 1989.
Several reports followed, although only two identi-
ed an underlying genetic defect. These reports of
PAI-1 deciency suggest that affected individuals
exhibit mild to moderate bleeding symptoms, includ-
ing epistaxis, menorrhagia, and delayed bleeding
after trauma or surgical procedures. Affected indi-
viduals rarely exhibit spontaneous bleeding events
commonly seen in other procoagulant deciencies.
The majority of bleeding events are controlled with
antibrinolytic agents, such as tranexamic acid and
-aminocaproic acid. A major issue that contrib-
utes to difculty in establishing an accurate
diagnosis of PAI-1 deciency is that the activity
assay is accurate in detection of elevated levels
but not at the lowest range. Reported normal
ranges begin at zero, thereby making a deciency
state because of a dysproteinaemia difcult to
distinguish from that of a normal unaffected
individual. Although the antigen assay may be
helpful in some circumstances, it assists only with
complete quantitative disorders. Because of lack of
standardized commercially available PAI-1 activity
assay sensitive in the lowest range, the true
prevalence of this rare condition has not been
established.
Keywords: antibrinolytic agents, bleeding, dyspro-
teinaemia, brinolysis, menorrhagia, plasminogen
activator inhibitor type 1
Introduction
The plasminogen activation system was a burgeoning
eld in the early 1980s, with the discovery of the rst
plasminogen activator inhibitor in 1984 [1,2]. After
purication of the inhibitor, the isolation of the
c-DNA was completed for what was later termed
plasminogen activator inhibitor, type 1 (PAI-1) [3].
Once PAI-1 was isolated, researchers began to study
the impact of perturbations of normal levels, either
those higher or lower than the established normal
range. While numerous investigations have evaluated
elevated levels of PAI-1and the documented associ-
ation of an increased risk of arterial thrombotic
events [4], reports of PAI-1 deciency are limited.
The rst reported case of low levels of PAI-1
resulting in a lifelong bleeding disorder was pub-
lished in 1989, when an elderly man was noted to
have decreased PAI-1 activity and normal PAI-1
antigen levels, leading to a presumed qualitative
defect of the protein [5]. The rst person with a
quantitative deciency (undetectable PAI-1 antigen
and activity levels) was described two years later [6].
In 1992, the rst identied homozygous PAI-1
genetic defect that led to a bleeding disorder was
documented [7]. Subsequently, other reports of
PAI-1 deciency leading to a bleeding diathesis have
been published, but only one other specic genetic
mutation associated with PAI-1 deciency has been
documented [817]. PAI-1 deciency appears to be
Correspondence: Rakesh Mehta, MD, Department of Clinical
Medicine, Section of Hematology/Oncology, Indiana University
School of Medicine, 535 Barnhill Dr, RT-473, Indianapolis, IN
46202, USA.
Tel.: +1 317 278 6871; fax: +1 317 274 3684;
e-mail: ramehta@iupui.edu
Accepted after revision 7 July 2008
Haemophilia (2008), 14, 12551260 DOI: 10.1111/j.1365-2516.2008.01834.x
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd 1255
quite rare, and is associated with a mild to moderate
bleeding disorder. Unfortunately, lack of a sensitive
PAI-1 activity assay hampers diagnosis of this
condition.
Materials and methods
This review was performed by an extensive literature
search through PubMed. Further references not
initially identied in the search but referenced within
these articles were also reviewed. All cases of PAI-1
deciency reported in the literature were reviewed.
Also, prior reviews on the history of the discovery of
PAI-1 were evaluated. Finally, documented cases of
PAI-1 deciency within the Indiana Amish popu-
lation were re-evaluated. Home visits to these
patients and their parents were performed within
the 2007 calendar year, with an extensive review of
personal bleeding histories completed (Rakesh
P. Mehta, Amy D. Shapiro, unpublished data).
Incidence
The true incidence of PAI-1 deciency is unknown in
large part because of the difculty in establishing the
diagnosis with present laboratory tests and the rarity
of the disorder. We performed a survey within the
Federal Network of Hemophilia Centers within the
United States to identify documented and/or sus-
pected cases in an effort to determine the prevalence
of this disorder. More than 100 surveys were mailed
with only six centres responding. Two of the six
responders reported PAI-1-decient patients. These
patients were noted to have a history of bleeding
with a negative evaluation other than undetectable
PAI-1 activity. A recent analysis screened 586 indi-
viduals with a bleeding tendency for decreased PAI-1
activity using a modied commercially available
assay for the study, and compared them with 200
controls [8]. In the group with a bleeding tendency,
23% had low PAI-1 activity levels compared with
1013% in the control group; the severity of
bleeding was minimal in most of these patients.
