Factor XI deficiency: phenotypic age-related considerations and clinical approach towards bleeding risk assessment

Factor XI (FXI) deficiency is a rare autosomal injury-related bleeding disorder with an estimated prevalence of 1 per million among White individuals.¹ It is, however, 1 of the most common inherited rare bleeding disorders (RBD), and it accounts for ∼20% to 30% of patients with RBD.^2,3 A higher prevalence is observed in several ethnic groups because of common founder mutations.^4,5 

Various mutations within the FXI gene cause inherited FXI deficiency. Thus far, >190 disease-causing mutations have been identified.¹ The majority are missense mutations yet nonsense, splice sites, insertions, and deletions have also been reported. Notably, among the Ashkenazi Jewish (AJ) population, the so-called type II p.Glu117X and type III p.Phe283Leu mutations prevail. Indeed, 1 in 450 individuals of the AJ population is expected to inherit type II homozygous, type III homozygous, or type II-III compound heterozygous FXI deficiency.^1,6,7 

FXI deficiency can be classified as quantitative or qualitative, based on concordance/discordance of FXI antigen and activity levels. Severe FXI deficiency is usually defined as an activity level of <15 to 20 IU/dL, which is most commonly found in those who are homozygous or compound heterozygous. Partial FXI deficiency is diagnosed among individuals who are heterozygous, who typically have FXI activity levels of 20 to 60 IU/dL.² 

Clinical symptoms of FXI deficiency are typically injury related. It has been suggested that in FXI deficiency, activation of FIX may be mediated directly by kallikrein, contributing to the mild bleeding diathesis observed.⁸ 

Genotype–phenotype correlations in FXI deficiency: bleeding tendency does not consistently correlate with FXI levels or genotypes.^3,9 Although some patients with severe FXI deficiency do not experience bleeding even during surgical procedures, others with milder deficiency may exhibit severe surgery-related bleeding complications, especially in sites with increased fibrinolytic activity.^2,3 Despite the general lack of correlation between FXI levels and bleeding phenotype, it has been suggested that among individuals of the AJ population with severe deficiency, patients with genotype III/III (FXI of ∼10%) had significantly fewer injury-related bleeding events than patients with genotype II/II (FXI <1%).⁷ The plethora of FXI mutations in various FXI apple domains and their associations with FXI binding partners and bleeding phenotype are delineated in an accompanying manuscript by Moellmer et al.¹⁰ 

The impact of FXI deficiency across an individual's lifespan, from infancy to older adulthood, will be further discussed in our manuscript. We will present our approach for bleeding risk assessment and potential treatments.

Although, beyond infancy, FXI levels remain constant throughout life, the risk of bleeding or thrombosis changes over time. In this section, our focus will be on the hemostatic impairment caused by FXI deficiency throughout the lifespan of individuals, ranging from birth to the elderly. Additionally, we will explore potential protective mechanisms that may mitigate the risk of thrombotic complications, especially during adulthood. Figure 1 summarizes the potential impact of FXI deficiency throughout life, focusing on bleeding symptoms, common surgical challenges, and potential age-related complications.

Although FXI levels in newborns are significantly lower than in older infants and adults,¹¹ major bleeding complications are exceedingly rare, even among the youngest pediatric population with FXI deficiency. One of the most feared complications in RBDs, especially during the neonatal period and infancy, is intracranial hemorrhage (ICH).¹² A comprehensive retrospective study conducted in the United States examined the incidence and characteristics of ICH in 3717 children aged <4 years with various inherited bleeding disorders and its correlation with head trauma.¹³ Sixteen children with FXI deficiency were included in this study. Although 255 (6.9%) of the study participants experienced any form of ICH, 206 (5.5%) had nontraumatic ICH, and none of the patients with FXI deficiency experienced any ICH. A recent pediatric cohort involving 60 children with severe FXI deficiency reported no spontaneous bleeds or perinatal ICH. However, 3 children (5%) did experience triggered ICH after trauma (n = 2) or bleeding from arteriovenous malformation.¹⁴ 

