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Haemophilia (2008), 14, 1261–1268
DOI: 10.1111/j.1365-2516.2008.01825.x
ORIGINAL ARTICLE
Plasminogen deficiency
R. MEHTA* and A. D. SHAPIRO *Department of Clinical Medicine, Section of Hematology/Oncology, Indiana University School of Medicine, Indianapolis,
IN; and Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, and Department of Pediatrics, Michigan State
University, East Lansing, MI, USA
Summary. Plasminogen deficiency has emerged as a
well-recognized disorder in which reduced levels of
plasminogen lead to the development of pseudo
membranes on mucosal surfaces, with subsequent
end-organ damage of the affected tissue. Ligneous
conjunctivitis is the most recognizable, well-documented, and common presentation of the clinical
syndromes associated with plasminogen deficiency,
although numerous other organs have been reported
to be affected. Interestingly, while plasminogen
deficiency was initially believed to be related to
development of venous thromboembolic disease,
more recent data suggest that decreased plasminogen
levels may not, in and of themselves, increase the
risk of thrombosis. Two types of plasminogen
deficiency have been described in the literature. Type
I represents a quantitative deficiency and type II a
qualitative deficiency. It appears that hypoplasminogenaemia (type I deficiency) is the type most associ-
Introduction
Pseudomembranes covering the eye were first
described in 1847 by Bouisson [1]. During the next
several decades, further cases of this chronic conjunctivitis were reported with an improved description of these lesions representing persistent
granulation tissue. In 1933, the term ligneous conjunctivitis was proposed because of the wood-like
appearance of these lesions [1]. Subsequently,
pseudomembranes were described that affected the
gingiva, ear, respiratory tract, female genitourinary
Correspondence: Rakesh Mehta, MD, Department of Clinical
Medicine, Section of Hematology/Oncology, Indiana University
School of Medicine, 535 Barnhill Drive, RT-473, Indianapolis, IN
46202, USA.
Tel.: 317 278 6871; fax: 317 274 3684;
e-mail: [email protected]
Accepted after revision 5 July 2008
Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
ated with pseudomembrane disease. A variety of
genetic mutations has been identified recently and is
reported to lead to these disorders. These defects have
been identified in diverse populations, with no
specific ethnic predilection. However, this disorder
may have increased prevalence in areas and communities where consanguinity is more common. Despite
the fact that the characteristic lesions are now better
recognized and plasminogen levels are accurately and
easily measured, adequate treatment of the clinical
manifestations of this disorder is lacking. For ligneous conjunctivitis, a plasminogen concentrate formulated into an ophthalmologic preparation has been
found to be an effective local therapy. Unfortunately,
no plasminogen concentrate is currently available
commercially for either systemic or local therapy.
Keywords: conjunctivitis, fibrinolysis, gingivitis,
ligneous, plasminogen, pseudomembranes
tract, skin and renal collecting system [1]. In addition, several children with ligneous conjunctivitis
were also reported to have developed hydrocephalus.
Concurrently, the pathophysiology of dissolution
of blood clots was undergoing investigation. It had
long been recognized that a component of blood was
capable of dissolving blood clots [2]. In the 19th
century, several investigators documented that blood
clots could spontaneously dissolve. Jules A. F. Dastre
recognized that once a clot in blood dissolved, it
could not reform into a clot. He deduced that the
fibrin had been broken down and coined the term
fibrinolysis [2]. The factor that could dissolve clots
was determined to be an enzyme and was isolated in
the 1940s. Christensen and MacLeod labelled the
zymogen plasminogen and the enzyme plasmin [2].
In 1978, the first patient with plasminogen deficiency was described [3]. This case related an
increased risk of venous thrombosis with low levels
of plasminogen. Interestingly, this initial case was
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because of a qualitative defect in plasminogen, and
was later labelled Plasminogen Tochigi I [4]. Subsequently, numerous other quantitative defects have
been discovered. These defects have been classified
based on the mutation in the active site, with further
differentiation based upon parameters including
alterations in charge, kinetics, and heterozygous vs.
homozygous mutations [4].