Another recent report evaluating 66 blood donors
revealed 14.6% of the females and 21% of the males
to have PAI-1 activity levels <2.0 IU mL
)1
. Detailed
histories of these subjects were not available, but
subjects that reported a bleeding history were not
included in this analysis [14]. Because the number of
case reports of PAI-1 deciency causing signicant
bleeding is limited, the true prevalence of this
disorder is not established but likely small [5
13,1517]. Unfortunately, the lack of precision of
currently available activity assays within the lowest
range of PAI-1 activity continues to hinder accurate
diagnosis. Although drawing conclusions from lim-
ited populations is often inaccurate, it does not
appear that there is an ethnic predilection for PAI-1
deciency, because cases of PAI-1 deciency have
been reported from North America, Europe and Asia.
Pathophysiology
Plasminogen activator inhibitor, type 1 plays a vital
role in regulating brinolysis within the circulation
and is responsible for the controlled degradation of
thrombi [18]. Importantly, brinolytic activity is
physiologically limited to the immediate vicinity of
the thrombus within a blood vessel. Plasmin, the
primary protease responsible for brinolysis, is
formed from the proteolytic cleavage of the zymogen
plasminogen. Plasmin formation is catalyzed by the
actions of the two major mammalian plasminogen
activators: tissue-Plasminogen activator (t-PA) and
urokinase-type plasminogen activator (u-PA). Impor-
tantly, the brin clot provides a surface to increase the
efciency of plasmin generation through formation of
a ternary complex of brin, t-PA and plasminogen.
Hence, brinolysis almost exclusively occurs on the
clot surface and not in the circulation [18]. Control of
this process is mediated through the plasminogen
activator inhibitors, with the primary plasminogen
activator inhibitor inplasma being PAI-1(Fig. 1). This
47 kDa protein is member of a superfamily of serine
protease inhibitors, called serpins [19,20]. PAI-1binds
in a stoichiometric manner to plasminogen activators
with rapid and irreversible inhibition, leading to the
description of PAI-1 as a suicide inhibitor.
The source of plasma PAI-1 is unclear. Hepato-
cytes, endothelial cells, adipocytes, and megakaryo-
cytes all are able to synthesize and secrete PAI-1 into
the circulation [1]. The human PAI-1 gene is located
on chromosome 7q21.3-22, and its expression may
be induced by several factors, including insulin,
endotoxin, and transforming growth factor-b. Inter-
estingly, PAI-1 plasma levels exhibit a diurnal
variation, with highest levels in the early morning
hours and nadir levels in the afternoon [21]. The rate
of transcription is assumed to be high, because of the
short plasma half-life of approximately 10 min, and
a brisk plasma level increase in response to stimuli
[20]. A common polymorphism in the promoter
region of the PAI-1 gene has been clearly associated
with increased PAI-1 levels. A change from ve
consecutive guanines to four guanines at a position
675 base pairs before the transcription site leads to
increased response to various stimuli that increase
PAI-1 production [19].
1256 R. MEHTA and A. D. SHAPIRO
2008 The Authors
Haemophilia (2008), 14, 12551260 Journal compilation 2008 Blackwell Publishing Ltd
Although plasma PAI-1 exists mostly in an active
form, there is also a latent inactive form that results
from inherent instability of the molecule [1]. In fact,
80% of the PAI-1 stored in the a-granules of platelets
is in the latent form. The latent form can be
converted back to the active form with denaturants
or negatively charged phospholipids in vitro, but this
conversion does not appear to occur within the
circulation. Therefore, the physiological signicance
at this time of the latent form is unclear. Importantly,
antigen testing kits may not be sensitive to distin-
guish between active vs. latent PAI-1.
