RARE DISEASE
Congenital factor XI deficiency
Congenital factor XI deficiency
Congenital factor XI deficiency
Synonyms: Hemophilia C, PTA deficiency, Plasma thromboplastin antecedent deficiency, Rosenthal factor deficiency, Rosenthal syndrome
Synonyms: Hemophilia C, PTA deficiency, Plasma thromboplastin antecedent deficiency, Rosenthal factor deficiency, Rosenthal syndrome
Synonyms: Hemophilia C, PTA deficiency, Plasma thromboplastin antecedent deficiency, Rosenthal factor deficiency, Rosenthal syndrome
Drug discovery
3
drugs
With orphan designations
Overview
Congenital Factor XI Deficiency (Hemophilia C) is a rare autosomal bleeding disorder characterized by reduced Factor XI activity, leading to moderate bleeding primarily post-trauma or surgery. Spontaneous bleeding is uncommon, but menorrhagia and procedural hemorrhage occur. Diagnosis relies on prolonged aPTT and FXI assays, though bleeding severity poorly correlates with FXI levels. Management tailors hemostatic prophylaxis using replacement therapies or antifibrinolytics [1][2][6][16].
Burden
Unpredictable bleeding complicates perioperative/obstetric care, necessitating multidisciplinary management [5][9][13].
Women face menorrhagia (30–50%) and postpartum hemorrhage risk, requiring tailored interventions [1][11][17].
Treatment-related risks: Thrombosis from plasma products, inhibitor development, and healthcare burden from frequent monitoring [5][8][13].
Therapies
Prophylaxis: FXI concentrates, fresh frozen plasma, or low-dose recombinant FVIIa for high-risk surgeries [3][5][9].
Antifibrinolytics (tranexamic acid) for mucosal/surgical bleeding due to hyperfibrinolysis [1][3][6].
Desmopressin for mild cases; individualized plans based on bleeding history and procedure site [3][5][13].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
353 drug discovery papers about Congenital factor XI deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
353 drug discovery papers about Congenital factor XI deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-29 | Advances in Hemophilia Therapy: From Conventional Factor Replacement Therapy, Extended Half-Life (EHL) Products to Non-Factor and Gene-Based Therapies
Objective: Hemophilia, a genetic bleeding disorder caused by deficiencies in clotting factors VIII, IX, or XI, has transitioned from a fatal disease to a chronic but manageable condition. Traditional management with plasma-derived and recombinant factor replacement improved survival and reduced bleeding but remains limited by frequent infusions, inhibitor development, and incomplete protection against joint damage.Methods: This narrative review was based on a literature search of PubMed/MEDLINE and Google Scholar, focusing on recent clinical studies, guidelines, and landmark publications on hemophilia therapies.Results: Recent therapeutic advances have transformed hemophilia management by reducing treatment burden, improving bleed prevention, and enhancing patient quality of life. Extended half-life factor concentrates have decreased infusion frequency, while non-factor therapies have expanded effective prophylaxis for patients with and without inhibitors through convenient subcutaneous administration. Gene therapy has demonstrated sustained endogenous factor expression with substantial reductions in bleeding episodes, offering the potential for long-term disease modification. Despite these advances, challenges related to treatment durability, immune responses, patient eligibility, accessibility, and cost continue to limit widespread implementation.Conclusion: This narrative review outlines the evolution of hemophilia therapy from replacement strategies to innovative mechanism-based approaches, emphasizing clinical outcomes, emerging challenges, and the imperative to translate advances into equitable, sustainable care.
2026-06-11 | Anticoagulation with mechanistically distinct FXI/FXIa antibodies amrecibart (REGN9933A2) and cenvacibart (REGN7508Cat).