Among infants, especially of Jewish and Muslim origin, the first and most common surgery is circumcision.¹⁵ Barg et al reported the presentation of severe FXI deficiency as postcircumcision bleeding in 4 of 21 babies (whose FXI level was <1%-15%) that were not previously diagnosed, whereas in 17 cases that were already identified and pretreated with tranexamic acid, no bleeding occurred.¹⁶ Tonsillectomies and adenoidectomies are commonly performed surgeries in the pediatric population. Bleeding complications among children with RBDs undergoing these operations have been reported ∼50% of procedures.¹⁷ To date, no publications have specifically addressed tonsillectomies in children with FXI deficiency. Among 28 surgeries performed in children who were severely FXI-deficient children, 2 were complicated by major bleeds (postcircumcision bleeding and teeth extraction). In both cases, no perioperative hemostatic treatment was applied because they were not diagnosed before the operation; in contrast, no bleeding occurred when 45 procedures were performed in previously diagnosed (and pretreated) children with FXI deficiency. Unlike previous studies in adults, this latter pediatric study suggested an association between the severity of FXI deficiency and the bleeding tendency among children.¹⁶ 

A special interest group is females at reproductive age with RBDs, because they may experience abnormal uterine bleeding, obstetrical bleeding, and may present with postpartum hemorrhage (PPH). Abnormal uterine bleeding is common in women with FXI deficiency.¹⁸ In a systematic review of 10 studies regarding gynecological bleeding in FXI deficiency, a total of 268 women were included. Among these, in 56 (21%) women with FXI deficiency, abnormal uterine bleeding prevailed.¹⁹ Notably, these studies included female patients with severe as well as partial FXI deficiency.

Extensive hemorrhage may be detected after spontaneous abortions.^20,21 In general, antepartum hemorrhage is scarce among women with FXI deficiency. However, FXI levels do not significantly increase during pregnancy,²² thus, gravidas with FXI deficiency may be prone to PPH. The Rare Bleeding Disorders in the Netherlands concluded that PPH was especially common in patients with FXI deficiency (70%). However, the study included only 10 women with FXI deficiency who gave birth. Notably, this report did not delineate the mode of delivery and the severity of FXI deficiency.⁹ Several large cohort studies addressed the variability in the propensity of pregnant women who are FXI deficient to bleed and their responses to prophylactic and therapeutic treatment. Chi et al examined 61 pregnancies in 30 women (2 of 30 had severe FXI deficiency, and 28 of 30 with partial deficiency) and observed 7 episodes of PPH; notably, 2 of 7 PPH cases occurred in pregnancies of women with severe FXI deficiency who did not receive intrapartum hemostatic prophylaxis.²³ Salomon et al studied 164 pregnancies in 62 women with severe FXI deficiency and observed no significant bleeding in women without a bleeding history.²⁴ Myers et al studied 105 pregnancies in 33 women (3 of 33 with severe deficiency, all of whom did not experience any PPH) and observed 9 episodes of PPH, mostly in females with a previously positive bleeding history.²¹ In an Italian retrospective study,²⁵ authors mention 10.5% of PPH (in 4 women, of whom 2 had severe FXI deficiency) among 31 deliveries and 8 cesarean sections (CS) performed without prophylaxis in women with FXI deficiency. A US study²⁶ that reviewed data from 28 women with FXI deficiency (8 of 28 with severe FXI deficiency) disclosed 17% of PPH (5 cases in women with partial FXI deficiency, and 4 in women with severe deficiency). In another recent study there was no PPH among 45 vaginal deliveries in women with partial FXI deficiency.²⁷ Recently, Handa et al²⁸ reported 198 patients with FXI deficiency who underwent 252 procedures in the United States, including 143 vaginal deliveries and 63 CS procedures. Personal history of bleeding was the strongest predictor of perioperative or obstetric bleeding, whereas FXI level of >40 U/dL predicted a lower bleeding risk. Overall, data regarding PPH in women with FXI deficiency are conflicting, and bleeding tendency seems to be associated with a positive bleeding history rather than with FXI levels.