Like most coagulation protein deciencies, quali-
tative or quantitative defects may lead to a deciency
state [57,913,15,17]. The rst case described in
1989 reported normal levels of PAI-1 antigen, with a
marked reduction in PAI-1 activity and t-PA:PAI-1
complexes, suggesting that the PAI-1 present lacked
activity [5]. Conversely, it is possible that much of
the PAI-1 may have been present in the latent form,
resulting in a normal antigenic assay but decreased
activity assay. Most of the subsequent reports doc-
umented true qualitative deciencies resulting in
decreased PAI-1 activity [57,913,15,17]. Interest-
ingly, two reports detail low plasma levels of PAI-1
activity and antigen, with normal platelet levels
[6,10]. Both of these patients had similar lifelong
bleeding histories, so that the low plasma levels were
believed to be clinically signicant and result in
the patients bleeding symptoms. Neither report
explained the discrepancy between the plasma and
platelet PAI-1 levels.
In reports of PAI-1 deciency, a variety of assays
have been used, making it difcult to extrapolate a
correlation between any specic level and degree of
clinical bleeding. Unfortunately, as currently available
activity assays include zerowithinthe reportednormal
range, the sensitivity of these assays at the lowest level
is insufcient to provide an adequate diagnostic tool,
and makes it difcult to correlate the degree of
deciency with specic bleeding symptoms. Arecently
published report utilizing a modied PAI-1 activity
assay suggests that PAI-1 activity levels <1 U mL
)1
in patients with bleeding symptoms was associated
with increased plasmin-antiplasmin complexes, thus
suggesting that this modied assay and level could be
used in the diagnosis of this disorder [22].
Genetic defects
Currently, two documented genetic defects have been
reported to be associated with PAI-1 deciency
[7,17,23]. In 1992, a young Amish girl in the United
States with a history of bleeding was noted to have
absent PAI-1 antigen and activity levels. On genetic
analysis, she was found to be homozygous for a
dinucleotide insertion within exon 4 of her PAI-1
gene. This insertion led to a frameshift, with
subsequent premature stop codon, producing a
truncated, non-functional protein [7]. This kindred
was further analysed for this mutation, with a total
of nine individuals identied to be homozygotes for
this mutation, all exhibiting a mild-moderate bleed-
ing disorder (Rakesh P. Mehta, Amy D. Shapiro,
unpublished data). More than 100 people within this
community have been found to be heterozygotes for
this mutation, none of whom have experienced
bleeding symptoms.
More recently, a second genetic defect in the PAI-1
gene has been found in a patient from China with a
lifelong bleeding disorder [17]. This patient was
found to have a G to A substitution at nucleotide
Fig. 1. The plasminogen activators
circulate in plasma as a complex with
PAI-1 as a reversible complex. When the
brin clot is formed, plasminogen and
t-PA (or u-PA) bind to the surface of the
clot. These proteins can then interact, and
plasmin is formed, which leads to lysis
of the cross-linked brin into the
brin-degradation products. PAI-1 also
binds to brin and, when bound, it can
irreversibly bind to inhibitor t-PA(or
u-PA) [4].
PAI-1 DEFICIENCY 1257
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Journal compilation 2008 Blackwell Publishing Ltd Haemophilia (2008), 14, 12551260
position 4497 in exon 2 of the gene, leading to a
single amino acid exchange of an Alanine for a
Threonine at codon 15 of the signal peptide. Inter-
estingly, this patient was a heterozygote for this
mutation, but had an activity level that was 10% of
the healthy controls. His father, who had the same
mutation had a lower than normal PAI-1 antigen and
activity level but much higher than his sons. In
addition, the patients mother, who did not have the
mutation, had a moderately reduced PAI-1 activity
and antigen level. Therefore, the authors concluded
that the patient was a compound heterozygote with
the documented mutation being partially responsible
for the markedly low PAI-1 levels.
