In this video lecture, Dr. Amy Shapiro discusses:
- The diagnosis of factor XIII deficiency and rare disorders affecting key components of the fibrinolytic pathway.
- The distinct clinical and laboratory features of alpha-2 antiplasmin, PAI-1, and plasminogen deficiencies.
- Disorder-specific treatment and prophylaxis, including factor replacement, antifibrinolytic therapy, and considerations during pregnancy.
Dr. Amy Shapiro, MD, is Chief Clinical Officer of Innovative Hematology/Indiana Hemophilia and Thrombosis Center in Indianapolis and Adjunct Senior Investigator, Clinical Track at the Blood Research Institute, Blood Center of Wisconsin in Milwaukee Wisconsin. After receiving her medical training at New York University School of Medicine in New York City, Dr Shapiro completed her pediatric internship, residency, and fellowship in pediatric hematology/oncology at the University of Colorado Health Sciences Center in Denver.
Author or co-author of more than 300 journal articles, abstracts, and textbook chapters, Dr Shapiro is clinically focused on improving treatment for people with rare bleeding disorders. She has served on the National Bleeding Disorders Foundation’s Medical and Scientific Advisory Council and as well as several boards for the National Institutes of Health in Data Safety Monitoring and Clinical Trial Review. As one of the founders of the American Thrombosis and Hemostasis Network (ATHN), she has served as Co-Chairman of the Board of Directors and remains active on various ATHN committees.
Dr Shapiro was elected to the Norvo Nordisk Hemophilia & Haemoglobinopathies Foundation (NNHF) in NNHF council in 201 and also serves on the Board of Directors of the Plasminogen Deficiency Foundation since its inception in 2020.
Dr Shapiro has been honored as the National Bleeding Disorders Foundation Physician of the Year Award in 2001 and the 2017 Leadership in Research Award. In 2025, she was awarded the Lifetime Achievement Award by HTRS. Among other accomplishments, she has also received the 2009 Distinguished Hoosier Award in Indiana. She is a member of numerous professional societies including the Hemostasis & Thrombosis Research Society, the International Society on Thrombosis and Haemostasis, the American Society of Hematology, and the World Federation of Haemophilia.
(Video Lecture Summary)
Introduction
Dr. Amy Shapiro reviews four under-recognized rare coagulation disorders involving the final stages of clot formation and the fibrinolytic pathway: factor XIII deficiency, alpha-2 antiplasmin deficiency, plasminogen activator inhibitor-1 (PAI-1) deficiency, and plasminogen deficiency. She discusses their clinical manifestations, specialized laboratory diagnosis, severity where defined, and approaches to treatment. A key diagnostic feature shared by these disorders is that routine coagulation screening tests are normal. Recognition therefore depends heavily on the clinical presentation and use of specific laboratory assays.
Antifibrinolytic Therapy
Before reviewing the individual disorders, Dr. Shapiro explains the mechanism of antifibrinolytic agents. These drugs act as lysine analogs that competitively bind lysine-binding sites on plasminogen. This prevents plasminogen from attaching to fibrin and subsequently being activated to plasmin. Antifibrinolytic agents are commonly used to prevent or control bleeding and become particularly important in the management of disorders characterized by excessive fibrinolysis.
Factor XIII Deficiency
Factor XIII is composed of two catalytic A subunits and two B subunits. Congenital factor XIII deficiency is most commonly autosomal recessive, with an estimated prevalence of approximately one in two million people. Most cases result from variants affecting the A subunit, while B subunit deficiency is considerably rarer. Identifying the affected subunit is important because it influences treatment selection. Factor XIII has a long plasma half-life of approximately 11 to 14 days. Unlike many coagulation factor deficiencies, factor XIII deficiency does not prolong routine screening coagulation tests.
Diagnosing Factor XIII Deficiency
General screening tests for severe factor XIII deficiency include the 5-molar urea clot lysis test and 1% monochloroacetic acid test. However, these tests detect only profound deficiencies with factor XIII levels below approximately 5%. Dr. Shapiro identifies a specific quantitative factor XIII assay as the more accurate approach because it provides an actual factor XIII activity level. Clinical findings that should prompt consideration of factor XIII deficiency include significant umbilical cord or stump bleeding and unexplained intracranial hemorrhage in a full-term newborn. Patients with more moderate or mild deficiency may lack these hallmark presentations, making factor XIII deficiency important to consider when other laboratory evaluations for bleeding are unrevealing.
