In 1992, a young Amish girl with marked post-procedural bleeding was found to have a PAI-1 deficiency with a homozygous frame shift mutation in exon 4 of the PAI-1 gene that results in a non-functional protein. This mutation was tracked within the ancestors of this Amish community and two individuals were identified that likely introduced this gene into the community. In 1997, seven children (including the proband) from two families within the kindred were described with symptoms consistent with a mild bleeding disorder. Two further homozygous children, one from a third family within the kindred, have subsequently been identified. Presently, over 300 members of this kindred have been tested with nearly 100 identified heterozygotes, none of whom have experienced bleeding complications. The homozygotes all have had bleeding problems with injury a common cause. Five of the nine homozygotes have had head trauma, resulting in significant bleeding complications. ε-aminocaproic acid (EACA) initiated early controls bleeding. One child had a recurrence of his subdural hematoma when he discontinued the EACA upon discharge from the hospital. But the bleeding was subsequently controlled with reinstitution of EACA, and the child had a full recovery. Another common bleeding complication is menorrhagia with all homozygous females experiencing this symptom, and two even requiring red blood transfusions due to severe anemia. Currently, these women require concurrent EACA with onset of menses to control bleeding. Of interest PAI-1 and the plasminogen activation system have been shown to play an important role in embryo implantation, and it was unknown whether homozygous PAI-1 deficient women would be able to conceive and maintain a pregnancy. We now report 2 of these homozygous deficient females have become pregnant; one remains pregnant at 28 weeks gestation, and one delivered at 32 weeks. This child represents that first documented birth to a woman with complete PAI-1 deficiency. The mother experienced abnormal cervical bleeding beginning at 27 weeks requiring EACA therapy which was continued until delivery and for about 7 days post-partum without abnormal bleeding at delivery or in the post-partum period, and without ill effect on the fetus. This cohort is the largest group of PAI-1 deficient patients ever documented. The molecular defect is well defined so that it is simple to differentiate normals from heterozygotes and homozygotes. Continued follow-up will allow further understanding of the role of PAI-1 in human physiology.

Author notes

Disclosure:Consultancy: Dr. Mehta - Kedrion; Dr. Shapiro - Baxter BioScience, Kedrion, Inspiration Biopharmaceuticals, Syntonix. Research Funding: Dr. Shapiro - Baxter BioScience, Novo Nordisk, Bayer, Wyeth, Octagen, CSL Behring, Syntonix, Inspiration Biopharmaceuticals. Membership Information: Dr. Shapiro - Baxter BioScience, Novo Nordisk, Wyeth, Bayer, Syntonix, Kedrion, Inspiration Biopharmaceuticals. Off Label Use: The use epsilon-aminocaproic acid in pregnant women. No other treatment options are available for these patients at this time.