HUMAN PLASMINOGEN-ACTIVATOR INHIBITOR-1 (PAI-1) DEFICIENCY - CHARACTERIZATION OF A LARGE KINDRED WITH A NULL MUTATION IN THE PAI-1 GENE

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of ti ssue- and urokinase-type plasminogen activators, is considered a criti cal regulator of the fibrinolytic system. We previously reported a chi ld with abnormal bleeding and complete PAI-1 deficiency caused by a fr ame-shift mutation in exon 4 of the PAI-1 gene. The purpose of this st udy was to provide genetic and clinical data on the extended pedigree of the original proband to better define the phenotype associated with PAI-1 deficiency. Allele-specific oligonucleotide hybridization was u sed to genotype individuals, and serum PAI-1 antigen was measured by e nzyme-linked immunosorbent assay. By this approach we have identified 19 individuals who are heterozygous for the PAI-1 null allele and 7 ho mozygous individuals with complete PAI-1 deficiency. Clinical manifest ations of PAI-1 deficiency were restricted to abnormal bleeding, which was observed only after trauma or surgery in homozygous affected indi viduals. A spectrum of bleeding patterns was observed, including intra cranial and joint bleeding after mild trauma, delayed surgical bleedin g, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhi bitors, including E-aminocaproic acid and tranexamic acid, were effect ive in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were obs erved in homozygous PAl-1-deficient individuals. Heterozygous PAI-1 de ficiency was not associated with abnormal bleeding, even after trauma or surgery. These observations define the clinical spectrum of PAI-1 d eficiency and provide additional evidence to support the hypothesis th at the primary function of plasminogen activator inhibitor-1 in vivo i s to regulate vascular fibrinolysis. (C) 1997 by The American Society of Hematology.