Download Plasminogen activator inhibitor type 1 deficiency

Haemophilia (2008), 14, 1255–1260
DOI: 10.1111/j.1365-2516.2008.01834.x
ORIGINAL ARTICLE
Plasminogen activator inhibitor type 1 deficiency
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 coagulation system that down-regulates fibrinolysis in the
circulation. Reduced PAI-1 levels may result in
increased fibrinolysis and an associated bleeding
diathesis. Clear documentation of PAI-1 deficiency
as a cause of a bleeding disorder has been rare. PAI-1
was initially identified in the 1980s, and the first
reported case of PAI-1 deficiency appeared in 1989.
Several reports followed, although only two identified an underlying genetic defect. These reports of
PAI-1 deficiency suggest that affected individuals
exhibit mild to moderate bleeding symptoms, including epistaxis, menorrhagia, and delayed bleeding
after trauma or surgical procedures. Affected individuals rarely exhibit spontaneous bleeding events
commonly seen in other procoagulant deficiencies.
The majority of bleeding events are controlled with
antifibrinolytic agents, such as tranexamic acid and
Introduction
The plasminogen activation system was a burgeoning
field in the early 1980s, with the discovery of the first
plasminogen activator inhibitor in 1984 [1,2]. After
purification 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
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: [email protected]
Accepted after revision 7 July 2008
Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
-aminocaproic acid. A major issue that contributes to difficulty in establishing an accurate
diagnosis of PAI-1 deficiency 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 deficiency
state because of a dysproteinaemia difficult 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: antifibrinolytic agents, bleeding, dysproteinaemia, fibrinolysis, menorrhagia, plasminogen
activator inhibitor type 1
range. While numerous investigations have evaluated
elevated levels of PAI-1and the documented association of an increased risk of arterial thrombotic
events [4], reports of PAI-1 deficiency are limited.
The first reported case of low levels of PAI-1
resulting in a lifelong bleeding disorder was published 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 first person with a
quantitative deficiency (undetectable PAI-1 antigen
and activity levels) was described two years later [6].
In 1992, the first identified homozygous PAI-1
genetic defect that led to a bleeding disorder was
documented [7]. Subsequently, other reports of
PAI-1 deficiency leading to a bleeding diathesis have
been published, but only one other specific genetic
mutation associated with PAI-1 deficiency has been
documented [8–17]. PAI-1 deficiency appears to be
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R. MEHTA and A. D. SHAPIRO
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 identified in the search but referenced within
these articles were also reviewed. All cases of PAI-1
deficiency 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 deficiency within the Indiana Amish population 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 deficiency is unknown in
large part because of the difficulty 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 suspected 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-deficient 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 individuals with a bleeding tendency for decreased PAI-1
activity using a modified 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
10–13% 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 deficiency causing significant
bleeding is limited, the true prevalence of this
disorder is not established but likely small [5–
13,15–17]. Unfortunately, the lack of precision of
currently available activity assays within the lowest
Haemophilia (2008), 14, 1255–1260
range of PAI-1 activity continues to hinder accurate
diagnosis. Although drawing conclusions from limited populations is often inaccurate, it does not
appear that there is an ethnic predilection for PAI-1
deficiency, because cases of PAI-1 deficiency have
been reported from North America, Europe and Asia.
Pathophysiology
Plasminogen activator inhibitor, type 1 plays a vital
role in regulating fibrinolysis within the circulation
and is responsible for the controlled degradation of
thrombi [18]. Importantly, fibrinolytic activity is
physiologically limited to the immediate vicinity of
the thrombus within a blood vessel. Plasmin, the
primary protease responsible for fibrinolysis, 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). Importantly, the fibrin clot provides a surface to increase the
efficiency of plasmin generation through formation of
a ternary complex of fibrin, t-PA and plasminogen.
Hence, fibrinolysis 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 in plasma being PAI-1 (Fig. 1). This
47 kDa protein is member of a superfamily of serine
protease inhibitors, called serpins [19,20]. PAI-1 binds
in a stoichiometric manner to plasminogen activators
with rapid and irreversible inhibition, leading to the
description of PAI-1 as a ÔsuicideÕ inhibitor.
The source of plasma PAI-1 is unclear. Hepatocytes, endothelial cells, adipocytes, and megakaryocytes 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. Interestingly, 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 five
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].
Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
PAI-1 DEFICIENCY
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Fig. 1. The plasminogen activators
circulate in plasma as a complex with
PAI-1 as a reversible complex. When the
fibrin 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 fibrin into the
fibrin-degradation products. PAI-1 also
binds to fibrin and, when bound, it can
irreversibly bind to inhibitor t-PA(or
u-PA) [4].
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 significance
at this time of the latent form is unclear. Importantly,
antigen testing kits may not be sensitive to distinguish between active vs. latent PAI-1.
Like most coagulation protein deficiencies, qualitative or quantitative defects may lead to a deficiency
state [5–7,9–13,15,17]. The first 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 documented true qualitative deficiencies resulting in
decreased PAI-1 activity [5–7,9–13,15,17]. Interestingly, 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 significant and result in
the patientsÕ bleeding symptoms. Neither report
explained the discrepancy between the plasma and
platelet PAI-1 levels.
