Factor XI Deficiency

Congenital factor XI deficiency (haemophilia C, PTA deficiency, Rosenthal syndrome), with reference to acquired deficiency, factor XI inhibitors and combined factor XI and prekallikrein deficiency

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and evolution of the concept

In 1953, Robert L. Rosenthal, Otto H. Dreskin and Nathan Rosenthal described a haemophilia-like disorder caused by deficiency of a third plasma thromboplastin factor, which they called plasma thromboplastin antecedent (PTA) [28]. The three initial families had a mild bleeding phenotype, and subsequent research was organised around this founding observation [7]. The disorder received the eponyms Rosenthal factor deficiency and Rosenthal syndrome, and for decades was called haemophilia C, by analogy with haemophilias A and B [1, 2]. The designation fell into disuse because inheritance is autosomal and not X-linked, the bleeding phenotype is different and the correlation between factor level and bleeding is much weaker than in the haemophilias [3].

In 1978, Uri Seligsohn demonstrated a high gene frequency of PTA deficiency in a population with a founder effect, which transformed a rarity into a frequent condition in that group and directed much of the subsequent clinical and epidemiological research towards Israel [29]. The following year, the same author estimated for Ashkenazi Jews in Israel a homozygote frequency of about 1 in 190 and a heterozygote frequency of about 1 in 8, figures that place the deficiency among the most frequent genetic disorders in that group [4]. The first compilations reinforced the ethnic association: in 1962 almost all published patients were of Jewish ancestry, and in 1964 Rosenthal gathered 72 cases from 46 Jewish families; later descriptions in a Muslim Arab family in Israel and in a Black family showed that the disease is not restricted to that group [4]. Orphanet defines the disease as a rare inherited bleeding disorder characterised by reduced level and/or activity of factor XI (FXI), with moderate bleeding symptoms that usually occur after trauma or surgery [1].

1.2. Milestones of molecular discovery

In 1986, Fujikawa and colleagues obtained the FXI cDNA from human liver: 2097 nucleotides encoding an 18-amino-acid leader peptide and 607 amino acids per chain of the mature protein, with a heavy chain of 369 residues organised in four tandem repeats of 90–91 amino acids (the Apple domains) and a catalytic light chain of 238 residues, of the trypsin type; activation by activated factor XII (FXIIa) occurs at the Arg369–Ile370 bond, and the sequence has 58% identity with plasma prekallikrein [30]. The following year, Asakai and colleagues described the organisation of the gene: 23 kb, 15 exons and 14 introns, with exon I corresponding to the 5' untranslated region, exon II to the signal peptide, exons III to X to the four Apple repeats and exons XI to XV to the catalytic region [9]. The gene was localised by in situ hybridisation to the distal end of the long arm of chromosome 4 (4q35) [31].

The first pathogenic variants were described in 1989 in six unrelated patients, with three types of point alteration designated type I (splicing), type II (premature termination) and type III (amino acid substitution) [32]. In 1991, in a study of 43 probands with severe deficiency, the type II (Glu117Stop in historical numbering, = NM_000128.4:c.403G>T p.(Glu135Ter)) and type III (Phe283Leu in historical numbering, = NM_000128.4:c.901T>C p.(Phe301Leu)) variants accounted for 49% and 47% of the 86 alleles, respectively [33]. There followed the demonstration that the type II variant has an ancient origin, at least 2500 years old [34], the haplotypic separation between this ancient founder and a more recent European founder associated with the type III variant [35], and the identification of a regional founder in the French Basque Country, Cys38Arg (historical numbering, = NM_000128.4:c.166T>C p.(Cys56Arg)) [10, 36]. By 2004, 53 variants were known, four with a founder effect [20]; by 2013, more than 220, seven with a founder effect [37]; the EAHAD (European Association for Haemophilia and Allied Disorders) database records 403 unique variants [3, 38].

1.3. Nomenclature and definitions used

The literature uses two numbering systems for F11 variants. Historical numbering counts the amino acids of the mature protein, without the signal peptide; HGVS (Human Genome Variation Society) nomenclature counts from the initiator methionine, and therefore adds 18 amino acids: the type II variant, Glu117Stop, corresponds to p.(Glu135Ter) and the type III variant, Phe283Leu, to p.(Phe301Leu) [10, 30, 39]. The terms "type I, II and III" applied to these variants do not coincide with the biochemical classification into type I deficiency (quantitative, with activity and antigen reduced in parallel) and type II deficiency (qualitative, with activity disproportionately low relative to antigen) [3].

The scope of this article comprises four entities. Congenital FXI deficiency (ORPHA:329) results from biallelic pathogenic F11 variants, in severe deficiency, or from monoallelic variants, in partial deficiency, with or without a dominant-negative effect [1, 12]. Acquired FXI deficiency (ORPHA:599507) results from autoantibodies or systemic disease [3, 5]. Anti-FXI alloinhibitors arise in patients with severe deficiency without detectable FXI, after exposure to plasma or concentrate [6, 40]. Combined FXI and prekallikrein deficiency results from contiguous deletions encompassing F11 and the neighbouring KLKB1 gene [7].

Severity thresholds are not uniform between sources. The review by Salomon and Seligsohn defines severe deficiency as FXI <15 U/dL [20]; the 2026 systematic review uses <20 IU/dL for severe deficiency and from 20 IU/dL to the lower limit of normal, generally 60–65 IU/dL, for partial deficiency [21]; the RCOG (Royal College of Obstetricians and Gynaecologists) places homozygotes and compound heterozygotes below 0.15–0.20 IU/mL and heterozygotes between 0.15 and 0.70 IU/mL [13]. The units IU/dL and U/dL are equivalent to the percentage of normal, and 1 IU/mL corresponds to 100 IU/dL. The OMIM phenotype entry, based on the 2009 review by Duga and Salomon, defines the deficiency as plasma FXI below 15 IU/dL, with bleeding mainly after trauma or surgery; this definition coincides with severe deficiency in the other sources and does not cover heterozygotes with partial deficiency, whom the same entry describes in other sections [4].

The role of the geneticist in families with a bleeding disorder is to clarify the nature of the disease, its severity and the consultand's risk, in coordination with the haemophilia centre. In a series of families referred for familial haemophilia, only about half had a relative with factor VIII or factor IX deficiency, and the other diagnoses included von Willebrand disease and FXI deficiency [2].

2. Molecular Genetics and Pathophysiology

2.1. The F11 gene and the protein

F11 is located at 4q35.2, adjacent to KLKB1, which encodes plasma prekallikrein; the two genes share structural homology and probably arose from a duplication of KLKB1 early in mammalian evolution [7]. The gene has 15 exons, 14 introns and about 23 kb, with no pseudogenes or guanine-cytosine-rich regions that would hamper sequencing; expression is mainly hepatic, regulated by hepatocyte nuclear factor 4α, with lower expression in mononuclear cells, granulocytes, pancreas and kidney [3]. In the promoter study, 381 base pairs upstream of exon 1 were sufficient for maximal activity in HepG2 hepatocarcinoma cells; hepatocyte nuclear factor 4α (HNF4A) binds to an ACTTTG motif between positions −375 and −360, whose alteration abolishes promoter activity, and in HeLa cells, lacking HNF4A, the promoter is weakly active and co-expression of HNF4A increases this activity about tenfold [11]. The hepatic origin of plasma FXI has clinical confirmation: the deficiency was transferred from donors with congenital deficiency to liver transplant recipients, including a 54-year-old man transplanted for chronic active hepatitis associated with hepatitis B virus, who received the liver of an Ashkenazi donor with bleeding after dental procedures and an isolated prolonged aPTT; the authors concluded that the liver is the only site of production of circulating FXI [4]. Extrahepatic expression is therefore not sufficient to maintain the plasma level. The reference transcript is the MANE Select (Matched Annotation from NCBI and EMBL-EBI) NM_000128.4, which encodes the protein NP_000119.1 [10].

FXI is a plasma zymogen that circulates as a homodimer of two identical chains linked by disulphide bridges, a property unique among the coagulation enzymes, and in plasma it is associated with high-molecular-weight kininogen (HMWK) [8, 22]. Each subunit has four Apple domains (A1 to A4) and a serine protease domain; dimerisation depends on the A4 domain [3, 30]. Cleavage of the Arg369–Ile370 bond in each chain generates activated FXI (FXIa), with two heavy and two light chains, which activates factor IX [8, 30].

2.2. Function in haemostasis and mechanism of bleeding

FXI can be activated by two pathways. The contact pathway, by FXIIa in the presence of HMWK, is the basis of the aPTT in the laboratory but has little physiological relevance; the main pathway is activation by thrombin generated by the tissue factor–activated factor VII complex, in the amplification phase, with additional activation on the platelet surface [3, 12]. FXIa activates factor IX, which, with activated factor VIII, activates factor X and sustains thrombin generation; once the clot has formed, this additional thrombin generation activates thrombin-activatable fibrinolysis inhibitor (TAFI), which protects the clot from lysis [3, 12].

