RESUMEN
ABSTRACT: Unique among coagulation factors, the coagulation factor XI (FXI) arose through a duplication of the gene KLKB1, which encodes plasma prekallikrein. This evolutionary origin sets FXI apart structurally because it is a homodimer with 2 identical subunits composed of 4 apple and 1 catalytic domain. Each domain exhibits unique affinities for binding partners within the coagulation cascade, regulating the conversion of FXI to a serine protease as well as the selectivity of substrates cleaved by the active form of FXI. Beyond serving as the molecular nexus for the extrinsic and contact pathways to propagate thrombin generation by way of activating FIX, the function of FXI extends to contribute to barrier function, platelet activation, inflammation, and the immune response. Herein, we critically review the current understanding of the molecular biology of FXI, touching on some functional consequences at the cell, tissue, and organ level. We conclude each section by highlighting the DNA mutations within each domain that present as FXI deficiency. Together, a narrative review of the structure-function of the domains of FXI is imperative to understand the etiology of hemophilia C as well as to identify regions of FXI to safely inhibit the pathological function of activation or activity of FXI without compromising the physiologic role of FXI.
Asunto(s)
Deficiencia del Factor XI , Factor XI , Humanos , Factor XI/genética , Deficiencia del Factor XI/genética , Coagulación Sanguínea/genética , Dominio Catalítico , Trombina/metabolismo , BiologíaRESUMEN
ABSTRACT: Direct oral anticoagulants (DOACs) that inhibit the coagulation proteases thrombin or factor Xa (FXa) have replaced warfarin and other vitamin K antagonists (VKAs) for most indications requiring long-term anticoagulation. In many clinical situations, DOACs are as effective as VKAs, cause less bleeding, and do not require laboratory monitoring. However, because DOACs target proteases that are required for hemostasis, their use increases the risk of serious bleeding. Concerns over therapy-related bleeding undoubtedly contribute to undertreatment of many patients who would benefit from anticoagulation therapy. There is considerable interest in the plasma zymogen factor XI (FXI) and its protease form factor XIa (FXIa) as drug targets for treating and preventing thrombosis. Laboratory and epidemiologic studies support the conclusion that FXI contributes to venous and arterial thrombosis. Based on 70 years of clinical observations of patients lacking FXI, it is anticipated that drugs targeting this protein will cause less severe bleeding than warfarin or DOACs. In phase 2 studies, drugs that inhibit FXI or FXIa prevent venous thromboembolism after total knee arthroplasty as well as, or better than, low molecular weight heparin. Patients with heart disease on FXI or FXIa inhibitors experienced less bleeding than patients taking DOACs. Based on these early results, phase 3 trials have been initiated that compare drugs targeting FXI and FXIa to standard treatments or placebo. Here, we review the contributions of FXI to normal and abnormal coagulation and discuss results from preclinical, nonclinical, and clinical studies of FXI and FXIa inhibitors.
Asunto(s)
Factor XI , Trombosis , Humanos , Factor XIa/farmacología , Warfarina/uso terapéutico , Warfarina/farmacología , Trombosis/tratamiento farmacológico , Trombosis/etiología , Trombosis/prevención & control , Coagulación Sanguínea , Anticoagulantes/efectos adversos , Hemorragia/inducido químicamente , Fibrinolíticos/uso terapéuticoRESUMEN
ABSTRACT: 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.
