plasminogenactivatorinhibitortype1deficiency

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ORIGINAL ARTICLE

Plasminogen activator inhibitor type 1 deficiency

R. MEHTA* and A. D. S HAPIRO

*Department of Clinical Medicine, Section of Hematology/Oncology, Indiana University School of Medicine; andIndiana

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 fibrinolysis in thecirculation. Reduced PAI-1 levels may result inincreased fibrinolysis and an associated bleeding

diathesis. Clear documentation of PAI-1 deficiencyas a cause of a bleeding disorder has been rare. PAI-1was initially identified in the 1980s, and the firstreported case of PAI-1 deficiency appeared in 1989.Several reports followed, although only two identi-fied an underlying genetic defect. These reports ofPAI-1 deficiency suggest that affected individualsexhibit mild to moderate bleeding symptoms, includ-ing epistaxis, menorrhagia, and delayed bleedingafter trauma or surgical procedures. Affected indi-viduals rarely exhibit spontaneous bleeding eventscommonly seen in other procoagulant deficiencies.

The majority of bleeding events are controlled withantifibrinolytic agents, such as tranexamic acid and

-aminocaproic acid. A major issue that contrib-utes to difficulty in establishing an accuratediagnosis of PAI-1 deficiency is that the activityassay is accurate in detection of elevated levelsbut not at the lowest range. Reported normal

ranges begin at zero, thereby making a deficiencystate because of a dysproteinaemia difficult todistinguish from that of a normal unaffectedindividual. Although the antigen assay may behelpful in some circumstances, it assists only withcomplete quantitative disorders. Because of lack ofstandardized commercially available PAI-1 activityassay sensitive in the lowest range, the trueprevalence of this rare condition has not beenestablished.

Keywords: antifibrinolytic agents, bleeding, dyspro-

teinaemia, fibrinolysis, menorrhagia, plasminogenactivator inhibitor type 1

Introduction

The plasminogen activation system was a burgeoningfield in the early 1980s, with the discovery of the firstplasminogen activator inhibitor in 1984 [1,2]. Afterpurification of the inhibitor, the isolation of thec-DNA was completed for what was later termedplasminogen activator inhibitor, type 1 (PAI-1) [3].

Once PAI-1 was isolated, researchers began to studythe impact of perturbations of normal levels, eitherthose higher or lower than the established normal

range. While numerous investigations have evaluatedelevated levels of PAI-1and the documented associ-ation of an increased risk of arterial thromboticevents [4], reports of PAI-1 deficiency are limited.The first reported case of low levels of PAI-1resulting in a lifelong bleeding disorder was pub-lished in 1989, when an elderly man was noted tohave decreased PAI-1 activity and normal PAI-1

antigen levels, leading to a presumed qualitativedefect of the protein [5]. The first person with aquantitative deficiency (undetectable PAI-1 antigenand activity levels) was described two years later [6].In 1992, the first identified homozygous PAI-1genetic defect that led to a bleeding disorder wasdocumented [7]. Subsequently, other reports ofPAI-1 deficiency leading to a bleeding diathesis havebeen published, but only one other specific geneticmutation associated with PAI-1 deficiency has beendocumented [817]. PAI-1 deficiency 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: [email protected]

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


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quite rare, and is associated with a mild to moderatebleeding disorder. Unfortunately, lack of a sensitivePAI-1 activity assay hampers diagnosis of thiscondition.

Materials and methods

This review was performed by an extensive literaturesearch through PubMed. Further references notinitially identified in the search but referenced withinthese articles were also reviewed. All cases of PAI-1deficiency reported in the literature were reviewed.Also, prior reviews on the history of the discovery ofPAI-1 were evaluated. Finally, documented cases ofPAI-1 deficiency within the Indiana Amish popu-lation were re-evaluated. Home visits to thesepatients and their parents were performed withinthe 2007 calendar year, with an extensive review ofpersonal bleeding histories completed (RakeshP. Mehta, Amy D. Shapiro, unpublished data).

Incidence

The true incidence of PAI-1 deficiency is unknown inlarge part because of the difficulty in establishing thediagnosis with present laboratory tests and the rarityof the disorder. We performed a survey within theFederal Network of Hemophilia Centers within theUnited States to identify documented and/or sus-pected cases in an effort to determine the prevalenceof this disorder. More than 100 surveys were mailed

with only six centres responding. Two of the sixresponders reported PAI-1-deficient patients. Thesepatients were noted to have a history of bleedingwith a negative evaluation other than undetectablePAI-1 activity. A recent analysis screened 586 indi-viduals with a bleeding tendency for decreased PAI-1activity using a modified commercially availableassay for the study, and compared them with 200controls [8]. In the group with a bleeding tendency,23% had low PAI-1 activity levels compared with1013% in the control group; the severity ofbleeding was minimal in most of these patients.