This dual function explains the phenotype. Deficiency reduces thrombin generation and no longer limits fibrinolysis, so the clot is more vulnerable in tissues rich in plasminogen activators, such as the oral cavity, nasopharynx and urogenital tract [3, 8]. In patients with severe deficiency operated on without replacement, bleeding occurred in 49% to 67% of procedures in tissues with fibrinolytic activity, compared with 1.5% to 40% at sites without local fibrinolysis (p=0.0015), unrelated to genotype [18]. The same difference explains why spontaneous bleeding is rare even at very low levels [13]. Absence of FXI in animal models, by gene inactivation or protein neutralisation, protects against arterial and venous thrombosis, an observation that underpins the development of anti-FXI(a) anticoagulants [37]. Spontaneous models also exist: an FXI deficiency analogous to the human one has been described in cattle and in a family of Springer Spaniel dogs [4].

2.3. Inheritance patterns

Inheritance follows two patterns, both documented in the primary sources and in the guidelines. The autosomal recessive form corresponds to severe deficiency in homozygotes and compound heterozygotes and is the most frequent in symptomatic patients [7, 20]. The autosomal dominant form corresponds to heterozygotes with partial deficiency and bleeding and, in particular, to missense variants with a dominant-negative effect: because FXI is a dimer, the abnormal subunit associates with the normal one and the mixed dimer is retained inside the cell, which reduces secretion to values below the expected 50% [3, 12]. The UKHCDO (United Kingdom Haemophilia Centre Doctors' Organisation) guideline describes the deficiency as autosomal recessive or dominant and advises caution in applying these terms, because carriers of dominant-negative variants may have FXI below 0.25 IU/mL and mild bleeding [12]. The RCOG likewise describes both patterns [13], and the ClinGen (Clinical Genome Resource) actionability report records recessive inheritance in the header and dominant inheritance in the probability estimate section, an internal discrepancy worth knowing when citing the document [15]. Orphanet lists both patterns [14]. Heterozygous null variants tend to behave recessively, owing to partial compensation by the normal allele [3]. The OMIM phenotype entry (#612416) records both phenotype–gene relationships, recessive and dominant, and describes inheritance as generally recessive, with a dominant pattern possible through the dominant-negative effect of intracellular heterodimer formation [4]. The experimental demonstration is due to Kravtsov and colleagues, in 2004: in two unrelated patients, with FXI below 20% of normal and dominant transmission in the family, the heterozygous catalytic domain variants Gly400Val and Trp569Ser (historical numbering, = NM_000128.4:c.1253G>T p.(Gly418Val) and c.1760G>C p.(Trp587Ser)) were not secreted by transfected fibroblasts and, on co-transfection with the normal allele, reduced secretion of normal FXI by about 50%; the father of one of the patients, also a carrier of Trp569Ser, had FXI between 25% and 30% of normal [11].

2.4. Molecular mechanisms and variant classes

Quantitative deficiency, or biochemical type I, results from three mechanisms: nonsense variants generating null alleles; missense variants that prevent dimerisation through the A4 domain, with retention of the monomer in the cytoplasm; and non-secretable homodimers [3]. Qualitative deficiency, or biochemical type II, is rare, with eight variants described, five in the catalytic domain and three in the Apple domains [3]. The same distinction appears in the literature with the terminology of cross-reacting material (CRM): CRM-negative deficiency, with antigen and activity reduced in parallel, is the most frequent, and CRM-positive deficiency, with antigen present and disproportionately low activity, is rare [4]. An example of a CRM-positive form is a homozygous girl whose ratio of FXI clotting activity to antigen was 0.04, compared with 0.70 to 0.74 in relatives and 1.04 ± 0.15 in 12 normal individuals [4]. In the EAHAD database, 58% of variants are missense, 10% nonsense, 9% frameshift changes including splicing and 1% insertions or deletions; 15% of single nucleotide variants lie in non-coding regions and 40% in the catalytic domain [3]. In the German cohort of 316 index cases, the 286 variants identified were distributed as missense (56%), nonsense (24%), small deletions or insertions (11%), splicing variants (6%) and large deletions (3%), with no duplications [7].

2.5. Founder and recurrent variants

The table brings together the variants with historical nomenclature and the corresponding HGVS nomenclature. The correspondences were obtained by searching the historical name in ClinVar and, for variants with a stated genomic coordinate, validated in VariantValidator on transcript NM_000128.4 [10, 39].

The rows corresponding to the allelic variants selected by OMIM were linked to HGVS nomenclature through the ClinVar record linked to each OMIM variant, and the 18-codon difference between historical and HGVS numbering remains constant in all of them [11, 39]. Some variants described as causal between 1995 and 2004 now have, in ClinVar, a classification of uncertain significance or conflicting interpretations (Thr386Asn, Phe442Val, Lys252Ile and Ala412Val in historical numbering, = NM_000128.4:c.1211C>A p.(Thr404Asn), c.1378T>G p.(Phe460Val), c.809A>T p.(Lys270Ile) and c.1289C>T p.(Ala430Val)), so presence in an OMIM entry does not amount to a current classification of pathogenicity [39].

The two most studied variants have distinct histories. Type II is found in Jewish communities of the Middle East and North Africa and in Arab populations, with a shared haplotype indicating a founder predating the divergence of these groups; the allele frequencies described were 0.0217 in Ashkenazi Jews, 0.0167 in Iraqi Jews, 0.0026 in Middle Eastern Jews excluding Iraqis, 0.0027 in North African and Sephardi Jews and 0.0065 in Arab populations [34, 35]. Type III is associated with a rare haplotype detected only in Ashkenazi Jews, with an allele frequency of 0.0254, and was not found in the other groups studied, pointing to a later European origin [34, 35]. In the ExAC (Exome Aggregation Consortium) analysis, with more than 60,000 exomes, the allele frequencies of causal variants were 0.0016 in Africans, 0.0045 in East Asians, 0.0036 in Europeans, 0.00030 in Finns, 0.0021 in Latinos and 0.0015 in South Asians [16]. The same work described recurrent variants by group: p.Phe223Leu in Africans (23.5% of mutated alleles), p.Gln263Ter and p.Leu424CysfsTer in East Asians (28.2% and 20.5%) and p.Ala412Thr in Latinos (25%), in the source's notation; the numbering convention used is not stated in the abstract, so the HGVS correspondence of these four variants is probable but has not been validated [16, 39].

The German cohort of 316 index cases illustrates the continental European spectrum: the Ashkenazi founder variants were the most frequent (14.3% of cases), and three variants apparently specific to that population — p.Gln134Ter, p.Ile215_Asp216del and p.Glu315Lys — accounted for 27% of cases; about 45% of all variants were located in exons 5, 7 and 9 [7]. In the southern Italian cohort, with 93 individuals from 39 families, 24 variants were identified, three of them novel (p.Val89Ter, p.Leu306Pro and p.Trp515Gly), with p.Glu135Ter and p.Glu315Lys being the most common [41]. In a Chinese series of 27 unrelated patients, 23 variants were found, six of them novel [42]. The German review also notes p.Gln106Ter described in Nantes and confirms p.Cys146Ter in British Caucasians and the variants p.Glu281Ter and p.Leu442CysfsTer8 in East Asians [7]. The 2025 laboratory diagnosis review attributes the variant "Cys88Stop" to the Basque Country; the primary source from the region describes Cys38Arg, so the review's notation should be treated as a typographical error [3, 36]. The same review mentions a fourth Ashkenazi founder, a 14-base-pair deletion at the exon 14–intron N junction, for which it gives no HGVS nomenclature [3].

2.6. Genotype–phenotype correlations, penetrance and allelic disorders

The correlation between genotype and bleeding is weak. In the 43 probands with severe deficiency studied in 1991, mean FXI activity was 1.2 ± 0.5% in type II homozygotes, 9.7 ± 3.8% in type III homozygotes and 3.3 ± 1.6% in compound heterozygotes, and type III homozygotes had significantly fewer post-traumatic bleeds; the three groups, however, had similar proportions of bleeding after surgery at sites of increased fibrinolysis or after dental extraction [33]. In an obstetric and surgical cohort of 198 patients, median FXI was 49.5% in type II, 52.5% in type III and 43.0% in other genotypes, without significant differences, and genotype was not associated with bleeding [43]. Antigen and genotype do not correlate with bleeding any better than activity [3]. ClinGen estimates clinical penetrance of at least 40%, with about 65% of individuals asymptomatic in a series of 128 cases and 20% to 50% of patients with partial deficiency presenting excessive bleeding [15]. The estimate of 20% to 50% dates back to reviews from the 1990s, which attributed the discrepancies between studies to the definitions of excessive bleeding, the variability of trauma and the proportion of patients never subjected to a haemostatic challenge; in a comparison of 25 families, the proportion of patients with and without bleeding did not differ between homozygotes and heterozygotes [4].

