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Complete Plasminogen Activator Inhibitor 1 Deficiency

Synonyms: Complete PAI-1 Deficiency, Homozygous PAI-1 Deficiency

, MS, , MD, , MD, , MD, and , MD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild to moderate bleeding, although in some instances bleeding can be life threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding does not occur. While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males due to menorrhagia and postpartum hemorrhage. Fewer than ten families with complete PAI-1 deficiency have been reported to date. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant. In one family from this Old Order Amish population, seven individuals had cardiac fibrosis ranging from minimal-to-moderate (6 individuals) to severe (1).

Diagnosis/testing.

The diagnosis of complete PAI-1 deficiency is established in a proband when PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL-1 and/or biallelic SERPINE1 pathogenic variants are identified on molecular genetic testing. Note that because the normal range of functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited.

Management.

Treatment of manifestations: Management of the bleeding disorder by a team of experts in the treatment of individuals with bleeding disorders is highly recommended. Intravenous antifibrinolytics (e.g., epsilon-aminocaproic acid [EACA] and tranexamic acid) can be used for severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation). Infusion of fresh-frozen plasma can be used as needed to increase PAI-1 activity prior to achieving therapeutic steady state levels of antifibrinolytics. Heavy menstrual bleeding can often be managed with antifibrinolytics or hormonal suppression therapy. Treatment of cardiac fibrosis is symptomatic.

Prevention of primary manifestations: Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures.

Surveillance: Regular follow up with a team of experts in the treatment of individuals with bleeding disorders is recommended. For all individuals with complete PAI-1 deficiency, screening echocardiogram for evidence of cardiac fibrosis is recommended beginning at age 15 years with follow up for those with positive findings as indicated by a cardiologist and every two years for those with no cardiac findings at the time of the last screening.

Agents/circumstances to avoid: Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies; high-risk activities such as contact sports.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Pregnancy management: Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are oral administration of either tranexamic acid or EACA for intermittent bleeding in the first and second trimester, from 26 weeks’ gestation through delivery, and for at least two weeks post partum. Note: Evidence that these recommendations would be effective in all pregnancies of women with complete PAI-1 deficiency is lacking; the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited.

Genetic counseling.

Complete PAI-1 deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SERPINE1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk for complete PAI-1 deficiency, and preimplantation genetic diagnosis are possible.

Diagnosis

No formal diagnostic criteria for establishing a diagnosis of complete plasminogen activator inhibitor 1 (PAI-1) deficiency have been published.

Suggestive Findings

Complete PAI-1 deficiency should be suspected in individuals with the following medical history and laboratory findings.

Medical History

Bleeding disorder that typically presents as:

  • Delayed bleeding following injury, trauma, or surgery
  • In females, menorrhagia and abnormal bleeding with pregnancy

Absence of other known bleeding disorders including:

  • von Willebrand disease
  • Factor V deficiency
  • Factor X deficiency
  • Factor II deficiency
  • Alpha 2 antiplasmin deficiency
  • Factor XIII deficiency
  • Platelet function disorders (including Scott syndrome and Quebec platelet disorder)

Laboratory Findings

Normal: common tests of coagulation including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin clotting time (TCT)

Abnormal tests indicative of a hyperfibrinolytic state; these may include the following:

  • Decreased plasma plasminogen
  • Decreased plasma α-2-antiplasmin
  • Decreased plasma total and free levels of tissue-type plasminogen activator antigen (t-PA)
  • Shortened euglobin lysis time (ECLT) in plasma. Note: While ECLT is shortened due to excessive fibrinolysis in persons with complete PAI-1 deficiency, and ECLT and whole blood clotting assays (e.g., the thromboelastogram) can be helpful in diagnosis of hyperfibrinolytic states, these tests are insufficient to confirm or exclude the diagnosis of complete PAI-1 deficiency.

PAI-1 specific assays:

  • PAI-1 antigen assay (to determine the level of PAI-1 antigen) can be helpful in identifying complete PAI-1 deficiency if no PAI-1 is produced, but is not helpful if dysfunctional protein is produced [Gupta et al 2014].
  • PAI-1 activity assay can be used to exclude a diagnosis of complete PAI-1 deficiency when PAI-1 activity levels are clearly within the normal range. Because the normal range of the functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited [Fay et al 1997, Mehta & Shapiro 2008].