Older males form a unique group that presents various challenges and concerns related to bleeding, yet to thrombosis as well. One of the commonest surgeries among older men is prostatectomy. There have been reports of excessive bleeding, including major bleeding events requiring prolonged hospitalization, among patients with FXI deficiency undergoing open prostatectomy.²⁹ However, a study that reported patients FXI deficiency treated with replacement therapy before planned prostatectomy revealed that excessive bleeding may be prevented once a minimum level of 30% factor XI activity was maintained.³⁰ Tranexamic acid is a viable therapeutic option in prostatic surgery as increased fibrinolytic activity is involved at this site. However, caution is warranted in case of gross hematuria.

Among the general older population, the risk of thrombosis increases³¹; consequently, antithrombotic therapy is commonly used. A recent single-center retrospective study of 269 patients with FXI deficiency identified 15 individuals, mostly with partial FXI deficiency, whose median age was 70 years, requiring anticoagulation, because of atrial fibrillation. Over >1000 months of anticoagulation, only 2 mild bleeding episodes occurred in 2 patients. Thus, the authors concluded that moderate FXI deficiency does not interfere with anticoagulant management or bleeding risk.³² 

Of note, thrombotic events have been reported in patients after the use of FXI concentrates, as well as after high doses of recombinant activated FVII (rFVIIa) therapy.^33-35 High levels of FXI are a risk factor for deep venous thrombosis as well as for venous thrombotic recurrence.^36,37 Several publications examined the potential protective role of FXI deficiency in late adulthood by mitigating the heightened thrombotic risk associated with age. A large population study demonstrated that deep venous thrombosis is exceedingly rare among individuals with severe FXI deficiency.³⁸ Nonetheless, rates of myocardial infarction (MI) among patients with severe FXI deficiency were similar to those observed in the general population.³⁹ Another large retrospective population study suggested that mild and moderate FXI deficiency confer some protection against cardiovascular events, including MI, stroke, and transient ischemic attacks.⁴⁰ Trials on FXI-directed inhibitors aimed at prevention of venous thromboembolism or stroke are based on such observations and show promising results.⁴¹ 

An important complication of severe FXI deficiency, whose frequency may increase with age and with exposure to fresh frozen plasma (FFP)/FXI therapy, is the occurrence of FXI inhibitors. Noncorrection of a prolonged activated partial thromboplastin time (aPTT) by normal plasma should arouse suspicion of the presence of an inhibitor. Patients with severe FXI deficiency are at a considerable risk of developing inhibitors to FXI at any age. Inhibitors against FXI have been described in patients with autoimmune and malignant diseases ^42-44 or as a rare complication of replacement therapy with FFP in patients with severe FXI deficiency.^45-47 It was suggested that patients with FXI deficiency with null mutations are the most susceptible to inhibitor formation after exposure to FFP, or to plasma-derived components.^45-47 In an Israeli cohort study, 7 of 21 patients (33%) homozygous for type II mutation developed inhibitors after exposure to plasma.⁴⁷ The appearance of inhibitors was not associated with any specific subtype of HLA class II. Characterization of the inhibitors revealed that they were all immunoglobulin G and inhibited activation of FXI by thrombin or FXIIa, and inhibited activation of FIX by FXIa. The presence of an inhibitor during pregnancy may pose a potential hemorrhagic risk to the fetus, because anti-FXI immunoglobulin G may cross the placenta.⁴⁸ 

Notably, patients with severe FXI deficiency who develop inhibitors directed against FXI do not experience any spontaneous bleeds. This observation is in line with the promising results of early trials on FXI-directed inhibitors aimed at prevention of venous thromboembolism or stroke.^49,50 Bleeding complications in patients treated by these novel anticoagulants were scarce. Data regarding the safety and efficacy of FXI-directed inhibitors are further discussed in the accompanying paper by Galiani et al.⁴¹ 