The cases gathered in the OMIM entries illustrate the dissociation between genotype, level and bleeding. Two relatives of European origin, compound heterozygotes Cys128Stop/Lys252Ile with severe deficiency discovered on preoperative aPTT, did not bleed after laparoscopic tubal ligation; conversely, three heterozygotes for missense variants (Arg308Cys, Ala412Val and Ser576Arg in historical numbering, = NM_000128.4:c.976C>T p.(Arg326Cys), c.1289C>T p.(Ala430Val) and c.1782C>A p.(Ser594Arg)), with FXI antigen between 22.9 and 38.6 and activity between 27% and 50%, had easy bruising, heavy menstrual bleeding, epistaxis or bleeding after cervical erosion [11]. In a family studied from a spontaneous subcutaneous haematoma, eight confirmed heterozygotes and a ninth presumed from position in the pedigree included several patients with recurrent epistaxis, easy bruising, gum bleeding or postoperative oozing for more than 72 hours [4].

Expressivity varies between individuals with the same level, within the same family and, in the same individual, over time and according to the haemostatic challenge [3, 13]. The explanations proposed include the contribution of other components of haemostasis, platelet FXI, which is not measured in plasma, and the insensitivity of the clotting assay to part of the functions of FXI, notably its antifibrinolytic effect [3]. Coexistence of von Willebrand disease or platelet dysfunction modulates the phenotype, and the RCOG recommends assessing von Willebrand factor and platelet function in women with FXI deficiency and bleeding [12, 13].

There are no allelic disorders of F11 in the sense of distinct phenotypes caused by the same gene. There is, however, a contiguous entity: in four of the seven index cases with large deletions in the German cohort, the deletion encompassed the whole of F11 and extended into KLKB1, and all these patients had a second defect in KLKB1 that reduced prekallikrein activity to almost undetectable values (<1 IU/dL); FXI levels were between 35 and 56 IU/dL and none had an additional bleeding diathesis, suggesting compensatory mechanisms, consistent with the fact that isolated prekallikrein deficiency does not cause bleeding [7]. One case from the same cohort was initially interpreted as homozygous for a missense variant, with FXI of 5 IU/dL, and later analysis revealed a large whole-gene deletion on the other allele, a pseudohomozygosity with direct consequences for family counselling [7].

3. Clinical Spectrum and Manifestations by System

3.1. Overall bleeding profile

FXI deficiency is a real but unpredictable bleeding disorder. In two British series totalling 128 cases, about 65% of patients were asymptomatic and the remainder had mainly bleeding after surgery and trauma; bleeding was more frequent after dental, oropharyngeal or urogenital surgery than after musculoskeletal or gastrointestinal surgery, and spontaneous bleeding and intracranial haemorrhage were very rare [12]. The 2025 laboratory diagnosis review identifies as the most common symptoms heavy menstrual bleeding, spontaneous bruising and epistaxis, with postpartum haemorrhage and heavy menstrual bleeding in about 20% of affected women, and emphasises that postoperative or post-traumatic bleeding may be potentially fatal [3]. The European patient association describes haemarthroses and spontaneous muscle haematomas as uncommon, unlike in the severe haemophilias [19].

The distinction between natural history and treated disease is essential. Older series of patients operated on without replacement describe bleeding rates of 49% to 67% in tissues with high local fibrinolysis [18]; contemporary cohorts, in which most risk procedures receive tranexamic acid or plasma, describe overall rates of 0% to about 19% and major bleeding in up to 7% [21].

3.2. Relationship between FXI level and bleeding

The weak correlation between FXI activity and phenotype is the feature that most distinguishes this disease from the other rare coagulopathies, an observation consolidated since the reviews of the 2000s, which already noted that the relationship between level and phenotype was much less clear than in the haemophilias [44, 45]. The consensus of the European Society of Cardiology Working Group on Thrombosis states that, in most rare bleeding disorders, the degree of deficiency correlates with bleeding severity, with the exception of factor XI [46]; the proposals of the French reference centre classify the laboratory–clinical correlation for FXI as non-existent, the only rare coagulopathy so classified [17]; the British guideline classifies it as very weak, in contrast to the strong correlation of factor X and factor XIII deficiencies [12].

The quantitative data support this position. In the European rare bleeding disorders registry, with 125 cases of FXI deficiency, major bleeding occurred with activities between 0.09 and 0.41 IU/mL and asymptomatic patients had activities between 0.14 and 0.39 IU/mL, ranges that overlap almost entirely [12, 47]. The classification of rare coagulopathies based on the association between activity and bleeding severity places FXI in the group in which this association is weakest [48]. In the ROC (receiver operating characteristic) curve analysis of the New York cohort, with 252 procedures, the area under the curve of FXI activity for predicting bleeding was 0.62, and a value of 40 U/dL had a sensitivity of 47% and a specificity of 75%; alternative thresholds gave a sensitivity of 16% to 69% and a specificity of 46% to 93% [43]. In that study, only 8 of the 33 bleeding episodes occurred in patients with FXI below 20 U/dL, and personal bleeding history was the strongest predictor (odds ratio 5.92; 95% confidence interval 1.98–17.71; p=0.001), with FXI activity contributing modestly (odds ratio 0.72 per 10 U/dL increase; 0.54–0.97; p=0.05) [43]. The 2026 systematic review, with more than 590 procedures, found no consistent association between FXI activity and perioperative bleeding, and concluded that procedure characteristics and personal bleeding history align better with outcomes [21]. Surgical risk is nevertheless greater with FXI below 0.2 IU/mL, but some patients below this value never bleed and others bleed at higher levels [12].

The Dutch rare bleeding disorders study (RBiN, Rare Bleeding disorders in the Netherlands), cross-sectional and national, included 263 patients from the country's six haemophilia centres and measured the correlation between baseline factor activity and ISTH-BAT score: the correlation was strong in factor II (r=−0.792) and factor X (r=−0.838) deficiencies, moderate in fibrinogen, factor V, factor VII, factor XIII and α2-antiplasmin deficiencies, and absent in FXI deficiency (r=−0.218) [49]. In the cohort as a whole, 48% of patients had more severe bleeding than predicted by factor level, and 34% of patients predicted to be asymptomatic had grade 2 or 3 bleeding, so the authors consider the activity thresholds previously proposed for rare coagulopathies to be inaccurate [49]. In the thrombin generation substudy of the same cohort, the 26 patients with FXI deficiency (median age 56 years; median activity 42 IU/dL, interquartile range 10–52) had a median ISTH-BAT score of 8 (5–11); seven (27%) were grade 1, without spontaneous bleeding, 19 (73%) grade 2, with mild spontaneous bleeding, and none grade 3, with severe spontaneous bleeding [50]. These proportions describe patients followed in haemophilia centres, not the population carrying the deficiency. In a Spanish cohort of 269 individuals with FXI deficiency, only 15 of whom had severe deficiency (FXI:C below 20%), 52 (19.3%; 95% confidence interval 15.1%–24.5%) had a bleeding history, and 36.5% of episodes occurred at sites of injury [51].

Among the modifiers of bleeding risk studied, tissue factor pathway inhibitor (TFPI) has the most data. In an in vitro model of FXI deficiency, TFPI inhibition increased thrombin generation and clot formation, increased fibrin network density and reduced fibrinolysis, whereas exogenous TFPI had the opposite effect; in two independent cohorts (16 patients and 10 controls; 56 patients and 48 controls), plasma from patients with a bleeding phenotype had higher total TFPI than that of controls, and TFPI concentration correlated with the clot formation and fibrinolysis parameters that distinguish patients with and without bleeding [52]. The 2026 review presents TFPI as a possible modulator of bleeding risk in FXI deficiency, with no established clinical application [53].

3.3. Manifestations by system and by age

In the neonatal period, FXI activity is physiologically low: in healthy term newborns it is between 0.1 and 0.68 IU/mL and increases during the first six months, so diagnosis at this age requires neonatal reference ranges and confirmation at six months; mild deficiency cannot be reliably diagnosed before the first months of life [12, 13]. There are no published cases of spontaneous bleeding or neonatal intracranial haemorrhage attributed to FXI deficiency [12, 13]. Circumcision performed on the eighth day of life was accompanied by bleeding, sometimes severe, in 19% of cases in a British series and in less than 2% in an Israeli series, a divergence that the British guideline classifies as conflicting evidence [12].