Note: If the PAI-1 antigen level is normal and PAI-1 activity is decreased, the phenotype is referred to as “qualitative PAI-1deficiency,” the clinical significance of which is unknown [Fay et al 1997, Mehta & Shapiro 2008].

Establishing the Diagnosis

The diagnosis of complete PAI-1 deficiency is established in a proband when [Fay et al 1997, Iwaki et al 2011]:

  • PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL
    Note: (1) Because the majority of PAI-1 activity assays are used to detect increased PAI-1 activity rather than decreased PAI-1 activity, they lack the sensitivity to differentiate between low normal activity and complete deficiency. Thus, a PAI-1 activity level of zero is often reported to be within the normal limits. (2) PAI-1 activity also demonstrates diurnal variation: because higher levels are observed in the morning and lower levels in the afternoon, the activity should be assayed in a sample drawn in the morning.

AND/OR

  • Biallelic SERPINE1 pathogenic variants are identified on molecular genetic testing (see Table 1). See also Molecular Genetics.

Molecular genetic testing approaches can include single-gene testing and use of a multi-gene panel.

Single-gene testing

  • Sequence analysis of SERPINE1 is performed first. If only one or no SERPINE1 pathogenic variant is identified, gene-targeted deletion/duplication analysis can be considered; however, to date no SERPINE1 exon or whole-gene deletions/duplications have been reported.
  • Targeted analysis for the c.699_700dupTA pathogenic variant can be performed first in individuals from the Old Order Amish community of eastern and southern Indiana. Note: This variant has not been identified in other Old Order Amish populations.

A multi-gene panel that includes SERPINE1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Plasminogen Activator Inhibitor 1 (PAI-1) Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
SERPINE1Sequence analysis 3Unknown
Gene-targeted deletion/duplication analysis 4None reported 5
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild to moderate bleeding, although in some instances bleeding can be life-threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding episodes such as those observed in classic hemophilia A and hemophilia B do not occur.

While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males, due to menorrhagia and postpartum hemorrhage. In addition, females experience bleeding with pregnancy and have difficulty carrying a pregnancy to term.

Bleeding disorder. Mucocutaneous bleeding, a hallmark of complete PAI-1 deficiency, includes oral bleeding, epistaxis and – in females – menorrhagia and postpartum bleeding.

Post-traumatic bleeding can include joint bleeds and hematomas [Schleef et al 1989, Diéval et al 1991, Minowa et al 1999]. Affected members of the kindred from the Old Order Amish community of eastern and southern Indiana developed knee and elbow hemarthroses after minor trauma, extensive subperiosteal bleeding after minor jaw trauma, and epidural hematoma (in an infant) after a head injury [Fay et al 1997].

The male reported by Zhang et al [2005] experienced soft tissue hematomas of the leg and hip following minor leg trauma that required treatment; he subsequently manifested muscle atrophy.

Post-surgical bleeding has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency:

  • A child age five years experienced postoperative bleeding following surgical repair of a ventricular septal defect [Iwaki et al 2011].
  • A member of the Old Order Amish community had delayed bleeding after surgical repair of an inguinal hernia [Fay et al 1997].
  • Delayed bleeding was reported after total hip arthroplasty [Hirose et al 2016].

Prolonged bleeding after dental extraction has been reported in individuals with a molecularly confirmed diagnosis of complete PAI-1 deficiency [Fay et al 1997, Iwaki et al 2011].

A palatal hemorrhage complicated a dental abscess, requiring hospitalization and transfusion [Fay et al 1992].

Prolonged wound healing occurred in one individual [Iwaki et al 2011].

Menorrhagia is a consistent characteristic of complete PAI-1 deficiency [Minowa et al 1999, Mehta & Shapiro 2008, Iwaki et al 2011]. In some instances treatment with transfusion of packed red blood cells [Mehta & Shapiro 2008] or whole blood is required [Iwaki et al 2011].

In one woman rupture of an ovarian follicle resulted in hemoperitoneum requiring hospitalization, treatment with antifibrinolytics, and red cell transfusion.