Severity and Treatment of Factor XIII Deficiency
Severe factor XIII deficiency is associated with residual activity below 5%. Patients with levels between 5% and 15% may also experience significant bleeding, and 15% has been proposed as a threshold below which prophylaxis should be considered. Levels between 15% and 30% may represent moderate disease, while levels above 30% are associated with milder disease that may still require intermittent treatment.
Patients who present at birth with severe deficiency require lifelong prophylaxis. Recombinant factor XIII contains the A subunit and is therefore appropriate when that subunit is deficient. Patients with B subunit deficiency require a plasma-derived factor XIII concentrate containing both A and B subunits. Cryoprecipitate and fresh frozen plasma may provide factor XIII when concentrates are unavailable, and antifibrinolytic agents may be used as concomitant therapy.
Factor XIII Deficiency and Pregnancy
Factor XIII and fibrinogen play important roles in implantation and maintenance of pregnancy. Factor XIII A crosslinks fibrinogen and fibronectin during implantation, contributing to placental attachment to the uterus. Women with factor XIII deficiency may therefore experience early miscarriage and placental abruption.
Dr. Shapiro emphasizes that women with factor XIII deficiency require factor XIII administration beginning by five weeks of gestation. Dosing is guided by trough levels and increased replacement may be required during labor and delivery to prevent bleeding complications, including postpartum hemorrhage.
Alpha-2 Antiplasmin Deficiency
Alpha-2 antiplasmin is the primary inhibitor of plasmin after it forms in the circulation. Congenital alpha-2 antiplasmin deficiency is an extremely rare autosomal recessive disorder with an undefined prevalence. The protein has a half-life of approximately two to three days. Routine coagulation screening tests are normal. A euglobulin clot lysis test, when available, may demonstrate shortened clot lysis because of excessive fibrinolysis. Definitive diagnosis requires a specific alpha-2 antiplasmin activity assay, and measurement of antigen is also recommended.
Clinical Presentation and Treatment of Alpha-2 Antiplasmin Deficiency
Bleeding manifestations may resemble factor XIII deficiency. Dr. Shapiro therefore recommends considering alpha-2 antiplasmin deficiency when suggestive bleeding is present but factor XIII activity is normal. Intramedullary hemorrhage into long bones is one distinctive manifestation that has been reported. Bleeding has also been described in heterozygous individuals.
Antifibrinolytic therapy is the mainstay of treatment and can be administered orally or intravenously. These agents have been used successfully for acute bleeding, surgery, and longer-term prophylaxis. Fresh frozen plasma has been used with variable results. Hormonal therapy may be considered for heavy menstrual bleeding according to patient preference. During pregnancy, treatment is tailored to bleeding history, and antifibrinolytics have been used in patients with miscarriage or preterm delivery.
PAI-1 Deficiency
PAI-1 is the physiologic inhibitor of plasminogen activators such as tissue plasminogen activator. Deficiency therefore leads to excessive activation of fibrinolysis and bleeding. Congenital PAI-1 deficiency is a very rare autosomal recessive disorder, and PAI-1 has a short half-life of approximately two hours.
Routine coagulation screening tests are normal. PAI-1 activity and antigen assays are available and both are needed for evaluation, but laboratory diagnosis can be challenging because the normal activity range includes very low values. When clinical suspicion remains high, Dr. Shapiro recommends genetic testing. She specifically cautions against confusing diagnostic genetic testing for PAI-1 deficiency with the PAI-1 4G/5G test, which assesses a variant associated with increased PAI-1 rather than deficiency.
Bleeding and Pregnancy in PAI-1 Deficiency
PAI-1 deficiency generally produces a moderate bleeding phenotype, although severe and life-threatening bleeding can occur. Women may experience heavy menstrual bleeding, hemoperitoneum from ruptured ovarian follicles or cysts, and bleeding during pregnancy associated with fetal loss or preterm delivery.
Antifibrinolytic agents are the mainstay of therapy. Based on experience with homozygous PAI-1-deficient women at her center, Dr. Shapiro describes using continuous antifibrinolytic treatment from at least the 26th week of pregnancy through at least two weeks postpartum because vaginal bleeding has consistently occurred near the end of the second trimester. Treatment is started earlier when bleeding develops sooner and is individualized according to symptoms.