Assessing the bleeding risk in FXI deficiency poses significant challenges, particularly when it comes to accurately predicting the bleeding risk in individual patients.² The bleeding phenotype does not consistently correlate with FXI levels or genotype, and traditional coagulation assays such as the aPTT and prothrombin time are inadequate for capturing the bleeding propensity in FXI deficiency. The foundations of any bleeding risk assessment rely on medical anamnesis, specifically the personal bleeding history. Our suggested diagnostic approach aimed at bleeding risk assessment of these patients is delineated in Figure 2. A detailed hemostatic evaluation should include a personal bleeding history combined with knowledge regarding the surgical site. Of note, because clinical assessment of the presence and severity of bleeding symptoms in patients with RBD is challenging, a number of bleeding score systems (BSSs) or bleeding assessment tools (BATs) were developed. Pala et al reported an assessment of 492 patients wit RBD (including 117 patients with FXI deficiency) using a new BSS, compared with the International Society of Thrombosis and Haemostasis BAT. In patients with RBD, there was a significant negative correlation between BSS and coagulant factor activity level, yet no specific data are delineated for patients with FXI deficiency.⁵¹ Currently, no studies have been published assessing the role of the BAT score as a prognostic factor for future bleeding in individuals with FXI deficiency. However, in a large prospective cohort of patients with a suspected bleeding disorder followed longitudinally for up to 4 years, the International Society of Thrombosis and Haemostasis BAT score failed to predict the risk of future bleeding.⁵² Beyond adequate medical history, assessing the bleeding risk associated with the specific contemplated procedure is paramount. Feedback activation of FXI by thrombin results in additional thrombin formation that protects fibrin clots from fibrinolysis via activation of thrombin-activatable fibrinolysis inhibitor.⁵³ Thus, anatomic sites prone to excessive bleeding in patients with FXI deficiency include organs with potentially increased fibrinolysis, such as the oral/nasal cavity, gastrointestinal tract, and the urogenital sites. In a study that examined bleeding among 120 patients with severe FXI deficiency undergoing surgery, it was estimated that procedures at tissues exhibiting fibrinolytic activity were associated with bleeding in 49% to 67% of the patients, whereas procedures involving sites with no local fibrinolytic activity were associated with a bleeding rate of 1.5% to 40%.⁵⁴ In case of a major procedure, it is advised to rule out additional coagulopathies. Specifically, it has been suggested that excessive bleeding may be noted in patients with FXI deficiency with lower than normal levels of von Willebrand factor.⁵⁵ Thus, the minimal recommended laboratory assessment includes prothrombin time, aPTT, and FXI activity levels. In patients with a significant bleeding history, it is suggested to exclude inherited bleeding disorders by further laboratory workup, including bleeding screen with complete blood count, fibrinogen, von Willebrand factor panel, platelet aggregation studies, FXIII, and looking for fibrinolytic pathway defects. Figure 2 outlines our suggested stepwise approach for assessing bleeding risk in patients with FXI deficiency before planned surgical interventions. Second-tier laboratory analyses, including FXI inhibitors, FXI mutation analysis, and global coagulation assays, may be considered in cases of severe FXI deficiency.

Beyond the clinical evaluation of patients and perioperative screening through laboratory assays, there still exists an unmet need for ancillary tests to evaluate the bleeding tendency in FXI deficiency. Various global laboratory assays, including thrombin generation assays (TGA), and viscoelastic tests such as rotational thromboelastometry and thromboelastography, have been used to determine the risk of surgery-related bleeding and guiding hemostatic management. As these assays require specialized equipment usually in a research setting they are not necessarily available worldwide. Although these methods have shown differentiation between cohorts of healthy patients, and patients with and without bleeding,^56-59 conflicting findings have emerged regarding the best preanalytical conditions for these assays, and thus, no assay standardization has yet been achieved.^33,56-58 Therefore, caution is advised when interpreting results, because these assays cannot be solely relied upon to predict the bleeding risk in a given patient with FXI deficiency. Delayed and decreased thrombin generation was demonstrated in patients with FXI deficiency who experienced bleeding related to surgical procedures, irrespective of their plasma FXI levels or underlying genetic mutation.⁵⁷ Recently a retrospective study by Désage et al conducted on a cohort of 49 patients, suggested that an algorithm taking into account TGA parameters, FXI activity, and the type of surgical procedure may have the potential to guide the hemostatic treatment strategies.⁶⁰ 

