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:
categories:
Small molecules
small molecules
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.
2026-01-30 | Rationale, design and baseline characteristics of participants in the OCEANIC-STROKE trial of FXIa inhibition for secondary stroke prevention.
Genetic deficiency of factor XI is associated with a reduced risk of ischemic stroke. Asundexian is a direct inhibitor of activated factor XIa (FXIa) with a low risk of bleeding in early trials. We seek to determine its efficacy and safety combined with antiplatelet therapy for prevention of ischemic stroke. Oral faCtor Eleven A iNhibitor asundexian as novel antithrombotiC (OCEANIC-STROKE) is a placebo-controlled, double-blind, event-driven randomised trial including participants with stroke (NIHSS ≤ 15) or high-risk TIA (ABCD2 6 or 7) within 72 h of onset. Participants had at least one of the following: atherosclerosis of extra- or intracranial vessels, a medical history of atherosclerosis or an imaged acute non-lacunar infarct. We excluded sources of stroke requiring anticoagulation and active non-trivial bleeding other than hemorrhagic infarction (HI 1 or 2). Participants received asundexian 50 mg daily or placebo stratified by planned concurrent antiplatelet therapy (single vs dual). The primary endpoint is time to ischemic stroke. We present baseline characteristics as of 5 June 2025. Between January 2023 and February 2025, we randomised 12,327 participants. Participants were 67% male with a mean (SD) age of 68 (11) years. Ischemic stroke was the index event for 95% of whom 27.4% had thrombolysis and/or mechanical thrombectomy. By TOAST classification, 43% of index strokes were LAA, 22% small vessel disease, 30% undetermined and 2% cardioembolic. Dual antiplatelets were planned in 63% as standard initial treatment. Trial completion is anticipated in October 2025. OCEANIC-STROKE will be the first completed trial of FXIa inhibition for prevention of stroke after non-cardioembolic stroke or TIA. ClinicalTrials.gov (NCT05686070).
2025-11-27 | Insights from the Evolution of Coagulation: A New Perspective on Anti-Inflammatory Strategies in the ICU-Focus on the Contact Activation System.
This review reappraises the anti-inflammatory potential of the contact activation system (CAS) in intensive care through an evolutionary lens. The authors propose that coagulation factor XII (FXII) and related components evolved in terrestrial animals as a "foreign-surface sensing-immunothrombosis" module, helping to explain the minimal bleeding phenotype of FXII deficiency and the secondary loss of F12 in marine mammals. CAS shares components with the kallikrein-kinin system (KKS): alpha-coagulation factor XIIa (α-FXIIa) drives coagulation factor XI (FXI) activation to amplify coagulation, whereas betacoagulation factor XIIa (β-FXIIa) activates the KKS to generate bradykinin, promoting vasodilation and vascular leak. Beyond proteolysis, zymogen FXII signals via urokinase-type plasminogen activator receptor (uPAR) to induce neutrophil extracellular trap formation (NETosis), thereby amplifying immunothrombosis. Clinically, the relevance spans sepsis and extracorporeal organ support: pathogens can hijack CAS/KKS to facilitate invasion, and artificial surfaces such as extracorporeal membrane oxygenation (ECMO) circuits chronically trigger contact activation. In animal models, selective inhibition of FXII/FXI prolongs circuit life and attenuates pulmonary edema and inflammation without materially increasing bleeding. The review also catalogs "non-coagulation" roles of CAS members: Activated coagulation factor XI (FXIa) modulates endothelial permeability and smooth-muscle migration, and the FXII heavy chain exhibits direct antimicrobial activity-underscoring CAS as a nexus for coagulation, inflammation, and host defense. Overall, CAS inhibitors may couple "safe anticoagulation" with "cascade-level anti-inflammation," offering a testable translational path for organ protection in the ICU alongside infection control and informing combined, precision strategies for anticoagulation and anti-inflammatory therapy.
2025-11-03 | Discovery and preclinical characterization of SB-01, a novel allosteric inhibitor of human factor XIa
Abstract Human factor XI (hFXI) is a key protein in the intrinsic coagulation pathway that amplifies clot formation under pathological conditions while having minimal impact on hemostasis. This unique profile makes hFXI an attractive target for anticoagulation. This approach is supported by strong clinical and genetic evidence: individuals with congenital FXI deficiency exhibit reduced thrombosis risk without spontaneous bleeding, while elevated FXI levels are associated with a dose-dependent increase in thrombosis. Although recent drug development has focused on small-molecule orthosteric inhibitors of FXIa, such as asundexian and milvexian, an alternative strategy of allosterically disrupting the catalytic triad offers a potentially superior mechanism. Allosteric sites are often less conserved than orthosteric sites, which can lead to enhanced selectivity and the possibility of partial antagonism, an outcome not achievable with traditional orthosteric inhibitors. Here, we present a novel, synthetic small molecule, SB-01, which is structurally and functionally distinct from other hFXIa inhibitors currently in development. In vitro, SB-01 potently inhibited hFXIa with a 130 nM potency and ~90% efficacy. This inhibition was highly selective, as SB-01 demonstrated 30–800-fold greater potency against hFXIa compared to other related serine proteases (FIIa, FXa, FIXa, FXIIa, and P.Kal). We further confirmed the allosteric mechanism of SB-01. Kinetic analyses revealed a dose-dependent reduction in Vmax and a slight increase in KM, suggesting a mixed-inhibition profile. To definitively ascertain allosterism, we first demonstrated that covalently blocking the active site only marginally increased affinity of SB-01 for hFXIa. Using spectrofluorimetry, we determined the affinity of SB-01 for hFXI to be ~80 nM. Furthermore, stoichiometric analysis of the hFXI::SB-01 co-complex revealed a 4:1 ratio, suggesting that allosteric binding occurs at both sites within the dimeric form of the target. Given these promising in vitro results, we evaluated SB-01 in preclinical models of arterial and venous thrombosis. Intravenous administration of SB-01 (6 mg/kg) significantly reduced thrombus formation in a FeCl3-induced arterial thrombosis model. Similarly, in a rat thromboplastin-induced vena cava thrombosis model, SB-01 significantly reduced thrombus formation at doses of 3 and 6 mg/kg. Importantly, we also evaluated SB-01 in a mouse lung cancer model, a patient population at high risk for venous thromboembolism (VTE). In this model, pre-treatment with SB-01 significantly reduced both thrombus weight and the incidence of thrombosis. Crucially, SB-01 showed a clean safety profile with no significant effects on body weight, bleeding time, human ether-à-go-go-related gene (hERG) activity, or CYP450 inhibition. In conclusion, this study introduces SB-01 as a highly promising, structurally unique, and potent allosteric inhibitor of hFXIa. Its high selectivity and proven efficacy in multiple preclinical thrombosis models, coupled with an excellent safety profile, position it as a strong candidate for pre-IND studies and future human clinical trials.