Asunto(s)
Trastornos de la Coagulación Sanguínea , Deficiencia del Factor XI , Trombosis , Embarazo , Femenino , Recién Nacido , Humanos , Deficiencia del Factor XI/complicaciones , Deficiencia del Factor XI/diagnóstico , Deficiencia del Factor XI/terapia , Hemorragia/etiología , Hemorragia/complicaciones , Trastornos de la Coagulación Sanguínea/complicaciones , Trombosis/complicaciones , Medición de Riesgo , Factor XIRESUMEN
BACKGROUND: Despite the ubiquitous utilization of central venous catheters in clinical practice, their use commonly provokes thromboembolism. No prophylactic strategy has shown sufficient efficacy to justify routine use. Coagulation factors FXI (factor XI) and FXII (factor XII) represent novel targets for device-associated thrombosis, which may mitigate bleeding risk. Our objective was to evaluate the safety and efficacy of an anti-FXI mAb (monoclonal antibody), gruticibart (AB023), in a prospective, single-arm study of patients with cancer receiving central line placement. METHODS: We enrolled ambulatory cancer patients undergoing central line placement to receive a single dose of gruticibart (2 mg/kg) administered through the venous catheter within 24 hours of placement and a follow-up surveillance ultrasound at day 14 for evaluation of catheter thrombosis. A parallel, noninterventional study was used as a comparator. RESULTS: In total, 22 subjects (n=11 per study) were enrolled. The overall incidence of catheter-associated thrombosis was 12.5% in the interventional study and 40.0% in the control study. The anti-FXI mAb, gruticibart, significantly prolonged the activated partial thromboplastin time in all subjects on day 14 compared with baseline (P<0.001). Gruticibart was well tolerated and without infusion reactions, drug-related adverse events, or clinically relevant bleeding. Platelet flow cytometry demonstrated no difference in platelet activation following administration of gruticibart. T (thrombin)-AT (antithrombin) and activated FXI-AT complexes increased following central line placement in the control study, which was not demonstrated in our intervention study. CRP (C-reactive protein) did not significantly increase on day 14 in those who received gruticibart, but it did significantly increase in the noninterventional study. CONCLUSIONS: FXI inhibition with gruticibart was well tolerated without any significant adverse or bleeding-related events and resulted in a lower incidence of catheter-associated thrombosis on surveillance ultrasound compared with the published literature and our internal control study. These findings suggest that targeting FXI could represent a safe intervention to prevent catheter thrombosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465760.
Asunto(s)
Neoplasias , Trombosis , Humanos , Factor XI/metabolismo , Estudios Prospectivos , Trombosis/etiología , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , Hemorragia/inducido químicamente , Catéteres/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/complicacionesRESUMEN
PURPOSE OF REVIEW: This review summarizes the pathophysiology and potential therapeutic options for treatment of multiple sclerosis, a common neuronal demyelinating disorder affecting 2.2 million people worldwide. As an autoimmune disorder, multiple sclerosis is associated with neuroinflammation and increased permeability of the blood-brain barrier (BBB), although the cause linking multiple sclerosis with compromised barrier function remains ill-defined. It has been previously shown that coagulation factors, including thrombin and fibrin, exacerbate the inflammatory processes and permeability of the BBB. RECENT FINDINGS: Increased levels of the coagulation factor (F) XII have been found in patients presenting with relapsing-remitting multiple sclerosis, with a deleterious role for FXII being validated in murine model of multiple sclerosis, experimental autoimmune encephalitis (EAE). Recent work has uncovered a role for the major substrate activated by FXII and thrombin, FXI, in the disorder of EAE. The study found that pharmacological targeting of FXI decreased clinical symptoms, lymphocyte invasion, and white matter destruction in a multiple sclerosis model. SUMMARY: This review emphasizes the role of FXII and FXI in regulating barrier function and the immune response in neuroinflammation. These new findings broaden the potential for therapeutic utility of FXI inhibitors beyond thrombosis to include neuroinflammatory diseases associated with compromised BBB function, including multiple sclerosis.
Asunto(s)
Factor XI , Esclerosis Múltiple , Humanos , Animales , Ratones , Factor XII , Enfermedades Neuroinflamatorias , Trombina , Esclerosis Múltiple/tratamiento farmacológicoRESUMEN
Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.
