In this video lecture, Dr. Amy Shapiro discusses:
- The clinical and laboratory approach to diagnosing selected rare bleeding disorders and interpreting bleeding severity across different factor deficiencies.
- The diagnosis and management of prothrombin, factor V, combined factor V/VIII, factor V short, factor VII, factor X, and factor XI deficiencies.
- Treatment and prophylaxis considerations based on the specific deficiency, bleeding phenotype, available therapies, and individual patient factors.
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 the diagnosis of selected rare bleeding disorders, focusing on their clinical presentation, laboratory evaluation, and treatment. The disorders discussed include prothrombin deficiency, factor V deficiency, combined factor V and VIII deficiency, factor V short and related disorders, and deficiencies of factors VII, X, and XI. She emphasizes that these conditions are heterogeneous and that diagnosis requires integration of bleeding symptoms, family history, and appropriate laboratory testing.
Rare Bleeding Disorders and Diagnostic Gaps
Definitions of a rare disease vary internationally but generally correspond to a prevalence of approximately one case per 1,500 to 2,500 people. Dr. Shapiro highlights substantial geographic disparities in the identification and reporting of rare bleeding disorders. World Federation of Hemophilia data show that reported cases are disproportionately concentrated in Europe compared with regions such as Asia and Africa. U.S. data similarly suggest that substantially fewer patients are identified through the Hemophilia Treatment Center Network than would be expected from published prevalence estimates, pointing to gaps in identification, diagnosis, and referral.
Bleeding Severity and Residual Factor Activity
Severity categories used for hemophilia A and B cannot simply be applied to other rare bleeding disorders. Dr. Shapiro reviews a European study that classified patients according to bleeding phenotype, ranging from asymptomatic disease to bleeding after trauma or medication exposure, spontaneous minor bleeding, and spontaneous major bleeding such as hemarthrosis, gastrointestinal or central nervous system bleeding, and intramuscular hematomas.
The relationship between residual factor activity and clinical bleeding differs by disorder. Strong correlations were observed for fibrinogen, combined factor V and VIII, factor X, and factor XIII deficiencies. Factor V and factor VII showed some correlation, while factor XI activity did not correlate with bleeding severity. Dr. Shapiro also cautions that heterozygous individuals should not automatically be considered asymptomatic because mucocutaneous, surgical, reproductive, and other bleeding has been reported in some carriers.
General Approach to Treatment
Management depends on the specific deficiency, severity of disease, type of bleeding, residual factor activity, factor half-life, and available therapies. When available, specific recombinant or plasma-derived concentrates are preferred. Adjunctive treatments may be useful for minor and mucocutaneous bleeding. Fresh frozen plasma requires attention to volume overload, while high or repeated doses of prothrombin complex concentrates or activated prothrombin complex concentrates have been associated with arterial and venous thrombosis.
Dr. Shapiro notes that evidence supporting treatment recommendations remains limited because the rarity of these disorders makes randomized controlled trials difficult. Much of current management is therefore based on expert consensus and experience from individual centers.
Prothrombin Deficiency
Prothrombin, or factor II, deficiency produces prolongation of both the PT and APTT. Diagnosis requires measurement of factor II activity as well as antigen to distinguish hypoprothrombinemia from dysprothrombinemia. The presence of an abnormal circulating protein without normal functional activity may be thrombogenic. Complete prothrombin deficiency appears incompatible with life. Hypoprothrombinemia may produce moderate to severe bleeding, while dysprothrombinemia may remain asymptomatic. Treatment options are limited. When prothrombin complex concentrates are used, the quantity of factor II within the specific product should be considered, along with the potential for coagulation activation, DIC, and thrombosis.
Factor V Deficiency
There is no specific replacement product currently available for factor V deficiency. Approximately 80% of factor V circulates in plasma, while the remaining 20% is stored within platelet alpha granules. Fresh frozen plasma can provide factor V, and platelets may also serve as a therapeutic option in some patients, with attention to alloimmunization. Dr. Shapiro also notes that a plasma-derived factor V concentrate is in preclinical studies.
Combined Factor V and VIII Deficiency
Combined factor V and VIII deficiency results from mutations affecting MCFD2 and LMAN1, which encode proteins involved in intracellular transport of both coagulation factors. Patients generally experience mild to moderate bleeding and usually do not require regular prophylaxis. Treatment requires addressing both deficiencies. DDAVP can be used for the associated mild factor VIII deficiency, while factor VIII concentrate can be used when greater replacement is required. Fresh frozen plasma and, when appropriate, platelets may provide factor V replacement.