Importantly, in 1997 the relationship between low
levels of plasminogen and ligneous conjunctivitis was
firmly established [5]. Since then, numerous reports
have confirmed the link between plasminogen deficiency and the development of pseudomembranes of
the conjunctiva and other areas. The ligneous lesions
seem to occur more commonly in patients with
quantitative rather than qualitative defects.
Materials and methods
This review was performed using an extensive
literature search through PubMed. Plasminogen
deficiency, ligneous conjunctivitis and ligneous gingivitis were used as search terms. Further references
not initially identified in the search but referenced
within these articles were also reviewed. A review of
the history of plasminogen was identified and
reviewed [2]. Review articles and textbooks were
used as a basis for the discussion of the physiology of
plasminogen.
Prevalence
The prevalence of this disorder has not been firmly
established. An evaluation of more than 9000 blood
donors in Scotland revealed a prevalence of 2.9 per
1000 heterozygous quantitative plasminogen-deficient subjects (type I deficiency), none of whom were
reportedly symptomatic [6]. With these data, the
theoretical prevalence of homozygotes or compoundheterozygotes has been calculated to be 1.6 per
1 000 000 [1]. Several other groups have attempted
to determine the prevalence of heterozygote plasminogen deficiency in various populations, with
reports of 0.35% in a United States population [7],
0.13% in Southern German population [8] and
0.42% in Japanese study [9]. However, further
epidemiological studies are required to better determine the prevalence of this condition. A variety of
issues make prevalence studies difficult, including
issues such as the waxing and waning of symptoms
of the disorder over time, the variability of affected
areas even within one family, and the wide variety of
medical specialties that are the initial point of care
for these patients.
Haemophilia (2008), 14, 1261–1268
Cases of patients with quantitative plasminogen
deficiency have been reported throughout the world,
including Europe, Asia and North America [1,10].
There appears to be an increased number of cases
identified and reported from Turkey or in patients of
Turkish descent, perhaps related to founder effects or
intermarriage within some communities.
Comparatively, qualitative type II plasminogen
deficiency appears to be more common in certain
populations. One study from Japan demonstrated a
heterozygote prevalence of 3.83% [9], and a study
from China and Korea demonstrated a prevalence of
1.5% and 1.6% respectively [11].
Pathophysiology
Plasmin is a serine protease and is the predominant
fibrinolytic enzyme in the human circulation [12].
A considerable quantity of plasmin is also found in
the extracellular matrix [13]. The zymogen plasminogen circulates in blood and is converted to plasmin
by the mammalian plasminogen activators tissueplasminogen activator (t-PA) and urokinase-type
plasminogen activator (u-PA) (Fig. 1) [12]. The gene
for plasminogen is located on chromosome 6, and
the zymogen is predominantly produced by the liver.
Native plasminogen is produced as two main forms,
Glu- and Lys-plasminogen. Glu-plasminogen includes a glutamic acid at the N-terminus and has a
half-life of 2.2 days. Alternatively, Lys-plasminogen
(lysine residue at N-terminus) is also present in the
circulation at a much lower concentration and has a
shorter half-life of 0.8 day. Plasmin cleaves Gluplasminogen to Lys-plasminogen, making it more
prone to activation by the plasminogen activators
and essentially creating a positive feedback loop [14].
Therefore, either of these two forms of plasminogen
could be used as a replacement product for this
deficiency. Plasmin, once formed, is inactivated by its
physiologic inhibitor a2-antiplasmin. Although
unbound plasmin is rapidly inhibited by a2-antiplasmin, plasmin remains relatively protected when
it sits on the lysine residues of the fibrin clot, with
a2-antiplasminÕs ability to inhibit plasmin having
been decreased more than 100-fold [12].