Thrombosis is a major contributor to global morbidity and mortality. Current standards of care target the extrinsic and/or common pathways of coagulation, effectively inhibiting thrombosis but also increasing bleeding risk, highlighting the unmet need for additional treatment options. Genetic deficiency in factor XI (FXI), a component of the intrinsic pathway, reduces thrombosis risk without spontaneous bleeding. We generated 2 FXI monoclonal antibodies (mAbs) with distinct profiles to provide new approaches to anticoagulation. Cenvacibart (REGN7508Cat) targets the catalytic domain to completely block FXI activity (induced by FXIIa or FXIa in the intrinsic pathway or thrombin in an intrinsic/common pathway amplification loop), thereby maximizing anticoagulation; amrecibart (REGN9933A2) targets the apple 2 domain of FXI/FXIa to specifically prevent FXI activity induced by FXIIa-delivering perhaps less anticoagulation but with potentially lower bleeding risk. We evaluated the anticoagulant effects of both mAbs in vitro in human/non-human primate plasma, in vivo in non-human primates, and healthy volunteers. Both mAbs inhibited intrinsic pathway-triggered coagulation, assessed by activated partial thromboplastin time (aPTT); cenvacibart exhibited a greater increase in aPTT versus amrecibart or other FXI-targeted inhibitors. Neither amrecibart nor cenvacibart affected the extrinsic pathway, assessed by prothrombin time (PT). In non-human primates, both mAbs prevented thrombosis without increasing bleeding. In first-in-human studies, both mAbs were generally well tolerated and dose-dependently inhibited intrinsic pathway-triggered coagulation, with durable aPTT prolongation without affecting PT. Amrecibart and cenvacibart may offer tailored therapies for patients with different bleeding risk profiles. The trials are registered at www.clinicaltrials.gov as #NCT05102136 and #NCT05603195.
2026-06-01 | FACTOR XI INHIBITORS AS THE NEXT GENERATION OF ANTICOAGULANTS: A COMPREHENSIVE PHARMACOLOGICAL REVIEW OF ASUNDEXIAN, MILVEXIAN, ABELACIMAB, FESOMERSEN, AND THE DECOUPLING OF THROMBOSIS FROM HEMOSTASIS
Anticoagulant therapy remains one of the most important and most challenging therapeutic interventions in cardiovascular medicine, with current direct oral anticoagulants (DOACs) — apixaban, rivaroxaban, edoxaban, dabigatran — and vitamin K antagonists offering effective thromboprophylaxis but at the cost of clinically significant bleeding, particularly intracranial and major gastrointestinal hemorrhage. The recognition that congenital factor XI (FXI) deficiency produces minimal spontaneous bleeding despite impaired thrombus formation, that FXI participates preferentially in pathological thrombus amplification rather than primary hemostasis, and that high FXI levels are associated with venous and arterial thrombosis has motivated development of FXI-targeting anticoagulants with the promise of decoupling antithrombotic efficacy from bleeding risk. This review provides a comprehensive pharmacological analysis of the FXI inhibitor class, which encompasses small-molecule oral inhibitors (asundexian, milvexian), monoclonal antibodies (abelacimab, osocimab, frunexian/MAA868), and antisense oligonucleotides (fesomersen). We examine FXI/FXIa biology and the contact pathway, the safety-efficacy rationale, pivotal clinical trial evidence including the AXIOMATIC-TKR phase 2 results, the AZALEA-TIMI 71 trial demonstrating reduced bleeding with abelacimab versus rivaroxaban in atrial fibrillation, the OCEANIC-AF trial in which asundexian failed to demonstrate non-inferiority to apixaban (terminated November 2023), and the ongoing development across multiple indications including venous thromboembolism prevention, atrial fibrillation stroke prevention, secondary stroke prevention, hemodialysis circuit thrombosis, and cancer-associated thrombosis. The review also addresses the Indian context including atrial fibrillation prevalence, venous thromboembolism epidemiology, DOAC access, and the prospective role of FXI inhibitors in low-resource settings. Future directions include reversal agent development, special populations, and the integration of FXI biology into broader anticoagulation strategies.
2026-02-20 | Direct Oral Anti-Xa Anticoagulants and the Future of Factor XI/FXIa Inhibition: A New Paradigm in Thrombosis Prevention.
