Factor XI and coagulation. Factor XI inhibitors - antithrombotic perspectives.

Factor XI is a zymogen with an important role in the coagulation cascade. It is activated by FXII, thrombin and or it can be autoactivated. It has a prothrombotic effect after being activated by thrombin, but also through its antifibrinolytic action, stabilizing the formed clot. Hereditary deficiency of FXI causes haemophilia C - a disease manifested by an usually provoked, small to moderate mucosal bleeding. People with severe FXI deficiency have a low risk of thrombotic events. Conversely, increased FXI values have been found to be associated with increased risk of venous thromboembolism and ischemic stroke. Lowering serum FXI levels has become a treatment target for the prevention of thrombotic events. New pharmacological agents - FXI inhibitors - have been investigated in phase II clinical trials, with promising results in terms of efficacy and safety in the prevention of thrombotic events. FXI inhibitors are emerging as new anticoagulant agents with broad indication prospects beyond direct oral anticoagulants and vitamin K antagonists.

A proposal for managing bleeding in patients on therapeutic factor XI(a) inhibitors.

Several drugs that reduce functional levels of the plasma protease zymogen factor XI (FXI), or that inhibit its activated form (FXIa), are being evaluated as treatments to prevent thrombosis. Based on the observation that individuals with inherited FXI deficiency have a relatively mild bleeding disorder, it is anticipated that therapeutic FXI(a) inhibitors will have a smaller impact on hemostasis than anticoagulants targeting thrombin or factor Xa. However, even if FXI(a) inhibitors are determined to be safer than currently used anticoagulants, some patients on these drugs will experience abnormal bleeding or require emergent surgery. Strategies for dealing with such situations are required. Treatment with antifibrinolytic agents and low doses of recombinant factor VIIa effectively prevent abnormal bleeding in FXI-deficient patients with alloantibody inhibitors to FXI who undergo surgery. We propose that a similar strategy can be used for patients on therapeutic FXI(a) inhibitors who are bleeding or require invasive procedures.

Anticoagulant therapy in patients with congenital FXI deficiency.

The bleeding phenotype of factor XI (FXI) deficiency is unpredictable. Bleeding is usually mild and mostly occurs after injury. Although FXI deficiency renders antithrombotic protection, some patients might eventually develop thrombosis or atrial fibrillation, requiring anticoagulant therapy. There is almost no evidence on the bleeding risk in this scenario. Our retrospective study of 269 white FXI-deficient subjects (1995-2021) identified 15 cases requiring anticoagulation. They harbored 8 different F11 variants, mainly in heterozygosis (1 case was homozygote), and had mild to moderate deficiency (FXI:C: 20% to 70%). Two subjects (13.3%) had bleeding history before anticoagulation. Atrial fibrillation was the main indication (12/15; 80%). Fourteen patients started therapy with vitamin K antagonists (VKA), but 4 subjects were on direct oral anticoagulants (DOACs) at the end of follow-up. Over >1000 months of anticoagulation, 2 mild bleeding episodes in 2 patients (13.3%, 95% confidence interval: 3.7% to 37.9%) were recorded. No major/fatal events were reported. "Pre-post" bleeding localization and severity did not change despite treatment. On VKA, drug dosing and management were also standard, unaltered by FXI deficiency. We provide the largest description of anticoagulant use in FXI deficiency, and the first cases receiving DOACs. Although further studies are needed, our observations suggest that moderate FXI deficiency does not interfere with anticoagulant management nor bleeding risk.

Gynaecological and obstetrical bleeding in Caucasian women with congenital factor XI deficiency: Results from a twenty-year, retrospective, observational study.

INTRODUCTION: Factor XI (FXI) deficiency is a mild bleeding disorder, common among Ashkenazis, that may be underestimated in Caucasians. Management of FXI deficiency in women is a challenge, due to its unpredictable bleeding tendency and the little evidence available on this issue. OBJECTIVE: To describe gynaecological/obstetrical bleeding complications and to analyze the effectiveness and safety of the antihaemorrhagic treatment among women with FXI deficiency. MATERIAL AND METHODS: A retrospective, observational study of 214 Caucasian subjects with FXI deficiency collected during 20 years (1994-2014) without clinical selection. RESULTS: We identified 95 women with FXI deficiency. Any haemorrhagic event was communicated by 26/95 (27.4%), being abnormal uterine bleeding the most frequently found (12/95, 12.6%). Nine postpartum haemorrhages were recorded from 136 deliveries (6.6%) in 57 women. Four postsurgical bleeding complications were registered among 25 gynaecological surgeries (16%) in 20 women. Abnormal uterine bleeding, postpartum and postsurgical haemorrhages were related to both a positive bleeding history and FXI:C values ≤43.5%. Prophylaxis with fresh frozen plasma, used in 12/25 (48%) gynaecological surgeries, did not prevent from postoperative bleeding in three cases, but two developed severe adverse reactions. CONCLUSION: Women with FXI deficiency, especially those with a positive history of bleeding or FXI:C ≤43.5%, are at risk of developing gynaecological/obstetrical haemorrhages, most of them mild/moderate. Systematic prophylaxis has questionable effectiveness, but might cause severe side effects.