A 2026 review organises risk by age. In early childhood, most bleeding complications in severe deficiency arise in not-yet-diagnosed children undergoing circumcision before six months; after six months, FXI activity reaches adult values; in adolescence and the premenopausal years, complications are concentrated in invasive procedures in tissues of high fibrinolysis; in men over 65 years, risk increases in prostatectomy without haemostatic therapy when FXI activity is below 30%; and the accumulation of comorbidities with age shifts the haemostatic balance towards thrombosis, with a need for antithrombotics that alter it again [53]. The 30% threshold in urological surgery comes from an Israeli series: after two cases of severe bleeding, systematic aPTT screening in a urology department in 1975 and 1976 identified ten more patients, all Ashkenazi Jews of Eastern European origin, five with severe deficiency and five with partial deficiency; the five with severe deficiency were operated on without complications with fresh frozen plasma at 5 to 20 mL/kg/day from the day before until 10 to 14 days after surgery, and one of three patients with partial deficiency operated on without transfusion had postoperative bleeding [54].

In childhood and adolescence, diagnosis is often difficult because haemostatic challenges are scarce; the laboratory review emphasises the difficulty of prediction in children and young men [3]. A published case illustrates traumatic risk: a 6-year-old child with severe deficiency developed a 12 by 8 cm subgaleal haematoma after a fall of about half a metre [55].

In the reproductive years, gynaecological and obstetric manifestations predominate. Heavy menstrual bleeding and postpartum haemorrhage are common [12]. In a cohort of 198 patients, 21.7% had a bleeding phenotype and 15.7% previous surgical bleeding; a bleeding complication occurred in 13% of the 252 procedures, with 23 episodes of postpartum haemorrhage, and the rate was 23.8% in caesarean sections versus 7.6% in vaginal deliveries (p=0.006) [43]. In the French multicentre study of 314 pregnancies in women with FXI below 60 IU/dL, 17.5% had postpartum haemorrhage or excessive bleeding, with 28.4% in the 102 caesarean sections [56]. The RCOG estimates an overall risk of postpartum haemorrhage of 16% to 22%, 17% to 30% in homozygous women, with a relative risk of 7.2 (1.99–25.90) in the presence of a bleeding phenotype [13].

The Dutch data quantify the burden of gynaecological and obstetric bleeding in rare coagulopathies. Among 111 women aged 16 years or older in the RBiN study, 80% reported heavy menstrual bleeding (a score of at least 1 on this ISTH-BAT item), 74% of those with a coagulation factor deficiency; 82% of those affected needed treatment, mainly hormonal (88%), and only 25% received antifibrinolytics; in the 61 women with heavy menstrual bleeding since menarche, the median age at diagnosis of the coagulopathy was 28 years (interquartile range 14–41) [57]. In the FXI deficiency subgroup, the 2026 review reports heavy menstrual bleeding in 60% of women, with an almost universal need for supportive treatment (iron, hormones, tranexamic acid) and a median age at diagnosis of 25 years, compared with 14 years at menarche [53]. In the obstetric analysis of the same cohort, with 244 pregnancies in 85 women, postpartum haemorrhage (loss of 500 mL or more) occurred in 44% of deliveries with haemostatic prophylaxis and in 53% of deliveries without prophylaxis, with a median blood loss of 400 mL versus 1000 mL (p=0.011) [58]; in the FXI deficiency subgroup, the 2026 review reports postpartum haemorrhage only in women without peripartum haemostatic therapy, in 19 of 33 deliveries (58%), mostly with severe deficiency and without tranexamic acid at delivery [53]. In a New York cohort of 28 women (24 Ashkenazi) and 64 pregnancies, between 2006 and 2018, postpartum haemorrhage occurred in 9 of 53 deliveries (17%), 14% in partial deficiency and 22% in severe deficiency [59]. Estimates diverge according to the definition of postpartum haemorrhage, the proportion of severe deficiency and the use of prophylaxis, and the 2026 review concludes that risk is associated more with bleeding history than with FXI level [53].

In old age, the clinical problem is twofold. The 2024 review identifies older people as the group in which bleeding and thrombotic complications must be weighed simultaneously, the latter mainly associated with replacement [60]. The European cardiology consensus notes that, despite congenital hypocoagulability, serious venous and arterial thromboembolic events can occur at any age, and describes a systematic review of cases published up to 2015 with 45 acute coronary events in rare bleeding disorders, 36 of them in patients with FXI deficiency, most with classical atherosclerotic risk factors; two patients had acute peripheral arterial occlusion [46].

3.4. Thrombotic profile: partial protection

A coherent body of Israeli studies documents protection against thrombotic events, but not against acute myocardial infarction. In 115 patients with severe deficiency aged 45 years or older, 8.56 ischaemic strokes were expected after adjustment for hypertension, diabetes, hypercholesterolaemia and smoking, and only one was observed (p=0.003), whereas the frequency of myocardial infarction (19 of 115) was similar to that expected [61]. In 219 unrelated patients with severe deficiency, aged 20 to 94 years, no case of deep vein thrombosis was recorded, against 4.68 expected [62]. In 96 patients with FXI below 15 U/dL aged 35 years or older, 16 had myocardial infarction, with an annual rate similar to that of the population in men and almost double in women, without statistical significance, and with at least one atherosclerotic risk factor in 81.3% of those with infarction [63]. In the historical cohort of an Israeli health system, with 10,193 adults tested between 2002 and 2014, the adjusted risk of cardiovascular events was 0.52 (0.31–0.87) in mild deficiency (30% to 50%) and 0.57 (0.35–0.93) in moderate to severe deficiency (≤30%), and the risk of venous thromboembolism with FXI below 50% was 0.26 (0.08–0.84) [64]. In a retrospective oncology study with 73 patients with FXI deficiency and 185 matched controls, venous thromboembolism at 12 months was 4.1% (1.1–11%) versus 10.6% (6.6–16%; p=0.052), with surgery-related major bleeding in 12.9% versus 2.1% in patients who underwent surgery [65]. Protection is therefore neither absolute nor uniform across outcomes, and coexists with an excess perioperative bleeding risk.

The excess bleeding risk was quantified in a matched cohort from another Israeli health system: among individuals tested between 2007 and 2018, fewer than 10% had FXI below 50%; compared with the general population, these had major bleeding with an adjusted risk of 2.56 (1.13–5.81), with a 10-year absolute risk of 1.90% versus 0.90%, and clinically relevant non-major bleeding with an adjusted risk of 1.45 (1.08–1.97), 11.60% versus 9.20%; the numbers of cardiovascular and venous events were too small for conclusions (two and one event, respectively) [66]. The relative excess is real and the absolute risk is low, a reading that is lost if only the relative risk is cited.

3.5. Alloinhibitors and acquired deficiency

Anti-FXI alloantibodies are polyclonal immunoglobulin G directed at several epitopes, which inhibit activation of FXI by thrombin or FXIIa and activation of factor IX by FXIa [3, 40]. They do not worsen the bleeding phenotype, but render replacement with plasma or concentrate ineffective [3, 6]. In the Israeli series of 118 patients with severe deficiency, seven had an inhibitor, all in the subgroup of 21 homozygotes for the null allele with a history of plasma replacement, that is, 7 of 21 (33%) [40]. Three additional patients with an inhibitor, from the United Kingdom and the United States, had the same genotype and previous exposure to plasma [4, 40]. In the experience of a British centre with 682 patients with FXI deficiency, 113 of whom had FXI below 20 IU/dL and 42 activity of 1 IU/dL or less, inhibitors arose in seven patients, six of them homozygous for the type II variant, with a prevalence of 30% in this genotype and a 50% risk after exposure to plasma; there were no inhibitors in other genotypes despite similar exposures, the bleeding phenotype did not change and the inhibitor disappeared spontaneously in four of the seven patients over 1 to 22 years [6]. The overall prevalence of antibodies in this population is between 3% and 5% [3].

In the French prospective post-marketing study of FXI concentrate, a patient homozygous for a null variant (C118X in exon 5, in the source's historical numbering, = NM_000128.4:c.408C>A p.(Cys136Ter)) developed an inhibitor three months after an inguinal herniorrhaphy; the inhibitor became undetectable a year later, but a new administration for another operation provoked an anamnestic response of more than 500 Bethesda units [67]. Spontaneous disappearance of the inhibitor does not therefore guarantee the absence of a response on re-exposure.

