Complete Plasminogen Activator Inhibitor 1 Deficiency

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 testing are possible.

Suggestive Findings

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

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 multigene 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 multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

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

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.

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.

See www.mothertobaby.org for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register 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.