Factor XI promotes hemostasis in factor IX-deficient mice.

Essentials Mice lacking factor IX (FIX) or factor XI (FXI) were tested in a saphenous vein bleeding model. FIX-deficient mice displayed a hemostatic defect and FXI-deficient mice were similar to wild type mice. Infusion of FXI or over-expression of FXI in FIX-deficient mice improved hemostasis. FXI may affect the phenotype of FIX-deficiency (hemophilia B). SUMMARY: Background In humans, deficiency of coagulation factor XI may be associated with a bleeding disorder, but, until recently, FXI-deficient mice did not appear to have a hemostatic abnormality. A recent study, however, indicated that FXI-deficient mice show a moderate hemostatic defect in a saphenous vein bleeding (SVB) model. Objectives To study the effect of FXI on bleeding in mice with normal levels of the FXI substrate FIX and in mice lacking FIX (a murine model of hemophilia B). Methods Wild-type mice and mice lacking either FIX (F9- ) or FXI (F11-/- ) were tested in the SVB model. The plasma levels of FXI in F11-/- mice were manipulated by infusion of FXI or its active form FXIa, or by overexpressing FXI by the use of hydrodynamic tail vein injection. Results F9- mice showed a significant defect in the SVB model, whereas F11-/- mice and wild-type mice were indistinguishable. Intravenous infusion of FXI or FXIa into, or overexpression of FXI in, F9- mice improved hemostasis in the SVB model. Overexpression of a FXI variant lacking a FIX-binding site also improved hemostasis in F9- mice. Conclusions Although we were unable to demonstrate a hemostatic defect in F11-/- mice in the SVB model, our results support the premise that supraphysiological levels of FXI improve hemostasis in F9- mice through FIX-independent pathways.

Successful hemostatic management of major surgery for cervical spondylotic myelopathy in a patient with severe factor XI deficiency.

Factor XI deficiency (FXID) is a rare bleeding disorder caused by mutations in the F11 gene. Spontaneous bleeding in patients with factor XI deficiency is rare, but major bleeding may occur after surgery or trauma. The basic method for hemostatic treatment is replacement of the missing factor using FXI concentrate or fresh frozen plasma (FFP). We report the case of a 72-year-old male with severe FXID who underwent a laminoplasty under sufficient, but minimal, FFP transfusion. Through detailed monitoring of activated partial thromboplastin time (APTT) and FXI activity at the perioperative period, we succeeded in hemostatic management of major surgery without significant blood loss and fluid overload. From the course of this case, we found that measuring FXI activity is superior to measuring APTT. Furthermore, we identified a novel homozygous mutation in F11 [NM_000128.3:c.1041C > A:p.(Tyr347*)] by whole exome sequencing.

Management of parturients with Factor XI deficiency-10year case series and review of literature.