The introduction of direct oral anticoagulants (DOACs), particularly factor Xa (FXa) inhibitors, has transformed the prevention and treatment of thromboembolic events. These agents have largely replaced vitamin K antagonists across most indications due to their predictable pharmacokinetics, reduced rates of intracranial bleeding, and overall ease of use. Nevertheless, a substantial residual bleeding risk remains, particularly gastrointestinal bleeding and clinically relevant non-major bleeding in elderly, frail, or polymedicated patients. Furthermore, the management of patients with severe renal dysfunction, active cancer, especially gastrointestinal or genitourinary malignancies and those requiring complex pharmacological regimens, continues to pose significant challenges. These limitations have intensified interest in targeting earlier steps of the coagulation cascade, specifically factor XI (FXI) and its activated form (FXIa). FXI occupies a unique mechanistic position: it contributes substantially to pathological thrombosis while playing only a limited role in physiological hemostasis. Genetic, observational, and mechanistic evidence consistently demonstrates that FXI deficiency confers protection against venous thromboembolism and cardiovascular events while causing minimal spontaneous bleeding. This biological paradigm has catalyzed the development of novel FXI/FXIa inhibitors, including small-molecule agents (asundexian, milvexian) and biological therapies (abelacimab). Clinical trials such as AXIOMATIC-TKR, PACIFIC-AF, and OCEANIC-AF, and ongoing programmes including ASTER and MAGNOLIA suggest that FXI inhibition may preserve antithrombotic efficacy while substantially reducing bleeding risk. This review summarizes the current landscape of oral FXa inhibitors, outlines the biological rationale for FXI/FXIa inhibition, and discusses the evolving clinical evidence supporting what may represent the next major advance in anticoagulant therapy.
2026-02-13 | Moderate hemophilia C in pregnancy: a rare case of transfusion-related complications and life-saving off-label use of recombinant factor VIIa
Hemophilia C (factor XI deficiency) is a rare bleeding disorder inherited in an autosomal recessive pattern. We present a case of a 32-year-old pregnant woman diagnosed with moderate hemophilia C who developed life-threatening complications after receiving fresh frozen plasma (FFP) for peripartum prophylaxis. After an initial mild allergic reaction to a single unit of FFP, she subsequently received a high-volume FFP transfusion for peripartum prophylaxis and developed acute respiratory deterioration requiring urgent evaluation for TACO versus TRALI. While awaiting the results of the differential diagnosis, she developed massive hemorrhage from the postoperative wound. Administration of further FFP doses was considered to carry a high risk of complications. Therefore, off-label recombinant factor VIIa (rFVIIa) was administered. This case highlights the clinical challenges and limited therapeutic options for pregnant patients with factor XI deficiency and supports the potential role of rFVIIa as a life-saving intervention.
2026-07-29 | Advances in Hemophilia Therapy: From Conventional Factor Replacement Therapy, Extended Half-Life (EHL) Products to Non-Factor and Gene-Based Therapies
Objective: Hemophilia, a genetic bleeding disorder caused by deficiencies in clotting factors VIII, IX, or XI, has transitioned from a fatal disease to a chronic but manageable condition. Traditional management with plasma-derived and recombinant factor replacement improved survival and reduced bleeding but remains limited by frequent infusions, inhibitor development, and incomplete protection against joint damage.Methods: This narrative review was based on a literature search of PubMed/MEDLINE and Google Scholar, focusing on recent clinical studies, guidelines, and landmark publications on hemophilia therapies.Results: Recent therapeutic advances have transformed hemophilia management by reducing treatment burden, improving bleed prevention, and enhancing patient quality of life. Extended half-life factor concentrates have decreased infusion frequency, while non-factor therapies have expanded effective prophylaxis for patients with and without inhibitors through convenient subcutaneous administration. Gene therapy has demonstrated sustained endogenous factor expression with substantial reductions in bleeding episodes, offering the potential for long-term disease modification. Despite these advances, challenges related to treatment durability, immune responses, patient eligibility, accessibility, and cost continue to limit widespread implementation.Conclusion: This narrative review outlines the evolution of hemophilia therapy from replacement strategies to innovative mechanism-based approaches, emphasizing clinical outcomes, emerging challenges, and the imperative to translate advances into equitable, sustainable care.
