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Congenital plasminogen activator inhibitor type 1 deficiency
Congenital plasminogen activator inhibitor type 1 (PAI-1) deficiency is a rare genetic bleeding disorder characterized by premature lysis of hemostatic clots and a moderate bleeding tendency.
Prevalence and incidence are unknown. Both partial and total PAI-1 deficiencies are extremely rare disorders. In the Amish community, eighteen homozygous patients with clinical symptoms and more than 100 heterozygous patients without bleeding symptoms have been reported to date.
Clinical signs of congenital PAI-1 deficiency may appear in early infancy. 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.
PAI-1 is the physiological inhibitor of tissue-type plasminogen activator (t-PA), the main source of intravascular fibrinolysis. PAI-1 deficiency may be qualitative or quantitative, and in a few patients the protein is present but functionally inactive. 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.
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 (see this term).
Both partial and total PAI-1 deficiencies are transmitted as autosomal recessive traits. Genetic counseling should be offered to affected families.
Management and treatment
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.