What are the other Names for this Condition? (Also known as/Synonyms)

• Hyperfibrinolysis due to PAI1 Deficiency
• PAI-1 Deficiency Disorder
• Plasminogen Activator Inhibitor 1 Deficiency Disorder

What is Plasminogen Activator Inhibitor Type 1 Deficiency Disorder? (Definition/Background Information)

• Plasminogen Activator Inhibitor Type 1 (PAI1) Deficiency Disorder is a rare bleeding disorder that causes excessive or prolonged bleeding due to blood clots being broken down too early
• PAI1 is a protein in the body needed for normal blood clotting. When the body does not have enough functional PAI1, the body's ability keep blood clots intact is impaired
• Some people with PAI1 Deficiency Disorder have some functional PAI1 (partial PAI1 deficiency), while others do not have any (complete PAI1 deficiency). Therefore, the severity of symptoms depends on how much functional PAI1 a person has
• People with complete PAI1 deficiency may have symptoms in infancy, while those with partial PAI1 deficiency may not have symptoms until later in life, after an injury or surgery
• Symptoms of PAI1 Deficiency Disorder include excessive or prolonged bleeding after an injury, or after a medical or dental procedure. The bleeding may be delayed if clots initially form but are broken down too early. Internal bleeding after an injury can be life-threatening, particularly if it occurs around the brain.
• Other symptoms may include delayed wound healing, nosebleeds that last a long time, easy bruising, bleeding in the joints, and excessive bleeding in females during menstruation, pregnancy or childbirth. Some people with Plasminogen Activator Inhibitor Type 1 Deficiency Disorder may have scar tissue in the heart (cardiac fibrosis)
• Plasminogen Activator Inhibitor Type 1 Deficiency Disorder is caused by mutations in the SERPINE1 gene and inheritance typically is autosomal recessive
• Treatment for severe bleeding episodes may include intravenous antifibrinolytics (drugs that help the blood clot) and infusion of fresh frozen plasma. Antifibrinolytics may also be used for heavy menstrual bleeding or to prevent bleeding during an invasive procedure or childbirth

(Source: Plasminogen Activator Inhibitor Type 1 Deficiency Disorder; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Plasminogen Activator Inhibitor Type 1 Deficiency Disorder? (Age and Sex Distribution)

• Plasminogen Activator Inhibitor Type 1 Deficiency Disorder is a rare congenital disorder. The exact prevalence of the condition is not known at the present time
• Disease manifestation occurs in infancy or childhood in those with complete deficiency of PAI1 protein. Those with some functional PAI1 protein may not exhibit symptoms until adulthood, which occurs often only after an injury or surgery
• Both males and females may be affected

What are the Risk Factors for Plasminogen Activator Inhibitor Type 1 Deficiency Disorder? (Predisposing Factors)

• A positive family history may be an important risk factor, since Plasminogen Activator Inhibitor Type 1 Deficiency Disorder can be inherited
• In individuals with a partial deficiency of PAI1 protein, a surgery or injury may be the trigger for onset of the characteristic signs and symptoms of the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder? (Etiology)

• Plasminogen Activator Inhibitor Type 1 Deficiency Disorder is reportedly caused by mutation(s) in the SERPINE1 gene
• This gene codes for the plasminogen activator inhibitor 1 or PA1 protein, which inhibits the activity of an important source of fibrinolysis
• Mutations in the SERPINE1 gene can either result in partial or complete loss of PA1 protein
• In most cases, the disorder is inherited in an autosomal recessive manner
• However, there are reported cases of autosomal dominant inheritance as well

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder?

The signs and symptoms of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder may vary among affected individuals in type and severity, and be determined by whether the deficiency of PAI1 protein is partial or complete. The signs and symptoms of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder may include:

• Excessive or prolonged bleeding after an injury, or after a medical or dental procedure
• Delayed wound healing
• Nosebleeds that last a long time
• Easy bruising
• Bleeding in the joints
• Excessive bleeding in females during menstruation, pregnancy or childbirth
• Scar tissue in the heart (cardiac fibrosis)

(Source: Plasminogen Activator Inhibitor Type 1 Deficiency Disorder; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Plasminogen Activator Inhibitor Type 1 Deficiency Disorder Diagnosed?

Plasminogen Activator Inhibitor Type 1 Deficiency Disorder is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests, including antigenic (ELISA) and functional (plasminogen activator inhibition test) assays of PAI-1
• Imaging studies
• Biopsy studies, if necessary
• Differential diagnosis to rule out other conditions that may present similar signs and symptoms
• Molecular genetic testing to check for or confirm causative SERPINE1 gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder?

The complications of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder may include:

• Internal, excessive bleeding following an injury, which may include bleeding in the brain
• Paralysis due to brain hemorrhage
• Arrhythmia due to cardiac fibrosis
• Heart attack

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Plasminogen Activator Inhibitor Type 1 Deficiency Disorder Treated?

There is no cure for Plasminogen Activator Inhibitor Type 1 Deficiency Disorder, since it is a genetic condition.

• The treatment is usually given to manage the signs and symptoms and any complication that develops
• Fibrinolysis inhibitors, such as epsilon amino-caproic acid or tranexamic acid, for hemorrhages (avoiding the use of blood and derivatives)

How can Plasminogen Activator Inhibitor Type 1 Deficiency Disorder be Prevented?

Currently, Plasminogen Activator Inhibitor Type 1 Deficiency Disorder may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis Plasminogen Activator Inhibitor Type 1 Deficiency Disorder? (Outcomes/Resolutions)

• The prognosis of Plasminogen Activator Inhibitor Type 1 Deficiency Disorder is generally good, if the condition is diagnosed properly and episodes of bleeding are treated promptly with an antifibrinolytic agent
• In general, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Plasminogen Activator Inhibitor Type 1 Deficiency Disorder:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/