Another recent report evaluating 66 blood donorsrevealed 14.6% of the females and 21% of the malesto have PAI-1 activity levels


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Although plasma PAI-1 exists mostly in an activeform, there is also a latent inactive form that resultsfrom inherent instability of the molecule [1]. In fact,80% of the PAI-1 stored in thea-granules of plateletsis in the latent form. The latent form can beconverted back to the active form with denaturantsor negatively charged phospholipids in vitro, but thisconversion does not appear to occur within thecirculation. Therefore, the physiological significanceat 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 deficiencies, quali-

tative or quantitative defects may lead to a deficiencystate [57,913,15,17]. The first case described in1989 reported normal levels of PAI-1 antigen, with amarked reduction in PAI-1 activity and t-PA:PAI-1complexes, suggesting that the PAI-1 present lackedactivity [5]. Conversely, it is possible that much ofthe PAI-1 may have been present in the latent form,resulting in a normal antigenic assay but decreasedactivity assay. Most of the subsequent reports doc-umented true qualitative deficiencies resulting indecreased 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 lifelongbleeding histories, so that the low plasma levels werebelieved to be clinically significant and result inthe patients bleeding symptoms. Neither reportexplained the discrepancy between the plasma andplatelet PAI-1 levels.

In reports of PAI-1 deficiency, a variety of assayshave been used, making it difficult to extrapolate acorrelation between any specific level and degree ofclinical bleeding. Unfortunately, as currently available

activity assays include zero within the reported normalrange, the sensitivity of these assays at the lowest levelis insufficient to provide an adequate diagnostic tool,and makes it difficult to correlate the degree ofdeficiency with specific bleeding symptoms. A recentlypublished report utilizing a modified PAI-1 activityassay suggests that PAI-1 activity levels


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position 4497 in exon 2 of the gene, leading to asingle amino acid exchange of an Alanine for aThreonine at codon 15 of the signal peptide. Inter-estingly, this patient was a heterozygote for thismutation, but had an activity level that was 10% ofthe healthy controls. His father, who had the same

mutation had a lower than normal PAI-1 antigen andactivity level but much higher than his sons. Inaddition, the patients mother, who did not have themutation, had a moderately reduced PAI-1 activityand antigen level. Therefore, the authors concludedthat the patient was a compound heterozygote withthe documented mutation being partially responsiblefor the markedly low PAI-1 levels.

Clinical manifestations

The bleeding symptoms associated with PAI-1 defi-ciency have been fairly consistent and appear com-patible with what might be predicted based on therole of this coagulation factor within the haemostaticsystem. Most reports have documented a mild-to-moderate, delayed bleeding disorder typically asso-ciated with injury, trauma or surgery. The initial caseof PAI-1 deficiency described a man with a longhistory of post-traumatic and postsurgical bleeding[5]. Most subsequent reports describe similar symp-toms. The Amish population with PAI-1 deficiencyhas a similar clinical expression [23]. Recent follow-up evaluations reveal a wide variety of bleedingcomplications, though most were post-traumatic

bleeding events, including intracranial haemorrhageand haemarthrosis. Importantly, menorrhagia repre-sented a significant clinical symptom in youngwomen, even resulting in the requirement of packedred blood cell transfusion in one patient because ofmarked anaemia and iron deficiency from menstrualblood loss (Rakesh P. Mehta, Amy D. Shapiro,unpublished data). Two other reports also documentmenorrhagia as a significant symptom in PAI-1-deficient females [11,13]. Postsurgical bleeding is acommon complication observed in this deficiencystate. Of reported events, dental procedures are

clearly associated with abnormal bleeding in PAI-1deficiency [6,11,12,15]. In fact, after having post-traumatic and postsurgical bleeding as a toddler, itwas an episode of recurrent oral bleeding in theproband in the Amish population that led to thediagnosis of the bleeding disorder [7]. Easy bruising,epistaxis, and muscle haematomas secondary toinjury or trauma have also been reported [6,7,10,17].

The age range of diagnosis is quite wide. The firstpatient described was 76 years old [5] but a child asyoung as 4 months has also displayed a bleeding

tendency [23]. Thus, there does not appear to be aspecific age at which symptoms either typicallymanifest or a time when they tend to decrease orresolve.

Although most reports of bleeding from PAI-1deficiency stem from inherited conditions, an

acquired deficiency also appears possible [24].A gentleman with end-stage liver disease presentedwith spontaneous, deep muscle bleeding. He wasfound to have detectable PAI-1 antigen but lackedPAI-1 activity. Levels of t-PA were markedlyincreased; therefore, his bleeding diathesis wasbelieved to have resulted from a profound imbalanceof the fibrinolytic system, because of lack of clear-ance of t-PA by the impaired liver with acquiredrelative PAI-1 deficiency. Interestingly, elevated lev-els of urinary t-PA after trans-urethral prostatectomy(TURP) also have been shown to correlate withincreased blood loss after these procedures [25].Potentially, the increased levels of t-PA released leadto a locally acquired deficiency of PAI-1 as well.