Clinical manifestations
The bleeding symptoms associated with PAI-1 de-
ciency have been fairly consistent and appear com-
patible with what might be predicted based on the
role of this coagulation factor within the haemostatic
system. Most reports have documented a mild-to-
moderate, delayed bleeding disorder typically asso-
ciated with injury, trauma or surgery. The initial case
of PAI-1 deciency described a man with a long
history of post-traumatic and postsurgical bleeding
[5]. Most subsequent reports describe similar symp-
toms. The Amish population with PAI-1 deciency
has a similar clinical expression [23]. Recent follow-
up evaluations reveal a wide variety of bleeding
complications, though most were post-traumatic
bleeding events, including intracranial haemorrhage
and haemarthrosis. Importantly, menorrhagia repre-
sented a signicant clinical symptom in young
women, even resulting in the requirement of packed
red blood cell transfusion in one patient because of
marked anaemia and iron deciency from menstrual
blood loss (Rakesh P. Mehta, Amy D. Shapiro,
unpublished data). Two other reports also document
menorrhagia as a signicant symptom in PAI-1-
decient females [11,13]. Postsurgical bleeding is a
common complication observed in this deciency
state. Of reported events, dental procedures are
clearly associated with abnormal bleeding in PAI-1
deciency [6,11,12,15]. In fact, after having post-
traumatic and postsurgical bleeding as a toddler, it
was an episode of recurrent oral bleeding in the
proband in the Amish population that led to the
diagnosis of the bleeding disorder [7]. Easy bruising,
epistaxis, and muscle haematomas secondary to
injury or trauma have also been reported [6,7,10,17].
The age range of diagnosis is quite wide. The rst
patient described was 76 years old [5] but a child as
young as 4 months has also displayed a bleeding
tendency [23]. Thus, there does not appear to be a
specic age at which symptoms either typically
manifest or a time when they tend to decrease or
resolve.
Although most reports of bleeding from PAI-1
deciency stem from inherited conditions, an
acquired deciency also appears possible [24].
A gentleman with end-stage liver disease presented
with spontaneous, deep muscle bleeding. He was
found to have detectable PAI-1 antigen but lacked
PAI-1 activity. Levels of t-PA were markedly
increased; therefore, his bleeding diathesis was
believed to have resulted from a profound imbalance
of the brinolytic system, because of lack of clear-
ance of t-PA by the impaired liver with acquired
relative PAI-1 deciency. Interestingly, elevated lev-
els of urinary t-PA after trans-urethral prostatectomy
(TURP) also have been shown to correlate with
increased blood loss after these procedures [25].
Potentially, the increased levels of t-PA released lead
to a locally acquired deciency of PAI-1 as well.
Diagnosis
The assays to establish the diagnosis of PAI-1
deciency have been reviewed. Several antigen tests
are available, but these are not able to detect
qualitative deciencies [8]. Unfortunately, the cur-
rently available PAI-1 activity assays are designed to
detect increased activity rather than a deciency state
and subsequently are not adequately sensitive at the
lowest levels. Because a PAI-1 activity level of zero is
often reported as being within the normal limit of
these assays, they cannot reliably discriminate a
deciency state from a non-decient individual.
Interestingly, correlating plasmin-antiplasmin levels
with markedly low PAI-1 activity levels
(<1 IU mL
)1
) may help distinguish patients with
clinically signicant PAI-1 deciency [22].
Therefore, the diagnosis of this disorder remains
challenging. However, it is worthwhile to analyse
both antigen and activity levels when evaluating a
patient for this deciency. If PAI-1 activity levels are
reported as <1 IU mL
)1
and the patient has charac-
teristic delayed post-traumatic or -surgical bleeding,
then the diagnosis should be considered and a trial
of antibrinolytic agents entertained. Furthermore,
because of the rarity of this condition and the
difculty making an accurate diagnosis, it is impor-
tant to consider other more common bleeding
conditions; disorders such as von Willebrand disease
and platelet function defects are far more common
and should be rmly ruled out prior to making the
diagnosis of PAI-1 deciency.