Pregnancy can be complicated by sporadic antenatal bleeding, preterm labor, postpartum bleeding, and miscarriage. Gupta et al [2014] (full text) followed two women with PAI-1 deficiency through a total of seven pregnancies: six live born premature infants and one miscarriage. Bleeding, which began between eight and 19 weeks’ gestation and recurred prior to delivery, was treated with epsilon-aminocaproic acid (EACA). Postpartum bleeding was treated with EACA for up to six weeks (see Pregnancy Management).

Iwaki et al [2012] also reported on three pregnancies in a woman with complete PAI-1 deficiency in which antenatal bleeding, preterm labor, and miscarriage were complications.

Cardiac fibrosis. Cardiac fibrosis has only been reported in an Old Order Amish kindred with complete PAI-1 deficiency, which is – to the authors’ knowledge – the largest number of affected individuals with this finding reported to date [Flevaris et al 2017; Author, personal observation]. Of the seven individuals with cardiac fibrosis, one had severe involvement and six had minimal to moderate cardiac fibrosis between ages 15 and 35 years. Thus, to date, information about cardiac fibrosis in complete PAI-1 deficiency is limited.

Genotype-Phenotype Correlations

Because data on the phenotype associated with biallelic SERPINE1 pathogenic variants are limited, no genotype-phenotype correlations can be made at this time.

Nomenclature

Complete plasminogen activator inhibitor 1 (PAI-1) deficiency, the topic of this GeneReview, is defined as undetectable PAI-1 antigen levels and undetectable PAI-1 activity. Complete PAI-1 deficiency may also be referred to as “quantitative PAI-1 deficiency” or “homozygous PAI-1 deficiency.”

Qualitative PAI-1 deficiency, not addressed in this GeneReview, refers to normal PAI-1 antigen levels and decreased PAI-1 activity and is thought to be associated with either a heterozygous SERPINE1 pathogenic variant (i.e., the carrier state for an autosomal recessive disorder) or compound heterozygosity for variants that produce a reduced amount of protein that is nonetheless sufficient to avoid complete deficiency. The clinical significance of qualitative PAI-1 deficiency is unknown. See also Molecular Genetics.

Prevalence

The prevalence of complete PAI-1 deficiency is unknown, in large part because of the inability of the majority of tests of PAI-1 activity to differentiate between low normal activity and complete deficiency (see Establishing the Diagnosis).

Fewer than ten families with complete PAI-1 deficiency have been reported to date.

Complete PAI-1 deficiency has no known racial or ethnic predominance. It has been reported in North America, Europe, and Asia.

Of note, the incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant (see Molecular Genetics). To date, this pathogenic variant has not been found in other Old Order Amish communities.

Differential Diagnosis

Table 2.

Disorders Associated with Mild to Moderate Bleeding (often Associated with Injury, Surgery, or Dental Procedures) to Consider in the Differential Diagnosis of Complete PAI-1 Deficiency

Disorder 1Gene(s)MOIClinical Feature Unique to Differential Diagnosis DisorderRelated GeneReview / OMIM Entry
Alpha-2 antiplasmin deficiencySERPINF2ARAbnormal PLI assay 2262850
Factor XIII deficiencyF13A1, F13BARLow factor XIII level613225
Factor II deficiencyF2ARLow factor II level613679
Factor V deficiencyF5ARLow factor V level227400
Factor X deficiencyF10ARLow factor X level227600
Platelet function defectsGP1BAADAbnormal platelet studies177820
GP1BBAR231200
GP9AR
ANO6AR262890
ITGA2BAD187800
ITGB3
von Willebrand disease (VWD)VWFAD, ARAbnormal VWD lab evaluationvon Willebrand Disease

MOI = mode of inheritance

AD = autosomal dominant

AR = autosomal recessive

1.

Disorders are listed alphabetically.

2.