Asunto(s)
Accidente Cerebrovascular , Trombosis , Tromboembolia Venosa , Humanos , Factor XI , Anticoagulantes/efectos adversos , Tromboembolia Venosa/tratamiento farmacológico , Coagulación Sanguínea , Trombosis/tratamiento farmacológico , Trombosis/prevención & control , Hemorragia/etiología , Accidente Cerebrovascular/tratamiento farmacológicoRESUMEN
Chronic hemodialysis patients exhibit an excessive cardiovascular risk and a marked increase in both thromboembolism and bleeding episodes. Factor XI inhibition may provide anticoagulation, with a low risk of bleeding, and several factor XI inhibitors, including fesomersen, an antisense oligonucleotide, are under development. Recently, a phase 2 study of fesomersen showed a good safety profile in chronic hemodialysis patients and suggested that clotting rates of the arteriovenous fistula and the dialysis circuit are lower.
Asunto(s)
Anticoagulantes , Factor XI , Hemorragia , Diálisis Renal , Humanos , Diálisis Renal/efectos adversos , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Factor XI/antagonistas & inhibidores , Factor XI/metabolismo , Coagulación Sanguínea/efectos de los fármacos , Oligonucleótidos Antisentido/uso terapéutico , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/administración & dosificación , Tromboembolia/prevención & control , Tromboembolia/etiología , Derivación Arteriovenosa Quirúrgica/efectos adversosRESUMEN
Patients with kidney failure on hemodialysis (KF-HD) are at high risk for both atherothrombotic events and bleeding. This Phase IIb study evaluated the dose-response of fesomersen, an inhibitor of hepatic Factor XI expression, versus placebo, for bleeding and atherothrombosis in patients with KF-HD. Patients were randomized to receive fesomersen 40, 80, or 120 mg once-monthly, or matching placebo, for up to 12 months. The primary safety endpoint was a composite of major bleeding and clinically relevant non-major bleeding (MB/CRNMB). Exploratory endpoints included post-dialysis arterio-venous (AV)-access bleeding, major atherothrombotic events (composite of fatal or non-fatal myocardial infarction, ischemic stroke, acute limb ischemia/major amputation, systemic embolism, symptomatic venous thromboembolism), AV-access thrombosis, and clotting of the hemodialysis circuit. Of 308 participants randomized, 307 received study treatment and were analyzed. Fesomersen led to a dose-dependent and sustained reduction of steady-state median FXI levels by 53.6% (40 mg group), 71.3% (80 mg group), 86.0% (120 mg group), versus 1.9% in the placebo group. MB/CRNMB events occurred in 6.5% (40 mg group), 5.1% (80 mg group), 3.9% (120 mg group), and in 4.0% of those receiving placebo (pooled fesomersen versus placebo P = 0.78). Major atherothrombotic events occurred in 1 patient (1.3%) in each treatment arm. MB/CRNMB bleeding and post-dialysis AV-access bleeding were not related to predicted FXI levels. Lower predicted FXI levels were associated with reductions in hemodialysis circuit clotting (P = 0.002) and AV-access thrombosis (P = 0.014). In patients with KF-HD, fesomersen produced a dose-dependent reduction in FXI levels associated with similar rates of major bleeding compared with placebo. REGISTRATION: URL: https://www.clinicaltrials.gov; unique identifier: NCT04534114.
Asunto(s)
Factor XI , Fibrinolíticos , Hemorragia , Diálisis Renal , Trombosis , Humanos , Diálisis Renal/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Factor XI/antagonistas & inhibidores , Factor XI/metabolismo , Fibrinolíticos/efectos adversos , Fibrinolíticos/administración & dosificación , Hemorragia/inducido químicamente , Hemorragia/etiología , Trombosis/etiología , Trombosis/prevención & control , Trombosis/sangre , Método Doble Ciego , Resultado del Tratamiento , Oligonucleótidos/efectos adversos , Oligonucleótidos/administración & dosificación , Oligonucleótidos/uso terapéutico , Fallo Renal Crónico/terapia , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/sangre , Fallo Renal Crónico/diagnóstico , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation. METHODS: In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery. RESULTS: Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group. CONCLUSIONS: This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Anthos Therapeutics; ANT-005 TKA EudraCT number, 2019-003756-37.).