Acquired FXI deficiency due to autoantibodies is rare and has been described in Waldenström macroglobulinaemia, chronic lymphocytic leukaemia, plasma cell leukaemia, autoimmune diseases, pregnancy and a patient with Crohn disease and SARS-CoV-2 infection [3]. The patient association recommends suspecting this form when an isolated prolonged aPTT appears de novo without a previous bleeding history [19].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Three situations lead to diagnosis: unexpected bleeding after a haemostatic challenge, screening of relatives of a known case and discovery of an isolated prolonged aPTT at a preoperative assessment [3]. Diagnosis is frequently late, which the French review of rare coagulopathies notes as a characteristic of FXI deficiency [17].

In children, suspicion arises after prolonged bleeding at tonsillectomy, dental extraction or circumcision, or after a haematoma disproportionate to the trauma [12, 55]. In adolescent girls and adult women, heavy menstrual bleeding, with or without iron-deficiency anaemia, is the most frequent manifestation; the European Hematology Association consensus recalls that heavy menstrual bleeding was reported by 27% of 4506 women in a European survey, of whom 15% sought care, and that hormones and pregnancy may mask the diagnosis by raising coagulation factors, so it recommends measuring ferritin and total iron-binding capacity even with normal haemoglobin [68]. In adults, the typical presentation is unexpected surgical bleeding, particularly after oral, nasopharyngeal, urological or gynaecological surgery [12, 18].

Objective quantification of the bleeding history is now the most useful tool. The European consensus proposes a stepwise approach, with standardised screening — aPTT, PT with international normalised ratio and platelet count — in all referred patients, and targeted investigation reserved for those with a qualifying bleeding phenotype or a relevant screening abnormality; the qualifying phenotype is defined by the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT), with abnormal thresholds of at least 4 in adult men, 6 in adult women and 3 in children, corresponding to a specificity of 97.5% [68]. The same document advises against indiscriminate preoperative screening of healthy individuals and does not support untargeted genetic testing outside a research context [68].

4.2. Warning signs and emergencies

The signs that call for immediate action are active bleeding in a territory of high fibrinolysis, postpartum haemorrhage and postoperative bleeding that does not respond to local measures. In these settings, management depends less on the FXI level than on personal history and the site of the procedure [21]. A patient with severe deficiency previously exposed to plasma or concentrate and with an insufficient response to replacement should be assessed for an alloinhibitor before a new intervention, a formal recommendation of the British guideline [12].

A recently appearing isolated prolonged aPTT in a patient without a previous bleeding history raises the possibility of acquired deficiency due to an autoantibody or of lupus anticoagulant, rather than congenital deficiency [3, 19]. An undiagnosed patient may develop significant haematomas after surgery, a situation ClinGen invokes to classify the condition as strongly actionable in adults: knowing the diagnosis before a procedure changes management [15].

4.3. Newborn screening and carrier screening

There is no newborn screening for FXI deficiency, and the RCOG considers prenatal diagnosis unnecessary because of the low morbidity of the disease; it recommends only avoiding cranial trauma in a newborn at risk of homozygosity and, if the baby is a boy and circumcision is planned, collecting a sample for assay [13]. Neonatal assay requires age-specific reference ranges and confirmation at six months [12].

FXI deficiency is detected by commercial expanded carrier screening panels. In a screening cohort of 23,453 individuals, the carrier frequency was 1 in 92 across all populations, with a 95% confidence interval between 1 in 80 and 1 in 108, and 1 in 12.6 (1 in 11 to 1 in 15) in the Ashkenazi subgroup, compared with 1 in 8 reported in the literature; in that table, FXI deficiency is the most frequent condition in the Ashkenazi group and does not appear among the ten most frequent in North-West Europe, and it is not flagged as recommended screening [69]. This incidental detection has practical consequences for counselling, discussed in section 8.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria and algorithm

Diagnosis rests on the combination of an isolated prolonged aPTT, with normal PT, thrombin time, fibrinogen and platelet count, correction of the aPTT in the mixing study and reduced FXI activity on a specific assay [3, 19]. The reference range for FXI:C is usually between 70 and 150 U/dL, with some laboratories using 65–125 U/dL; each laboratory should establish its own range [3]. The German cohort uses 60 to 150 IU/dL as the normal range, 20 to 60 IU/dL for partial deficiency and values below 20 IU/dL for severe deficiency [7].

The practical algorithm unfolds in four steps. First, confirm the screening abnormality and exclude pre-analytical and pharmacological causes. Second, perform the 1:1 mixing study with normal plasma, with incubation at 37 °C for 30 minutes, or 2 hours if a time-dependent inhibitor is suspected; the Rosner index, calculated as the difference between the mixture time and the normal plasma time divided by the patient's time, indicates correction if it is 10% or less, absence of correction if it is 15% or more, and requires repetition between 10% and 15% [3]. Third, assay FXI activity by a one-stage assay with at least three dilutions, adding antigen when quantitative and qualitative deficiency need to be distinguished. Fourth, in patients with confirmed deficiency, consider molecular study of F11, indicated for counselling, cascade screening, unusual phenotypes and assessment of alloinhibitor risk [7, 19].

5.2. The aPTT and reagent sensitivity

Prolongation of the aPTT generally appears below about 30 U/dL, and partial deficiencies between 20 and 60 U/dL may go undetected depending on the reagent used [3]. The German cohort estimates that the aPTT fails to detect partial deficiencies in more than one third of patients, particularly above 30% activity [7]. In a study of heterozygotes, the silica reagent gave an aPTT of 41.9 ± 4.4 seconds for FXI:C of 42.8 ± 11.8%, whereas another reagent gave 32.9 ± 3.5 seconds for FXI:C of 48.4 ± 12%, showing the superiority of silica for screening; for mild deficiency, sensitivity to FXI between 40 and 50 U/dL is needed, achieved with some reagents and not with others, and a correlation study between an automated reagent and FXI activity between 1% and 50% obtained a coefficient of determination of 0.600 [3]. The sensitivity of the local reagent should be assessed according to CLSI (Clinical and Laboratory Standards Institute) document H47-A2, using dilutions of calibrator plasma in deficient plasma with activity below 1 U/dL [3].

A clinical consequence follows, expressed by the British guideline: FXI assay should be considered even with a normal aPTT in patients with bleeding, because some reagents are insensitive to activities between 0.5 and 0.7 IU/mL, a range in which bleeding has been described [12]. Some symptomatic heterozygotes have FXI within the normal range, and in these cases diagnosis is possible only genetically [3]. In pregnancy, the aPTT shortens owing to the rise in factor VIII and is insufficient to assess heterozygous women [56].

Dependence on the activator is measurable in the same patient. In a primigravida with FXI activity of 52.6%, the silica aPTT was 34.4 seconds against 31 seconds for reference plasma (ratio 1.10; range 28–35 seconds), therefore within range, whereas the kaolin aPTT was 41.3 seconds (ratio 1.33; range 28–36 seconds) and the ellagic acid aPTT 37 seconds against a reference of 26 seconds (ratio 1.42; range 28–36 seconds); the deficiency was then confirmed by parallelism of the dilutions [70]. This pattern is the reverse of that in the study of heterozygotes cited by the laboratory review, in which silica was the most sensitive reagent, and the divergence shows that the hierarchy between activators depends on the commercial formulation and the reagent–analyser pair, not on the chemical class of the activator [3, 70]. The practical consequence is that the reagent used for screening must be characterised locally for its sensitivity to FXI, and that an aPTT ratio close to 1.0 obtained with a single reagent does not exclude partial deficiency.

Two cohorts quantify the extent of this insensitivity. In the New York obstetric series, with 28 women and a median FXI activity of 42 IU/dL (range below 1 to 73 IU/dL), the median aPTT at the first haematology visit was 32.2 seconds, within the laboratory reference range of 25.9 to 35.1 seconds; in the third trimester, the median aPTT was 30.3 seconds in partial deficiency, likewise normal, versus 43.1 seconds in severe deficiency [59]. In the thrombin generation substudy of the Dutch RBiN cohort, with a silica reagent on an automated analyser and a reference range of 26 to 34 seconds, the sensitivity of the aPTT in the 26 patients with FXI deficiency was 52% for a specificity fixed at 95%, that is, almost half of the patients with confirmed deficiency had an aPTT within range [50]. Triage based on the aPTT alone therefore fails to identify a substantial fraction of partial deficiencies, which supports direct FXI assay in patients with a bleeding phenotype or family history, regardless of the screening result [12, 50].