Although the role of plasmin in haemostasis is well
defined, it also has other functions, including functioning as an integral component of wound-healing
[12]. A fibrin-rich extracellular matrix forms after
cellular damage, with plasmin playing several roles in
the degradation of this tissue. Plasmin directly
degrades fibrin and other matrix glycoproteins,
activates the matrix metalloproteinases, and stimulates the release of transforming growth factor b, all
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PLASMINOGEN DEFICIENCY
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Fig. 1. Plasminogen is activated to plasmin
by the plasminogen activators u-PA and t-PA.
Plasmin degrades fibrin into the fibrin
degradation products and also can lead to
extracellular matrix proteolysis, growth factor activation, and activation of the matrix
metalloproteinases, which promote cellular
adhesion and wound healing. The plasminogen activators are regulated by the plasminogen activator inhibitors (PAIs), whereas
plasmin is inhibited by a2-antiplasmin and
also a2-macroglobulin. (Gilabert-Estelles J
et al. Front Biosci 2005; 10: 1162–76).
functions representing critical steps in wound-healing [12]. In patients with plasminogen deficiency,
wound-healing capability is markedly diminished
and is most pronounced in mucous membranes, such
as the conjunctiva. Therefore, lesions in these areas
are typically rich in fibrin because of lack of
proteolytic capacity [15,16]. As fibrin degradation
is limited, the process halts at the stage of granulation tissue formation [1].
The degree of reduction of plasminogen plasma
levels is variable in reported cases. The largest study
of plasminogen deficiency investigated and reported
the genetic defect in 50 patients. In this report,
plasminogen activity ranged from 4% to 51% [10].
Other reports have been consistent with these results
[1]. Interestingly, these reports delineate family
members with activity levels less than 50%, without
the presence of ligneous lesions, thereby underscoring the variability of presentation of this disorder and
making tight correlation of levels with clinical
symptoms difficult.
As with many disorders of haemostatic proteins,
the deficiency state may result from two types of
plasminogen abnormalities: type I resulting from a
quantitative defect and type II a qualitative defect.
The initial report of plasminogen deficiency was in a
patient with recurrent thrombotic events who had a
functional or type II defect [3]. This patient and his
family members had normal antigen levels with
decreased activity, suggestive of a dysfunctional
protein. It now appears that it is the type I deficient
patients who develop ligneous lesions [1]. The initial
case report linking ligneous conjunctivitis to plasminogen deficiency documented low plasminogen
antigen and activity levels [5]. Subsequent reports
have consistently documented ligneous lesions in a
variety of mucosal areas with hypoplasminogenaemia [1,10,17–23].
A plasminogen gene knock-out mouse model has
been developed to study the effects of aplasminogÓ 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd
enaemia. Interestingly, these mice may develop
ligneous conjunctivitis, similar to humans [24], with
lesions observed more frequently as the mice age;
interestingly these lesions do not occur in mice with
concomitant fibrinogen deficiency. Also, while male
plasminogen mice are fertile, the females seemed to
have reduced fertility [25]. It is unclear if the
plasminogen deficiency resulted in infertility, or
whether it was because of cachexia that was also
observed in these mice.
Genetics
Pseudomembranous disease associated with plasminogen deficiency is typically an autosomal recessive
disorder that results from a homozygous or compound heterozygous defect [1]. At this time, several
genetic defects have been documented that lead to
plasminogen deficiency [10,20,21,26]. In the largest
report of genetic investigation of patients with
plasminogen deficiency, DNA was analysed from
50 subjects [10]. From this group, 38 distinct
mutations in the plasminogen gene were identified.
The most common abnormality identified in this
report was a lysine replaced by a glutamine at codon
19 (K19E mutation), also documented in other
reports [1,26,27]. Of interest, this mutation was
evaluated in the Scottish blood donor population and
was found in 13 of the 15 subjects evaluated with
documented decreased plasminogen levels [27].
