OOA (Old Order Amish)

Inheritance: autosomal recessive
Genes: PAI-1

PAI1
PLANH1
Serpine 1

Bleeding
Bruising
Hemophilia
Bleeding disorder

Plasminogen Activator Inhibitor-1 Deficiency

Clinical Characteristics

General description (for patients):

Individuals with 2 copies of this mutation have abnormal bleeding in response to trauma including surgery.  Carriers (such as parents of affected children) have no symptoms.  However, relatively mild blunt trauma to the head or joints can lead to extensive and even life-threatening hemorrhage. Frequent bruising is a feature. Females may experience excessive menstrual bleeding.  Prophylactic treatment before surgery can reduce the risk of extensive postoperative bleeding.  It should also be used before major dental work.

Medical description:  

Reduced PAI-1 activity may result in major excessive bleeding following relatively minor trauma, especially to the head and joints.  Even dental extractions can be followed by prolonged, even life-threatening, bleeding.  Women may suffer menorrhagia.  Spontaneous bleeding such as epistaxis does not occur and heterozygotes have no bleeding problems.  Prophylactic treatment with fibrinolysis inhibitors greatly improves clotting and should be given prior to surgical procedures and upon evidence of abnormal bleeding, including abnormal menses.

Genetics:

This autosomal recessive bleeding disorder results from a 2-BP (TA) insertion in exon 4 of the PAI-1 (SERPINE1) gene located on chromosome 7 (7q21.3-q22).   The resulting frameshift leads to a defective inhibitor-1 product.  It has been reported in 7 Midwestern Amish individuals with homozygous mutations, and was also found among 19 of their relatives.  Interestingly, the only common ancestor to all of these was a male born in 1881 who married into the Amish community.

Treatment:

Fibrinolysis inhibitors such as epsilon-aminocaproic acid and tranexamic acid can be effective in both treatment and the prevention of bleeding.  These can also be useful in managing menorrhagia.  As yet not described in the Amish, elevated plasma PAI-1 levels are associated with increased risk of thrombotic events such as myocardial infarctions and deep vein thrombosis.

Prognosis:

The outlook for a normal life is excellent.  Prompt evaluation and treatment is important following even minor trauma to detect bleeding into joints and especially for potential subdural hematomas.

Ancillary treatments and support:

National Hemophilia Foundation.

Specialists and specialty centers: 

Hematologists.

References:

Fay, W.P., Shapiro, A.D., Shih, J.L., Schleef, R.R., and Ginsburg, D.:  Complete deficiency of plasminogen-activator inhibitor type I due to a frameshift mutation.  New Eng. J. Med. 327: 1729-1733, 1992.  PubMed ID: 1435917

Fay, W.P., Parker, A.C., Condrey, L.R., and Shapiro, A.D.:  Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene.  Blood 90: 204-208, 1997.  PubMed ID: 9207454

Schleef, R.R, Higgins, D.L., Pillemer, E., and Levitt, L.J.:  Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor.  J. Clin. Invest. 83: 1747-1752, 1989.  PubMed ID: 2496147

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