Factor V Short and Related Bleeding Disorders
Dr. Shapiro discusses factor V short and the East Texas Bleeding Disorder, along with the Amsterdam and Atlanta factor V variants. These autosomal dominant disorders result from alternative splicing within exon 13 of the F5 gene. The resulting factor V short protein binds tightly to tissue factor pathway inhibitor alpha, or TFPIα, increasing its concentration in plasma. Although factor V short itself has procoagulant activity, increased TFPIα dampens coagulation and paradoxically produces a bleeding disorder. Standard coagulation screening may be normal or show only mild, variable prolongation of the PT or APTT depending on assay sensitivity. Evaluation of TFPIα levels and genetic sequencing can therefore be important for diagnosis.
Factor VII Deficiency
Congenital factor VII deficiency has a highly variable clinical phenotype. Patients may experience epistaxis, heavy menstrual bleeding, and spontaneous or post-traumatic bleeding, with clinical severity sometimes correlating poorly with laboratory abnormalities. The characteristic laboratory finding is a prolonged PT that corrects with normal plasma in a mixing study. Factor VII deficiency is the most frequent rare congenital bleeding disorder discussed in the lecture, with approximately one symptomatic individual per 500,000 people. Plasma-derived factor VII concentrates are available in Europe but not in the United States. Other treatment options include fresh frozen plasma and four-factor prothrombin complex concentrates. Dr. Shapiro identifies recombinant factor VIIa as the first-line treatment supported by the most substantial research evidence.
Factor X Deficiency
Factor X deficiency is one of the most severe rare bleeding disorders. Patients with severe deficiency may present early in life with serious bleeding, including umbilical stump, central nervous system, or gastrointestinal hemorrhage. Bleeding can also occur in heterozygous patients, including postpartum bleeding and post-traumatic hemarthrosis requiring treatment. A high-purity plasma-derived factor X concentrate has been approved for treatment and prophylaxis of bleeding episodes and perioperative management in patients with hereditary factor X deficiency.
Factor XI Deficiency
Factor XI deficiency is the second most commonly reported rare bleeding disorder and has a particularly high prevalence among Ashkenazi Jewish populations. Its clinical phenotype is highly heterogeneous. Even patients with very low factor XI levels may remain asymptomatic, while patients with partial deficiency may experience bleeding following trauma or surgery. A central feature is the poor correlation between measured factor XI activity and bleeding severity. Treatment must therefore be individualized. Dr. Shapiro identifies antifibrinolytic agents as the preferred initial therapy. Low-dose recombinant factor VIIa has also been used off-label with antifibrinolytics for surgery and in patients with inhibitors or a history of allergy to fresh frozen plasma. Factor XI concentrates are available in Europe but not the United States, and thrombotic events have been reported with some concentrates.
Considering Prophylaxis
Decisions about prophylaxis should reflect the frequency of bleeding, risk of severe spontaneous hemorrhage associated with the particular deficiency, and possibility of long-term consequences from bleeding. Dr. Shapiro distinguishes primary prophylaxis, initiated before a bleeding event occurs, from secondary prophylaxis, initiated after bleeding or to prevent recurrence.
Evidence supporting prophylaxis in rare bleeding disorders remains limited. Secondary prophylaxis may be considered following musculoskeletal or life-threatening bleeding, particularly in patients with severe factor X, factor VII, or factor V deficiency. Primary prophylaxis may also be considered in affected individuals from families with histories of severe bleeding.
Women with Rare Bleeding Disorders
Women require particular attention because gynecologic and obstetric conditions can compound bleeding risk. Heavy menstrual bleeding is common across rare bleeding disorders, while miscarriage has been reported in fibrinogen, factor XI, and factor XIII deficiencies. Bleeding during and after delivery occurs in several disorders, including deficiencies of fibrinogen and factors V, VII, X, XI, and XIII.
Treatment should account for age, overall health, medical history, cause and extent of bleeding, tolerance of medications and procedures, effects on lifestyle, and patient preference. Management also requires monitoring of hemostatic parameters and recognition of increased bleeding risk with surgical intervention.
Conclusion
Dr. Shapiro concludes that rare bleeding disorders represent a heterogeneous group of coagulation deficiencies with widely varying clinical manifestations. Diagnosis depends on the combination of bleeding symptoms, family history when informative, and appropriately selected laboratory testing. Routine screening assays may not identify every disorder, and residual factor activity does not consistently predict clinical severity.
Treatment options and access to specific replacement products vary substantially across disorders and geographic regions. Because much of current management relies on expert consensus rather than high-quality clinical trial evidence, additional research and new therapeutic approaches remain important.