Watch a moderator and three leading experts discuss the practical challenges of diagnosing and managing rare bleeding disorders (RBDs), with a focus on fibrinogen disorders, factor VII deficiency, and factor XIII deficiency.
Meet the Moderator and Panelists:
Rolf Bekendam, MD, PhD, is a hematologist at Beth Israel Deaconess Medical Center and Harvard Medical School. He earned his medical degree at the University of Groningen in the Netherlands and a PhD in coagulation and platelet biology at Aix-Marseille University in France. He completed his internal medicine residency at Boston Medical Center and his hematology/oncology fellowship at Beth Israel Deaconess Medical Center and Harvard Medical School, where he continued his research on platelet and megakaryocyte biology. He practices classical hematology and attends on the bone marrow transplant service, and his main interest is coagulation, particularly bleeding and clotting disorders.
Kenneth A. Bauer, MD is Professor of Medicine, Harvard Medical School at Beth Israel Deaconess Medical Center. He specializes in the evaluation and management of patients with thrombotic and hemostatic disorders. He also serves as Chief of the Hematology Division at New England Baptist Hospital. He was previously Chief of the Hematology Section at VA Boston Healthcare System. Dr. Bauer received his medical degree from Stanford University School of Medicine in Stanford, California. He completed his residency in medicine at the University of Chicago Hospitals and Clinics in Illinois. He was a Fellow in Medical Oncology and a Clinical/Research Fellow in the Division of Thrombosis and Hemostasis at Dana Farber Cancer Institute and was also a Clinical/Research Fellow in the Hematology-Oncology Division at Beth Israel Deaconess Medical Center. He currently serves as Deputy Editor of the ASH Hematology Education Book and has published over 250 original reports, reviews, and book chapters.
Barbara A. Konkle, MD, is a hematologist and Professor of Medicine Emeritus of Hematology-Oncology at the University of Washington, an Affiliate Hematologist at the Washington Center for Bleeding Disorders and Medical Director of the Bleeding Disorders Laboratory at Bloodworks NW, all in Seattle. She has decades of experience in the diagnosis and treatment of inherited bleeding disorders and in research related to these disorders. She has a clinical and laboratory interest in phenotype/genotype relationships and she led the US ‘My Life Our Future’ project which genotyped over 11,000 patients with hemophilia or potentially so affected, including females. Her research includes studies of outcomes in bleeding disorders, including in women, and trials of new therapies for bleeding disorders. She recently completed 8 years of service on the Board of Directors of the World Federation of Hemophilia and is a founding Board member of the Foundation for Women and Girls with Blood Disorders.
Flora Peyvandi, MD, PhD is professor of Internal Medicine at the University of Milan, Italy and director of the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center of the Milan Policlinic Hospital, Italy. Her research started with molecular and biochemical characterization of coagulation disorders aiming at the development of novel treatment for the affected patients. Her research continued with the understanding of the microvascular dysfunctions in order to implement/develop and standardize innovative diagnostic and therapeutic strategies. Since many years, Dr. Peyvandi has been participating in clinical, educational and research activities of different European and International scientific societies and patients’ organizations. She served as President of the International Society of Thrombosis and Haemostasis and President of the Executive Committee of the European Association for Haemophilia and Allied Disorders. She is currently advisor on the European Agency of Medicine and member of the Technical Health Committee of the Italian Ministry of Health. Her clinical, teaching and research experience combined with her life in different countries, led her to familiarize with patient management, scientific projects and educational systems of different parts of the world.
(Video Lecture Summary)
Beyond the Guidelines: Expert Perspectives on Rare Bleeding Disorders
This roundtable discussion brings together Drs. Flora Peyvandi, Kenneth Bauer, and Barbara Konkle for a practical conversation about the diagnosis and management of rare bleeding disorders. Moderated by Dr. Rolf Bekendam, the discussion focuses on inherited fibrinogen disorders, factor VII deficiency, and factor XIII deficiency. The panel examines the challenges of interpreting laboratory findings, assessing bleeding risk, selecting replacement therapies, and managing patients during pregnancy and other high-risk situations. Throughout the conversation, the experts emphasize the considerable variability in clinical presentation and the importance of tailoring management to each patient’s bleeding history and individual circumstances.
Fibrinogen disorders present with diverse bleeding and thrombotic risks
The discussion begins with the broad clinical spectrum of inherited fibrinogen disorders. Dr. Bauer describes how patients with afibrinogenemia may experience severe bleeding early in life, while others with hypofibrinogenemia or dysfibrinogenemia may have mild symptoms or remain entirely asymptomatic. The panel also highlights an important paradox: some patients with dysfibrinogenemia develop venous or arterial thrombosis rather than bleeding. Dr. Konkle adds that fibrinogen replacement itself can introduce thrombotic risk, creating additional challenges for treatment.