Diagnosis

The assays to establish the diagnosis of PAI-1deficiency have been reviewed. Several antigen testsare available, but these are not able to detectqualitative deficiencies [8]. Unfortunately, the cur-rently available PAI-1 activity assays are designed todetect increased activity rather than a deficiency stateand subsequently are not adequately sensitive at the

lowest levels. Because a PAI-1 activity level of zero isoften reported as being within the normal limit ofthese assays, they cannot reliably discriminate adeficiency state from a non-deficient individual.Interestingly, correlating plasmin-antiplasmin levelswith markedly low PAI-1 activity levels(


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Management

Antifibrinolytic agents remain the mainstay of treat-ment for this disorder with all published reportsdocumenting the benefit of EACA or tranexamic acidfor 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 preventbleeding when instituted prophylactically beforeinterventions or invasive procedures. For example,a young Amish boy developed recurrent bleeding ofhis subdural haematoma after he discontinued use ofthe prescribed EACA upon discharge from thehospital. Reinstitution of this agent helped stop therecurrent bleeding and led to a full recovery (RakeshP. Mehta, Amy D. Shapiro, unpublished data). Theefficacy of these agents has also been documented asprophylactic medications in prevention of bleeding inassociation with surgical procedures [5,23]. Inpatients with menorrhagia, EACA has been effectivein limiting the amount of menstrual blood loss andappears most effective when instituted a few daysbefore the anticipated onset of the menstrual cycle[13,23].

Prognosis

Patients with PAI-1 deficiency may do quite well, asbleeding once recognized can be controlled withcurrently available agents. In fact, 1 patient was

76 years of age before the diagnosis was establishedand had lived a relatively long life without priorspecific treatment. However, some patients experi-ence life-threatening bleeding events in associationwith injury or menses. Therefore, early diagnosis andprompt initiation of therapy are required to achieveoptimal outcome. The identified PAI-1-deficientAmish kindred is still relatively young with none ofthe identified homozygous deficient patients cur-rently older than 25 years. Consequently, longevitywith complete absence of PAI-1 remains unestab-lished. Of interest, almost 100 heterozygotes in this

Amish population have been identified with noadults identified to be homozygosity-deficient despiteapproximately 500 members of the kindred tested.(Rakesh P. Mehta, Amy D. Shapiro, unpublisheddata) It is anticipated that with early identification ofPAI-1-deficient patients and appropriate therapy, anormal lifespan may be achieved. However, there arenumerous unanswered questions for this population,including fertility, ability to carry a pregnancy toterm, and development of atherosclerosis. The linkbetween PAI-1 and cancer prognosis has been firmly

established [26]. Increased levels of PAI-1 expressionin breast cancer tissue are associated with aworse prognosis [27]. Theoretically, PAI-1-deficientpatients may have improved survival with cancerbecause of decreased PAI-1 levels; in PAI-1 knockoutmice, there was significantly less tumour invasion

then in the controls [28]. Only long-term follow-upof these patients will provide the informationnecessary to answer these unresolved questions.

Conclusion

Plasminogen activator inhibitor, type 1 deficiency is arare bleeding disorder whose mainstay of treatmentis antifibrinolytic agents. The accurate diagnosis ofthis disorder remains a challenge and the develop-ment of a readily available standardized sensitiveactivity assay capable of differentiation between lownormal levels and a true deficiency state is needed.Once available, the correlation of specific levels ofdeficiency with particular clinical symptoms could beestablished. Because this disorder results from eithera qualitative or quantitative defect, an accuratePAI-1 activity assay is critical to establish thediagnosis. Also, with improved assays, the trueprevalence of clinically significant PAI-1 deficiencycould be determined. Although rare, PAI-1 deficiencyshould be considered in patients with delayedpost-traumatic or postsurgical bleeding after othermore common bleeding disorders have beenexcluded. If PAI-1 deficiency is established, then a

trial of antifibrinoltyic agents should be considered.In the future, a database of patients with thisdisorder should be created to establish the range ofclinical symptoms experienced, the genetic defectsleading to a deficiency state, and the association ofspecific levels with clinical events.

Research Interests

Most research regarding PAI-1 currently pertains toelevated levels. The laboratory of Dr DouglasVaughan and Dr Mohan Sathyamoorthy of the

Cardiovascular Medicine Section at Vanderbilt Uni-versity is very interested in the long-term effects ofPAI-1 deficiency on the development of atheroscle-rosis. Dr Sathyamoorthy can be contacted [email protected].

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1260 R. MEHTA and A. D. SHAPIRO

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