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Congenital plasminogen activator inhibitor type 1 (PAI-1) prevalence and incidence remain unknown. Both partial and total PAI-1 deficiencies are extremely rare disorders. In the Amish community (Indiana, USA), eighteen homozygous patients with clinical symptoms and more than 100 heterozygous patients without bleeding symptoms have been reported to date. Additional cases have been reported from North America, Europe and Asia.

Clinical signs of congenital PAI-1 deficiency may appear in early childhood. Spontaneous bleeding is rarely observed, whereas easy bruising or moderate hemorrhage localized to the joints (knees, elbows), nose and gingiva are usually triggered by mild trauma. Menstrual bleeding may be severe, and prolonged bleeding after surgery is common. Hemorrhage is less frequent and less severe (or absent) in heterozygous individuals (partial deficiency) and clinical manifestations, if any, may appear late in life after a traumatic or surgical event.

Affected patients carry one (heterozygote) or two (homozygote) alleles with a mutation in the SERPINE1 gene (7q22.1), resulting in partial or total antigenic PAI-1 deficiency. PAI-1 is the physiological inhibitor of tissue-type plasminogen activator (t-PA), the main source of intravascular fibrinolysis. PAI-1 deficiency is a quantitative defect; however, in some patients the protein is present but functionally inactive.

The diagnosis is based on antigenic (ELISA) and functional (plasminogen activator inhibition test) assays of PAI-1. A genotype analysis may be necessary in family studies. Molecular genetic testing confirms the diagnosis.

Differential diagnosis includes acquired PAI-1 deficiency and alpha2-antiplasmin deficiency.

Heterozygotes are asymptomatic carriers. Carrier testing must be performed for relatives of affected patients with the SERPINE1 genetic variant.

Prompt diagnosis is essential since hemorrhages can be safely and efficiently treated with fibrinolysis inhibitors (epsilon amino-caproic acid or tranexamic acid), avoiding the use of blood and derivatives. Menstruation and pregnancy require special consideration with regard to diagnosis and treatment with antifibrinolytics.

The prognosis is generally good as bleeding can be prevented and controlled with antifibrinolytic treatment.