Approach to Prophylaxis in RBDs

Introduction

Dr. Flora Peyvandi reviews the approach to prophylaxis in rare bleeding disorders (RBDs), a heterogeneous group of inherited conditions caused by deficiencies or dysfunction of coagulation proteins. She discusses challenges in diagnosis and clinical assessment, differences in bleeding phenotype across individual disorders, currently available prophylactic treatments, and the particular needs of women throughout menstruation, pregnancy, and delivery. She concludes by considering how novel therapies developed for hemophilia could potentially expand prophylactic options for patients with RBDs.

Rare Bleeding Disorders and Their Prevalence

Rare bleeding disorders include deficiencies of fibrinogen and factors II, V, VII, X, XI, and XIII. Dr. Peyvandi highlights World Federation of Hemophilia data showing that diagnoses of bleeding disorders have increased substantially over the past decade, reflecting greater awareness and improved diagnostic capabilities. However, reported cases remain unevenly distributed around the world. RBDs are generally inherited as autosomal recessive conditions and would be expected to occur more frequently in populations with higher rates of consanguinity, yet many patients in lower-income countries remain undiagnosed or unregistered. Genetic database analyses also suggest that the true prevalence of several rare bleeding disorders may be substantially higher than estimates based on diagnosed cases.

Clinical Heterogeneity

The type and severity of bleeding vary considerably among RBDs. Patients may experience mucosal bleeding or excessive bleeding after surgery, dental extraction, circumcision, or other hemostatic challenges. Some individuals have few manifestations early in life and experience their first significant bleeding only after a procedure. More serious manifestations, including central nervous system bleeding, umbilical cord bleeding, hemarthrosis, soft tissue hematomas, gastrointestinal bleeding, and pregnancy loss, occur with different frequencies depending on the specific factor deficiency.

Dr. Peyvandi emphasizes that this heterogeneity makes it important to consider each RBD separately. The relationship between residual factor level and clinical severity also differs by disorder. European data demonstrated a strong relationship between factor level and bleeding phenotype in deficiencies such as factor X, factor XIII, and fibrinogen, a weaker association in factor V and factor VII deficiencies, and no clear association in factor XI deficiency.

Women with Rare Bleeding Disorders

Women with inherited bleeding disorders may face bleeding challenges throughout their lives, beginning with menarche and continuing through menstruation, pregnancy, delivery, and the postpartum period. Heavy menstrual bleeding can have a substantial effect on quality of life and may be normalized within families when mothers and grandmothers have experienced similar symptoms. Pregnancy creates additional challenges because coagulation factors do not change uniformly. Some factor levels increase during pregnancy while others do not. Dr. Peyvandi stresses the importance of counseling, monitoring, and maintaining adequate factor levels, particularly during early pregnancy. She highlights fibrinogen and factor XIII deficiencies as especially important because of their association with pregnancy loss and spontaneous abortion.

Laboratory and Molecular Diagnosis

Initial laboratory evaluation may include prothrombin time, activated partial thromboplastin time, thrombin time, and mixing studies, followed by specific factor assays. Dr. Peyvandi emphasizes that routine screening tests may be normal in some deficiencies. Factor XIII deficiency, for example, requires specific quantitative testing because PT and APTT remain normal. Fibrinogen disorders also require an appropriate functional assay, and antigen measurements are important in selected disorders to distinguish reduced protein quantity from dysfunctional protein. Molecular characterization can further define the underlying disorder. Dr. Peyvandi describes genetic defects affecting the coagulation factor itself, defects in secretion pathways, and abnormalities involving post-translational modification of vitamin K-dependent proteins. While conventional sequencing identifies many pathogenic variants, whole-exome, whole-genome, and long-read sequencing have expanded the ability to identify previously unresolved genetic abnormalities.

Who Should Receive Prophylaxis?

Dr. Peyvandi argues that patients with severe RBDs should be considered for prophylaxis when their clinical circumstances warrant it. The decision depends on the frequency of bleeding, the risk of severe spontaneous hemorrhage, the potential for long-term disability from events such as central nervous system, gastrointestinal, or joint bleeding, and the patient’s previous bleeding history.

Unlike hemophilia, however, prophylaxis cannot be approached uniformly across RBDs. Differences in bleeding phenotype, factor half-life, available concentrates, and treatment-related risks mean that the strategy must be tailored to the specific deficiency and individual patient.

Available Prophylactic Treatments

Treatment options differ substantially among individual RBDs. Fibrinogen deficiency can be managed with available plasma-derived concentrates, while factor II deficiency lacks a specific replacement product and may require prothrombin complex concentrates, with consideration of thrombotic risk. Factor VII deficiency can be treated with plasma-derived or recombinant products, although the short half-life of recombinant factor VII makes long-term prophylaxis challenging. Specific plasma-derived factor X concentrates are available, while factor XI concentrate has more limited availability and may be associated with thrombosis.