TGA and rotational thromboelastometry have been found to be sensitive tools for monitoring the effects of either FFP or FXI concentrate therapy.^61,62 Pike et al suggested that although both FXI concentrates improve TGA in vitro, they may differ in dose response and thrombogenic potential.⁶³ Moreover, results of ex vivo spiking assays with low rFVIIa doses, obtained as part of patients' bleeding risk evaluation, may refine treatment strategy in the perisurgical setting.^33,62 

Laboratory assays focusing on clot structure and fibrinolysis offer another potential approach for distinguishing patients with FXI deficiency defined as “bleeders” from “nonbleeders.” Analyses of a fibrin network structure using laser scanning confocal microscopy revealed that bleeders exhibited lower fibrin network density and lower clot stability in the presence of tissue plasminogen activator than nonbleeders.⁶⁴ However, using confocal microscopy to predict bleeding risk in real-world settings may not be practical.

Gidley et al⁶⁵ expanded upon previous work by investigating a large cohort of patients with severe and partial FXI deficiency. Patients were categorized as nonbleeders or bleeders based on their documented history of bleeding after tonsillectomy and/or dental extraction before being diagnosed with FXI deficiency. The researchers demonstrated that turbidity assays could effectively detect abnormal plasma clot formation and resistance to fibrinolysis in plasma samples from patients with FXI deficiency. The nontensile clots of patients with FXI deficiency were more susceptible to fibrinolysis with faster clot breakdown, resulting in prolonged bleeding. Considering the need for specialized equipment and standardization studies, the potential of such assays to be easily incorporated in clinical settings warrants further evaluation.

Contrary to other bleeding disorders such as severe hemophilia A and B in which regular prophylaxis serves as the primary treatment strategy,⁶⁶ patients with even the most severe form of FXI deficiency (FXI of <1%) can often go years without experiencing significant bleeding symptoms. Despite progress in understanding the role of FXI in hemostasis and thrombosis, there is currently no standardized prophylactic approach for patients with severe FXI deficiency undergoing surgery or bleeding after trauma.

Therapeutic options for patients in the surgical setting, particularly those with an increased hemostatic risk such as neurosurgery, include tranexamic acid, applied as adjunct antifibrinolytic therapy, as well as administration of replacement therapy or bypass agents (FFP, FXI concentrate, and off-label rFVIIa).

Replacement therapy may play a critical role in uro-epithelial surgeries, because gross hematuria may be considered a contraindication for antifibrinolytic therapy.⁶⁷ In contrast to this concept, emerging evidence suggests that tranexamic acid may be used intravenously and locally in urological surgery to reduce associated blood loss without significant complications.⁶⁸ 

FFP is a nonspecific replacement therapy used in many patients with FXI deficiency undergoing major surgery, because specific FXI concentrates are not readily available worldwide. It contains normal levels of various clotting factors, including factors II, V, VII, IX, X, XI, and XIII. Additionally, FFP contains albumin, immunoglobulins, and natural inhibitors of coagulation.⁶⁹ Adverse reactions to FFP transfusion may include allergic reactions, transfusion-related acute lung injury, febrile reactions, the transmission of viral pathogens and prions,⁷⁰ and circulatory overload. In children, the large volume of FFP required to reach sufficiently high plasma levels of FXI can frequently hinder therapy.⁷¹ In patients with severe FXI deficiency, especially those with levels <1%, the development of inhibitors directed against FXI after exposure to FFP is also a concern.⁴⁷ 