Alpha-2 antiplasmin deficiency. Moderate bleeding seen in alpha-2 antiplasmin deficiency is not characteristically associated with injury, surgery, or dental procedures.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with complete plasminogen activator inhibitor 1 (PAI-1) deficiency, the following evaluations are recommended:

  • Questions to elicit a patient’s history of:
    • Epistaxis
    • Poor wound healing
    • Bleeding in association with injury or trauma
    • Bleeding with dental extractions
    • Additional oral bleeding
    • Post-surgical bleeding
    • In females:
      • Heavy menstrual bleeding
      • Postpartum bleeding
      • Bleeding during pregnancy
      • Preterm delivery
      • Bleeding in association with ovulation
  • History of therapies tried in the past and the response to each specific therapy
    Note that response to antifibrinolytic therapy supports the diagnosis of complete PAI-1 deficiency (see Treatment of Manifestations).
  • Evaluation by a hematologist with training in hemostasis
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Bleeding disorder. Management by a team of experts in the treatment of individuals with bleeding disorders is highly recommended. In the US, such teams are often identified through the federally funded hemophilia treatment center network.

Severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation) have been successfully managed with intravenous antifibrinolytics. Response to both epsilon-aminocaproic acid and tranexamic acid have been documented.

If PAI-1 activity needs to be increased prior to achieving the therapeutic steady state level of antifibrinolytics, infusion of fresh-frozen plasma (FFP) (10-15 mL/kg) can be used. Duration of use of FFP is individualized based on clinical course and response to therapy. Note: The use of FFP does not appear to be effective in pregnancy for the prevention of bleeding in women with complete PAI-1 deficiency [Iwaki et al 2012]. Fresh-frozen plasma to replace PAI-1 during pregnancy may be difficult due to the PAI-1 level achieved with plasma, the volume required, and the need for repeated infusion, all of which may be associated with risk of volume overload and/or infusion reactions [Gupta et al 2014].

Heavy menstrual bleeding can often be effectively managed with antifibrinolytics or hormonal suppression therapy (oral contraceptives).

Occasionally, patients with complete PAI-1 deficiency experience excessive menstrual bleeding or bleeding following a procedure or trauma that requires infusion of packed red blood cells to manage the acute blood loss.

Education regarding bleeding manifestations and when to seek treatment includes the following:

  • For females, anticipatory counseling regarding onset of menses and potential complications
  • Prompt reporting of injuries and planned procedures to allow early initiation of treatment to prevent significant bleeding

Cardiac fibrosis. There is currently no specific treatment for cardiac fibrosis associated with complete PAI-1 deficiency; treatment is symptomatic.

Prevention of Primary Manifestations

Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures. Antifibrinolytics can be administered IV, PO, or topically, the latter especially during dental procedures.

Women who have heavy menstrual bleeding often benefit from continuous or intermittent prophylactic use of the antifibrinolytics tranexamic acid and epsilon-aminocaproic acid.

Surveillance

Bleeding disorder. Regular follow up with a team of experts in the treatment of individuals with bleeding disorders is recommended. Such teams are often identified through the federal hemophilia treatment center network in the US.

For menstruating females:

  • Regular monitoring: hemoglobin and/or hematocrit and iron studies including ferritin for possible iron deficiency and/or anemia
  • Assessment of the effectiveness of therapeutic interventions such as antifibrinolytics or hormonal suppressive agents (oral contraceptives)

Cardiac fibrosis. Because of clinical experience (albeit limited to date) with cardiac fibrosis in persons with complete PAI-1 deficiency [Flevaris et al 2017; Author, personal observation], screening echocardiogram can be considered beginning at age 15 years. In those with no cardiac findings, follow-up screening in two years is indicated; and in those with cardiac findings, follow up yearly or more frequently if indicated by a cardiologist [Ghosh et al 2010; Ghosh et al 2013; Author, personal observation].

Agents/Circumstances to Avoid

The following should be avoided:

  • Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies
  • High-risk activities such as contact sports

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Evaluations can include:

  • Molecular genetic testing if the SERPINE1 pathogenic variants in the family are known;
  • Measurement of PAI-1 antigen levels and PAI-1 activity if the SERPINE1 pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are administration of either tranexamic acid (25 mg kg-1 per dose, maximum 1300 milligrams, orally 3-4x/day) or epsilon-aminocaproic acid (EACA) (100 mg kg-1 per dose, maximum 3 g, orally 4x/day) for intermittent bleeding in the first and second trimester, from 26 weeks’ gestation through delivery, and for at least two weeks post partum [Heiman et al 2014]. Note that evidence that these recommendations would be effective in all pregnancies of women with complete PAI-1 deficiency is lacking.