2026-06-11 | Anticoagulation with mechanistically distinct FXI/FXIa antibodies amrecibart (REGN9933A2) and cenvacibart (REGN7508Cat).
Thrombosis is a major contributor to global morbidity and mortality. Current standards of care target the extrinsic and/or common pathways of coagulation, effectively inhibiting thrombosis but also increasing bleeding risk, highlighting the unmet need for additional treatment options. Genetic deficiency in factor XI (FXI), a component of the intrinsic pathway, reduces thrombosis risk without spontaneous bleeding. We generated 2 FXI monoclonal antibodies (mAbs) with distinct profiles to provide new approaches to anticoagulation. Cenvacibart (REGN7508Cat) targets the catalytic domain to completely block FXI activity (induced by FXIIa or FXIa in the intrinsic pathway or thrombin in an intrinsic/common pathway amplification loop), thereby maximizing anticoagulation; amrecibart (REGN9933A2) targets the apple 2 domain of FXI/FXIa to specifically prevent FXI activity induced by FXIIa-delivering perhaps less anticoagulation but with potentially lower bleeding risk. We evaluated the anticoagulant effects of both mAbs in vitro in human/non-human primate plasma, in vivo in non-human primates, and healthy volunteers. Both mAbs inhibited intrinsic pathway-triggered coagulation, assessed by activated partial thromboplastin time (aPTT); cenvacibart exhibited a greater increase in aPTT versus amrecibart or other FXI-targeted inhibitors. Neither amrecibart nor cenvacibart affected the extrinsic pathway, assessed by prothrombin time (PT). In non-human primates, both mAbs prevented thrombosis without increasing bleeding. In first-in-human studies, both mAbs were generally well tolerated and dose-dependently inhibited intrinsic pathway-triggered coagulation, with durable aPTT prolongation without affecting PT. Amrecibart and cenvacibart may offer tailored therapies for patients with different bleeding risk profiles. The trials are registered at www.clinicaltrials.gov as #NCT05102136 and #NCT05603195.
2026-06-01 | FACTOR XI INHIBITORS AS THE NEXT GENERATION OF ANTICOAGULANTS: A COMPREHENSIVE PHARMACOLOGICAL REVIEW OF ASUNDEXIAN, MILVEXIAN, ABELACIMAB, FESOMERSEN, AND THE DECOUPLING OF THROMBOSIS FROM HEMOSTASIS
Anticoagulant therapy remains one of the most important and most challenging therapeutic interventions in cardiovascular medicine, with current direct oral anticoagulants (DOACs) — apixaban, rivaroxaban, edoxaban, dabigatran — and vitamin K antagonists offering effective thromboprophylaxis but at the cost of clinically significant bleeding, particularly intracranial and major gastrointestinal hemorrhage. The recognition that congenital factor XI (FXI) deficiency produces minimal spontaneous bleeding despite impaired thrombus formation, that FXI participates preferentially in pathological thrombus amplification rather than primary hemostasis, and that high FXI levels are associated with venous and arterial thrombosis has motivated development of FXI-targeting anticoagulants with the promise of decoupling antithrombotic efficacy from bleeding risk. This review provides a comprehensive pharmacological analysis of the FXI inhibitor class, which encompasses small-molecule oral inhibitors (asundexian, milvexian), monoclonal antibodies (abelacimab, osocimab, frunexian/MAA868), and antisense oligonucleotides (fesomersen). We examine FXI/FXIa biology and the contact pathway, the safety-efficacy rationale, pivotal clinical trial evidence including the AXIOMATIC-TKR phase 2 results, the AZALEA-TIMI 71 trial demonstrating reduced bleeding with abelacimab versus rivaroxaban in atrial fibrillation, the OCEANIC-AF trial in which asundexian failed to demonstrate non-inferiority to apixaban (terminated November 2023), and the ongoing development across multiple indications including venous thromboembolism prevention, atrial fibrillation stroke prevention, secondary stroke prevention, hemodialysis circuit thrombosis, and cancer-associated thrombosis. The review also addresses the Indian context including atrial fibrillation prevalence, venous thromboembolism epidemiology, DOAC access, and the prospective role of FXI inhibitors in low-resource settings. Future directions include reversal agent development, special populations, and the integration of FXI biology into broader anticoagulation strategies.