Cardiac Fibrosis in PAI-1 Deficiency
The consequences of PAI-1 deficiency extend beyond bleeding. Dr. Shapiro describes accelerated fibrotic cardiomyopathy associated with PAI-1 deficiency, involving increased TGF-beta levels and cardiac fibrosis. Cardiac fibrosis has been observed in her center’s PAI-1-deficient population and contributed to the death of one patient at age 32, likely due to an arrhythmia.
There is currently no specific treatment for this complication, and predictors of its development and progression remain unknown. Based on her center’s experience, Dr. Shapiro recommends regular evaluation for cardiac fibrosis in individuals with genetically confirmed PAI-1 deficiency.
Plasminogen Deficiency
Plasminogen deficiency differs substantially from the other fibrinolytic disorders discussed. Plasminogen circulates as an inactive zymogen and is converted to plasmin by activators including tissue-type and urokinase plasminogen activators. Congenital plasminogen deficiency is autosomal recessive and has an estimated prevalence of approximately 1.6 affected individuals per million. Two forms are recognized. Type 1, or hypoplasminogenemia, is characterized by reduced plasminogen activity and antigen and represents the clinically relevant disorder. Type 2, or dysplasminogenemia, is characterized by reduced functional activity with normal or near-normal antigen levels. Individuals with type 2 deficiency are typically asymptomatic.
Diagnosing Plasminogen Deficiency
Routine coagulation screening tests are normal. Diagnosis requires plasminogen activity and antigen assays, generally prompted by characteristic symptoms or a known affected family member. Genetic testing can further establish the diagnosis but is not required.
The characteristic manifestations are ligneous lesions, named for their woody appearance, that primarily affect mucosal surfaces. These lesions can occur throughout multiple organ systems and may initially resemble more common conditions, contributing to delayed diagnosis.
Clinical Manifestations of Plasminogen Deficiency
Clinical expression is highly heterogeneous. Some individuals develop lesions affecting multiple organ systems while others remain asymptomatic for prolonged periods. Disease severity and course cannot currently be predicted from plasminogen activity or the underlying genetic defect.
Ligneous lesions may involve the eyes, gingiva, respiratory tract, glottis, vocal cords, and other tissues. Respiratory lesions can obstruct airways and may become life-threatening, particularly in young children. Dr. Shapiro also emphasizes that spontaneous venous thromboembolism is not a manifestation of plasminogen deficiency despite plasminogen’s role in fibrinolysis.
Treatment of Plasminogen Deficiency
A plasminogen replacement therapy was approved by the FDA in 2021 and has demonstrated efficacy and safety. Dosing is individualized to maintain an appropriate trough above the patient’s native baseline and to suppress recurrence of lesions. Young children with respiratory involvement require particular caution when treatment begins because lesions may slough and obstruct their smaller airways. Surgical stripping or removal of lesions without replacement therapy leads to rapid regrowth and recurrent lesions that may impair organ function. Once diagnosed, patients should be followed by a hematologist familiar with the disorder who can assess its multisystem manifestations and determine when treatment should begin or be adjusted.
An Important Difference in Antifibrinolytic Therapy
The role of antifibrinolytic therapy differs fundamentally across these disorders. Antifibrinolytics are effective therapies in alpha-2 antiplasmin and PAI-1 deficiencies because these conditions involve excessive fibrinolysis.
In plasminogen deficiency, however, antifibrinolytic agents are contraindicated because further suppression of fibrinolysis may worsen disease manifestations unless adequate replacement therapy is also being provided.
Conclusion
Dr. Shapiro concludes that factor XIII deficiency and disorders of the fibrinolytic pathway are rare and clinically heterogeneous conditions that can be challenging to recognize. Importantly, routine coagulation screening tests are normal in all four disorders discussed, making clinical suspicion, family history when informative, and disorder-specific laboratory testing essential to diagnosis.
Specific replacement therapies are available for factor XIII and plasminogen deficiencies, while antifibrinolytic agents play a central role in alpha-2 antiplasmin and PAI-1 deficiencies. The need for prophylaxis depends on the particular disorder, its severity, and the patient’s clinical circumstances.