2025-08-26 | Novel Insights into the Dual Anticoagulant and Antiplatelet Potency of Fructose - 1,6 - Diphosphate In Vitro: Precision Inhibition of Coagulation Initiation and Comprehensive Suppression of Platelet Aggregation
Background Fructose-1,6-diphosphate (FDP), a metabolic intermediate widely used in clinical practice for managing ischemic conditions (e.g., myocardial infarction, hemorrhagic shock) due to its cytoprotective and ATP-enhancing properties, has poorly characterized effects on hemostasis. The current study aimed to systematically evaluate its in vitro impacts on coagulation and platelet function to address this knowledge gap. Methods Global hemostasis was assessed via thromboelastography (TEG) using three platforms (Maiketian, Lepu, Dingrun). Coagulation factor activities (II, V, VII, VIII, IX, X, XI, XII) were quantified with Sysmex CS5100. Platelet aggregation in platelet-rich plasma (PRP) from 5 healthy donors was tested with agonists (adenosine diphosphate [5 µmol/L], arachidonic acid [1 mmol/L], collagen [2.5 µg/mL], epinephrine [10 µmol/L]). Dose-response relationships (FDP: 0–6 mg/mL) were analyzed by linear regression. Results FDP prolonged TEG clot reaction time (R-time) concentration-dependently (P < 0.01). At therapeutic concentration (3.71 mg/mL), R-time increased by 21.8% (Maiketian), 48.3% (Lepu), and 34.1% (Dingrun) vs. controls (n=11). FDP inversely correlated with activities of factors V, VII, IX, XI, and XII (r = −0.989 to −0.997, all P < 0.001), but not factors II, VIII, X. FDP also inhibited platelet aggregation dose-dependently (maximal suppression: 94–95% at 6 mg/mL, P < 0.001), with epinephrine-induced aggregation most sensitive. Conclusions FDP exerts dual effects via selective inhibition of coagulation initiation factors and broad suppression of platelet aggregation. Caution is advised in high-risk populations (e.g., coagulation factor deficiencies, antithrombotic therapy). Further studies are needed to evaluate its clinical implications in anticoagulation therapy and bleeding risk.
antibodies
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.
2024-07-26 | An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency.
Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia. To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity. We screened for anti-ZPI sdAbs in a llama-derived phage display immune library of sdAbs. The sdAbs that bound ZPI were produced and purified for characterization. The binding of sdAbs to ZPI or other serpins was evaluated using ELISAs, and ZPI inhibition was measured in an anti-FXa or anti-FXIa chromogenic assay. The sdAbs's procoagulant activity was assessed in a thrombin generation assay in normal plasma, factor VIII- and FXI-deficient plasma. Of the four sdAbs found to bind to ZPI, one (referred to as ZPI-sdAb2) dose-dependently inhibited ZPI's anti-FXa and anti-FXIa activities with a mean half-maximal inhibitory concentration of 1.8 and 1.3 µM, respectively. ZPI-sdAb2 did not cross-react with other plasma serpins, such as antithrombin and α1-antitrypsin. ZPI-sdAb2 induced a significant increase in thrombin generation in plasma samples from healthy donors, patients with severe hemophilia A, and patients with FXI deficiency. ZPI-sdAb2 is the first specific, direct ZPI inhibitor found to exhibit procoagulant activity in plasma. This sdAb might have potential as a treatment for hemophilia or other bleeding disorders.
2024-01-25 | The AZALEA-TIMI 71 Study and the Future of Factor XI Inhibition: Reflections from the American Heart Association Scientific Congress 2023
Since its earliest days, the effective use of anticoagulation for prevention of stroke and other thromboembolic events has been limited by the risk and fear of bleeding, which was long believed to be inevitable. However, new understanding of the coagulation cascade suggests that, by targeting factor XI, it may be possible to protect patients from pathological thrombosis without significantly affecting physiological haemostasis, and thus greatly reduce the risk of bleeding. The AZALEA-TIMI 71 trial is the first study to provide definitive evidence that factor XI inhibition substantially reduces bleeding compared to a standard-of-care direct oral anticoagulant (DOAC). Based on an interview with Principal Investigator Christian T. Ruff, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Boston, Massachusetts, USA, this article explains the significance of the AZALEA-TIMI 71 trial results, which showed an unprecedented reduction in the rate of bleeding with abelacimab, an investigational dual-acting factor XI/XIa inhibitor, compared with the DOAC rivaroxaban in patients with atrial fibrillation (AF) at moderate-to-high risk of stroke.
2023-07-10 | Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors.
Thrombosis remains one of the leading causes of death in the world. The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Since the last decade, DOAC are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring, particularly for venous thromboembolism treatment and prevention and stroke prevention in atrial fibrillation. However, despite having a better safety profile than VKA, their bleeding risk is not negligible. Therefore, research is underway to develop new anticoagulant therapies with a better safety profile. One of these news approaches to reduce the risk of bleeding is to target the coagulation in the intrinsic pathway, in particular the contact activation, with the ultimate goal of preventing thrombosis without impairing hemostasis. Based on epidemiological data with patients with inherited factor XI (FXI) deficiency and preclinical studies, FXI emerged as the most promising candidate target separating hemostasis from thrombosis. This review summaries the role of FXI and FXIa in hemostasis, provides evidence of initial success with FXI pathway inhibitors in clinical trials (such as IONIS-FXIRx, fesomersen, osocimab, abelacimab, milvexian, asundexian or xisomab 3G3) and highlights the opportunities and challenges for this next generation of anticoagulants.
oligonucleotides
2025-08-01 | Molecular Aspects of Rare Coagulation Factor Deficiencies.
Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.
2024-11-05 | A Phase 1, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered SRSD107 in Healthy Subjects
Background: While anticoagulation therapy is a cornerstone of the prevention and treatment of thrombosis, a safer anticoagulant remains an important therapeutic goal. The available evidence suggests that factor XI (FXI) is important for thrombosis but has a minor role in hemostasis. Epidemiological studies suggest that severe FXI deficiency confers a reduced risk of ischemic stroke and deep vein thrombosis (DVT), whereas increased levels of FXI confer a higher risk for DVT, myocardial infarction, and ischemic stroke. Individuals with congenital FXI deficiency rarely have spontaneous bleeding, and FXI inhibition attenuates arterial and venous thrombosis in animals without increasing bleeding. Therefore, FXI is a promising target for the development of safer anticoagulants SRSD107 is a synthetic, chemically modified, double-stranded, small interfering ribonucleic acid (siRNA) that specifically targets human FXI mRNA. In studies in cynomolgus monkeys, SRSD107 was well tolerated and produced dose-dependent reductions in circulating FXI levels for at least 12 weeks, with maximal reductions in FXI antigen > 90%, after single subcutaneous doses up to 5 mg/kg. By selectively modulating coagulation through inhibition of FXI, SRSD107 could prevent thromboembolic events without significantly increasing the risk of bleeding. Methods: This is a first-in-human, Phase 1, single-site, randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously administered SRSD107 in healthy subjects in Australia (Clinicaltrials.gov NCT03702725). Eligible subjects were males or females 18 to 65 years of age, with a body mass index between 18.0 and 32.0 kg/m2. Five cohorts comprising 8 subjects apiece (randomized 6:2 to SRSD107 and placebo, respectively) evaluated 5 doses (15, 45, 120, 240 and 450 mg). The PK of SRSD107, as well as its PD effect on FXI, activated partial thromboplastin time (aPTT), and prothrombin time (PT) were investigated. Results: Forty subjects were enrolled from January to June 2024. The median age was 33 years (range: 18-57 years) and 18 were male. All subjects received a single dose of investigational drug or placebo. One serious adverse event occurred, acute appendicitis, which was not related to the study drug. There was no excess bleeding during laparoscopic appendectomy. Other treatment-emergent adverse events (AE) were all Grade 1 or Grade 2. The tmax (2-4 hours) and t1/2 (~6 hours) showed moderate absorption and rapid elimination, respectively. The increase in Cmax and AUC was generally proportional to the dose. Marked changes from baseline in PD biomarkers were observed, with maximal reductions in FXI antigen and activity > 85% and an aPTT increase > 100% (i.e., an aPTT ratio > 2.0) at the highest doses tested. No meaningful changes in the PT were observed. The PD effects were durable, with FXI antigen and activity levels remaining suppressed at least 12 weeks after dosing. Conclusions: In healthy volunteers, a single dose of SRSD107 was safe and well tolerated, with PK parameters consistent with a typical siRNA product. Marked, prolonged changes from baseline in FXI activity and aPTT were observed, suggesting that SRSD107 could be a potent anticoagulant with a sustained effect over time.
