Alternative titles; symbols
ORPHA: 465;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7q22.1 | Plasminogen activator inhibitor-1 deficiency | 613329 | Autosomal dominant; Autosomal recessive | 3 | PAI1 | 173360 |
A number sign (#) is used with this entry because plasminogen activator inhibitor-1 (PAI1) deficiency is caused by homozygous or compound heterozygous mutation in the SERPINE1 gene (173360) on chromosome 7q22.
Plasminogen inhibitor-1 deficiency is a rare autosomal recessive hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of PAI1, which inhibits tissue (PLAT; 173370) and urinary (PLAU; 191840) activators of plasminogen (PLG; 173350) (review by Mehta and Shapiro, 2008).
Schleef et al. (1989) reported an elderly man with a history of lifelong severe bleeding after surgery or trauma and with evidence of persistent increased fibrinolysis. Laboratory studies showed decreased binding of plasminogen activator inhibitor to radiolabeled tissue plasminogen activator (t-PA). Low patient PAI1 activity was confirmed in serum and in platelet lysates, although PAI1 antigen levels were in the normal range. Schleef et al. (1989) concluded that the patient's bleeding diathesis was due to defective PAI1 and hyperfibrinolysis, supporting a role for PAI1 in control of vivo fibrinolysis.
Fay et al. (1992) reported an Amish girl with PAI1 deficiency and bleeding tendency. Fay et al. (1997) identified 7 additional affected Amish individuals in the family of the proband reported by Fay et al. (1992). Clinical manifestations of complete PAI1 deficiency were restricted to abnormal bleeding only after trauma or surgery. Bleeding patterns included intracranial and joint bleeding after mild trauma, delayed surgical bleeding, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhibitors, including epsilon-aminocaproic acid and tranexamic acid, were effective in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were observed in homozygous PAI1-deficient individuals. Nineteen heterozygous individuals were also identified, and none had abnormal bleeding, even after trauma or surgery. These observations defined the clinical spectrum of PAI1 deficiency and suggested that the primary function of PAI1 is to regulate vascular fibrinolysis.
Minowa et al. (1999) reported 4 probands with PAI1 deficiency characterized by recurrent episodes of subcutaneous bleeding beginning in early childhood. Other bleeding episodes later occurred after trauma, tooth extraction, surgical procedures, or during menses. All had decreased PAI1 activity, and 3 had decreased PAI1 antigen as well. Euglobin lysis time was shorter than controls, indicating increased fibrinolysis. Treatment with tranexamic acid improved the hemorrhagic symptoms. Two probands had a family history consistent with autosomal dominant inheritance, including a Japanese family that was previously reported by Takahashi et al. (1996) with 'partial' PAI1 deficiency.
Zhang et al. (2005) reported a Chinese man with a lifelong history of bleeding in response to trauma and surgery, including multiple hematomas. There was no history of spontaneous hemorrhage. Laboratory studies showed decreased activity and antigen levels of PAI1 to about 10% of normal controls. Genetic analysis identified a heterozygous mutation in the SERPINE1 gene (A15T; 173360.0003) inherited from his father. Although a second mutation was not identified in the maternal allele, the authors concluded that the patient likely had a heterozygous mutation in the noncoding region on this allele, since both clinically unaffected parents had moderately decreased PAI1 activity and antigen.
In affected members of an Amish family with PAI1 deficiency, Fay et al. (1992, 1997) identified a homozygous frameshift mutation in the SERPINE1 gene (173360.0001) resulting in complete absence of the protein.
Fay, W. P., Parker, A. C., Condrey, L. R., 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: 9207454]
Fay, W. P., Shapiro, A. D., Shih, J. L., Schleef, R. R., Ginsburg, D. Complete deficiency of plasminogen-activator inhibitor type I due to a frameshift mutation. New Eng. J. Med. 327: 1729-1733, 1992. [PubMed: 1435917] [Full Text: https://doi.org/10.1056/NEJM199212103272406]
Mehta, R., Shapiro, A. D. Plasminogen activator inhibitor type 1 deficiency. Haemophilia 14: 1255-1260, 2008. [PubMed: 19141166] [Full Text: https://doi.org/10.1111/j.1365-2516.2008.01834.x]
Minowa, H., Takahashi, Y., Tanaka, T., Naganuma, K., Ida, S., Maki, I., Yoshioka, A. Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency. Haemostasis 29: 286-291, 1999. [PubMed: 10754381] [Full Text: https://doi.org/10.1159/000022514]
Schleef, R. R., Higgins, D. L., Pillemer, E., Levitt, L. J. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J. Clin. Invest. 83: 1747-1752, 1989. [PubMed: 2496147] [Full Text: https://doi.org/10.1172/JCI114076]
Takahashi, Y., Tanaka, T., Minowa, H., Ookubo, Y., Sugimoto, M., Nakajima, M., Miyauchi, Y., Yoshioka, A. Hereditary partial deficiency of plasminogen activator inhibitor-1 associated with a lifelong bleeding tendency. Int. J. Hemat. 64: 61-68, 1996. [PubMed: 8757969] [Full Text: https://doi.org/10.1016/0925-5710(96)00460-4]
Zhang, Z. Y., Wang, Z. Y., Dong, N. Z., Bai, X., Zhang, W., Ruan, C. G. A case of deficiency of plasma plasminogen activator inhibitor-1 related to ala15thr mutation in its signal peptide. Blood Coagul. Fibrinolysis. 16: 79-84, 2005. [PubMed: 15650551] [Full Text: https://doi.org/10.1097/00001721-200501000-00013]