This is an article reviewing the management of pregnant women with factor XI (FXI) deficiency. Retrospective review of the electronic records of 67 pregnancies in 25 women with FXI deficiency over a ten-year period was undertaken. All women received care at St Mary's Tertiary Referral Obstetric/Haematology Clinic for some or all of their pregnancies. Outcome measures included antenatal complications, mode of delivery, anaesthesia provided and postpartum haemorrhage (PPH) and management required. A positive bleeding history was identified in 50% of women prior to pregnancy. Fifteen pregnancies (22%) ended in first trimester miscarriage; there was 1 termination of pregnancy. Two pregnancies were complicated by Antepartum haemorrhage. Of the remaining 51 pregnancies there were 50 live births - 2 preterm and 48 at term. There was one antenatal (34 weeks gestation) stillbirth of a growth restricted baby and one neonatal death secondary to severe prematurity (24 weeks gestation). Twenty -five babies delivered vaginally (20 spontaneous and 5 instrumental). The remaining 26 were delivered by Caesarean section (9 elective and 17 emergency). A sub-analysis of 22 operative deliveries was reviewed; this suggested that regional anaesthesia was safe in selected women with FXI deficiency - a selection that was based on FXI level/range, presence/absence of bleeding history and intended operative intervention.Solvent detergent treated Fresh Frozen Plasma (SD-FFP/Octaplas) and Tranexamic Acid (TXA) were given to those considered vulnerable -an individualised decision made by the multidisciplinary team in accordance with BCSH guidance. Primary PPH complicated 10/51 (15%) deliveries. The commonest cause of PPH was due to atony. Secondary PPH was only seen in only one case. Bleeding in women with FXI deficiency is highly variable and, whilst it does not directly correlate with Factor XI levels, provision of replacement therapy is required if FXI levels are <15 IU/dL as per BCSH guidance. Women with Factor XI levels >40 IU/dL are considered safe for regional anaesthesia following prophylactic FFP as suggested by sub group analysis. Treatment of women with rare bleeding disorders during pregnancy should be by a multidisciplinary team of specialists, to include Haematologist, Anaesthetist and Obstetrician, all of whom have an interest in bleeding disorders in pregnancy. Decisions should then be individualised, based on the presence/absence of a bleeding history and the third trimester FXI levels. Delivery does not have to be by Elective Caesarean. With appropriate care both operative vaginal delivery and regional anaesthesia can be facilitated.

Evaluation of the use of global haemostasis assays to monitor treatment in factor XI deficiency.

INTRODUCTION: Previous guidelines recommend that FXI:C levels should be used to monitor FXI replacement in factor XI (FXI) deficiency. However, FXI:C levels do not correlate with bleeding tendency in this disorder and may not be the optimal test by which to monitor and determine further treatment in the postoperative period. AIM: To assess whether the thrombin generation assay (TGA) and rotational thromboelastometry can be used to monitor FXI replacement peri-operatively in FXI deficiency and to determine if changes in FXI:C levels correlate with changes in thrombin generation and clot formation parameters following treatment with solvent-detergent fresh frozen plasma (SD-FFP). METHODS: The TGA and rotational thromboelastometry were used to measure thrombin generation and clot formation in 11 adults with FXI deficiency who were treated with either SD-FFP (n = 8) or FXI concentrate (n = 3) as prophylaxis peri-operatively. Blood samples were taken pre- and 30 min post-treatment. RESULTS: Global haemostasis assays can be used to measure the effect of FXI replacement with SD-FFP or FXI concentrate in FXI deficiency. Both treatment types improved thrombin generation and clot formation. However, the remaining response to treatment at 24 h post SD-FFP was variable and changes in FXI:C levels were not predictive of changes in thrombin generation/thromboelastometry parameters after treatment with SD-FFP. CONCLUSION: Global haemostasis assays may provide a more reliable means of monitoring SD-FFP treatment with the potential to prevent individuals receiving unnecessary treatment, however, their clinical use in decision making needs to be tested in a larger prospective study.

The Management of Factor XI Deficiency in Pregnancy.

Management of factor XI (FXI) deficiency in pregnancy is complicated by lack of correlation between FXI level and bleeding risk. Clinicians should be vigilant about the potential for prolonged or excessive bleeding following miscarriage or termination of pregnancy, or postpartum hemorrhage (PPH). A multidisciplinary approach along with an individual care plan is recommended to prevent bleeding complications. Assessment of bleeding history, FXI level, and global tests of hemostasis can aid management decisions regarding hemostatic prophylaxis. The risk of PPH can be minimized by obstetric measures to avoid uterine atony and genital trauma, in addition to provision of appropriate hemostatic prophylaxis for labor and delivery. Women with FXI deficiency can be given the option of regional anesthesia, provided that prior consideration has been given to assessment of potential bleeding risk and appropriate treatment strategies are implemented. Antifibrinolytic agents are effective for the majority of women with FXI deficiency, but those with severe deficiency/phenotype require FXI concentrate. Recombinant activated factor VII (rFVIIa) has also been used successfully to prevent bleeding in FXI deficiency. However, all treatments should be used with caution in pregnancy due to thrombogenic potential. Neonatal bleeding complications are rare in FXI deficiency; however, hemostatic assessment and cover are important for invasive procedures such as circumcision.

The hemostatic role of factor XI.