2024-04-12 | Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment.
Factor XI (FXI) deficiency is a rare bleeding disorder that presents complex challenges in patient assessment and bleeding risk management. Despite generally causing mild to moderate bleeding symptoms, clinical manifestations can vary, and bleeding tendency does not always correlate with FXI plasma levels or genotype. Our manuscript delves into the age-related nuances of FXI deficiency across an individual's lifespan. We emphasize issues faced by specific groups, including neonates and females of reproductive age experiencing abnormal uterine bleeding and postpartum hemorrhage. Older patients present unique challenges and concerns related to the management of bleeding as well as thrombotic complications. The current assortment of diagnostic laboratory assays shows limited success in predicting bleeding risk in the perisurgical setting of patients with FXI deficiency. This review explores the intricate interplay between individual bleeding profiles, surgical sites, and FXI activity levels. We also evaluate the accuracy of existing laboratory assays in predicting bleeding and discuss the potential role of investigational global assays in perioperative assessment. Furthermore, we outline our suggested diagnostic approach to refine treatment strategies and decision making. Available treatment options are presented, including antifibrinolytics, replacement products, and recombinant activated FVII. Finally, we discuss promising nonreplacement therapies for the treatment of rare bleeding disorders that can potentially address the challenges faced when managing FXI deficiency-related bleeding complications.
2017-09-15 | Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.
Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.
2017-06-19 | Factor XI as a Therapeutic Target.
Factor XIa is a plasma serine protease that contributes to thrombin generation primarily through proteolytic activation of factor IX. Traditionally considered part of the intrinsic pathway of coagulation, several lines of evidence now suggest that factor XIa serves as an interface between the vitamin-K-dependent thrombin generation mechanism and the proinflammatory kallikrein-kinin system, allowing the 2 systems to influence each other. Work with animal models and results from epidemiological surveys of human populations support a role for factor XIa in thromboembolic disease. These data and the clinical observation that deficiency of factor XI, the zymogen of factor XIa, produces a relatively mild bleeding disorder suggest that drugs targeting factor XI or XIa could produce an antithrombotic effect while leaving hemostasis largely intact. Results of a recent trial comparing antisense-induced factor XI reduction to standard-dose low molecular-weight heparin as prophylaxis for venous thrombosis during knee replacement are encouraging in this regard. Here, we discuss recent findings on the biochemistry, physiology, and pathology of factor XI as they relate to thromboembolic disease.
proteins
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.
2025-11-06 | Laboratory and Clinical Analysis of Rare Coagulation Factor Deficiencies-A Respective Study of a Single Center from Northwest China.
ObjectiveRare coagulation factor deficiencies (RCFDs) is a disease characterized by heterogeneous clinical manifestations and low prevalence. This study aimed to thoroughly analyze the clinical characteristics, routine laboratory results, and perioperative treatment plans of patients with RCFDs, enabling clinicians and laboratory professionals to manage these patients effectively.MethodsDemographic data, laboratory diagnoses, clinical symptoms, bleeding symptoms, perioperative treatment regimens, and outcomes of patients diagnosed with RCFDs (including fibrinogen (FI), FV, FVII, FX, and FXI) were collected and analyzed from 2020 to 2024 at the first affiliated hospital of Xi' an Jiaotong university.ResultsA total of 60 patients were diagnosed with RCFDs (male: female = 0.62: 1), aged from 1 year to 73 years. 9 patients were diagnosed with FXII deficiency. Fibrinogen disorders were the most common deficient factor (35, 58.3%), in which dysfibrinogenemia accounted for 20 cases, followed by FXI deficiency (10, 16.7%) and FVII deficiency (8, 13.7%). 63 patients (91.3%) had no prior bleeding tendencies, while 6 patients (8.7%) exhibited mucocutaneous bleeding symptom. Fresh frozen plasma (FFP), and fibrinogen concentrate are the main preoperative alternative therapy. Nearly 100% patients with dysfibrinogenemia and hypo-dysfibrinogenemia displayed prolonged TT and normal thromboelastometry parameters. Most of them were asymptomatic, but they may have postoperative bleeding manifestations.ConclusionThe clinical manifestations of RCFDs are highly heterogeneous. It is difficult to judge the bleeding risk by coagulation factors activity in RCFDs. Fibrinogen disorders account for the highest proportion among all RCFDs. Patients with dysfibrinogenemia and hypo-dysfibrinogenemia may experience postoperative hemorrhage or thrombosis.
2025-10-30 | Subgaleal Hematoma in a Pediatric Patient with Factor XI Deficiency: A Case Report of Combined Rare Pathologies.
BACKGROUND Factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder, often characterized by variable and unpredictable bleeding tendencies. The clinical severity in FXI deficiency typically does not correlate with factor levels, making diagnosis and management particularly challenging. When FXI deficiency coexists with other hemostatic abnormalities, such as von Willebrand factor deficiency, the bleeding risk increases, especially in pediatric patients. Subgaleal hematomas, although typically seen in neonates following birth trauma, are rare in older children and can signal an underlying coagulopathy when occurring after minor trauma. CASE REPORT We report the case of a 6-year-old Saudi girl with a known diagnosis of FXI deficiency who presented with recurrent subgaleal hematomas following trivial head trauma. Despite plasma replacement with fresh frozen plasma, she experienced hematoma expansion and required intensive management, including recombinant activated factor VII and antifibrinolytic therapy with tranexamic acid. Her FXI levels ranged from less than 15% to 52% during different episodes, and a persistently prolonged activated partial thromboplastin time was observed. Further evaluation revealed a coexisting deficiency in von Willebrand factor activity, suggesting a combined congenital bleeding disorder. The patient's clinical course stabilized following a multi-modal treatment approach, and she was discharged in good condition. CONCLUSIONS This case highlights the diagnostic complexity and clinical severity of combined bleeding disorders in children. It underscores the importance of comprehensive coagulation workup in pediatric patients presenting with disproportionate or recurrent bleeding. Individualized, multidisciplinary management is critical for optimal outcomes, especially in the setting of rare and coexisting coagulopathies.