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticoagulantes/uso terapéutico , Artroplastia de Reemplazo de Rodilla , Enoxaparina/uso terapéutico , Factor XI/antagonistas & inhibidores , Complicaciones Posoperatorias/prevención & control , Tromboembolia Venosa/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Relación Dosis-Respuesta a Droga , Enoxaparina/efectos adversos , Factor XI/metabolismo , Femenino , Hemorragia/inducido químicamente , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina ParcialRESUMEN
BACKGROUND: Elevated factor XI (FXI) has been shown to predispose to thromboembolism. We investigated whether it is associated with left ventricular thrombus (LVT) formation, its recurrence and subsequent thromboembolic events. METHODS: In 54 patients with prior LVT of unknown origin, who stopped anticoagulation and 54 controls, we determined FXI, along with plasma clot permeability (Ks), fibrinolysis time (CLT), endogenous thrombin potential (ETP), von Willebrand factor (vWF) and fibrinolysis proteins. During follow-up, the primary endpoint involving the recurrence of LVT a symptomatic ischemic stroke or systemic embolism was recorded. RESULTS: Elevated (>120%) FXI levels were more often observed in LVT patients when compared to the control group (14 [25.9%] vs. 6 [11.1%], p = .048) in association with the presence of active FXI. FXI correlated with age (r = .406, p = .002), Ks (r = -.542, p < .001) and CLT (r = .406, p = .002), also after adjustment for age, but not with ETP, vWF or fibrinolysis proteins. During follow-up of 77.6 ± 18.5 months the primary endpoint occurred in 17 (31.5%) LVT patients, including 11 (20.4%) recurrent LVT, and in 4 (7.4%) controls (annual incidence rate 4.9% vs. 1.1%, respectively; p = .002). On multivariate logistic regression analysis, elevated FXI was independently associated with the primary endpoint (OR 1.18; 95% CI 1.09-1.28). CONCLUSIONS: Elevated FXI in association with a prothrombotic state characterizes patients with prior LVT of unknown origin and predisposes to its recurrence and/or ischemic stroke during follow-up. It might be speculated that the measurement of FXI helps identify patients who could benefit from prolonged anticoagulation and FXI inhibitors in the future.
Asunto(s)
Factor XI , Ventrículos Cardíacos , Recurrencia , Trombosis , Humanos , Femenino , Factor XI/metabolismo , Masculino , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Cardiopatías/sangre , Factor de von Willebrand/metabolismo , Accidente Cerebrovascular Isquémico/epidemiología , Tiempo de Lisis del Coágulo de FibrinaRESUMEN
FXI (factor XI) and FXII (factor XII) have emerged as targets for new anticoagulants that have the potential to be both more efficacious and safer than the currently available direct oral anticoagulants for the prevention and treatment of venous thromboembolism. In this review, we discuss the role of FXI and FXII in the pathogenesis of venous thromboembolism, explain why FXI is a better target, and explain why FXI inhibitors have potential advantages over currently available anticoagulants. Finally, we describe the FXI inhibitors under development and discuss their potential to address unmet needs in venous thromboembolism management.
Asunto(s)
Trombosis , Tromboembolia Venosa , Humanos , Factor XI , Coagulación Sanguínea , Trombosis/tratamiento farmacológico , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/prevención & control , Anticoagulantes/efectos adversos , Factor XIIRESUMEN
During the past decade, direct oral anticoagulants (DOACs) have advanced and simplified the prevention and treatment of venous thromboembolism (VTE). However, there remains a high incidence of bleeds, which calls for agents that have a reduced risk of bleeding. Factor XI (FXI) deficiency is associated with lower rates of venous thrombosis and stroke compared to the general population with a lower risk of bleeding. In conjunction with this, phase 2 studies have demonstrated safety and the potential for reduced thrombotic events with FXI inhibitors as compared to currently available medications. The aim of this review is to summarize key data on the clinical pharmacology of FXI, the latest developments in clinical trials of FXI inhibitors, and to describe the efficacy and safety profiles of FXI inhibitors for the prevention of venous and arterial thromboembolism.