A woman with complete PAI-1 deficiency was treated with FFP during three pregnancies at eight to 11 weeks’ gestation two to three times per week; treatment was increased to daily at 20-28 weeks’ gestation. The first pregnancy ended in miscarriage at 19 weeks. The second and third pregnancies were delivered at 32 and 27 weeks’ gestation, respectively, as a result of uncontrollable contractions and placental abruption [Iwaki et al 2012].

Of note, the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited. There is a need to establish dosing guidelines for the use of antifibrinolytics during pregnancy and the postpartum period.

To access further information on medication use during pregnancy, see www.mothertobaby.org.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Complete plasminogen activator inhibitor 1 (PAI-1) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one SERPINE1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing complete PAI-1 deficiency.

Offspring of a proband

  • The offspring of an individual with complete PAI-1 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in SERPINE1.
  • The incidence of PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana, increasing the risk that an affected individual may have a reproductive partner who is heterozygous for a SERPINE1 pathogenic variant (see Prevalence). The offspring of an affected individual and a heterozygous reproductive partner are at 50% risk of being affected and 50% risk of being heterozygous.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a SERPINE1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SERPINE1 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. This includes issues related to pregnancy in affected women and the risk to the fetus due to risk for prematurity.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SERPINE1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for complete PAI-1 deficiency are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Complete Plasminogen Activator Inhibitor 1 Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SERPINE17q22​.1Plasminogen activator inhibitor 1SERPINE1 databaseSERPINE1SERPINE1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Complete Plasminogen Activator Inhibitor 1 Deficiency (View All in OMIM)

173360SERPIN PEPTIDASE INHIBITOR, CLADE E (NEXIN, PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1), MEMBER 1; SERPINE1
613329PLASMINOGEN ACTIVATOR INHIBITOR-1 DEFICIENCY

Molecular Genetic Pathogenesis

PAI-1, a protein that is a member of the serine protease inhibitor (SERPIN) superfamily, is involved in a variety of pathophysiologic systems including embryogenesis, angiogenesis, ovulation, inflammation, and tumor metastasis. These observations suggest that the plasminogen activation system is an important mediator of tissue remodeling and cell migration [Gupta et al 2014] (full text).

In hemostasis, PAI regulates fibrinolysis (i.e., the degradation of thrombi) [Gupta et al 2014]. PAI-1 is an inhibitor of tissue type plasminogen activators (t-PA) and urokinase type plasminogen activators (u-PA), which convert plasminogen to plasmin, the primary protease responsible for fibrinolysis. Thus, complete PAI-1 deficiency results in excessive fibrinolysis manifesting as mild to moderate bleeding [Heiman et al 2014]. Physiologic fibrinolysis occurs exclusively on the clot surface within a blood vessel and not in the circulation [Gupta et al 2014] (see Figure 1).

Figure1. . Plasminogen activators – urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) – circulate in plasma as a reversible complex with PAI-1.

Figure1.

Plasminogen activators – urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) – circulate in plasma as a reversible complex with PAI-1. When the fibrin clot is formed, plasminogen and t-PA or u-PA bind to the (more...)

Heterozygous pathogenic variants in SERPINE1 may be associated with qualitative PAI-1 deficiency (i.e., normal PAI-1 antigen levels and decreased PAI-1 activity), the clinical significance of which is unknown. Thus, the significance of reports of families with qualitative PAI-1 deficiency and a heterozygous SERPINE1 variant should be interpreted with caution because (1) the PAI-1 activity assays used in these families lack the sensitivity to differentiate between low normal activity and complete deficiency, and (2) the SERPINE1 variants identified are of uncertain clinical significance (i.e., some variants reported as pathogenic may actually be benign).

Although beyond the scope of diagnostic laboratories, studies to determine the functional consequences of a SERPINE1 variant may be of value in these circumstances. Of note, in vitro expression analyses demonstrated that the c.699_700dupTA variant of the Old Order Amish community resulted in the synthesis of an insoluble, unstable protein [Fay et al 1992]. However, currently there are no clinically useful functional PAI-1 assays. Note: A fibrinolysis assay with a euglobulin clot lysis time is not sensitive or specific to PAI-1.