Accurate diagnosis requires more than identifying a reduced fibrinogen level. Dr. Peyvandi emphasizes the importance of measuring both fibrinogen activity and antigen levels to distinguish quantitative from qualitative abnormalities. Dr. Bauer discusses the additional diagnostic value of thrombin time and reptilase time, while Dr. Konkle notes that genetic testing can provide useful information about variants associated with thrombosis, particularly in younger patients whose clinical histories may be limited.
Treatment decisions become especially complex when patients face competing bleeding and thrombotic risks. The panel discusses fibrinogen concentrates for acute bleeding, surgery, and pregnancy, while acknowledging that replacement requirements can vary considerably. Dr. Bauer describes cases in which pregnant patients required substantially more concentrate than anticipated to reach desired fibrinogen levels. The experts also consider the difficult balance between fibrinogen replacement and anticoagulation in patients who develop thrombosis, reinforcing the need for individualized management.
Factor VII levels do not always predict bleeding severity
Factor VII deficiency presents another example of the limited relationship between laboratory measurements and clinical bleeding. Dr. Bauer explains that the condition can range from mild laboratory abnormalities without significant symptoms to severe bleeding resembling hemophilia. Although a prolonged prothrombin time (PT) may prompt investigation, the panel cautions that mildly reduced factor VII activity does not necessarily indicate a clinically significant bleeding disorder.
The experts describe considerable variability even among patients with similarly low factor VII levels or shared genetic variants. Dr. Peyvandi distinguishes between patients who primarily experience mucocutaneous bleeding and those with severe manifestations such as hemarthroses or hematomas. Drs. Bauer and Konkle share clinical experiences involving heavy menstrual bleeding, recurrent joint bleeding, and, in rare severe cases, intracranial hemorrhage. These examples illustrate why factor activity alone cannot reliably determine the need for treatment.
For patients who require prophylaxis, available therapies present practical limitations. Dr. Peyvandi discusses the short half-life of factor VII replacement products, which complicates the prevention of serious bleeding in severely affected patients. The panel notes that treatment frequency and intensity remain difficult decisions, particularly in young children at risk of central nervous system bleeding. Dr. Konkle emphasizes the need for better preventive therapies for this small but clinically important patient population.
Genetic findings and evolving laboratory methods require careful interpretation
The panel then considers whether advances in genetic testing can improve the assessment of patients with factor VII deficiency. Although genetic variants can help explain reduced factor activity, the experts agree that genotype-phenotype correlations remain difficult to establish. Dr. Konkle notes that genetic findings may correlate more closely with factor VII levels than with bleeding severity, limiting their usefulness in predicting an individual’s clinical course.
Dr. Bauer provides a historical example involving factor VII Padua, a variant associated with discrepancies in laboratory results depending on the tissue factor reagent used. Patients could appear to have markedly reduced factor VII activity when tested with certain reagents despite having little or no bleeding tendency. The panel discusses how changes in laboratory methods can affect the interpretation of older diagnoses and why reviewing the circumstances of previous testing may be important when reassessing patients.
The conversation also explores the potential of large genomic datasets and next-generation sequencing to improve understanding of rare bleeding disorders. Dr. Peyvandi suggests that inherited coagulation deficiencies may be more prevalent than traditionally estimated, particularly when individuals with milder or previously unrecognized variants are considered. Dr. Konkle adds that multiple genetic influences may contribute to differences in bleeding and thrombotic risk. While these developments offer opportunities for research, the panel acknowledges that their immediate clinical implications remain uncertain.
Factor XIII deficiency can be missed by routine coagulation tests
Unlike factor VII deficiency, factor XIII deficiency typically does not produce abnormalities in routine screening tests such as PT and activated partial thromboplastin time (aPTT). Dr. Bekendam introduces this diagnostic challenge by asking when clinicians should consider measuring factor XIII activity in patients with otherwise unexplained bleeding.
Dr. Konkle identifies umbilical stump bleeding as an important clinical clue in severe factor XIII deficiency, particularly because early recognition may help prevent life-threatening intracranial hemorrhage. The panel also discusses recurrent pregnancy loss and mucocutaneous bleeding as manifestations that may prompt further investigation. Dr. Peyvandi emphasizes that traditional clot solubility tests can miss milder deficiencies and that quantitative factor XIII activity testing is necessary for a more complete assessment. She also describes limitations of certain activity assays at very low factor levels.
The experts distinguish factor XIII deficiency from other rare bleeding disorders because of the relatively long half-life of factor XIII replacement products. This allows prophylaxis to be administered at substantially longer intervals than with factor VII replacement. Dr. Peyvandi strongly advocates prophylaxis for patients with severe deficiency, particularly those with very low residual activity, to reduce the risk of serious bleeding.