5.3. Pre-analytical requirements and causes of error

The sample should be collected in 105–109 mmol/L (3.1% to 3.2%) trisodium citrate in a 1 to 9 ratio; EDTA, serum and sodium heparin are unsuitable; processing should take place within four hours, with platelet-poor plasma (less than 10 × 10⁹/L), obtained by centrifugation at 1500 g for 15 minutes or 1700 g for 10 minutes; storage allows two weeks at −20 °C or three to six months between −40 °C and −70 °C, with thawing at 37 °C for five minutes [3]. Haemolysis, lipaemia, icterus, underfilling of the tube and the presence of clots interfere, and a haematocrit above 0.55 L/L falsely prolongs the aPTT, requiring correction of the citrate volume [3]. Before interpreting a result, it is essential to exclude vitamin K antagonists, unfractionated heparin, low-molecular-weight heparin, dabigatran, rivaroxaban, edoxaban and apixaban; fondaparinux prolongs the aPTT by about 20% at therapeutic doses [3].

Non-genetic causes of low FXI include the neonatal period, liver disease, disseminated intravascular coagulation and acquired inhibitors; lupus anticoagulant and anticoagulants may mimic a deficiency in the assay [3, 12]. Raised C-reactive protein interacts with the reagent phospholipids and prolongs the aPTT, and raised factor VIII in inflammation may shorten it [3]. FXI pseudodeficiency, in the sense of a variant that reduces measured activity without biological consequence, has not been described in the sources consulted.

5.4. Specialised assays and global tests

The two-stage chromogenic assay, with kaolin for 60 minutes, corn trypsin inhibitor and para-nitroanilide substrate read at 405 nm, is linear up to 150% with a detection limit of 5%, but is available for research only; FXI antigen by ELISA (enzyme-linked immunosorbent assay) is likewise limited to research use and is necessary to distinguish quantitative from qualitative deficiency [3]. Absence of parallelism between dilutions in the one-stage assay suggests lupus anticoagulant or an inhibitor [3]. The inhibitor is quantified by the Nijmegen-modified Bethesda assay, one unit being defined as the amount that inactivates half of the FXI; investigation of a patient with a suspected inhibitor also includes screening for lupus anticoagulant and assay of factor VIII and factor IX, because of the possibility of cross-reacting antibodies [3].

Global tests have been studied precisely because the assay does not predict bleeding, but none is established. In rotational thromboelastometry with corn trypsin inhibitor and tissue factor at 0.12 pM, applied to 93 patients and 50 controls, whole blood distinguished activities of 15 IU/dL or less but not partial deficiency or phenotype; in platelet-rich plasma, patients with a bleeding phenotype had a clot formation time of 434 ± 179 seconds versus 277 ± 70 seconds and an α angle of 43.8 ± 9.5° versus 52.4 ± 5.8° (p<0.05), but specificity was 38.5% for a sensitivity of 100%, which limits clinical application [71]. Turbidimetric assays of clot formation and lysis in plasma treated with corn trypsin inhibitor showed reduced formation and lower resistance to fibrinolysis in patients with a history of bleeding after tonsillectomy or dental extraction, and a model combining aPTT, clot formation rate and the area under the fibrinolysis curve identified most of these patients, still in a research setting [72]. For thrombin generation, the literature uses tissue factor concentrations between 0.5 and 5 pM; at 1 pM some studies did not discriminate bleeding from non-bleeding patients, and the ISTH scientific committee recommends concentrations below 1 pM, possibly 0.5 pM, in FXI deficiency [3]. The British guideline and later reviews conclude that no laboratory assay reliably predicts perioperative bleeding [12, 21, 60].

The literature on global assays in FXI deficiency is concentrated on three platforms — thrombin generation, rotational thromboelastometry and the Nijmegen haemostasis assay — and the results depend more on the predefined assay conditions than on the platform: inhibition of contact activation with corn trypsin inhibitor, the presence or absence of platelets, the tissue factor concentration and the addition of plasminogen activator or thrombomodulin determine whether the assay separates patients from controls, FXI activities from one another or bleeding phenotypes.

Reading these studies together allows three operational conclusions. First, discrimination of the bleeding phenotype requires the FXI-dependent pathway to be interrogated under conditions of low extrinsic stimulation: conditions that suppress the contribution of FXI, whether by excess tissue factor or by inhibition of contact activation without platelets, abolish the difference between patients and controls [75, 76]. Second, sensitivity for detecting the deficiency is higher than that of the aPTT, and this is the use with the most consistent evidence, unlike individual prediction of bleeding [50]. Third, monitoring of replacement by these assays has not been validated: in a series of 11 adults treated before surgery with solvent/detergent-treated plasma (n=8) or FXI concentrate (n=3), with samples before and 30 minutes after, both products improved thrombin generation and clot formation, but the residual response at 24 hours after plasma was variable and changes in FXI activity did not predict changes in global assay parameters [80]. None of these assays has a prospectively validated decision threshold, so their use remains restricted to research protocols and multidisciplinary discussions in selected cases [12, 21].

5.5. Molecular diagnosis, yield and limits

Sanger sequencing and next-generation sequencing have high sensitivity for single nucleotide variants; deletions are detected by read-depth analysis in next-generation sequencing or by MLPA; non-coding variants are difficult to interpret, and complex rearrangements have not been described and are not detectable by current methods [3]. In the German cohort of 316 index cases, sequenced by Sanger (76%) or by next-generation sequencing (24%) with a minimum coverage of 30-fold, with screening for large deletions and duplications by MLPA or copy number analysis, a genetic defect was identified in 249 patients, a variant detection rate of 79% [7]. The rate varied with activity: 96% in severe deficiency (below 20 IU/dL), 80% between 21 and 30 IU/dL, 70% to 92% up to 60 IU/dL, and only 14% above 60 IU/dL, with a Pearson correlation coefficient of −0.891 between activity and detection rate [7]. This variant detection rate is not a clinical sensitivity: it measures the proportion of cases with an identified variant in a population already selected for reduced activity, and not the ability of the test to identify who will bleed.

Of the 129 unique variants identified in that cohort, 81 (63%) were classified as pathogenic and 48 (37%) as variants of uncertain significance; 15 were reclassified as likely pathogenic on the basis of defect type, 16 by family segregation analysis, and 17 remained variants of uncertain significance [7]. Among patients without an identified defect, activities ranged from 3 to 60 IU/dL, including three with severe deficiency, which the authors attribute to the limitation of the analysis to exonic and flanking regions [7]. In three patients with compound heterozygosity and activity between 50 and 55 IU/dL, family analysis showed that both variants were on the same allele [7]. In an earlier study cited by ClinGen, 24 of 25 index cases with FXI below 50 IU/dL had an F11 variant, 22 in the heterozygous state and two in the homozygous state [15].

The laboratory report should state the gene, the transcript with version (NM_000128.4), the HGVS description at cDNA and protein level, the zygosity and the classification according to ACMG (American College of Medical Genetics and Genomics) and AMP (Association for Molecular Pathology) criteria, conventions followed by the German cohort, which compared causality with HGMD (Human Gene Mutation Database) and with the ClinGen database [7]. A negative result does not exclude the diagnosis, which is biochemical; conversely, identification of a variant does not predict the bleeding phenotype.

5.6. Prenatal and preimplantation diagnosis

Prenatal diagnosis is technically possible when the familial variants are known, but the RCOG considers it unnecessary because of the low morbidity of the disease and the absence of described spontaneous neonatal bleeding [13]. The sources consulted contain no series of preimplantation genetic testing in families with FXI deficiency; the decision, when it arises, follows the general principles applicable to treatable conditions of variable severity.

6. Differential Diagnosis

6.1. Comparative table

6.2. Isolated aPTT prolongation: the central distinction

The most frequent diagnostic problem is that of an isolated prolonged aPTT with a normal PT. FXI deficiency, factor XII deficiency, prekallikrein deficiency and HMWK deficiency produce the same laboratory abnormality, but only the first causes a bleeding tendency; extrapolating from aPTT prolongation to bleeding risk is therefore a recurrent error [8, 19]. The genomic proximity of F11 and KLKB1 adds a nuance: in contiguous deletions, the two deficiencies coexist, with almost undetectable prekallikrein activity and no worsening of bleeding [7]. Correction of the aPTT in the mixing study separates factor deficiencies from inhibitors, and investigation for an inhibitor is mandatory in any patient previously exposed to plasma [3, 12].

6.3. Differential diagnosis with the haemophilias and von Willebrand disease

Haemophilias A and B and von Willebrand disease are part of the differential diagnosis. The three entities are distinguished from FXI deficiency by inheritance, bleeding profile and the correlation between level and severity. The X-linked haemophilias present with spontaneous joint and muscle bleeding in severe forms, and factor activity correlates well with phenotype; von Willebrand disease presents with mucocutaneous bleeding and may occur with normal PT and aPTT, so a normal screen does not exclude it [2]. Type 2N von Willebrand disease and forms with reduced factor VIII are the most misleading differentials within the group of mucosal bleeding disorders, and the European patient association lists them explicitly in the differential diagnosis of FXI deficiency [19]. For the same reason, coexistence of these entities should be sought: the British guideline identifies the presence of another coagulopathy as an independent predictor of bleeding in FXI deficiency [12], and a published case documents the association of FXI deficiency with reduced von Willebrand factor activity in a child with recurrent subgaleal haematoma [55].