Asunto(s)
Tromboembolia Venosa , Trombosis de la Vena , Humanos , Anticoagulantes/efectos adversos , Factor XI/uso terapéutico , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/tratamiento farmacológico , Trombosis de la Vena/prevención & control , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/prevención & controlRESUMEN
Direct oral anticoagulants (DOACs) revolutionized the management of thromboembolic disorders. Clinical care may be further improved as Factor XIs undergo large-scale outcome trials. What role can non-randomized database studies play in expediting understanding of these drugs in clinical practice? The RCT-DUPLICATIVE Initiative emulated the design of eight DOAC randomized clinical trials (RCT) using non-randomized claims database studies. RCT study design parameters and measurements were closely emulated by the database studies and produced highly concordant results. The results of the single database study that did not meet all agreement metrics with the specific RCT it was emulating were aligned with a meta-analysis of six trials studying similar questions, suggesting the trial result was an outlier. Well-designed database studies using fit-for-purpose data came to the same conclusions as DOAC trials, illustrating how database studies could complement RCTs for Factor XI inhibitors-by accelerating insights in underrepresented populations, demonstrating effectiveness and safety in clinical practice, and testing broader indications.
Asunto(s)
Anticoagulantes , Bases de Datos Factuales , Factor XI , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Anticoagulantes/uso terapéutico , Factor XI/antagonistas & inhibidores , Proyectos de Investigación , Tromboembolia/prevención & control , Tromboembolia/tratamiento farmacológicoRESUMEN
Cerebral venous sinus thrombosis (CVST) has no identified cause in 15% of cases. Elevated factors (F) VIII and FXI have been associated with thromboembolism, but data on CVST are limited. We hypothesized that elevated plasma FVIII and FXI predispose to first and recurrent CVST. In 50 CVST survivors aged < 60 years, following anticoagulant cessation and in 50 controls, we determined plasma FVIII and FXI, along with fibrin clot properties: lysis time, permeability, maximum D-dimer (D-Dmax), and maximum rate of D-dimer increase (D-Drate). We recorded CVST recurrence during a follow-up of 58.5 (55.0-60.0) months. Plasma FVIII was 22.7% higher in CVST than in controls, with elevated FVIII > 150% in 13 (26%) vs. 4 (8%) patients, respectively (p = 0.02). Median FXI tended to be higher in CVST vs. controls (110.5 [99.0-117-0]% vs. 104.5 [97.0-116.0]%, p = 0.07), while FXI > 120% was observed more commonly in the former group (12 [24%] vs. 4 [8%], respectively, p = 0.03). Patients with FVIII > 150% were less likely to achieve complete recanalization compared with the remainder (2 [15.4%] vs. 28 [75.7%], respectively; p < 0.001). Eight patients (16%) experienced CVST recurrence. They had higher baseline FXI, but not FVIII, as compared with the remainder (125.5 [114.5-140.0]% vs. 107.5 [102.0-117.0]%, respectively, p = 0.01). Patients with FXI > 120% were four times more likely to have recurrent CVST (5 [62.5%] vs. 7 [16.7%], respectively; p = 0.01). Plasma FXI > 120% could represent a novel risk factor for first and recurrent CVST. Given advances in anti-FXI agents, CVST might be another indication for this emerging treatment.