Product selection also requires attention to the underlying deficiency. Recombinant factor XIII replaces the A subunit and is therefore appropriate for A-subunit deficiency, but it does not correct B-subunit deficiency. Drs. Peyvandi, Bauer, and Konkle discuss how identifying the affected subunit, supported by genetic testing when appropriate, can directly influence treatment selection. This provides a clear example of genetic information having immediate therapeutic relevance.
Pregnancy requires individualized hemostatic planning
Pregnancy introduces additional challenges across rare bleeding disorders. The panel identifies afibrinogenemia and factor XIII deficiency as particularly important because of their associations with miscarriage and other pregnancy complications. Dr. Peyvandi discusses the need to maintain adequate fibrinogen levels during pregnancy, while Dr. Konkle emphasizes the importance of beginning and continuing prophylaxis in women with severe factor XIII deficiency who are planning pregnancy.
Replacement requirements may also change throughout gestation. The experts discuss adjusting treatment frequency and monitoring factor levels to maintain appropriate hemostatic protection. Dr. Bauer describes the challenges of achieving target fibrinogen levels near delivery, while Dr. Peyvandi notes that factor XIII replacement may need to be administered more frequently during pregnancy. For factor VII deficiency, the panel considers the limited increase in factor activity during pregnancy and the importance of planning for delivery based on the patient’s clinical presentation and factor levels.
When discussing delivery and neuraxial anesthesia, the panel emphasizes collaboration between hematology and obstetric teams. Dr. Peyvandi explains that a rare bleeding disorder does not automatically require cesarean delivery. The mode of delivery should reflect obstetric considerations alongside maternal and fetal bleeding risks. Dr. Konkle adds that cesarean delivery is itself a surgical procedure requiring appropriate hemostatic coverage.
The experts also acknowledge the uncertainty surrounding prophylaxis for patients with laboratory deficiencies but little or no bleeding history. Dr. Bauer describes how decisions about replacement therapy, antifibrinolytics, and neuraxial procedures can become especially difficult in these situations. Rather than proposing a uniform approach, the panel emphasizes individualized assessment of the disorder, procedure, and patient’s bleeding history.
Tranexamic acid plays an important role in supportive care
The discussion of pregnancy leads to a broader consideration of tranexamic acid as a supportive treatment for patients with rare bleeding disorders. Dr. Konkle describes its usefulness in managing heavy menstrual bleeding and preventing or treating postpartum hemorrhage. Depending on the clinical circumstances, it may be prescribed alongside factor replacement, used prophylactically, or provided for patients to take if significant bleeding develops.
A central point in this exchange is the importance of preparing patients for bleeding after hospital discharge. Dr. Konkle emphasizes that women with bleeding disorders should leave the hospital with a clear plan for managing potential postpartum hemorrhage. The specific plan may differ according to the underlying disorder, previous bleeding, and pregnancy complications, but anticipating these risks remains essential.
Dr. Bauer discusses the longstanding concern about thrombosis associated with antifibrinolytic therapy and refers to reassuring safety findings from a large surgical trial, while acknowledging that thrombotic risk remains relevant in certain clinical populations. Dr. Peyvandi also describes the use of tranexamic acid in combination with replacement concentrates during labor. Collectively, the discussion highlights its practical value as part of an individualized approach to bleeding prevention and treatment.
Emerging therapies offer promise but require further study
The final portion of the roundtable considers whether newer therapeutic approaches developed for hemophilia might eventually benefit patients with rare bleeding disorders. Dr. Peyvandi discusses the potential application of rebalancing therapies and bispecific antibodies, while emphasizing the limited clinical evidence currently available for these conditions. Although laboratory studies have explored some of these approaches, she cautions that laboratory measures of coagulation do not necessarily predict clinical outcomes.
The panel also recognizes that the suitability of emerging therapies may differ substantially across disorders. Dr. Konkle expresses particular interest in their potential for conditions with limited treatment options, such as factor V deficiency, and for severe factor VII deficiency, where the short half-life of existing products complicates prophylaxis. She is more cautious about applying rebalancing therapies to fibrinogen disorders because of concerns about thrombosis. For factor XIII deficiency, she notes that existing concentrates already permit relatively convenient prophylaxis.
Developing evidence for new treatments remains challenging because each disorder affects a small patient population. Dr. Bauer raises the regulatory difficulties of conducting separate trials for individual deficiencies. The panel considers basket trials, which could bring several rare bleeding disorders into a shared study structure, as one possible strategy. However, the experts acknowledge that differences in safety and efficacy across disorders would still need careful evaluation.
Across the discussion, the experts return to the importance of understanding each patient’s clinical presentation rather than relying exclusively on laboratory measurements or diagnostic labels. Their perspectives illustrate how the management of rare bleeding disorders requires balancing bleeding and thrombotic risks, recognizing the limitations of available treatments, and adapting care to individual circumstances. As diagnostic methods improve and new therapies emerge, the panel emphasizes the continuing need for clinical judgment and stronger evidence to guide treatment decisions.