Gene structure. SERPINE1 spans approximately 12 kb and comprises nine exons. A variety of regulatory elements have been identified in SERPINE1, including AP-1 sites, a glucocorticoid response element, a VLDL response site, and two Sp1 sites that appear to mediate glucose responsiveness. See Table A, Gene for a detailed summary of gene and protein information.

Modulator. The SERPINE1 c.-820_-817G(4_5) (commonly known as 4G/5G) benign variant is a common insertion/deletion of four or five G-nucleotide residues in the SERPINE1 promoter region; the 4G allele is associated with higher plasma PAI-1 activity. An elevation in plasma PAI-1 activity leads to depressed fibrinolytic activity and a theoretically increased risk for arterial and venous thrombosis, a significant risk factor for coronary artery disease, myocardial infarction, and recurrent miscarriage [Huang et al 2017]. This benign variant is mentioned only to point out that testing for the 4G/5G variant will not aid in diagnosing an individual with complete PAI-1 deficiency.

Pathogenic variants. The first individual reported to have a bleeding disorder resulting from biallelic SERPINE1 pathogenic variants was a child from the Old Order Amish community of eastern and southern Indiana who was homozygous for a dinucleotide insertion in exon 4 (c.699_700dupTA), resulting in a frameshift leading to a premature stop codon [Fay et al 1992]. Subsequently in this Old Order Amish community: (1) eleven additional individuals with a bleeding disorder have been determined to be homozygous for this pathogenic variant, and (2) 96 individuals heterozygous for this pathogenic variant – none of whom experienced bleeding – have been identified [Indiana Hemophilia and Thrombosis Center, unpublished data].

Since 1992 two additional SERPINE1 pathogenic variants associated with a bleeding disorder have been reported:

  • c.43G>A. A Chinese man age 34 years with a lifelong history of bleeding associated with surgery and trauma had a heterozygous missense SERPINE1 variant; the authors ultimately concluded that a second pathogenic variant was present but undetectable [Zhang et al 2005].
  • c.356dupC. A woman age 47 years with a lifelong history of major bleeding (including extreme menorrhagia and post-surgical and postpartum bleeding) and impaired wound healing had an undetectable PAI-1 antigen level. She was homozygous for a 1-bp duplication leading to a frameshift and a premature stop codon [Iwaki et al 2011].

Table 3.

SERPINE1 Variants Discussed in This GeneReview

Variant ClassificationDNA Nucleotide Change (Alias) 1Predicted Protein Change 2Reference Sequences
Modulatorc.-820_-817G(4_5) 3
(4G/5G)
--NM_000602​.4NP_000593​.1
Pathogenicc.43G>Ap.Ala15Thr
c.356dupCp.Ile120AspfsTer42
c.699_700dupTAp.Thr234IlefsTer45

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

Numbering relative to full-length protein

3.

Not associated with the complete PAI-1 deficiency phenotype but can affect measured PAI-1 activity levels. A 1-bp guanine deletion/insertion variant in promoter (rs587776796) associated with higher transcription and activity levels and other phenotypes, including coronary artery disease (see OMIM 173360).

Normal gene product. The full-length gene product, PAI-1, is a 47-kd protein of 402 amino acids in length including the 23-residue signal peptide. The active mature form of PAI-1 in plasma is 379 amino acids in length.

The key functional domains of the full-length protein are:

  • The Arg-Met reactive site at residues 369-370;
  • A vitronectin binding site;
  • Glycosylation sites at residues 232, 288, and 352.

Abnormal gene product. PAI-1 deficiency may result from either complete plasma protein deficiency (absence of PAI-1 activity and antigen) as in the kindred described above or a dysproteinemic state with presence of the antigen but absence of activity.

The loss-of-function pathogenic variant c.699-700 dup TA resides in exon 4 of the coding sequence at amino acid 210, resulting in a frame shift and formation of a premature stop codon and the synthesis of a truncated, non-functional PAI-1 protein.

The c.43G>A variant in the signal peptide may partly impair secretion of PAI-1 [Zhang et al 2005].