2024-11-05 | Relationship between Coagulation Factor Levels and Bleeding Post-Cardiopulmonary Bypass
Introduction: Post-Cardiopulmonary Bypass (CPB) coagulopathy results in bleeding, transfusion and re-exploration, and increases morbidity, mortality and cost. Some studies have reported a relationship between individual factor levels and chest tube drainage as a marker of bleeding, but few have reported that relationship for multiple factors. Methods: With IRB approval and informed consent, 98 patients, ages 18 - 85, undergoing cardiac surgery with cardiopulmonary bypass (CPB) were studied. Factor levels measured five minutes post-protamine included fibrinogen (FIB), and factors II, V, VII, VIII, Von Willebrand Factor Antigen (VWF Ag), Ristocetin Cofactor (VWF Activity), IX, X, XI and XIII. Linear regression models examined the relationship between factor levels and post-op chest tube drainage over 24 hours as a surrogate marker for bleeding. An effect size (ES) was calculated so that each factor deficiency multiplied by the ES and the patient's weight in kg would estimate the contribution of that factor to bleeding. Factors were ranked from most to least impact on bleeding. Conversely, said ES would estimate the decrease in bleeding achieved by a percentage increase in a deficient factor level if such factor was known to be deficient. Results: F:II was 1st (most associated with bleeding), ES = -0.137, 95% CI -0.214 - -0.059, p < 0.001; F:X was 2nd, ES = -0.130, 95% CI -0.202 - -0.058, p < 0.001; F:VII ES = -0.121, 95% CI -0.198 - -0.045, p = 0.002; F:XI ES = -0.109, 95% CI -0.16 - -0.058, p < 0.001; F:IX ES = -0.100; 95% CI -0.135 - -0.065, p < 0.001; F:V ES = - 0.065; 95% CI -0.114 - -0.016, p = 0.011; F:XIII ES = - 0.055; 95% CI -0.099 - -0.011, p = 0.016; FIB ES = - 0.042; 95% CI -0.063 - -0.022, p < 0.001; F:VIII ES = - 0.007; 95% CI -0.020 - 0.006, p = 0.318; VWF Ag ES = 0.002; 95% CI -0.016 - 0.019, p = 0.855; VWF Activity ES = 0.004; 95% CI -0.015 - 0.023, p = 0.671. Conclusions: Factors VIII, VWF Ag and Ristocetin Cofactor demonstrated no relationship with bleeding, perhaps because they are elevated as acute-phase reactants. In theory, raising F:II level post-CPB by 30% in an 80 kg patient might decrease bleeding by 328 ml, and raising F:X level post-CPB by 30% in an 80 kg patient might decrease bleeding by 312 ml, etc. A weakness of this study is that the sample size was too small to perform a multi-variate analysis considering all factor levels. Still, the data suggest four-factor prothrombin complex concentrate (PCC) might be a more effective treatment for post-CPB coagulopathy than FFP. The data do not confirm cause and effect; that would require a large study with control and treatment arms. If multiple factor levels could be measured in a rapid and cost-effective manner it might aid in targeted treatment of post-CPB coagulopathy. The data suggest that work should be performed to better elucidate the contribution of coagulation factor deficiencies to post-CPB bleeding, as improved treatment of such factor deficiencies might decrease bleeding and transfusion requirements.
2024-07-23 | Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency-A large single-centre experience.
Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management. A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records. A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years. FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.
other
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.
2025-02-28 | Gene therapy for hemophilia: Recent developments and challenges (Review)
Hemophilia is an X‑linked disease marked by the absence or impaired function of specific coagulation factors. Hemophilia A is characterized by a deficiency in factor VIII, and hemophilia B is characterized by a deficiency in factor IX. Factor XI deficiency, referred to as hemophilia C, is a very uncommon bleeding illness characterized by moderate symptoms; although the condition is not widespread, standard management poses significant challenges linked to socioeconomic factors. The introduction of FDA‑approved gene therapy for hemophilia B in 2022 holds transformative potential; however, certain issues demand careful consideration. The present review provides insight into the existing hemophilia landscape, discusses the latest strides in gene therapy for hemophilia, and examines the hurdles that need to be addressed to make this innovative treatment more accessible to individuals afflicted by this condition.
2024-03-07 | Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies
Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: a) engineering vectors to increase transgene expression; b) aligning interests of the health system with costs and challenges for pharmaceutical industry; c) refining patient eligibility criteria, and endpoints definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are poorly available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy; be functional in a restricted cellular subset; avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should be also explored. Aligning interests and obligations of pharmaceutical industry with those of the health system is critical for AAV-based GT success. Costs and challenges for pharmaceutical industry include a) removing impurities from AAV; b) validating tests to measure treatment efficacy, c) promoting training programs to standardize vector genomes delivery, d) collecting long-term follow-up data, and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clearcut outcomes are mandatory as endpoints of unequivocal efficacy data.
2016-04-29 | Gene Therapy for Coagulation Disorders
Molecular genetic details of the human coagulation system were among the first successes of the genetic revolution in the 1980s. This information led to new molecular diagnostic strategies for inherited disorders of hemostasis and the development of recombinant clotting factors for the treatment of the common inherited bleeding disorders. A longer term goal of this knowledge has been the establishment of gene transfer to provide continuing access to missing or defective hemostatic proteins. Because of the relative infrequency of inherited coagulation factor disorders and the availability of safe and effective alternative means of management, the application of gene therapy for these conditions has been slow to realize clinical application. Nevertheless, the tools for effective and safe gene transfer are now much improved, and we have started to see examples of clinical gene therapy successes. Leading the way has been the use of adeno-associated virus-based strategies for factor IX gene transfer in hemophilia B. Several small phase 1/2 clinical studies using this approach have shown prolonged expression of therapeutically beneficial levels of factor IX. Nevertheless, before the application of gene therapy for coagulation disorders becomes widespread, several obstacles need to be overcome. Immunologic responses to the vector and transgenic protein need to be mitigated, and production strategies for clinical grade vectors require enhancements. There is little doubt that with the development of more efficient and facile strategies for genome editing and the application of other nucleic acid-based approaches to influence the coagulation system, the future of genetic therapies for hemostasis is bright.
1999-02-22 | Defective vaccinia virus as a biologically safe tool for the overproduction of recombinant human secretory proteins.
We have described recently the construction of a defective vaccinia virus (VV) lacking the essential D4R open reading frame and have shown furthermore the selection of a complementing cell line providing the essential D4R gene product. The D4R gene belongs to the group of early transcribed vaccinia genes preventing a virus defective in D4R from entering into the intermediate and late phase of replication under noncomplementing conditions. Here we show that this property, which is unique among the group of so called nonreplicating poxviruses, is helpful for the production of (secretable) recombinant human proteins. Recombinant VV based on a D4R-defective parental strain expressing cDNAs coding for the human blood coagulation factors VII and XI produced significantly more recombinant protein than the corresponding recombinants based on wild-type VV. Moreover, the complementing cell line RK-D4R-44.20 was a more effective production cell system for both vD4 and wild-type VV recombinants compared to wild-type RK-13 cells. Surprisingly, recombinant human factor VII was more efficiently produced with the defective vaccinia recombinant even under noncomplementing conditions, suggesting that persistence of the early phase of vaccinia replication in combination with a delayed host shutoff is advantageous for the overproduction of certain recombinant proteins using the VV expression system.
small molecules
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.
2026-01-30 | Rationale, design and baseline characteristics of participants in the OCEANIC-STROKE trial of FXIa inhibition for secondary stroke prevention.
Genetic deficiency of factor XI is associated with a reduced risk of ischemic stroke. Asundexian is a direct inhibitor of activated factor XIa (FXIa) with a low risk of bleeding in early trials. We seek to determine its efficacy and safety combined with antiplatelet therapy for prevention of ischemic stroke. Oral faCtor Eleven A iNhibitor asundexian as novel antithrombotiC (OCEANIC-STROKE) is a placebo-controlled, double-blind, event-driven randomised trial including participants with stroke (NIHSS ≤ 15) or high-risk TIA (ABCD2 6 or 7) within 72 h of onset. Participants had at least one of the following: atherosclerosis of extra- or intracranial vessels, a medical history of atherosclerosis or an imaged acute non-lacunar infarct. We excluded sources of stroke requiring anticoagulation and active non-trivial bleeding other than hemorrhagic infarction (HI 1 or 2). Participants received asundexian 50 mg daily or placebo stratified by planned concurrent antiplatelet therapy (single vs dual). The primary endpoint is time to ischemic stroke. We present baseline characteristics as of 5 June 2025. Between January 2023 and February 2025, we randomised 12,327 participants. Participants were 67% male with a mean (SD) age of 68 (11) years. Ischemic stroke was the index event for 95% of whom 27.4% had thrombolysis and/or mechanical thrombectomy. By TOAST classification, 43% of index strokes were LAA, 22% small vessel disease, 30% undetermined and 2% cardioembolic. Dual antiplatelets were planned in 63% as standard initial treatment. Trial completion is anticipated in October 2025. OCEANIC-STROKE will be the first completed trial of FXIa inhibition for prevention of stroke after non-cardioembolic stroke or TIA. ClinicalTrials.gov (NCT05686070).