Asunto(s)
Factor XI , Trombosis de los Senos Intracraneales , Humanos , Estudios de Cohortes , Factores de Riesgo , Fibrina , Trombosis de los Senos Intracraneales/etiologíaRESUMEN
Kallikrein (PKa), generated by activation of its precursor prekallikrein (PK), plays a role in the contact activation phase of coagulation and functions in the kallikrein-kinin system to generate bradykinin. The general dogma has been that the contribution of PKa to the coagulation cascade is dependent on its action on FXII. Recently this dogma has been challenged by studies in human plasma showing thrombin generation due to PKa activity on FIX and also by murine studies showing formation of FIXa-antithrombin complexes in FXI deficient mice. In this study, we demonstrate high-affinity binding interactions between PK(a) and FIX(a) using surface plasmon resonance and show that these interactions are likely to occur under physiological conditions. Furthermore, we directly demonstrate dose- and time-dependent cleavage of FIX by PKa in a purified system by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis and chromogenic assays. By using normal pooled plasma and a range of coagulation factor-deficient plasmas, we show that this action of PKa on FIX not only results in thrombin generation, but also promotes fibrin formation in the absence of FXII or FXI. Comparison of the kinetics of either FXIa- or PKa-induced activation of FIX suggest that PKa could be a significant physiological activator of FIX. Our data indicate that the coagulation cascade needs to be redefined to indicate that PKa can directly activate FIX. The circumstances that drive PKa substrate specificity remain to be determined.
Asunto(s)
Bradiquinina/metabolismo , Factor IX/metabolismo , Factor XII/metabolismo , Fibrina/metabolismo , Calicreínas/metabolismo , Trombina/metabolismo , Coagulación Sanguínea/fisiología , Bradiquinina/química , Calcio/química , Calcio/metabolismo , Cationes Bivalentes , Factor IX/química , Factor XI/química , Factor XI/metabolismo , Factor XII/química , Fibrina/química , Humanos , Calicreínas/química , Cinética , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/metabolismo , Fosfatidilserinas/química , Fosfatidilserinas/metabolismo , Unión Proteica , Trombina/químicaRESUMEN
Anticoagulants are the cornerstone for prevention and treatment of thrombosis but are not completely effective, and concerns about the risk of bleeding continue to limit their uptake. Animal studies and experience from patients with genetic coagulation factor XI deficiency suggesting that this factor is more important for thrombosis than for haemostasis raises the potential for drugs that target factor XI to provide safer anticoagulation. Multiple factor XI inhibitors are currently under evaluation in clinical trials, including parenterally administered antisense oligonucleotides, monoclonal antibodies, and orally active small-molecule inhibitors. Promising results of phase 2 trials in patients undergoing major orthopaedic surgery, and in those with end-stage kidney disease, atrial fibrillation and acute coronary syndromes have led to large phase 3 trials that are currently ongoing. We here review premises for the use of these agents, results so far accrued, ongoing studies, and perspectives for future patient care.
Asunto(s)
Factor XI , Trombosis , Animales , Anticoagulantes/uso terapéutico , Coagulación Sanguínea , Factor XI/genética , Factor XI/farmacología , Factor XI/uso terapéutico , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Trombosis/prevención & control , Trombosis/tratamiento farmacológico , HumanosRESUMEN
Skeletal muscle myosin (SkM) has been shown to possess procoagulant activity; however, the mechanisms of this coagulation-enhancing activity involving plasma coagulation pathways and factors are incompletely understood. Here, we discovered direct interactions between immobilized SkM and coagulation factor XI (FXI) using biolayer interferometry (Kd = 0.2 nM). In contrast, we show that prekallikrein, a FXI homolog, did not bind to SkM, reflecting the specificity of SkM for FXI binding. We also found that the anti-FXI monoclonal antibody, mAb 1A6, which recognizes the Apple (A) 3 domain of FXI, potently inhibited binding of FXI to immobilized SkM, implying that SkM binds FXI A3 domain. In addition, we show that SkM enhanced FXI activation by thrombin in a concentration-dependent manner. We further used recombinant FXI chimeric proteins in which each of the four A domains of the heavy chain (designated A1 through A4) was individually replaced with the corresponding A domain from prekallikrein to investigate SkM-mediated enhancement of thrombin-induced FXI activation. These results indicated that activation of two FXI chimeras with substitutions of either the A3 domains or A4 domains was not enhanced by SkM, whereas substitution of the A2 domain did not reduce the thrombin-induced activation compared with wildtype FXI. These data strongly suggest that functional interaction sites on FXI for SkM involve the A3 and A4 domains. Thus, this study is the first to reveal and support the novel intrinsic blood coagulation pathway concept that the procoagulant mechanisms of SkM include FXI binding and enhancement of FXI activation by thrombin.
