Complete Plasminogen Activator Inhibitor 1 Deficiency

Excerpt

Clinical characteristics: Untreated complete plasminogen activator inhibitor 1 (PAI-1) deficiency is characterized by mild-to-moderate bleeding, although in some instances bleeding can be life-threatening. Most commonly, delayed bleeding is associated with injury, trauma, or surgery; spontaneous bleeding does not occur. While males and females with complete PAI-1 deficiency are affected equally, females may present more frequently with clinical manifestations or earlier in life than males due to menorrhagia and postpartum hemorrhage. Fewer than ten families with complete PAI-1 deficiency have been reported to date. The incidence of complete PAI-1 deficiency is higher than expected in the genetic isolate of the Old Order Amish population of eastern and southern Indiana due to a pathogenic founder variant. In one family from this Old Order Amish population, seven individuals were diagnosed to have cardiac fibrosis of varying degrees.

Diagnosis/testing: The diagnosis of complete PAI-1 deficiency is established in a proband when PAI-1 antigen is undetectable and PAI-1 activity is lower than 1 IU/mL and/or biallelic SERPINE1 pathogenic variants are identified on molecular genetic testing. Note that because the normal range of functional PAI-1 activity assay starts at zero in most laboratories, the ability to discriminate between normal and abnormal levels of activity is limited.

Management: Treatment of manifestations: Management of the bleeding disorder by a team of experts in the treatment of individuals with bleeding disorders is highly recommended. Intravenous antifibrinolytics (e.g., epsilon-aminocaproic acid [EACA] and tranexamic acid) can be used for severe bleeding manifestations, including intracranial hemorrhage (with or without hematoma evacuation). Infusion of fresh-frozen plasma can be used as needed to increase PAI-1 activity prior to achieving therapeutic steady-state levels of antifibrinolytics. Heavy menstrual bleeding can often be managed with oral antifibrinolytics or hormonal suppression therapy. Since there is no specific treatment of cardiac fibrosis, symptomatic treatment as needed.

Prevention of primary manifestations: Antifibrinolytics should be used to prevent bleeding for surgical and dental procedures, childbirth, and other invasive procedures.

Surveillance: Regular follow up with a team of experts in the treatment of individuals with bleeding disorders is recommended. For all individuals with complete PAI-1 deficiency, screening echocardiogram and EKG for assessment of cardiac function and cardiac MRI for quantification of fibrosis is recommended at diagnosis with close monitoring by a cardiologist based on the initial findings. The age of onset of cardiac fibrosis is unknown; therefore, an initial normal evaluation does not rule out the need for further surveillance.

Agents/circumstances to avoid: Medications that affect coagulation including aspirin, ibuprofen, and some herbal remedies; high-risk activities such as contact sports.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with complete PAI-1 deficiency in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Pregnancy management: Recommendations based on published findings during pregnancies in two women with complete PAI-1 deficiency are oral administration of either tranexamic acid or EACA for intermittent bleeding in the first and second trimester, continuous administration from 26 weeks' gestation through delivery to prevent preterm labor, and for at least two weeks postpartum to prevent postpartum bleeding. Note: Evidence that these recommendations would be effective in all pregnancies of women with complete PAI-1 deficiency is lacking; the teratogenicity of EACA and tranexamic acid is unknown and information regarding their safety during pregnancy and lactation is limited.

Genetic counseling: Complete PAI-1 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a SERPINE1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SERPINE1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk for complete PAI-1 deficiency, and preimplantation genetic testing are possible.