2025-11-27 | Insights from the Evolution of Coagulation: A New Perspective on Anti-Inflammatory Strategies in the ICU-Focus on the Contact Activation System.
This review reappraises the anti-inflammatory potential of the contact activation system (CAS) in intensive care through an evolutionary lens. The authors propose that coagulation factor XII (FXII) and related components evolved in terrestrial animals as a "foreign-surface sensing-immunothrombosis" module, helping to explain the minimal bleeding phenotype of FXII deficiency and the secondary loss of F12 in marine mammals. CAS shares components with the kallikrein-kinin system (KKS): alpha-coagulation factor XIIa (α-FXIIa) drives coagulation factor XI (FXI) activation to amplify coagulation, whereas betacoagulation factor XIIa (β-FXIIa) activates the KKS to generate bradykinin, promoting vasodilation and vascular leak. Beyond proteolysis, zymogen FXII signals via urokinase-type plasminogen activator receptor (uPAR) to induce neutrophil extracellular trap formation (NETosis), thereby amplifying immunothrombosis. Clinically, the relevance spans sepsis and extracorporeal organ support: pathogens can hijack CAS/KKS to facilitate invasion, and artificial surfaces such as extracorporeal membrane oxygenation (ECMO) circuits chronically trigger contact activation. In animal models, selective inhibition of FXII/FXI prolongs circuit life and attenuates pulmonary edema and inflammation without materially increasing bleeding. The review also catalogs "non-coagulation" roles of CAS members: Activated coagulation factor XI (FXIa) modulates endothelial permeability and smooth-muscle migration, and the FXII heavy chain exhibits direct antimicrobial activity-underscoring CAS as a nexus for coagulation, inflammation, and host defense. Overall, CAS inhibitors may couple "safe anticoagulation" with "cascade-level anti-inflammation," offering a testable translational path for organ protection in the ICU alongside infection control and informing combined, precision strategies for anticoagulation and anti-inflammatory therapy.
2025-11-03 | Discovery and preclinical characterization of SB-01, a novel allosteric inhibitor of human factor XIa
Abstract Human factor XI (hFXI) is a key protein in the intrinsic coagulation pathway that amplifies clot formation under pathological conditions while having minimal impact on hemostasis. This unique profile makes hFXI an attractive target for anticoagulation. This approach is supported by strong clinical and genetic evidence: individuals with congenital FXI deficiency exhibit reduced thrombosis risk without spontaneous bleeding, while elevated FXI levels are associated with a dose-dependent increase in thrombosis. Although recent drug development has focused on small-molecule orthosteric inhibitors of FXIa, such as asundexian and milvexian, an alternative strategy of allosterically disrupting the catalytic triad offers a potentially superior mechanism. Allosteric sites are often less conserved than orthosteric sites, which can lead to enhanced selectivity and the possibility of partial antagonism, an outcome not achievable with traditional orthosteric inhibitors. Here, we present a novel, synthetic small molecule, SB-01, which is structurally and functionally distinct from other hFXIa inhibitors currently in development. In vitro, SB-01 potently inhibited hFXIa with a 130 nM potency and ~90% efficacy. This inhibition was highly selective, as SB-01 demonstrated 30–800-fold greater potency against hFXIa compared to other related serine proteases (FIIa, FXa, FIXa, FXIIa, and P.Kal). We further confirmed the allosteric mechanism of SB-01. Kinetic analyses revealed a dose-dependent reduction in Vmax and a slight increase in KM, suggesting a mixed-inhibition profile. To definitively ascertain allosterism, we first demonstrated that covalently blocking the active site only marginally increased affinity of SB-01 for hFXIa. Using spectrofluorimetry, we determined the affinity of SB-01 for hFXI to be ~80 nM. Furthermore, stoichiometric analysis of the hFXI::SB-01 co-complex revealed a 4:1 ratio, suggesting that allosteric binding occurs at both sites within the dimeric form of the target. Given these promising in vitro results, we evaluated SB-01 in preclinical models of arterial and venous thrombosis. Intravenous administration of SB-01 (6 mg/kg) significantly reduced thrombus formation in a FeCl3-induced arterial thrombosis model. Similarly, in a rat thromboplastin-induced vena cava thrombosis model, SB-01 significantly reduced thrombus formation at doses of 3 and 6 mg/kg. Importantly, we also evaluated SB-01 in a mouse lung cancer model, a patient population at high risk for venous thromboembolism (VTE). In this model, pre-treatment with SB-01 significantly reduced both thrombus weight and the incidence of thrombosis. Crucially, SB-01 showed a clean safety profile with no significant effects on body weight, bleeding time, human ether-à-go-go-related gene (hERG) activity, or CYP450 inhibition. In conclusion, this study introduces SB-01 as a highly promising, structurally unique, and potent allosteric inhibitor of hFXIa. Its high selectivity and proven efficacy in multiple preclinical thrombosis models, coupled with an excellent safety profile, position it as a strong candidate for pre-IND studies and future human clinical trials.
2025-08-26 | Novel Insights into the Dual Anticoagulant and Antiplatelet Potency of Fructose - 1,6 - Diphosphate In Vitro: Precision Inhibition of Coagulation Initiation and Comprehensive Suppression of Platelet Aggregation
Background Fructose-1,6-diphosphate (FDP), a metabolic intermediate widely used in clinical practice for managing ischemic conditions (e.g., myocardial infarction, hemorrhagic shock) due to its cytoprotective and ATP-enhancing properties, has poorly characterized effects on hemostasis. The current study aimed to systematically evaluate its in vitro impacts on coagulation and platelet function to address this knowledge gap. Methods Global hemostasis was assessed via thromboelastography (TEG) using three platforms (Maiketian, Lepu, Dingrun). Coagulation factor activities (II, V, VII, VIII, IX, X, XI, XII) were quantified with Sysmex CS5100. Platelet aggregation in platelet-rich plasma (PRP) from 5 healthy donors was tested with agonists (adenosine diphosphate [5 µmol/L], arachidonic acid [1 mmol/L], collagen [2.5 µg/mL], epinephrine [10 µmol/L]). Dose-response relationships (FDP: 0–6 mg/mL) were analyzed by linear regression. Results FDP prolonged TEG clot reaction time (R-time) concentration-dependently (P < 0.01). At therapeutic concentration (3.71 mg/mL), R-time increased by 21.8% (Maiketian), 48.3% (Lepu), and 34.1% (Dingrun) vs. controls (n=11). FDP inversely correlated with activities of factors V, VII, IX, XI, and XII (r = −0.989 to −0.997, all P < 0.001), but not factors II, VIII, X. FDP also inhibited platelet aggregation dose-dependently (maximal suppression: 94–95% at 6 mg/mL, P < 0.001), with epinephrine-induced aggregation most sensitive. Conclusions FDP exerts dual effects via selective inhibition of coagulation initiation factors and broad suppression of platelet aggregation. Caution is advised in high-risk populations (e.g., coagulation factor deficiencies, antithrombotic therapy). Further studies are needed to evaluate its clinical implications in anticoagulation therapy and bleeding risk.
antibodies
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.
2024-07-26 | An Inhibitory Single-Domain Antibody against Protein Z-Dependent Protease Inhibitor Promotes Thrombin Generation in Severe Hemophilia A and FXI Deficiency.
Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that targets factor Xa (FXa) in the presence of protein Z (PZ), and factor XIa (FXIa). In factor-VIII-deficient mice, PZ or ZPI gene knock-out mitigates the bleeding phenotype, and pharmacological inhibition of PZ enhances thrombin generation in plasma from patients with hemophilia. To develop a single-domain antibody (sdAb) directed against ZPI to inhibit its anticoagulant activity. We screened for anti-ZPI sdAbs in a llama-derived phage display immune library of sdAbs. The sdAbs that bound ZPI were produced and purified for characterization. The binding of sdAbs to ZPI or other serpins was evaluated using ELISAs, and ZPI inhibition was measured in an anti-FXa or anti-FXIa chromogenic assay. The sdAbs's procoagulant activity was assessed in a thrombin generation assay in normal plasma, factor VIII- and FXI-deficient plasma. Of the four sdAbs found to bind to ZPI, one (referred to as ZPI-sdAb2) dose-dependently inhibited ZPI's anti-FXa and anti-FXIa activities with a mean half-maximal inhibitory concentration of 1.8 and 1.3 µM, respectively. ZPI-sdAb2 did not cross-react with other plasma serpins, such as antithrombin and α1-antitrypsin. ZPI-sdAb2 induced a significant increase in thrombin generation in plasma samples from healthy donors, patients with severe hemophilia A, and patients with FXI deficiency. ZPI-sdAb2 is the first specific, direct ZPI inhibitor found to exhibit procoagulant activity in plasma. This sdAb might have potential as a treatment for hemophilia or other bleeding disorders.
2024-01-25 | The AZALEA-TIMI 71 Study and the Future of Factor XI Inhibition: Reflections from the American Heart Association Scientific Congress 2023
Since its earliest days, the effective use of anticoagulation for prevention of stroke and other thromboembolic events has been limited by the risk and fear of bleeding, which was long believed to be inevitable. However, new understanding of the coagulation cascade suggests that, by targeting factor XI, it may be possible to protect patients from pathological thrombosis without significantly affecting physiological haemostasis, and thus greatly reduce the risk of bleeding. The AZALEA-TIMI 71 trial is the first study to provide definitive evidence that factor XI inhibition substantially reduces bleeding compared to a standard-of-care direct oral anticoagulant (DOAC). Based on an interview with Principal Investigator Christian T. Ruff, Thrombolysis in Myocardial Infarction (TIMI) Study Group, Boston, Massachusetts, USA, this article explains the significance of the AZALEA-TIMI 71 trial results, which showed an unprecedented reduction in the rate of bleeding with abelacimab, an investigational dual-acting factor XI/XIa inhibitor, compared with the DOAC rivaroxaban in patients with atrial fibrillation (AF) at moderate-to-high risk of stroke.
2023-07-10 | Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors.
Thrombosis remains one of the leading causes of death in the world. The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Since the last decade, DOAC are widely used in clinical practice because of their ease to use with favorable pharmacological profile and not requiring monitoring, particularly for venous thromboembolism treatment and prevention and stroke prevention in atrial fibrillation. However, despite having a better safety profile than VKA, their bleeding risk is not negligible. Therefore, research is underway to develop new anticoagulant therapies with a better safety profile. One of these news approaches to reduce the risk of bleeding is to target the coagulation in the intrinsic pathway, in particular the contact activation, with the ultimate goal of preventing thrombosis without impairing hemostasis. Based on epidemiological data with patients with inherited factor XI (FXI) deficiency and preclinical studies, FXI emerged as the most promising candidate target separating hemostasis from thrombosis. This review summaries the role of FXI and FXIa in hemostasis, provides evidence of initial success with FXI pathway inhibitors in clinical trials (such as IONIS-FXIRx, fesomersen, osocimab, abelacimab, milvexian, asundexian or xisomab 3G3) and highlights the opportunities and challenges for this next generation of anticoagulants.
oligonucleotides
2025-08-01 | Molecular Aspects of Rare Coagulation Factor Deficiencies.
Rare coagulation factor deficiencies are inherited disorders affecting factors I, II, V, VII, X, XI, XIII, and combined forms. They mainly present with bleeding symptoms of variable severity. These deficiencies show significant clinical heterogeneity, with no consistent correlation between factor levels and bleeding intensity. Prevalence is higher in populations with high consanguinity rates. Understanding relies on the study of genetic and molecular mechanisms. Diagnosis is based on hemostasis testing, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and factor activity assays. In case of abnormalities, Molecular analysis is undertaken using genomic DNA extracted from peripheral blood samples. Depending on the clinical context and the level of detail required, sequencing is performed using either Sanger sequencing or next-generation sequencing (NGS) platforms, enabling the identification of pathogenic variants responsible for the coagulation disorder. Variant interpretation follows American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines. Large deletions or duplications are assessed via Multiplex Ligation-dependent Probe Amplification (MLPA) or Copy number variations (CNV) analysis. Molecular analysis revealed a wide range of mutations depending on the deficient factor. Missense mutations are the most common, followed by nonsense, splicing, and insertion/deletion mutations. Some mutations prevent factor production, while others alter its structure or secretion. Each mutation type has a distinct impact on the bleeding phenotype. Genetic characterization improves diagnostic accuracy and guides clinical management. Modern molecular tools have enhanced the understanding of these disorders' pathophysiology. A multidisciplinary approach is essential for optimal patient care. Ongoing research is key to developing targeted therapies.
2024-11-05 | A Phase 1, Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered SRSD107 in Healthy Subjects
Background: While anticoagulation therapy is a cornerstone of the prevention and treatment of thrombosis, a safer anticoagulant remains an important therapeutic goal. The available evidence suggests that factor XI (FXI) is important for thrombosis but has a minor role in hemostasis. Epidemiological studies suggest that severe FXI deficiency confers a reduced risk of ischemic stroke and deep vein thrombosis (DVT), whereas increased levels of FXI confer a higher risk for DVT, myocardial infarction, and ischemic stroke. Individuals with congenital FXI deficiency rarely have spontaneous bleeding, and FXI inhibition attenuates arterial and venous thrombosis in animals without increasing bleeding. Therefore, FXI is a promising target for the development of safer anticoagulants SRSD107 is a synthetic, chemically modified, double-stranded, small interfering ribonucleic acid (siRNA) that specifically targets human FXI mRNA. In studies in cynomolgus monkeys, SRSD107 was well tolerated and produced dose-dependent reductions in circulating FXI levels for at least 12 weeks, with maximal reductions in FXI antigen > 90%, after single subcutaneous doses up to 5 mg/kg. By selectively modulating coagulation through inhibition of FXI, SRSD107 could prevent thromboembolic events without significantly increasing the risk of bleeding. Methods: This is a first-in-human, Phase 1, single-site, randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of subcutaneously administered SRSD107 in healthy subjects in Australia (Clinicaltrials.gov NCT03702725). Eligible subjects were males or females 18 to 65 years of age, with a body mass index between 18.0 and 32.0 kg/m2. Five cohorts comprising 8 subjects apiece (randomized 6:2 to SRSD107 and placebo, respectively) evaluated 5 doses (15, 45, 120, 240 and 450 mg). The PK of SRSD107, as well as its PD effect on FXI, activated partial thromboplastin time (aPTT), and prothrombin time (PT) were investigated. Results: Forty subjects were enrolled from January to June 2024. The median age was 33 years (range: 18-57 years) and 18 were male. All subjects received a single dose of investigational drug or placebo. One serious adverse event occurred, acute appendicitis, which was not related to the study drug. There was no excess bleeding during laparoscopic appendectomy. Other treatment-emergent adverse events (AE) were all Grade 1 or Grade 2. The tmax (2-4 hours) and t1/2 (~6 hours) showed moderate absorption and rapid elimination, respectively. The increase in Cmax and AUC was generally proportional to the dose. Marked changes from baseline in PD biomarkers were observed, with maximal reductions in FXI antigen and activity > 85% and an aPTT increase > 100% (i.e., an aPTT ratio > 2.0) at the highest doses tested. No meaningful changes in the PT were observed. The PD effects were durable, with FXI antigen and activity levels remaining suppressed at least 12 weeks after dosing. Conclusions: In healthy volunteers, a single dose of SRSD107 was safe and well tolerated, with PK parameters consistent with a typical siRNA product. Marked, prolonged changes from baseline in FXI activity and aPTT were observed, suggesting that SRSD107 could be a potent anticoagulant with a sustained effect over time.