In reports of PAI-1 deficiency, a variety of assays
have been used, making it difficult to extrapolate a
correlation between any specific level and degree of
clinical bleeding. Unfortunately, as currently available
Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
activity assays include zero within the reported normal
range, the sensitivity of these assays at the lowest level
is insufficient to provide an adequate diagnostic tool,
and makes it difficult to correlate the degree of
deficiency with specific bleeding symptoms. A recently
published report utilizing a modified 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 modified 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 deficiency
[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 identified to be homozygotes for
this mutation, all exhibiting a mild-moderate bleeding 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
Haemophilia (2008), 14, 1255–1260
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R. MEHTA and A. D. SHAPIRO
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. Interestingly, 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 sonÕs. In
addition, the patientÕs 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 deficiency have been fairly consistent and appear compatible with what might be predicted based on the
role of this coagulation factor within the haemostatic
system. Most reports have documented a mild-tomoderate, delayed bleeding disorder typically associated with injury, trauma or surgery. The initial case
of PAI-1 deficiency described a man with a long
history of post-traumatic and postsurgical bleeding
[5]. Most subsequent reports describe similar symptoms. The Amish population with PAI-1 deficiency
has a similar clinical expression [23]. Recent followup evaluations reveal a wide variety of bleeding
complications, though most were post-traumatic
bleeding events, including intracranial haemorrhage
and haemarthrosis. Importantly, menorrhagia represented a significant 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 deficiency from menstrual
blood loss (Rakesh P. Mehta, Amy D. Shapiro,
unpublished data). Two other reports also document
menorrhagia as a significant symptom in PAI-1deficient females [11,13]. Postsurgical bleeding is a
common complication observed in this deficiency
state. Of reported events, dental procedures are
clearly associated with abnormal bleeding in PAI-1
deficiency [6,11,12,15]. In fact, after having posttraumatic 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 first
patient described was 76 years old [5] but a child as
young as 4 months has also displayed a bleeding
Haemophilia (2008), 14, 1255–1260
tendency [23]. Thus, there does not appear to be a
specific 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
deficiency stem from inherited conditions, an
acquired deficiency 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 fibrinolytic system, because of lack of clearance of t-PA by the impaired liver with acquired
relative PAI-1 deficiency. Interestingly, elevated levels 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 deficiency of PAI-1 as well.
Diagnosis
The assays to establish the diagnosis of PAI-1
deficiency have been reviewed. Several antigen tests
are available, but these are not able to detect
qualitative deficiencies [8]. Unfortunately, the currently available PAI-1 activity assays are designed to
detect increased activity rather than a deficiency 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
deficiency state from a non-deficient individual.
Interestingly, correlating plasmin-antiplasmin levels
with markedly low PAI-1 activity levels
(<1 IU mL)1) may help distinguish patients with
clinically significant PAI-1 deficiency [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 deficiency. If PAI-1 activity levels are
reported as <1 IU mL)1 and the patient has characteristic delayed post-traumatic or -surgical bleeding,
then the diagnosis should be considered and a trial
of antifibrinolytic agents entertained. Furthermore,
because of the rarity of this condition and the
difficulty making an accurate diagnosis, it is important to consider other more common bleeding
conditions; disorders such as von Willebrand disease
and platelet function defects are far more common
and should be firmly ruled out prior to making the
diagnosis of PAI-1 deficiency.
Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
PAI-1 DEFICIENCY
Management
Antifibrinolytic agents remain the mainstay of treatment for this disorder with all published reports
documenting the benefit of EACA or tranexamic acid
for bleeding control or prevention [5–7,12,
13,15,23]. These agents function to control inappropriate plasmin generation, and subsequently minimize 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
efficacy 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 deficiency 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
specific treatment. However, some patients experience 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 identified PAI-1-deficient
Amish kindred is still relatively young with none of
the identified homozygous deficient patients currently older than 25 years. Consequently, longevity
with complete absence of PAI-1 remains unestablished. Of interest, almost 100 heterozygotes in this
Amish population have been identified with no
adults identified to be homozygosity-deficient despite
approximately 500 members of the kindred tested.
(Rakesh P. Mehta, Amy D. Shapiro, unpublished
data) It is anticipated that with early identification of
PAI-1-deficient 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 firmly
Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
1259
established [26]. Increased levels of PAI-1 expression
in breast cancer tissue are associated with a
worse prognosis [27]. Theoretically, PAI-1-deficient
patients may have improved survival with cancer
because of decreased PAI-1 levels; in PAI-1 knockout
mice, there was significantly 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 deficiency is a
rare bleeding disorder whose mainstay of treatment
is antifibrinolytic agents. The accurate diagnosis of
this disorder remains a challenge and the development of a readily available standardized sensitive
activity assay capable of differentiation between low
normal levels and a true deficiency state is needed.
Once available, the correlation of specific levels of
deficiency 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 significant PAI-1 deficiency
could be determined. Although rare, PAI-1 deficiency
should be considered in patients with delayed
post-traumatic or postsurgical bleeding after other
more common bleeding disorders have been
excluded. If PAI-1 deficiency is established, then a
trial of antifibrinoltyic 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 deficiency state, and the association of
specific 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 University is very interested in the long-term effects of
PAI-1 deficiency on the development of atherosclerosis. Dr Sathyamoorthy can be contacted at
[email protected].
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