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.
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].
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.
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.
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:
History of therapies tried in the past and the response to each specific therapy
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.
See www.mothertobaby.org for further information on medication use during pregnancy.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
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
Sibs of a proband
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.
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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
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
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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)
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|
173360 | SERPIN PEPTIDASE INHIBITOR, CLADE E (NEXIN, PLASMINOGEN ACTIVATOR INHIBITOR TYPE 1), MEMBER 1; SERPINE1 |
|
613329 | PLASMINOGEN 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 ).
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.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
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| Variant Classification | DNA Nucleotide Change (Alias 1) | Predicted Protein Change 2 | Reference Sequences |
|---|
| Modulator | c.-820_-817G(4_5) 3
(4G/5G) | -- | NM_000602.4NP_000593.1 |
| Pathogenic | c.43G>A | p.Ala15Thr |
| c.356dupC | p.Ile120AspfsTer42 |
| c.699_700dupTA | p.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].