2024-04-12 | Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment.
Factor XI (FXI) deficiency is a rare bleeding disorder that presents complex challenges in patient assessment and bleeding risk management. Despite generally causing mild to moderate bleeding symptoms, clinical manifestations can vary, and bleeding tendency does not always correlate with FXI plasma levels or genotype. Our manuscript delves into the age-related nuances of FXI deficiency across an individual's lifespan. We emphasize issues faced by specific groups, including neonates and females of reproductive age experiencing abnormal uterine bleeding and postpartum hemorrhage. Older patients present unique challenges and concerns related to the management of bleeding as well as thrombotic complications. The current assortment of diagnostic laboratory assays shows limited success in predicting bleeding risk in the perisurgical setting of patients with FXI deficiency. This review explores the intricate interplay between individual bleeding profiles, surgical sites, and FXI activity levels. We also evaluate the accuracy of existing laboratory assays in predicting bleeding and discuss the potential role of investigational global assays in perioperative assessment. Furthermore, we outline our suggested diagnostic approach to refine treatment strategies and decision making. Available treatment options are presented, including antifibrinolytics, replacement products, and recombinant activated FVII. Finally, we discuss promising nonreplacement therapies for the treatment of rare bleeding disorders that can potentially address the challenges faced when managing FXI deficiency-related bleeding complications.
2017-09-15 | Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.
Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.
2017-06-19 | Factor XI as a Therapeutic Target.
Factor XIa is a plasma serine protease that contributes to thrombin generation primarily through proteolytic activation of factor IX. Traditionally considered part of the intrinsic pathway of coagulation, several lines of evidence now suggest that factor XIa serves as an interface between the vitamin-K-dependent thrombin generation mechanism and the proinflammatory kallikrein-kinin system, allowing the 2 systems to influence each other. Work with animal models and results from epidemiological surveys of human populations support a role for factor XIa in thromboembolic disease. These data and the clinical observation that deficiency of factor XI, the zymogen of factor XIa, produces a relatively mild bleeding disorder suggest that drugs targeting factor XI or XIa could produce an antithrombotic effect while leaving hemostasis largely intact. Results of a recent trial comparing antisense-induced factor XI reduction to standard-dose low molecular-weight heparin as prophylaxis for venous thrombosis during knee replacement are encouraging in this regard. Here, we discuss recent findings on the biochemistry, physiology, and pathology of factor XI as they relate to thromboembolic disease.
proteins
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.
2025-11-06 | Laboratory and Clinical Analysis of Rare Coagulation Factor Deficiencies-A Respective Study of a Single Center from Northwest China.
ObjectiveRare coagulation factor deficiencies (RCFDs) is a disease characterized by heterogeneous clinical manifestations and low prevalence. This study aimed to thoroughly analyze the clinical characteristics, routine laboratory results, and perioperative treatment plans of patients with RCFDs, enabling clinicians and laboratory professionals to manage these patients effectively.MethodsDemographic data, laboratory diagnoses, clinical symptoms, bleeding symptoms, perioperative treatment regimens, and outcomes of patients diagnosed with RCFDs (including fibrinogen (FI), FV, FVII, FX, and FXI) were collected and analyzed from 2020 to 2024 at the first affiliated hospital of Xi' an Jiaotong university.ResultsA total of 60 patients were diagnosed with RCFDs (male: female = 0.62: 1), aged from 1 year to 73 years. 9 patients were diagnosed with FXII deficiency. Fibrinogen disorders were the most common deficient factor (35, 58.3%), in which dysfibrinogenemia accounted for 20 cases, followed by FXI deficiency (10, 16.7%) and FVII deficiency (8, 13.7%). 63 patients (91.3%) had no prior bleeding tendencies, while 6 patients (8.7%) exhibited mucocutaneous bleeding symptom. Fresh frozen plasma (FFP), and fibrinogen concentrate are the main preoperative alternative therapy. Nearly 100% patients with dysfibrinogenemia and hypo-dysfibrinogenemia displayed prolonged TT and normal thromboelastometry parameters. Most of them were asymptomatic, but they may have postoperative bleeding manifestations.ConclusionThe clinical manifestations of RCFDs are highly heterogeneous. It is difficult to judge the bleeding risk by coagulation factors activity in RCFDs. Fibrinogen disorders account for the highest proportion among all RCFDs. Patients with dysfibrinogenemia and hypo-dysfibrinogenemia may experience postoperative hemorrhage or thrombosis.
2025-10-30 | Subgaleal Hematoma in a Pediatric Patient with Factor XI Deficiency: A Case Report of Combined Rare Pathologies.
BACKGROUND Factor XI (FXI) deficiency is a rare autosomal recessive bleeding disorder, often characterized by variable and unpredictable bleeding tendencies. The clinical severity in FXI deficiency typically does not correlate with factor levels, making diagnosis and management particularly challenging. When FXI deficiency coexists with other hemostatic abnormalities, such as von Willebrand factor deficiency, the bleeding risk increases, especially in pediatric patients. Subgaleal hematomas, although typically seen in neonates following birth trauma, are rare in older children and can signal an underlying coagulopathy when occurring after minor trauma. CASE REPORT We report the case of a 6-year-old Saudi girl with a known diagnosis of FXI deficiency who presented with recurrent subgaleal hematomas following trivial head trauma. Despite plasma replacement with fresh frozen plasma, she experienced hematoma expansion and required intensive management, including recombinant activated factor VII and antifibrinolytic therapy with tranexamic acid. Her FXI levels ranged from less than 15% to 52% during different episodes, and a persistently prolonged activated partial thromboplastin time was observed. Further evaluation revealed a coexisting deficiency in von Willebrand factor activity, suggesting a combined congenital bleeding disorder. The patient's clinical course stabilized following a multi-modal treatment approach, and she was discharged in good condition. CONCLUSIONS This case highlights the diagnostic complexity and clinical severity of combined bleeding disorders in children. It underscores the importance of comprehensive coagulation workup in pediatric patients presenting with disproportionate or recurrent bleeding. Individualized, multidisciplinary management is critical for optimal outcomes, especially in the setting of rare and coexisting coagulopathies.
