Plasminogen activator inhibitor type 1 deficiency

Other Names: Plasminogen activator inhibitor 1 deficiency; PAI-1 deficiency; Hyperfibrinolysis due to PAI1 deficiency; PAI1 deficiency

Plasminogen activator inhibitor type 1 (PAI1) deficiency is a rare bleeding disorder that causes excessive or prolonged bleeding due to blood clots being broken down too early. PAI1 is a protein in the body needed for normal blood clotting. When the body does not have enough functional PAI1, the body's ability keep blood clots intact is impaired.

Types

Some people with PAI1 deficiency have some functional PAI1 (partial PAI1 deficiency), while others do not have any (complete PAI1 deficiency). Therefore, the severity of symptoms depends on how much functional PAI1 a person has. People with complete PAI1 deficiency may have symptoms in infancy, while those with partial PAI1 deficiency may not have symptoms until later in life, after an injury or surgery.

Cause

PAI1 deficiency is caused by mutations in the SERPINE1 gene.This gene provides instructions for making a protein called plasminogen activator inhibitor 1 (PAI-1). PAI-1 is involved in normal blood clotting (hemostasis). After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss.

The PAI-1 protein blocks (inhibits) the action of other proteins called plasminogen activators. These proteins promote the dissolution of clots (fibrinolysis). By inhibiting plasminogen activators, the PAI-1 protein helps ensure that clots remain intact until they are no longer needed to stop bleeding.

The SERPINE1 gene mutations that cause partial/complete PAI-1 deficiency result in the production of a PAI-1 protein that is nonfunctional or that is unstable and quickly broken down. Absence of functional PAI-1 protein allows plasminogen activators to dissolve blood clots prematurely, resulting in the abnormal bleeding associated with this disorder.

Inheritance

The inheritance typically is autosomal recessive. The specific mutations present determine whether a person has complete or partial PAI1 deficiency. In rare cases partial PAI1 deficiency has appeared to be autosomal dominant, but the genetic causes in these cases were not determined.

Signs and symptoms

Symptoms of PAI1 deficiency include excessive or prolonged bleeding after an injury, or after a medical or dental procedure. The bleeding may be delayed if clots initially form but are broken down too early. Internal bleeding after an injury can be life-threatening, particularly if it occurs around the brain. Other symptoms may include delayed wound healing, nosebleeds that last a long time, easy bruising, bleeding in the joints, and excessive bleeding in females during menstruation, pregnancy or childbirth. Some people with PAI1 deficiency may have scar tissue in the heart (cardiac fibrosis).

Diagnosis

A diagnosis of PAI1 deficiency may be made based on evaluation of symptoms, various blood tests, and genetic testing of the SERPINE1 gene. 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.

Treatment

Treatment for severe bleeding episodes may include intravenous antifibrinolytics (drugs that help the blood clot) and infusion of fresh frozen plasma. Antifibrinolytics may also be used for heavy menstrual bleeding or to prevent bleeding during an invasive procedure or childbirth.

NIH genetic and rare disease info

• NIH info on Plasminogen activator inhibitor type 1 deficiency

Plasminogen activator inhibitor type 1 deficiency is a rare disease.

Plasminogen activator inhibitor type 1 deficiency Resources
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