Despite its introduction in 1992,⁷² the use of FXI concentrate as a therapeutic option has not gained widespread acceptance worldwide. Two plasma-derived products, namely FXI concentrate (Bio Products Laboratory [BPL], Elstree, United Kingdom) and Hemoleven (Laboratoire français du Fractionnement et des Biotechnologies, Les Ulis, France), are currently available. The use of both products has been associated with venous and arterial thrombotic complications. In a postmarketing prospective study of Hemoleven, 44 patients underwent 67 treatments, primarily in a surgical setting. One patient in this study experienced a fatal massive pulmonary embolism. The authors of this publication urged cautious usage of this product, considering the risk-to-benefit ratio.⁷³ Another retrospective study included 29 patients who received over 64 treatment episodes, with BPL’s FXI and Hemoleven used in 39 episodes and 25 episodes, respectively. Among these cases, 6 clinically significant bleeding events occurred, 4 of which were managed with a single additional dose of FXI concentrate. Despite careful usage, 2 patients with severe FXI deficiency experienced thrombotic events, including a transient ischemic attack and pulmonary emboli.⁷⁴ Currently, heparin and antithrombin have been added to both FXI concentrates in an attempt to mitigate thrombotic risk.⁷⁵ The largest study evaluating the safety of FXI therapy included 86 patients who received 242 treatment episodes of FXI concentrate (90% BPL FXI and 10% Laboratoire français du Fractionnement et des Biotechnologies Hemoleven); 12 (5%) adverse events were recorded, with 8 (3.3%) related to persistent bleeding after concentrate infusion. There were 2 recorded inhibitors and 1 thrombotic event (central retinal artery occlusion).⁷⁵ Importantly, in all these studies, most thrombotic complications were observed in older patients or those with cardiovascular risk factors.⁷⁶ Of note, to date, the use of plasma-derived FXI concentrates therapy has not been described in pediatric patients.

Treatment with rFVIIa was initially attempted in patients with FXI deficiency who developed acquired FXI inhibitors after exposure to FXI concentrate or FFP.

Data suggest that rFVIIa is an effective treatment option for patients with FXI inhibitor.

Initially, dosing was adopted from regimens implemented for patients with hemophilia (90 μg/kg per dose),⁷⁷ yet thrombotic complications among older patients with cardiovascular risk factors were observed.³⁵ Further studies have demonstrated that a much lower dose of rFVIIa may be used, reducing the risk of thrombosis, without compromising bleeding safety.^35,61,78 Off-label application of low-dose rFVIIa for treating patients with partial to severe FXI deficiency has been described despite the lack of FXI inhibitors.^34,61,79 Of note, arterial thromboses were reported in patient with FXI deficiency after administration of rFVIIa.^35,80 However, this risk should be relatively low once rFVIIa doses of 10 to 15 μg/kg are applied, as demonstrated in ex vivo studies (Figure 3) and recently redcommended.^61,81 

Most minor procedures can be safely performed using adjunct tranexamic acid, eliminating the need for replacement therapy (Table 1).⁸² Additionally, certain major surgeries, such as appendectomy, may be conducted without upfront replacement therapy. Nonetheless, it is advisable to have such therapy readily available if required.

The peripartum period of women with FXI deficiency introduces specific hemostatic challenges. Overall, the therapeutic management of such pregnant women should be multidisciplinary. Generally, for vaginal or CS delivery in women who have not bled previously, recommendations support clinical monitoring as long as antifibrinolytic therapy is applied. Yet, some guidelines suggest perioperative replacement therapy in women with severe FXI deficiency undergoing obstetrical interventions.¹⁹ Low doses of rFVIIa may facilitate CS among patients who are severely deficient.⁷⁹ In cases of PPH, aggressive replacement therapy should be provided and the use of FFP, FXI concentrates, rFVIIa, and antifibrinolytics is recommended.¹⁹ 