References

Literature Cited

  • Diéval J, Nguyen G, Gross S, Delobel J, Kruithof EK. A lifelong bleeding disorder associated with deficiency of plasminogen activator inhibitor type 1. Blood. 1991;77:528–32. [PubMed: 1899347]
  • Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor -1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood. 1997;90:204–8. [PubMed: 9207454]
  • Fay WP, Shapiro AD, Shih JL, Schleef RR, Ginsburg D. Brief report: complete deficiency of plasminogen activator inhibitor type 1 due to a frameshift mutation. NEJM. 1992;327:1729–33. [PubMed: 1435917]
  • Flevaris P, Khan SS, Eren M, Schuldt AJ, Shah SJ, Lee DC, Gupta S, Shapiro A, Burridge P, Ghosh AK, Vaughan DE. PAI-1 controls cardiomyocyte TGF-β and cardiac fibrosis. Circulation. 2017 June 6; [PMC free article: PMC5784400] [PubMed: 28588076]
  • Ghosh AK, Bradham WS, Gleaves LA, De Taeye B, Murphy SB, Covington JW, Vaughan DE. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice. Circulation. 2010;122:1200–9. [PubMed: 20823384]
  • Ghosh AK, Murphy SB, Kishore R, Vaughan DE. Global gene expression profiling PAI-1 knockout murine heart and kidney: Molecular basis of cardiac-selective fibrosis. PLoS One. 2013;8:e63825. [PMC free article: PMC3665822] [PubMed: 23724005]
  • Gupta S, Sealls W, Shapiro AD. Plasminogen Activator Inhibitor Type 1 Deficiency – Disease Overview. Available online. 2014. Accessed 8-1-17.
  • Heiman M, Gupta S, Shapiro AD. The obstetric, gynaecological and fertility implications of homozygous PAI-1 deficiency: single-centre experience. Haemophilia. 2014;20:407–12. [PubMed: 24261743]
  • Hirose J, Takedani H, Kubota M, Kinkawa J, Noguchi M. Total hip arthroplasty and total knee arthroplasty in a patient with congenital deficiency of plasminogen activator inhibitor-1. Haemophilia. 2016;22:e237–9. [PubMed: 27030314]
  • Huang Z, Tang W, Chen Q, Li M, Lao S, Pan H, Huang L, Huang M, Hu X, Zhao J. Plasminogen activator inhibitor-1 polymorphism confers a genetic contribution to the risk of spontaneous abortion: an updated meta-analysis. Reprod Sci. 2017;(Jan):1. [PubMed: 28395596]
  • Iwaki T, Nagahashi K, Kobayashi T, Umemura K, Terao T, Kanayama N. The first report of uncontrollable subchorionic retroplacental haemorrhage inducing preterm labour in complete PAI-1 deficiency in a human. Thromb. Res. 2012;129:e161–3. [PubMed: 22099705]
  • Iwaki T, Tanaka A, Miyawaki Y, Suzuki A, Kobayashi T, Takamatsu J, Matsushita T, Umemura K, Urano T, Kojima T, Terao T, Kanayama N. Life-threatening hemorrhage and prolonged wound healing are remarkable phenotypes manifested by complete plasminogen activator inhibitor-1 deficiency in humans. J Thromb Haemost. 2011;9:1200–6. [PubMed: 21486382]
  • Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. NEJM. 2000;342:1792–801. [PubMed: 10853003]
  • Mehta R, Shapiro AD. Plasminogen activator inhibitor type 1 deficiency. Haemophilia. 2008;14:1255–60. [PubMed: 19141166]
  • Minowa H, Takahashi Y, Tanaka T, Naganuma K, Ida S, Maki I, Yoshioka A. Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency. Haemostasis. 1999;29:286–91. [PubMed: 10754381]
  • Schleef RR, Higgins DL, Pillemer E, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest. 1989;83:1747–52. [PMC free article: PMC303885] [PubMed: 2496147]
  • Zhang ZY, Wang ZY, Dong NZ, Bai X, Zhang W, Ruan CG. A case of deficiency of plasma plasminogen activator inhibitor-1 related to Ala15Thr mutation in its signal peptide. Blood Coagul Fibrinolysis. 2005;16:79–84. [PubMed: 15650551]

Chapter Notes

Revision History

  • 3 August 2017 (bp) Review posted live
  • 30 June 2016 (mh) Original submission
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