Asunto(s)
Coagulación Sanguínea , Factor XI , Miosinas del Músculo Esquelético , Trombina , Anticuerpos Monoclonales/química , Sitios de Unión , Factor XI/química , Factor XI/genética , Factor XI/metabolismo , Precalicreína/química , Precalicreína/metabolismo , Dominios Proteicos , Proteínas Recombinantes de Fusión/química , Miosinas del Músculo Esquelético/metabolismo , Trombina/metabolismoRESUMEN
Mammalian plasma kallikrein (PK) and coagulation factor XI (fXI) are serine proteases that play in the kinin-kallikrein cascade and in the blood clotting pathway. These proteases share sequence homology and have four apple domains (APDs) and a serine protease domain (SPD) from their N-terminus to C-terminus. No homologs of these proteases are believed to be present in fish species, except for lobe-finned fish. Fish, however, have a unique lectin, named kalliklectin (KL), which is composed of APDs only. In the present study, we found genomic sequences encoding a protein with both APDs and SPD in a few cartilaginous and bony fishes, including the channel catfish Ictalurus punctatus, using bioinformatic analysis. Furthermore, we purified two ~ 70 kDa proteins from the blood plasma of the catfish using mannose-affinity and gel filtration chromatography sequentially. Using de novo sequencing with quadrupole time-of-flight tandem mass spectrometry, several internal amino acid sequences in these proteins were mapped onto possible PK/fXI-like sequences that are thought to be splicing variants. Exploration of APD-containing proteins in the hagfish genome database and phylogenetic analysis suggested that the PK/fXI-like gene originated from hepatocyte growth factor, and that the gene was acquired in a common ancestor of jawed fish. Synteny analysis provided evidence for chromosomal translocation around the PK/fXI-like locus that occurred in the common ancestor of holosteans and teleosts after separation from the lobe-finned fish lineage, or gene duplication into two chromosomes, followed by independent gene losses. This is the first identification of PK/fXI-like proteins in teleosts.
Asunto(s)
Ictaluridae , Calicreína Plasmática , Animales , Ictaluridae/genética , Lectinas , Factor XI/genética , Factor XI/química , Filogenia , MamíferosRESUMEN
Cancer-associated thrombosis, with the incidence rising over the years, is associated with significant morbidity and mortality in patients with cancer. Recent advances in the treatment of cancer-associated venous thromboembolism (VTE) include the introduction of direct oral anticoagulants (DOACs), which provide a more convenient and effective option than low-molecular-weight heparin (LMWH). Nonetheless, important unmet needs remain including an increased risk of bleeding in certain patient subgroups such as those with gastroesophageal cancer, concerns about drug-drug interactions, and management of patients with severe renal impairment. Although DOACs are more convenient than LMWH, persistence can decline over time. Factor XI inhibitors have potential safety advantages over DOACs because factor XI appears to be essential for thrombosis but not hemostasis. In phase II trials, some factor XI inhibitors were superior to enoxaparin for the prevention of VTE after knee replacement surgery without increasing the risk of bleeding. Ongoing trials are assessing the efficacy and safety of factor XI inhibitors for the treatment of cancer-associated VTE.
Asunto(s)
Neoplasias , Trombosis , Tromboembolia Venosa , Humanos , Heparina de Bajo-Peso-Molecular/efectos adversos , Anticoagulantes , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/etiología , Tromboembolia Venosa/prevención & control , Factor XI/uso terapéutico , Trombosis/etiología , Trombosis/complicaciones , Hemorragia/inducido químicamente , Hemorragia/complicaciones , Hemorragia/tratamiento farmacológico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológicoRESUMEN
OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.