Neuraxial anesthesia (NA) during deliveries for women with FXI deficiency is controversial, and the comfort level of anesthetists requires consideration as well, given that the closed space increases bleeding risk.^{26,28,79,83,84} British guidelines suggest against NA in women with low FXI levels with a known bleeding phenotype.⁸³ Eleven studies addressing 66 NA procedures in patients with FXI deficiency were included in a recent scoping review.⁸⁴ Some women received hemostatic support including rFVIIa, FFP, or tranexamic acid before NA.⁷⁹ Reported data were not comprehensive because the exact treatment strategy was not well described.⁸⁴ Of note, in most Israeli medical centers, NA is avoided in women with severe FXI deficiency, however, it may be successfully applied in women with no bleeding tendency and partial FXI deficiency.⁸⁵ 

Accurate assessment of bleeding risk in individual patients with FXI deficiency remains a significant challenge in clinical practice.

Despite studies assessing various ancillary laboratory tests, optimal tools and strategies have yet to be elucidated. Prospective studies evaluating the implementation of BATs, their correlation with global coagulation assays, and their association with bleeding and/or thrombotic complications are warranted.

Moreover, the current therapeutic arsenal has room for improvement and expansion. Nonreplacement therapy is currently being investigated in hemophilia A and B and can potentially be used in FXI deficiency (formerly known as hemophilia C). Therapeutic options include drugs that aim to rebalance the anticoagulant potential by inhibiting natural anticoagulants.⁸⁶ Fitusiran, an investigational small interfering RNA agent, has shown promise in reducing antithrombin synthesis in hepatocytes, ultimately rebalancing hemostasis⁸⁷; however, its use has been associated with thrombotic events in clinical trials among patients with hemophilia.⁸⁸ Lately, inhibition of tissue factor pathway inhibitor (TFPI), which is the primary inhibitor of the TF-FVIIa complex, by monoclonal antibodies (such as concizumab and marstacimab) has demonstrated promising results in reducing bleeding among patients with hemophilia A and B.^89,90 In a TGA-guided study examining the effect of anti-TFPI ex vivo spiking in various RBDs, improved endogenous thrombin potential and peak height were noted in plasma obtained from patients with severe FXI deficiency.¹⁴ Another study examined an in vitro FXI deficiency model and demonstrated that inhibition of TFPI enhanced thrombin generation and clot formation, increased network density, and decreased fibrinolysis.⁹¹ These findings make the therapeutic option of inhibiting TFPI particularly attractive for patients with FXI deficiency and inhibitors.

In summary, further research is required to develop more effective tools for assessing bleeding risk and to explore and optimize therapeutic options for FXI deficiency. The recent advancements can potentially improve patient outcomes and address the challenges faced in managing bleeding complications in clinical practice.

Contribution: A.A.B. analyzed data and wrote the first drafts of the manuscript; T.L. was responsible for data acquisition, providing analytical tools, and critical review of the manuscript; and G.K. wrote the manuscript and critically reviewed it.

Conflict-of-interest disclosure: G.K. reports grants and/or research support from US-Israel Binational Science Foundation, Opko Biologics, Pfizer, Roche, and Shire; received consultation fees from ASC Therapeutics, Bayer, Biomarine, Novonordisk, Pfizer, Roche, Sanofi-Genzyme, Sobi, Takeda, and Uniqure; reports honoraria from ASC Therapeutics, Bayer, Biomarine, Novonordisk, Pfizer, Roche, Sanofi-Genzyme, Sobi, Takeda, and Uniquore; and reports membership on an entity’s board of directors or advisory committees of PedNet foundation. A.A.B. reports honoraria for lectures from Roche. T.L. declares no competing financial interests.

Correspondence: Gili Kenet, National Hemophilia Center, Coagulation Unit and Amalia Biron Research Institution of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer 52621, Israel; email: gili.kenet@sheba.gov.il.