Clinical manifestations
The most common and well-known consequence of
hypoplasminogenaemia from type I deficiency is
ligneous conjunctivitis [10]. Plasminogen deficiency
affects wound-healing throughout the body, most
especially within the mucous membranes [13]. As a
result, quantitative plasminogen deficiency can result
in the development of pseudomembranes in a variety
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of areas. Interestingly, the production of these
pseudomembranes does not seem to appear to
develop in the patients with type II deficiency [9].
Ligneous conjunctivitis
Descriptions of ligneous conjunctivitis have appeared
in the literature since the 1850s [1,16]. However, the
link of this clinical entity to plasminogen deficiency
was not established until the 1990s [5]. An excellent
review by Schuster and Seregard [1] integrated the
numerous reports of ligneous conjunctivitis and
better defined the distinct qualities of these lesions.
The pseudomembranes typically are preceded by
erythema of the conjunctiva and chronic tearing,
followed by the development of white, yellow-white,
or red masses that form on the conjunctiva and have
the characteristic wood-like texture (Figs 2a,b).
Corneal involvement from these lesions occurs in
20–30% of cases and may result in loss of sight.
Pseudomembranes occur more frequently on the
upper compared with the lower eyelid; approximately 50% of patients have bilateral ocular involvement. Often the pseudomembranes result from some
stimulus or irritation, such as infection, trauma, and
surgery.
Classically, ligneous conjunctivitis was described
in infants and children, yet it is now apparent that
older individuals may manifest this symptom as well
[10,16]. In fact, a case report documented two sisters
with ligneous conjunctivitis who were older than
55 years [28]. There appears to be a higher incidence
in females compared with males, with a ratio of
1.27:1–1.39:1 [1,10]. Lesions, once they develop,
may be present for a variable period, ranging from a
few months up to 44 years [1].
Of note is a case ligneous conjunctivitis induced by
tranexamic acid, an inhibitor of fibrinolysis [29].
A 25-year-old woman was treated with tranexamic
acid for control of menorrhagia. She developed
pseudomembranes of the conjunctiva, gingiva, and
(a)
the peritoneum shortly after she started taking the
tranexamic acid. After 9 months, she sought care for
these lesions. Three months later, after lack of
response to local therapies, use of all medications
was discontinued; subsequently, after 3 weeks the
lesions began to resolve. The tranexamic acid therapy was restarted, and after 2 days, the lesions began
to re-accumulate but again promptly resolved after
cessation of the medication. Although it appears that
the anti-fibrinolytic contributed to the formation of
these lesions, the triggering event was unclear and
her plasminogen level did not appear to have been
measured.
Oropharynx involvement
The second most commonly affected site with
ligneous lesions is the mouth, as reported in the
largest series in the literature to date [10]. The lesions
are not painful and appear as nodular ulcerations or
gingival hyperplasia and often result in loss of dental
integrity (Figs 3a,b) [30]. Lesions may appear solely
in the oral cavity or may be associated with ligneous
conjunctivitis [1]. Furthermore, pseudo-membranous
lesions have been found in the middle ear and
tympanic membrane and may contribute to chronic
otitis media and hearing loss [1].
Respiratory involvement
Pseudomembranes have been documented to develop
in the larynx, vocal cords, and tracheobronchial tree
[1]. Significant complications may result from these
lesions, including recurrent pneumonia and airway
obstruction. Persistent ligneous lesions in this area
have been associated with a poor prognosis [1].
Genitourinary tract
Pseudomembranes involving the female genital tract
have been well described [31]. In the female genital
(b)
Fig. 2. (a, b) Ligneous conjunctivitis.
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PLASMINOGEN DEFICIENCY
(a)
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ligneous conjunctivitis can be an associated symptom
in these patients as well.
Congenital occlusive hydrocephalus
Congenital occlusive hydrocephalus has been observed in several children with ligneous conjunctivitis, with seven out of 16 of these children having
clearly documented plasminogen deficiency [1]. Most
of those affected required surgical intervention to
relieve the obstruction.