6.4. Secondary FXI deficiencies

A reduced FXI may be a manifestation of another disease. In congenital disorders of glycosylation, hypoglycosylation of serum proteins simultaneously reduces FXI, antithrombin, protein C and other glycoproteins, with a mixed bleeding and thrombotic profile; in PMM2-CDG, monitoring of electrolytes, blood glucose, coagulation factors, notably factors IX and XI, and proteins C and S, antithrombin and heparin cofactor II is recommended in the setting of fever, dehydration, anaesthesia and surgery, even with a normal aPTT [81, 82]. In Noonan syndrome, partial intrinsic pathway deficiencies, including FXI, are part of a multifactorial bleeding diathesis [83]. Thus, a low FXI accompanied by other haemostatic abnormalities or a syndromic picture should point towards the underlying disease and not towards a diagnosis of isolated congenital FXI deficiency. A deficiency may also be acquired through liver transplantation from a donor with congenital deficiency, a situation described in at least two recipients, who came to have the donor's deficiency, through hepatic production of FXI by the graft [4]; a history of liver transplantation should therefore be part of the history taken for a recently appearing low FXI.

7. Treatments and Risk Management Strategies

7.1. General principles

Treatment is guided by the procedure and the bleeding episode, and is not given as continuous prophylaxis; the French proposals state that long-term prophylaxis is not justified in FXI deficiency [17, 60]. The decision rests on four elements: personal bleeding history, the site and type of procedure, FXI activity and the presence of another coagulopathy or an inhibitor [12, 21]. The British guideline identifies as higher-risk factors activity below 0.1 IU/mL, the presence of another coagulopathy, personal bleeding history and surgery with dental extraction or involving the oropharyngeal or genitourinary mucosa (grade 2C recommendation) [12].

Classification of procedural risk follows the distinction between territories of high fibrinolysis — oral cavity, nasopharynx, urological, obstetric and gynaecological tracts — and of low fibrinolysis, such as cardiac, orthopaedic and general surgery, a descriptive and unvalidated framework [21]. The French proposals also use a classification by surgical magnitude: they consider as major surgery resections, osteotomy and arthrodesis, extraction of three or more teeth including wisdom teeth, organ incisions, arthroplasty, endoscopic polypectomies, mucosectomies and biopsies, synovectomy, fracture reduction, amputation and arthroscopy, and as minor surgery insertion or removal of a central venous catheter, synoviorthesis, extraction of fewer than three teeth other than wisdom teeth, cataract surgery and debridement [17].

General measures include avoiding high-risk activities, preferring lower-risk procedures, having a written treatment plan issued by the haemophilia centre, using topical haemostatic agents and treating heavy menstrual bleeding with endocrine therapy [12]. ClinGen recommends avoiding non-steroidal anti-inflammatory drugs because of their antiplatelet effect [15].

7.2. Antifibrinolytics

Tranexamic acid is the first-line treatment in most situations. The 2025 laboratory diagnosis review states that tranexamic acid alone is sufficient in most cases, including in severe deficiency, reserving replacement and bypassing agents for patients whose phenotype or procedural risk justifies them [3]. The mechanism is competitive inhibition of plasminogen binding to fibrin, which prevents clot lysis; the half-life is about two hours, which determines administration every six hours [3]. The safety profile is favourable and it does not increase thrombotic risk; the drug may be given orally, parenterally or topically in the oral cavity and is considered safe in pregnancy and childhood [3]. The specific limitation is bleeding from the renal tract, in which clot formation may cause ureteric obstruction, so use is relatively contraindicated at that site [3, 12].

The most convincing direct evidence is old and remains valid: in 19 patients with severe deficiency (FXI:C below 14 U/dL) who had previously bled after dental extraction or other trauma, tranexamic acid 1 g four times daily, started 12 hours before and continued for seven days, without plasma, prevented excessive bleeding in all; one patient had slight oozing on the third day, which resolved spontaneously [84]. A recent urological series, with seven patients with severe deficiency undergoing seven procedures, five with a bleeding phenotype and two with anti-FXI antibodies, combined tranexamic acid 1 g four times daily for 7 to 10 days with a single low dose of rFVIIa and continuous bladder irrigation, without significant bleeding, transfusions or thrombosis; the only patient with controllable bleeding was continuing acetylsalicylic acid [85].

The reference dose is that of the guidelines. The UKHCDO recommends considering tranexamic acid 15–20 mg/kg or 1 g four times daily for 5 to 7 days for minor bleeding, minor surgery in high-risk patients and any bleeding or surgery in low-risk patients (2C), given orally or intravenously up to two hours before the procedure [12]. The French proposals use, as a general rule for rare coagulopathies, 15–20 mg/kg or 1 g every six hours [17]. At delivery, the UKHCDO recommends 15–20 mg/kg in established labour or before caesarean section in women with FXI below 0.15 IU/mL, and 15 mg/kg or 1 g four times daily for at least three days in women with FXI between 0.15 and 0.70 IU/mL with a bleeding history or without previous challenges (2C) [12]. The guideline does not define a maximum daily dose; the regimen of 1 g four times daily corresponds to 4 g/day in adults [12]. The RCOG repeats the dosing of 15–20 mg/kg or 1 g four times daily for rare coagulopathies in general, alone for minor bleeding and combined with replacement in higher-risk situations, and notes that the amount excreted in breast milk is limited and that an antifibrinolytic effect in the infant is unlikely [13].

The doses in the official labels are cited for comparison, because none of them has FXI deficiency as an approved indication. The US label for the injectable formulation indicates the drug in patients with haemophilia, for a short period of 2 to 8 days, to reduce or prevent bleeding and the need for replacement during and after dental extraction, with 10 mg/kg actual body weight intravenously before extraction and then 10 mg/kg three to four times daily for 2 to 8 days, infused at no more than 1 mL/min; renal adjustment reduces this to twice daily with serum creatinine between 1.36 and 2.83 mg/dL, once daily between 2.83 and 5.66 mg/dL and 10 mg/kg every 48 hours or 5 mg/kg every 24 hours above 5.66 mg/dL, with no maximum dose defined in the source [86]. This dose is about half the guideline dose, which is therefore above the label conditions; the clinical reference in FXI deficiency is the guideline dose [12, 86]. The same label has a boxed warning for intravenous use only, because neuraxial administration errors have caused seizures and fatal arrhythmias, and contraindicates the neuraxial route, subarachnoid haemorrhage and active intravascular coagulation, with warnings for thromboembolism (in particular with prothrombotic products such as prothrombin complex concentrates, anti-inhibitor coagulant complexes and hormonal contraceptives), seizures, hypersensitivity, visual disturbances and dizziness [86]. The US oral label, for cyclic heavy menstrual bleeding, indicates 1300 mg three times daily (3900 mg/day) for a maximum of five days per cycle, with reductions in renal impairment, and contraindicates concomitant use of combined hormonal contraception and active thromboembolic disease or intrinsic risk of thrombosis, including retinal vascular occlusion [87].

In Portugal, the summary of product characteristics of oral tranexamic acid (Tafixyl® 500 mg, first authorisation 11 November 2016, revised July 2026) indicates primary hyperfibrinolysis and local secondary fibrinolysis, including menorrhagia, bladder and prostate surgery, cervical conisation, dental extraction in patients with haemophilia A and B, and hereditary angioedema; dosing is 1 to 1.5 g two to three times daily in local fibrinolysis, 1 to 1.5 g three to four times daily for three to four days in menorrhagia and, for dental extraction in patients with coagulation disorders, 25 mg/kg three to four times daily for 6 to 8 days after a single intravenous dose; the medicine is indicated in adults and there is no experience below 15 years of age, the paediatric dose described is 25 mg/kg per dose and renal adjustment uses serum creatinine (15 mg/kg twice daily between 120 and 249 µmol/L, 15 mg/kg every 24 hours between 250 and 500 µmol/L and 7.5 mg/kg every 24 hours above 500 µmol/L), with no maximum daily dose defined in the source [88]. The injectable formulation (Tafixyl® 100 mg/mL, first authorisation 24 February 2015, revised February 2026) provides for 0.5 to 1 g by slow intravenous injection, at a rate of 1 mL/min, two to three times daily in localised fibrinolysis, 1 g every 6 to 8 hours (about 15 mg/kg) in generalised fibrinolysis, about 20 mg/kg/day above one year of age, with a contraindication in severe renal impairment and absolute prohibition of the intrathecal or epidural route [89]. Other injectable brands of tranexamic acid are authorised in Portugal [88].