1258 R. MEHTA and A. D. SHAPIRO
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Haemophilia (2008), 14, 12551260 Journal compilation 2008 Blackwell Publishing Ltd
Management
Antibrinolytic agents remain the mainstay of treat-
ment for this disorder with all published reports
documenting the benet of EACA or tranexamic acid
for bleeding control or prevention [57,12,
13,15,23]. These agents function to control inappro-
priate plasmin generation, and subsequently mini-
mize bleeding once it has occurred or prevent
bleeding when instituted prophylactically before
interventions or invasive procedures. For example,
a young Amish boy developed recurrent bleeding of
his subdural haematoma after he discontinued use of
the prescribed EACA upon discharge from the
hospital. Reinstitution of this agent helped stop the
recurrent bleeding and led to a full recovery (Rakesh
P. Mehta, Amy D. Shapiro, unpublished data). The
efcacy of these agents has also been documented as
prophylactic medications in prevention of bleeding in
association with surgical procedures [5,23]. In
patients with menorrhagia, EACA has been effective
in limiting the amount of menstrual blood loss and
appears most effective when instituted a few days
before the anticipated onset of the menstrual cycle
[13,23].
Prognosis
Patients with PAI-1 deciency may do quite well, as
bleeding once recognized can be controlled with
currently available agents. In fact, 1 patient was
76 years of age before the diagnosis was established
and had lived a relatively long life without prior
specic treatment. However, some patients experi-
ence life-threatening bleeding events in association
with injury or menses. Therefore, early diagnosis and
prompt initiation of therapy are required to achieve
optimal outcome. The identied PAI-1-decient
Amish kindred is still relatively young with none of
the identied homozygous decient patients cur-
rently older than 25 years. Consequently, longevity
with complete absence of PAI-1 remains unestab-
lished. Of interest, almost 100 heterozygotes in this
Amish population have been identied with no
adults identied to be homozygosity-decient despite
approximately 500 members of the kindred tested.
(Rakesh P. Mehta, Amy D. Shapiro, unpublished
data) It is anticipated that with early identication of
PAI-1-decient patients and appropriate therapy, a
normal lifespan may be achieved. However, there are
numerous unanswered questions for this population,
including fertility, ability to carry a pregnancy to
term, and development of atherosclerosis. The link
between PAI-1 and cancer prognosis has been rmly
established [26]. Increased levels of PAI-1 expression
in breast cancer tissue are associated with a
worse prognosis [27]. Theoretically, PAI-1-decient
patients may have improved survival with cancer
because of decreased PAI-1 levels; in PAI-1 knockout
mice, there was signicantly less tumour invasion
then in the controls [28]. Only long-term follow-up
of these patients will provide the information
necessary to answer these unresolved questions.
Conclusion
Plasminogen activator inhibitor, type 1 deciency is a
rare bleeding disorder whose mainstay of treatment
is antibrinolytic agents. The accurate diagnosis of
this disorder remains a challenge and the develop-
ment of a readily available standardized sensitive
activity assay capable of differentiation between low
normal levels and a true deciency state is needed.
Once available, the correlation of specic levels of
deciency with particular clinical symptoms could be
established. Because this disorder results from either
a qualitative or quantitative defect, an accurate
PAI-1 activity assay is critical to establish the
diagnosis. Also, with improved assays, the true
prevalence of clinically signicant PAI-1 deciency
could be determined. Although rare, PAI-1 deciency
should be considered in patients with delayed
post-traumatic or postsurgical bleeding after other
more common bleeding disorders have been
excluded. If PAI-1 deciency is established, then a
trial of antibrinoltyic agents should be considered.
In the future, a database of patients with this
disorder should be created to establish the range of
clinical symptoms experienced, the genetic defects
leading to a deciency state, and the association of
specic levels with clinical events.
Research Interests
Most research regarding PAI-1 currently pertains to
elevated levels. The laboratory of Dr Douglas
Vaughan and Dr Mohan Sathyamoorthy of the
Cardiovascular Medicine Section at Vanderbilt Uni-
versity is very interested in the long-term effects of
PAI-1 deciency on the development of atheroscle-
rosis. Dr Sathyamoorthy can be contacted at
mohan.sathyamoorthy@vanderbilt.edu.
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