Factor XIII deficiency is particularly amenable to prophylaxis because both plasma-derived and recombinant products are available and its long half-life permits relatively infrequent treatment. Dr. Peyvandi also discusses non-replacement approaches including antifibrinolytic agents, fibrin glue, hormonal therapy, and DDAVP. Fresh frozen plasma and cryoprecipitate continue to be used in some lower-income settings where specific concentrates are unavailable.

Prophylaxis for Heavy Menstrual Bleeding

For women with heavy menstrual bleeding, prophylactic management should account for reproductive plans, age, overall health, the cause and severity of menstrual bleeding, tolerance of medications or procedures, effects on daily life, personal preferences, and cultural considerations. Dr. Peyvandi emphasizes that adequate treatment should be offered to women whose bleeding requires prophylaxis rather than accepting heavy menstrual bleeding as an unavoidable feature of the disorder.

Prophylaxis During Pregnancy

Pregnancy management requires attention to how the patient’s particular deficient factor changes during gestation. Some coagulation factors rise naturally while others remain relatively unchanged. Dr. Peyvandi recommends maintaining adequate levels during pregnancy, with particular attention during the first trimester.

Existing recommendations particularly emphasize prophylaxis for fibrinogen and factor XIII deficiencies because spontaneous abortion is more frequently reported in these disorders. Dr. Peyvandi notes, however, that better data are needed to determine optimal pregnancy prophylaxis across the other rare factor deficiencies.

Limitations of Current Prophylaxis

Traditional prophylaxis frequently depends on intravenous plasma-derived factor concentrates administered once or several times per week. This treatment burden can be particularly difficult for women requiring long-term management of recurrent bleeding. Differences in factor half-life further complicate prophylaxis. Some deficient proteins require frequent replacement while others allow substantially longer dosing intervals. These limitations lead Dr. Peyvandi to consider whether therapies developed for hemophilia could eventually provide easier and more effective prophylaxis for patients with RBDs.

Rebalancing Hemostasis

Dr. Peyvandi introduces the concept of rebalancing hemostasis by increasing thrombin generation rather than directly replacing the missing coagulation factor. The objective is to achieve enough thrombin generation to prevent bleeding while avoiding excessive generation that could increase thrombosis risk.

She discusses several therapeutic strategies that reduce natural anticoagulant activity or otherwise enhance coagulation. These include inhibition of antithrombin, inhibition of tissue factor pathway inhibitor (TFPI), neutralization of protein S, and approaches that stabilize factor VIIa. While several of these strategies have been developed or evaluated in hemophilia, Dr. Peyvandi considers how they might eventually be adapted to selected rare bleeding disorders.

Emerging Therapeutic Strategies

Fitusiran reduces antithrombin production through RNA interference and has been shown experimentally to restore thrombin generation in selected factor deficiencies. Dr. Peyvandi also discusses TFPI inhibitors such as concizumab and marstacimab, which enhance the extrinsic coagulation pathway and could potentially have future applications in disorders such as factor VII deficiency or combined pathway defects.

Additional approaches include an antibody targeting protein S, which may have potential applications in factor VII, XI, and XIII deficiencies, and HMB-001, a bispecific antibody designed to bind and stabilize factor VIIa and extend its half-life. Dr. Peyvandi identifies this latter strategy as particularly promising for future prophylaxis in factor VII deficiency because it could reduce the burden of frequent infusions.

Balancing Bleeding and Thrombosis

Applying these novel therapies to RBDs requires caution. Dr. Peyvandi notes that rare bleeding disorders are generally less severe than hemophilia and that some rebalancing therapies have demonstrated thrombotic activity. The doses developed for hemophilia therefore cannot automatically be assumed to be appropriate for RBDs.

The challenge will be identifying a therapeutic level that generates enough thrombin to prevent bleeding without shifting the patient toward thrombosis. Other potential adverse effects will also require monitoring. Dr. Peyvandi suggests that basket-type clinical trials involving multiple RBDs could help determine how these therapies perform across different deficiencies while still accounting for the distinct biology of each disorder.

Conclusion

Dr. Peyvandi concludes that rare bleeding disorders should be understood as a heterogeneous collection of diseases rather than managed as a single group. Prophylaxis should reflect the specific deficiency, bleeding phenotype, available therapies, and individual circumstances, with particular attention to women who experience recurrent bleeding during menstruation, pregnancy, and delivery.

Novel therapies have transformed prophylaxis in hemophilia and may eventually provide similar opportunities for RBDs. Dr. Peyvandi emphasizes the need for innovation that reduces bleeding and treatment burden while maintaining an appropriate balance between thrombin generation and thrombosis risk. Further clinical investigation, including studies across multiple rare disorders, will be necessary to determine how these emerging approaches can be safely incorporated into prophylactic care.