Coagulation factor (F)XI has been described as a component of the early phase of the contact pathway of blood coagulation, acting downstream of factor XII. However, patients deficient in upstream members of the contact pathway, including FXII and prekallikrein, do not exhibit bleeding complications, while FXI-deficient patients sometimes experience mild bleeding, suggesting FXI plays a role in hemostasis independent of the contact pathway. Further complicating the picture, bleeding risk in FXI-deficient patients is difficult to predict because bleeding symptoms have not been found to correlate with FXI antigen levels or activity. However, recent studies have emerged to expand our understanding of FXI, demonstrating that activated FXI is able to activate coagulation factors FX, FV, and FVIII, and inhibit the anti-coagulant tissue factor pathway inhibitor (TFPI). Understanding these activities of FXI may help to better diagnose which FXI-deficient patients are at risk for bleeding. In contrast to its mild hemostatic activities, FXI is known to play a significant role in thrombosis, as it is a demonstrated independent risk factor for deep vein thrombosis, ischemic stroke, and myocardial infarction. Recent translational approaches have begun testing FXI as an antithrombotic, with one promising clinical study showing that an anti-sense oligonucleotide against FXI prevented venous thrombosis in elective knee surgery. A better understanding of the varied and complex role of FXI in both thrombosis and hemostasis will help to allow better prediction of bleeding risk in FXI-deficient patients and also informing the development of targeted agents to inhibit the thrombotic activities of FXI while preserving hemostasis.

In vitro comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major FXI deficiency.

INTRODUCTION: Bleeding risk in factor XI (FXI) deficiency following surgery may be reduced by treatment with either of two FXI concentrates, but indications for their use are unclear and treatment has been associated with thrombosis. AIM: To quantify and compare the effects of two different FXI concentrates on thrombin generation (TG) in major FXI deficiency (FXI:C < 15 IU dL(-1) ). METHODS: Thrombin generation was measured in controls (n = 50), FXI-deficient individuals pre and post in vitro spiking with FXI concentrates (n = 10), and in ex vivo samples following treatment with FXI concentrate (n = 3). RESULTS: Thrombin generation was significantly impaired in FXI deficiency but improved following FXI replacement in vitro and in vivo. LFB Hemoleven(®) had greater effect on TG than BPL FXI concentrate in vitro (equivalent in vivo doses 10, 20 and 30 U kg(-1) ): higher endogenous thrombin potential (ETP) (P < 0.0001), peak height (P < 0.01) velocity (P < 0.0002) and shorter lag time and time to peak (both P < 0.003). Some measurements with LFB Hemoleven(®) exceeded the reference range. At lower dose (5 U kg(-1) ), BPL FXI concentrate normalized all TG parameters and LFB Hemoleven(®) normalized the ETP but exceeded the reference range with other parameters. CONCLUSION: Both FXI concentrates improve TG in vitro in major FXI deficiency but differ in dose response, and for both products, doses lower than previously recommended normalized TG in vitro. Comparison of in vitro spiked and ex vivo samples suggest that in vitro results could be used to estimate an expected in vivo response to FXI replacement.

Safety and efficacy of factor XI (FXI) concentrate use in patients with FXI deficiency: a single-centre experience of 19 years.

AIM: Factor XI (FXI) concentrate is a pooled human plasma-derived factor concentrate used as replacement therapy for patients with FXI deficiency, which provides a predictable response and consistent haemostatic cover in emergency or elective situations. It has previously been implicated in adverse events such as thrombosis and inhibitor formation, with rare case reports of fatal incidents. We sought to establish the incidence of such complications in a retrospective case series between 1994 and 2012 at the Haemophilia Comprehensive Care Centre at Royal Free Hospital, London, UK. METHODS: Patients who received FXI concentrate had their medical records reviewed to extract information and specific adverse events recorded such as failure of treatment with further bleeding, suspected viral transfusion transmitted infection (TTI), thrombosis or inhibitor formation. RESULTS: Eighty-six patients received 242 treatment episodes of FXI concentrate. Ninety percent of treatment episodes were covered with BPL FXI concentrate and 10% with LFB Hemoleven. Twelve (5%) adverse events were recorded, with eight (3.3%) of all treatment episodes were related to persistent bleeding postconcentrate infusion and there were 4 (1.7%) non-bleeding adverse events. No viral TTIs were identified. There were two recorded inhibitors, one thrombotic event (central retinal artery occlusion) and one transfusion reaction. No patient suffering an adverse event resulted in long-term morbidity. CONCLUSION: Our experience of FXI concentrate use demonstrates infrequent minor adverse events related to its administration and is a safe product to use.

Ongoing risk of thrombosis with factor XI concentrate: 5 years experience in two centres.

