In this video lecture, Dr. Peter Kouides discusses:
- The clinical and laboratory features that help identify and diagnose rare bleeding disorders.
- How bleeding phenotype and factor level can differ substantially in several rare factor deficiencies.
- Factor replacement and adjunctive treatment strategies for specific rare bleeding disorders and clinical situations.
Dr. Peter A. Kouides is Medical and Research director of the Mary M. Gooley Hemophilia Center. He is Clinical Professor of Medicine of the University of Rochester School of Medicine. He is a member of the 2021 VWD guideline working group of ASH/ISTH/NHF/WFH and an appointed co-chair of the Geriatric Care Guidelines for PwH Task Force. He is past president of the Thrombosis and Hemostasis Societies of North America, and past president of the Hemostasis and Thrombosis Research Society. He is a long-time member Foundation of Women and Girls with Blood Disorders (FWGBD) Learning Action Network and 2019 recipient of the FWGBD Ann-Marie Nazzaro award for advancing the mission and vision of the foundation. He is a prior recipient of the National Hemophilia Foundation Physician of the Year award.
(Video Lecture Summary)
Introduction
Dr. Peter Kouides reviews the diagnosis and treatment of rare bleeding disorders, focusing on deficiencies of fibrinogen and factors II, V, VII, X, XI, and XIII, as well as rarer conditions such as combined factor V and VIII deficiency and combined vitamin K-dependent factor deficiency.
Most of these disorders are inherited in an autosomal recessive pattern and are considerably less common than hemophilia A, hemophilia B, von Willebrand disease, and platelet function disorders. Their rarity and highly variable clinical phenotypes can make both diagnosis and management challenging.
Bleeding Phenotype and Factor Levels
A central challenge in rare bleeding disorders is the variable relationship between measured factor activity and clinical bleeding. Dr. Kouides particularly emphasizes factor V, VII, and XI deficiencies, in which factor levels may correlate poorly with bleeding severity.
Two patients with similar or even substantially different factor levels can therefore have very different bleeding histories. In factor XI deficiency, Dr. Kouides describes patients with extremely low levels and little bleeding alongside patients with higher levels who experience significant hemorrhage.
Recognizing Characteristic Bleeding Patterns
Clinical presentation varies according to the deficiency. Some patients experience mucocutaneous bleeding, including epistaxis, gingival bleeding, easy bruising, or heavy menstrual bleeding. Others have deeper bleeding resembling severe hemophilia, including hemarthroses and hematomas.
Certain patterns can provide important diagnostic clues. Factor XIII deficiency should be considered with umbilical stump bleeding or delayed bleeding after surgery. Recurrent miscarriage can occur with factor XIII and fibrinogen deficiencies. Intracranial hemorrhage and deep tissue bleeding may also occur in some of the more severe disorders.
Women may be more likely to come to clinical attention because menstruation and childbirth create additional hemostatic challenges.
Laboratory Evaluation
Initial laboratory evaluation includes a CBC, PT/INR, APTT, and fibrinogen. When a clotting time is prolonged, mixing studies using pooled normal plasma can help evaluate whether the abnormality reflects a factor deficiency or an inhibitor.
The traditional urea clot solubility test can identify severe factor XIII deficiency below approximately 5%, but it can miss patients with levels between 5% and 30% who may still experience bleeding. Dr. Kouides therefore cautions against relying on this test alone. Genetic testing is also encouraged in newly identified index cases and can help confirm an inherited rare bleeding disorder.
Classifying Severity
Severity classifications for rare bleeding disorders differ from those conventionally used for hemophilia A and B. The relationship between laboratory-defined severity and clinical phenotype also varies by disorder. Dr. Kouides again emphasizes that classification based on factor level cannot replace assessment of the individual patient’s bleeding history, particularly in factor V, VII, and XI deficiencies.
A Stepwise Approach to Treatment
Treatment begins with consideration of adjunctive and nonreplacement therapies. This is especially important where factor concentrates are unavailable and for disorders characterized by mucocutaneous bleeding. Antifibrinolytic agents such as tranexamic acid can be effective, particularly in factor V, VII, and XI deficiencies. Dr. Kouides cautions that combining antifibrinolytic therapy with an activated prothrombin complex concentrate may increase thrombotic risk.
Multidisciplinary Management of Bleeding in Women
Management of women with rare bleeding disorders requires close collaboration with gynecology and obstetrics. Hormonal therapies, including combined hormonal contraception and long-acting reversible contraception, may provide important control of heavy menstrual bleeding and reduce the need for factor replacement.
Dr. Kouides emphasizes integrating these approaches into multidisciplinary care rather than relying exclusively on hematologic therapies.
Plasma and Factor Replacement
Patients with more severe bleeding may require replacement of the deficient factor. Historically, fresh frozen plasma has been an important source of replacement, although transfusion reactions and the volume required can present challenges. Solvent-detergent-treated plasma can reduce the risk of transfusion reactions where available.
Prothrombin complex concentrates provide concentrated vitamin K-dependent factors and historically offered another replacement option. Single-factor concentrates are now available for several rare deficiencies, including both plasma-derived and recombinant products. Availability, however, differs considerably across countries and between individual factor deficiencies.