Thrombotic risk
(b)
Although the initial case of plasminogen deficiency
was documented in a patient with recurrent venous
thromboembolic disease, there now does not appear
to be a clear association between plasminogen
deficiency as a sole abnormality resulting in an
increased risk of thrombosis [3,6,9,10,32]. In fact,
while several case reports suggested an additive
thrombotic risk when dysplasminogenaemia is
observed in association with Factor V Leiden, other
reports have not confirmed this observation [33,34].
Currently, it is not clear that plasminogen deficiency
in and by itself should be considered a hypercoagulable condition.
Fig. 3. (a, b) Ligneous gingivitis.
tract, cervical lesions termed ligneous cervicitis have
been the most commonly reported pathology, with at
least eight women described to date [31]. The age
range for presentation or diagnosis of ligneous
cervicitis ranged in these women from 2 to 65 years,
with dysmenorrhoea as the most common presenting
symptom. While six of the eight women were
infertile in this review, it is unknown if all patients
with severe deficiency would have had associated
infertility. Ligneous lesions have also been reported
to involve the vagina, fallopian tubes, ovary and
endometrium [31]. Not surprisingly, many of these
patients also had ligneous conjunctivitis.
Two siblings were reported to develop pseudomembranous plaques in their kidneys [22]. Both
patients had numerous other affected areas, including
the conjunctiva, gingiva and tracheobronchial tree.
Skin
A skin condition called juvenile colloid milium has
been associated with plasminogen deficiency [1].
These lesions typically occur in children and appear
as small, translucent, yellow-brown papules, typically in sun-exposed areas of the skin. Again,
Ó 2008 The Authors
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Acquired plasminogen deficiency
As with tranexamic acid, other medications and
conditions have been associated with low levels of
plasminogen or decreased fibrinolytic capacity
[35,36]. Unfortunately, there is insufficient data to
draw firm conclusions regarding the significance of
decreased levels or activity. While l-asparaginase has
been documented to lower plasminogen levels, it also
lowers other haemostatic proteins, such as antithrombin, important in the down regulation of
coagulation [35]. Therefore, the specific contribution
of decreased plasminogen levels to thrombosis is
unclear. A case of a thrombosis associated with low
levels of plasminogen resulting from plasmapheresis
in a patient with multiple sclerosis has been reported
[36]. Here again, the specific contribution of
decreased plasminogen levels to the thrombosis is
not clear because of the presence of other haemostatic alterations associated with both the plasmapheresis and multiple sclerosis.
Diagnosis
Making the diagnosis of pseudo-membranous disease
secondary to plasminogen deficiency requires both
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clinical and laboratory findings [1]. The ligneous
lesions should be documented to include the classic
histological findings. A family history may potentially help support the diagnosis if other affected
siblings or family members are available. Laboratory
analysis should confirm this disorder with an abnormality of plasminogen activity and/or antigen. Activity and antigen testing is readily available in most
clinical coagulation laboratories. Because ligneous
lesions are most commonly seen in type I plasminogen deficiency, the antigen test alone is insufficient
to rule out this entity [1].
Many genetic abnormalities have been documented to lead to hypoplasminogenaemia, with the
K19 mutation seeming to be the most commonly
reported defect [10]. Genetic testing in clinically
approved laboratories is not yet available. Individual
laboratories with an interest in these entities can be
contacted to determine their interest in genetic
analysis. As documented genetic mutations are identified, prenatal testing has been shown to be possible
for this condition [37].
Management
Numerous management strategies for these lesions
have been tried with minimal success [38]. Although
surgical excision of these lesions may appear to be
initially helpful, it often results in pseudomembrane
re-growth. Medical therapies, such as local use of
heparin, corticosteroids, cyclosporine, azathioprine,
hyaluronidase, and a-chymotrypsin, have not been
consistently or completely successful [1]. One report
recently suggested that oral contraceptives could
increase plasminogen levels and subsequently result
in an improvement of the lesions in ligneous
conjunctivitis [39], while another report suggested
that high doses of corticosteroids was effective in one
child with ligneous gingivitis [40]. Anecdotally,
patients cared for by the authors with ligneous
gingivitis had no improvement in their lesions with
the use of these agents.