2024-11-05 | Relationship between Coagulation Factor Levels and Bleeding Post-Cardiopulmonary Bypass
Introduction: Post-Cardiopulmonary Bypass (CPB) coagulopathy results in bleeding, transfusion and re-exploration, and increases morbidity, mortality and cost. Some studies have reported a relationship between individual factor levels and chest tube drainage as a marker of bleeding, but few have reported that relationship for multiple factors. Methods: With IRB approval and informed consent, 98 patients, ages 18 - 85, undergoing cardiac surgery with cardiopulmonary bypass (CPB) were studied. Factor levels measured five minutes post-protamine included fibrinogen (FIB), and factors II, V, VII, VIII, Von Willebrand Factor Antigen (VWF Ag), Ristocetin Cofactor (VWF Activity), IX, X, XI and XIII. Linear regression models examined the relationship between factor levels and post-op chest tube drainage over 24 hours as a surrogate marker for bleeding. An effect size (ES) was calculated so that each factor deficiency multiplied by the ES and the patient's weight in kg would estimate the contribution of that factor to bleeding. Factors were ranked from most to least impact on bleeding. Conversely, said ES would estimate the decrease in bleeding achieved by a percentage increase in a deficient factor level if such factor was known to be deficient. Results: F:II was 1st (most associated with bleeding), ES = -0.137, 95% CI -0.214 - -0.059, p < 0.001; F:X was 2nd, ES = -0.130, 95% CI -0.202 - -0.058, p < 0.001; F:VII ES = -0.121, 95% CI -0.198 - -0.045, p = 0.002; F:XI ES = -0.109, 95% CI -0.16 - -0.058, p < 0.001; F:IX ES = -0.100; 95% CI -0.135 - -0.065, p < 0.001; F:V ES = - 0.065; 95% CI -0.114 - -0.016, p = 0.011; F:XIII ES = - 0.055; 95% CI -0.099 - -0.011, p = 0.016; FIB ES = - 0.042; 95% CI -0.063 - -0.022, p < 0.001; F:VIII ES = - 0.007; 95% CI -0.020 - 0.006, p = 0.318; VWF Ag ES = 0.002; 95% CI -0.016 - 0.019, p = 0.855; VWF Activity ES = 0.004; 95% CI -0.015 - 0.023, p = 0.671. Conclusions: Factors VIII, VWF Ag and Ristocetin Cofactor demonstrated no relationship with bleeding, perhaps because they are elevated as acute-phase reactants. In theory, raising F:II level post-CPB by 30% in an 80 kg patient might decrease bleeding by 328 ml, and raising F:X level post-CPB by 30% in an 80 kg patient might decrease bleeding by 312 ml, etc. A weakness of this study is that the sample size was too small to perform a multi-variate analysis considering all factor levels. Still, the data suggest four-factor prothrombin complex concentrate (PCC) might be a more effective treatment for post-CPB coagulopathy than FFP. The data do not confirm cause and effect; that would require a large study with control and treatment arms. If multiple factor levels could be measured in a rapid and cost-effective manner it might aid in targeted treatment of post-CPB coagulopathy. The data suggest that work should be performed to better elucidate the contribution of coagulation factor deficiencies to post-CPB bleeding, as improved treatment of such factor deficiencies might decrease bleeding and transfusion requirements.
2024-07-23 | Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency-A large single-centre experience.
Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management. A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records. A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years. FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.
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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.
2025-02-28 | Gene therapy for hemophilia: Recent developments and challenges (Review)
Hemophilia is an X‑linked disease marked by the absence or impaired function of specific coagulation factors. Hemophilia A is characterized by a deficiency in factor VIII, and hemophilia B is characterized by a deficiency in factor IX. Factor XI deficiency, referred to as hemophilia C, is a very uncommon bleeding illness characterized by moderate symptoms; although the condition is not widespread, standard management poses significant challenges linked to socioeconomic factors. The introduction of FDA‑approved gene therapy for hemophilia B in 2022 holds transformative potential; however, certain issues demand careful consideration. The present review provides insight into the existing hemophilia landscape, discusses the latest strides in gene therapy for hemophilia, and examines the hurdles that need to be addressed to make this innovative treatment more accessible to individuals afflicted by this condition.
2024-03-07 | Next-generation strategies to improve safety and efficacy of adeno-associated virus-based gene therapy for hemophilia: lessons from clinical trials in other gene therapies
Three major directions for the global progress of adeno-associated virus (AAV) vectors for gene therapies (GT) are analyzed: a) engineering vectors to increase transgene expression; b) aligning interests of the health system with costs and challenges for pharmaceutical industry; c) refining patient eligibility criteria, and endpoints definition. Currently employed AAV vectors may cause toxicity and adverse events. Furthermore, studies in animals do not fully predict risks and clinical benefits of AAV-based GT, and animal models reflecting the heterogeneity of certain clinical settings (e.g., congestive heart failure) are poorly available for improving AAV-based GT. Finally, antisense and gene editing approaches will soon complement gene augmentation strategies for the stable solution of unsolved issues of AAV-based GT. While minimizing toxicity, next-generation AAV vectors should decrease the viral load needed to achieve therapeutic efficacy; be functional in a restricted cellular subset; avoid transgene expression in unwanted cells (e.g., hepatocytes), and escape immune oversight in AAV-based GT. The role of stress-induced apoptosis in the loss of transgene expression in GT should be also explored. Aligning interests and obligations of pharmaceutical industry with those of the health system is critical for AAV-based GT success. Costs and challenges for pharmaceutical industry include a) removing impurities from AAV; b) validating tests to measure treatment efficacy, c) promoting training programs to standardize vector genomes delivery, d) collecting long-term follow-up data, and e) maintaining sustainability and cost-effectiveness of AAV-based GT. In rare disorders with small patient numbers (e.g., hemophilia), clearcut outcomes are mandatory as endpoints of unequivocal efficacy data.
2016-04-29 | Gene Therapy for Coagulation Disorders
Molecular genetic details of the human coagulation system were among the first successes of the genetic revolution in the 1980s. This information led to new molecular diagnostic strategies for inherited disorders of hemostasis and the development of recombinant clotting factors for the treatment of the common inherited bleeding disorders. A longer term goal of this knowledge has been the establishment of gene transfer to provide continuing access to missing or defective hemostatic proteins. Because of the relative infrequency of inherited coagulation factor disorders and the availability of safe and effective alternative means of management, the application of gene therapy for these conditions has been slow to realize clinical application. Nevertheless, the tools for effective and safe gene transfer are now much improved, and we have started to see examples of clinical gene therapy successes. Leading the way has been the use of adeno-associated virus-based strategies for factor IX gene transfer in hemophilia B. Several small phase 1/2 clinical studies using this approach have shown prolonged expression of therapeutically beneficial levels of factor IX. Nevertheless, before the application of gene therapy for coagulation disorders becomes widespread, several obstacles need to be overcome. Immunologic responses to the vector and transgenic protein need to be mitigated, and production strategies for clinical grade vectors require enhancements. There is little doubt that with the development of more efficient and facile strategies for genome editing and the application of other nucleic acid-based approaches to influence the coagulation system, the future of genetic therapies for hemostasis is bright.
1999-02-22 | Defective vaccinia virus as a biologically safe tool for the overproduction of recombinant human secretory proteins.
We have described recently the construction of a defective vaccinia virus (VV) lacking the essential D4R open reading frame and have shown furthermore the selection of a complementing cell line providing the essential D4R gene product. The D4R gene belongs to the group of early transcribed vaccinia genes preventing a virus defective in D4R from entering into the intermediate and late phase of replication under noncomplementing conditions. Here we show that this property, which is unique among the group of so called nonreplicating poxviruses, is helpful for the production of (secretable) recombinant human proteins. Recombinant VV based on a D4R-defective parental strain expressing cDNAs coding for the human blood coagulation factors VII and XI produced significantly more recombinant protein than the corresponding recombinants based on wild-type VV. Moreover, the complementing cell line RK-D4R-44.20 was a more effective production cell system for both vD4 and wild-type VV recombinants compared to wild-type RK-13 cells. Surprisingly, recombinant human factor VII was more efficiently produced with the defective vaccinia recombinant even under noncomplementing conditions, suggesting that persistence of the early phase of vaccinia replication in combination with a delayed host shutoff is advantageous for the overproduction of certain recombinant proteins using the VV expression system.
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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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