Fibrinogen Disorders
Fibrinogen disorders may be inherited or acquired. Acquired fibrinogen abnormalities can occur in settings such as cirrhosis, L-asparaginase treatment, and disseminated intravascular coagulation.
Bleeding correlates more strongly with very low fibrinogen levels, while patients with higher levels may have variable clinical manifestations. Dysfibrinogenemia and, to some degree, hypodysfibrinogenemia can present with both bleeding and thrombosis.
Fibrinogen concentrate provides a specific replacement option and has a sufficiently long half-life that daily dosing is generally unnecessary. Fresh frozen plasma or cryoprecipitate may be used where fibrinogen concentrate is unavailable.
Factor II Deficiency
Factor II deficiency is among the rarest inherited coagulation disorders. Complete absence of factor II is incompatible with life, while levels below approximately 10% are more consistently associated with bleeding.
An acquired reduction in factor II can also occur in association with antiphospholipid antibodies, reinforcing the importance of distinguishing inherited from acquired disease. Because there is no specific factor II concentrate, replacement may involve fresh frozen plasma or a prothrombin complex concentrate containing factors II, VII, IX, and X.
Factor V Deficiency
Factor V deficiency presents a particular management challenge because factor activity correlates poorly with bleeding risk. Decisions about replacement therefore need to incorporate the patient’s bleeding history and the anticipated hemostatic challenge.
Fresh frozen plasma is used for replacement. Dr. Kouides also highlights the role of platelets, which contain a portion of the body’s factor V. He describes using platelet transfusion in addition to plasma for major surgery.
Factor VII Deficiency
Factor VII deficiency also has a poor correlation between factor level and bleeding phenotype, although bleeding becomes more likely at levels below approximately 10%. Factor VII levels can fluctuate, further complicating management.
Recombinant factor VIIa can be used for replacement, including prophylaxis in selected patients and perioperative management. Dr. Kouides emphasizes that dosing for congenital factor VII deficiency can be lower than doses used to treat inhibitor-related bleeding in hemophilia.
Factor X Deficiency
Factor X deficiency has a stronger relationship between factor level and clinical bleeding. Severe deficiency can resemble hemophilia A or B, with hemarthroses, hematomas, gastrointestinal bleeding, intracranial hemorrhage, umbilical stump bleeding, and postpartum hemorrhage.
A specific plasma-derived factor X concentrate is available and provides effective replacement. Dr. Kouides describes its use in the surgical management of a patient with a very large hip pseudotumor.
Factor XI Deficiency
Factor XI deficiency is uncommon overall but considerably more frequent in certain populations. Bleeding severity correlates poorly with factor XI activity, making the patient’s personal bleeding history particularly important when planning treatment.
Antifibrinolytic therapy with tranexamic acid or aminocaproic acid has an important role. In the United States, fresh frozen plasma remains the primary source of factor XI replacement because a specific factor XI concentrate is unavailable. Recombinant factor VIIa provides another treatment approach and can support thrombin generation when factor XI is deficient.
Factor XIII Deficiency
Factor XIII deficiency is extremely rare and can produce distinctive clinical manifestations, including umbilical stump bleeding, delayed wound healing, recurrent miscarriage, and central nervous system bleeding.
Severe bleeding is most commonly associated with factor XIII levels below 5%, although patients with levels between 5% and 30% may also experience bleeding, including around surgery. Specific factor XIII replacement products are available, including recombinant and plasma-derived options.
Perioperative Management
Surgical planning requires consideration of the specific deficiency, bleeding history, procedure-related risk, available replacement product, and the pharmacokinetics of that therapy.
Dr. Kouides repeatedly emphasizes the value of antifibrinolytic therapy as an adjunct. The duration and frequency of replacement depend on the procedure and the factor being replaced. Recombinant factor VIIa requires relatively frequent redosing, whereas factor XIII replacement can be administered at much longer intervals. Prothrombin complex concentrates also require attention to thrombotic risk.
Pregnancy and Obstetric Care
Women with rare bleeding disorders require particular attention during menstruation, pregnancy, delivery, and the postpartum period. Dr. Kouides emphasizes close collaboration between hematologists and obstetric teams.
Tranexamic acid can be useful for heavy menstrual bleeding. Factor levels and the patient’s bleeding history inform planning for delivery and neuraxial anesthesia. Postpartum bleeding and potential neonatal bleeding also need to be considered.
Conclusion
Dr. Kouides concludes that rare bleeding disorders encompass a heterogeneous group of deficiencies with widely varying clinical presentations. Diagnosis requires recognition of characteristic bleeding patterns, appropriate coagulation testing, and increasingly genetic confirmation.
Management should be individualized because factor activity does not always predict bleeding risk. Antifibrinolytics, hormonal approaches, plasma products, and specific factor concentrates all have roles depending on the disorder and clinical situation. Careful attention to bleeding history and multidisciplinary planning are particularly important for surgery and the management of women with rare bleeding disorders.