2026-02-20 | Direct Oral Anti-Xa Anticoagulants and the Future of Factor XI/FXIa Inhibition: A New Paradigm in Thrombosis Prevention.
The introduction of direct oral anticoagulants (DOACs), particularly factor Xa (FXa) inhibitors, has transformed the prevention and treatment of thromboembolic events. These agents have largely replaced vitamin K antagonists across most indications due to their predictable pharmacokinetics, reduced rates of intracranial bleeding, and overall ease of use. Nevertheless, a substantial residual bleeding risk remains, particularly gastrointestinal bleeding and clinically relevant non-major bleeding in elderly, frail, or polymedicated patients. Furthermore, the management of patients with severe renal dysfunction, active cancer, especially gastrointestinal or genitourinary malignancies and those requiring complex pharmacological regimens, continues to pose significant challenges. These limitations have intensified interest in targeting earlier steps of the coagulation cascade, specifically factor XI (FXI) and its activated form (FXIa). FXI occupies a unique mechanistic position: it contributes substantially to pathological thrombosis while playing only a limited role in physiological hemostasis. Genetic, observational, and mechanistic evidence consistently demonstrates that FXI deficiency confers protection against venous thromboembolism and cardiovascular events while causing minimal spontaneous bleeding. This biological paradigm has catalyzed the development of novel FXI/FXIa inhibitors, including small-molecule agents (asundexian, milvexian) and biological therapies (abelacimab). Clinical trials such as AXIOMATIC-TKR, PACIFIC-AF, and OCEANIC-AF, and ongoing programmes including ASTER and MAGNOLIA suggest that FXI inhibition may preserve antithrombotic efficacy while substantially reducing bleeding risk. This review summarizes the current landscape of oral FXa inhibitors, outlines the biological rationale for FXI/FXIa inhibition, and discusses the evolving clinical evidence supporting what may represent the next major advance in anticoagulant therapy.
2026-02-13 | Moderate hemophilia C in pregnancy: a rare case of transfusion-related complications and life-saving off-label use of recombinant factor VIIa
Hemophilia C (factor XI deficiency) is a rare bleeding disorder inherited in an autosomal recessive pattern. We present a case of a 32-year-old pregnant woman diagnosed with moderate hemophilia C who developed life-threatening complications after receiving fresh frozen plasma (FFP) for peripartum prophylaxis. After an initial mild allergic reaction to a single unit of FFP, she subsequently received a high-volume FFP transfusion for peripartum prophylaxis and developed acute respiratory deterioration requiring urgent evaluation for TACO versus TRALI. While awaiting the results of the differential diagnosis, she developed massive hemorrhage from the postoperative wound. Administration of further FFP doses was considered to carry a high risk of complications. Therefore, off-label recombinant factor VIIa (rFVIIa) was administered. This case highlights the clinical challenges and limited therapeutic options for pregnant patients with factor XI deficiency and supports the potential role of rFVIIa as a life-saving intervention.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Congenital factor XI deficiency.
3 orphan drug designations for Congenital factor XI deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
human coagulation factor XI | proteins | FDA | 2018-02-15 | — | Bio Products Laboratory Limited |
Human plasma derived conagulation protein-Factor XI | proteins | FDA | 2014-04-30 | — | Cambryn Biologics |
human coagulation factor XI | proteins | FDA | 2007-11-08 | — | Laboratoire francais du Fractionnement et des Biot |
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