INTRODUCTION: Factor XI (FXI) deficiency is the commonest of the rare bleeding disorders, affecting 2079 individuals in the United Kingdom. Treatment options for bleeding or surgery include antifibrinolytics, fresh frozen plasma or plasma-derived (pd) FXI concentrates. There were a number of reports of thrombosis following treatment with FXI concentrates prior to changes in their manufacturing processes made in the mid-1990's. AIMS: The aim of the study was to determine the occurrence of adverse events (haemorrhagic and thrombotic) following usage of pd-FXI concentrates at two large UK haemophilia centres. Retrospective chart review of all consecutively treated patients with BPL Factor XI(®) or Hemoleven(®) over a 5-year period (11/06-11/11) was performed. RESULTS: Twenty-nine patients (median age = 57.1 years) received treatment over 64 treatment episodes (surgery = 56, bleeding = 5, other = 3), using 126 000 U of concentrate. Median baseline FXI:C was 9 U dL(-1) (range = <1-51), with 21 having severe and eight partial deficiency. BPL Factor XI(®) was used in 39 episodes (79 110 U) and Hemoleven(®) 25 episodes (46 890 U). There were six clinically significant bleeding events, managed either with a single additional dose of FXI concentrate (n = 4) or requiring no further intervention (n = 2). One patient required blood transfusion and one oral iron replacement. Two thrombotic events (transient ischaemic attack and pulmonary emboli), occurred in two patients with severe FXI deficiency, despite cautious FXI concentrate usage in the perioperative period. CONCLUSIONS: FXI concentrate use is efficacious and safe in the majority of cases although physicians should remain mindful of the possibility of thrombotic complications.

Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study.

Factor XI (FXI)-deficient patients may develop excessive bleeding after trauma or surgery. Replacement therapy should be considered in high-risk situations, especially when FXI levels are below 20 IU dL(-1) . HEMOLEVEN is a human plasma-derived factor XI concentrate available in France since 1992, but there are few data regarding its use by physicians. This prospective study assessed the use, efficacy and safety of HEMOLEVEN in common clinical practice. HEMOLEVEN was evaluated in FXI-deficient patients in 13 French centres in a 3-year postmarketing study. Forty-four patients (30 females, 14 males) received 67 treatments. The median age was 37 years (8 months-91 years). Basal FXI levels were <1 to 51 IU dL(-1) (median: 5.5); 29 patients were severely FXI-deficient (<20 IU dL(-1) ). FXI was administered prophylactically before 43 surgical procedures, 10 invasive procedures, 8 vaginal deliveries, or as curative treatment for six bleeds. The efficacy was assessed as excellent/good in 63, moderate in two and undetermined in two treatments. Seven patients experienced seven adverse effects, including two rated as serious: one sudden massive pulmonary embolism with fatal outcome and one case of inhibitor to FXI. HEMOLEVEN is effective for bleeding prevention in FXI deficiency. However, considering the benefit/risk ratio observed in relation to dosage in this study; firstly, it should be used sparingly due to its potential prothrombotic effect; secondly, new prescription procedures should be defined to adapt the dosage, especially in patients with intrinsic and/or acquired risk factors for thrombosis.

Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre.

Bleeding phenotype in factor XI (FXI)-deficient patients is variable, and not related to baseline FXI:Act. Aims of our study were to describe the characteristics and the management of surgery and deliveries in FXI-deficient patients, and to investigate the relationship between the haemorrhagic phenotype and the baseline FXI:Act. Ninety-five patients were diagnosed and followed in our centre for a median follow-up of 0.9 years (0.1-36.2); median FXI:Act of all patients: 38% (0.5-69%). Fifty-six patients (59%) experienced bleeding episodes not surgery-related. Prior to diagnosis, 64 patients underwent 132 surgeries, and after diagnosis, 23 patients underwent 36 surgeries. Globally 26 of 168 surgeries were prophylactically treated, whereas 142 of 168 were not. As regard as surgeries performed without prophylaxis, 30 bleeding events (21%) occurred in 21 patients. At diagnosis, the median FXI:Act of bleeding and non-bleeding patients was 28% and 37%, respectively, without statistically significant difference between the two groups (P = 0.26). As regard as surgeries performed under prophylactic treatment just 1 bleeding event occurred. Prior to diagnosis, 31 spontaneous deliveries (SD) and eight caesarian sections (CS) were performed without prophylaxis: 4 postpartum haemorrhages (10.5%) occurred (patients FXI:Act: 2%, 6%, 27%, 52.3% respectively). After diagnosis, four SD and five CS were performed with prophylaxis: no postpartum haemorrhages occurred. We confirm the wide bleeding phenotype variability in FXI-deficient patients, not related to the baseline FXI:Act levels. We highlight the importance of performing a correct diagnosis and follow-up, because a good management of prophylactic treatment, dramatically reduces the bleeding rate in case of surgery or deliveries.