The one clearly documented effective therapy that
leads to resolution and halts re-formation of these
lesions is systemic or topical plasminogen concentrates [38,41,42]. In 1998, a young infant with
ligneous conjunctivitis was treated with systemic
Lys-plasminogen with resultant resolution of the
lesions [42]. Subsequently, two reports documented
improvement in the lesions with a local ophthalmologic solution made from plasminogen concentrate
[38,41]. Interestingly, plasmin ophthalmologic solution is not an effective modality, most likely because
of its local rapid inhibition by a2-antiplasmin [41].
Haemophilia (2008), 14, 1261–1268
Unfortunately, plasminogen ophthalmologic solution
is not currently commercially available; however, a
pharmaceutical company has developed a compassionate care product for use in Italy. Because
plasminogen deficiency is, in most respects, a multisystem or systemic disorder, optimal therapy for
ligneous lesions, both those clinically visible and not
clinically evident lesions, is a systemic purified
plasminogen concentrate to use as a replacement
therapy. Such a preparation is not currently commercially available.
Thromobolytic agents that contain plasminogen
are a further treatment modality that has been
utilized for treatment of ligneous conjunctivitis
(Amy D. Shapiro, Christoph von Buch, personal
communication). After surgery to remove the
pseudomembranes of ligneous conjunctivitis, a patient was treated with an ophthalmologic solution
containing anistreplase (EminaseÒ), which is a combination of bacterial streptokinase and acylated
plasminogen. Initially, the drops were given every
30 min for 3 weeks, and then the frequency was
reduced to three times per day. This regimen led to a
resolution of the lesions.
Prognosis
The prognosis for this disease is variable based on
the extent, length, and site of the symptoms;
although many identified patients have lived into
adulthood, a number of them have died from the
effects of this disorder or have experienced considerable morbidity, including loss of affected organ
function, such as loss of sight and dentition.
Tracheobronchial lesions can result in respiratory
failure. It is clear that this population is in need of
specific therapies that treat and prevent these lesions
and their sequelae. The quality of life of affected
individuals in the absence of effective therapy is not
optimal.
Conclusion
The clinical range of symptoms and the long-term
effects of ligneous lesions associated with plasminogen deficiency have during the past 15 years been
well described. Decreased levels of this enzyme result
in development of pseudomembranes because of the
inability to break down the accumulation of fibrinrich tissue. There is a predilection toward involvement of mucous membranes, with conjunctiva being
the hallmark of this clinical entity. The clinical
constellation of symptoms in the face of an abnormally decreased plasminogen level establishes the
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PLASMINOGEN DEFICIENCY
diagnosis; the identification of genetic mutations that
led to this disorder is now possible and may be
performed to support the diagnosis. Topical or
systemic therapy with a plasminogen preparation
improves the clinical course in these patients; it is our
hope that effective therapies for this patient population become available in the next decade.
8
9
Individuals with interest in area
Dr. Volker Schuster and his laboratory have been the
leaders in studying this disease and have the largest
library of genetic alterations associated with this
disorder. Contact for information: Dr. Volker
Schuster, MD, ChildrenÕs Hospital, University
of Würzburg, Josef-Schneider-Strasse 2, D-97080
Würzburg, Germany; e-mail: [email protected].
Kedrion SpA, an Italy-based biopharmaceutical
company, has received the Orphan Drug Designation
for its Human Plasminogen eye drop preparation in
EU.
The Company is now working on a clinical trial
protocol aimed to evaluate efficacy and safety of its
Human Plasminogen preparation in patients affected
by Ligneous Conjunctivitis.
10
11
12
13
14
Disclosures
The authors stated that they had no interests which
might be perceived as posing a conflict or bias.
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Ó 2008 The Authors
Journal compilation Ó 2008 Blackwell Publishing Ltd