In Brazil, tranexamic acid has active registration under several brands, including Transamin® (Zydus Nikkho), Hemoblock®, Traneger®, Ryvka® and Trexacont®, as well as generics [90]. The package insert for Transamin® 250 mg tablets indicates the drug for control and prevention of bleeding due to surgery, trauma and diseases with a bleeding tendency, and for hereditary angioedema; the adult dose in localised bleeding is 15 to 25 mg/kg, corresponding to two or three tablets, two to three times daily, and treatment may be started with the injectable form and switched to oral if prolonged beyond three days; the paediatric dose is 10 mg/kg per administration, two to three times daily; in preparation for dental extraction in patients with haemophilia it indicates two to three tablets every eight hours, and in excessive menstrual bleeding two to three tablets three to four times daily for three to four days; renal adjustment uses serum creatinine (25 mg/kg twice daily between 120 and 150 µmol/L, 25 mg/kg once daily between 250 and 500 µmol/L and 12.5 mg/kg once daily above 500 µmol/L); the recommended maximum daily dose is 12 tablets (3 g), which may rise to 18 tablets (4.5 g) in special situations under medical supervision; it recommends caution in urinary bleeding because of the risk of urinary tract obstruction, advises against use in disseminated intravascular coagulation and in the first three months of pregnancy and notes that only a small amount is excreted in breast milk [91]. The Brazilian indications are broader than those of the Portuguese and US labels and cover diseases with a bleeding tendency, but no label names FXI deficiency; the reference dose remains that of the guideline [12, 91].

For heavy menstrual bleeding, recommended practice combines the combined oral contraceptive and tranexamic acid, sometimes with desmopressin or replacement, in a multidisciplinary approach; ClinGen adds cyclical oral progestogen for 21 days and the levonorgestrel intrauterine device [3, 15, 68]. There is a divergence here that the clinician should know: the US oral label for tranexamic acid contraindicates concomitant use of combined hormonal contraception, whereas the reviews and ClinGen describe the two therapies as coordinated options in the same woman [3, 15, 87]. None of the sources consulted specifies strictly simultaneous administration, and the decision requires individual assessment of thrombotic risk.

The US reference body includes FXI deficiency in its document on licensed products: the Medical and Scientific Advisory Council (MASAC) of the National Bleeding Disorders Foundation, in document no. 299, adopted in September 2024 and revised in August 2026, states that there are no licensed products in the United States for the other rare coagulopathies, including FXI deficiency, and indicates fresh frozen plasma — from retested donors or solvent/detergent-treated from pools of 630 to 1520 donors — as an option for factor deficiencies without a specific concentrate [92]. The same document describes two antifibrinolytics: aminocaproic acid as a 1.25 g/5 mL syrup or tablets, at a dose of 50 to 100 mg/kg every six hours for 10 to 14 days, for oral and other mucosal bleeding, with the instruction to give the factor first to form the clot; and tranexamic acid, approved in the United States for heavy menstrual bleeding from 12 years of age, 1300 mg (two 650 mg tablets) every eight hours for five days of menstruation [92]. The document recommends that patients with an inherited coagulopathy should not use antiplatelet agents or non-selective non-steroidal anti-inflammatory drugs without instruction from the treating haematologist, and that a newborn with a bleeding disorder should receive intramuscular vitamin K with a 23-gauge or smaller needle, firm pressure on the site for at least two minutes without rubbing and information to carers about the risk of haematoma [92]. The reference dose of tranexamic acid remains that of the British guideline; aminocaproic acid has no published dose for FXI deficiency and the dose given applies to inherited bleeding disorders in general [12, 92]. In the New York obstetric cohort, aminocaproic acid was used in three deliveries and tranexamic acid in one, all in women with severe deficiency and always combined with plasma [59].

7.3. Solvent/detergent-treated plasma

Plasma was for decades the treatment of choice for surgery in severe deficiency [20]. It remains the main option in countries without access to FXI concentrate, with the uniform recommendation to use pathogen-reduced plasma [12, 13]. Solvent/detergent-treated plasma obtained from donor pools has a mean FXI concentration of 0.7 to 0.9 IU/mL, with product control above 0.5 IU/mL for factors V, VIII and XI, whereas single-donor methylene blue-treated plasma has variable content, and viral inactivation processes may reduce factors V, VIII and XI and fibrinogen [12]. The limitations are volume overload, allergic and transfusion reactions and the residual risk of infectious transmission [21]. Unlike the concentrate, plasma has not been associated with thrombosis [12].

The guideline dose is 15 to 25 mL/kg for severe bleeding and major surgery in high-risk patients, combined with tranexamic acid (UKHCDO, 2C), and 15 to 20 mL/kg to achieve FXI activity of 30 to 40 IU/dL in severe bleeding according to the French proposals, which keep 15 to 25 mL/kg as an alternative to the concentrate in major surgery [12, 17]. The label doses are lower and correspond to different indications: the US label for Octaplas® (revised October 2024, initial approval in 2013) indicates 10 to 15 mL/kg for replacement of multiple factors in acquired deficiencies — liver disease, cardiac surgery and liver transplantation — and 40 to 60 mL/kg (1 to 1.5 plasma volumes) in plasma exchange for thrombotic thrombocytopenic purpura, not including congenital FXI deficiency among the approved indications [93]. In Portugal, the summary of product characteristics of Octaplas® (authorisation of 29 December 1998, revised August 2026) explicitly includes in the indication "isolated deficiency of a coagulation factor whenever the specific coagulation factor concentrate is not available (for example: FV, FXI)", so use in FXI deficiency is within the approved indication; dosing provides for an initial dose of 12 to 15 mL/kg, which raises factors by about 25%, and states that in minor to moderate bleeding or surgery the haemostatic effect is normally obtained with 5 to 20 mL/kg, a dose that raises factors by 10% to 33%, referring major bleeding and surgery to specialist assessment [94]. The same document recommends monitoring the aPTT, the PT with international normalised ratio and specific factors, limits the rate to 1 mL/kg/min because of citrate toxicity, requires ABO group identity (with group AB as universal plasma in emergencies) and acknowledges limited experience in paediatric patients up to 16 years; the contraindications are hypersensitivity, IgA deficiency with anti-IgA antibodies and severe protein S deficiency [94]. The US label adds the risk of hyperfibrinolysis due to low α2-antiplasmin levels and of thrombosis due to low protein S levels, controlled in the product above 0.4 IU/mL, and describes a post-marketing paediatric study with 91 patients aged 0 to 20 years without hyperfibrinolytic or thromboembolic events attributed to the product [93]. In Brazil, the Octaplas® registration is inactive and there is an active registration of a nationally produced human plasma protein product [90].

In practice, the doses actually used are lower than those of the guidelines. In the New York cohort, the institutional protocol used 10 to 20 mL/kg (10 mL/kg if FXI above 20 U/dL or no bleeding history, 20 mL/kg if below 20 U/dL or with previous bleeding), without an FXI target because results were not available in time; prophylactic plasma was given in 8.3% of procedures, in 47.6% of procedures in patients with severe deficiency and in 4.7% of those with partial deficiency, and 8 of the 21 procedures with prophylactic plasma (38%) bled, three of them with a dose below 10 mL/kg [43]. In the case reports gathered by the systematic review, the typical dose was 10 to 20 mL/kg before the procedure with additional doses as needed [21].

7.4. Factor XI concentrate

There are two plasma-derived FXI concentrates, both of limited availability. The Bio Products Laboratory product (United Kingdom) is obtained by heparin-Sepharose affinity chromatography of non-UK plasma, with dry-heat inactivation, presented in 1000 IU vials, with a recovery of 0.021 IU/mL per IU/kg and a half-life of 48 hours; it has no marketing authorisation in the United Kingdom and is used on a named-patient basis [12]. Hemoleven® (LFB-Biomédicaments, Les Ulis, France) is obtained by depth filtration, ion exchange, solvent/detergent treatment and nanofiltration, likewise in 1000 IU vials, with a recovery of 0.019 IU/mL per IU/kg and a half-life of 46 hours [12]. The approximate recovery of 0.02 IU/mL per IU/kg and the half-life of about 50 hours mean that a dose of 10 to 20 IU/kg raises activity by 20 to 40 IU/dL, sufficient for most procedures without a further infusion; the text of the British guideline expresses this increase in "IU/mL", a unit incompatible with the calculation presented, which is a unit error in the source [12]. No recombinant FXI concentrate is in development [3], and in the United States no FDA (Food and Drug Administration)-approved FXI concentrate was identified in the databases consulted [90, 93].

The prospective post-marketing study of the French concentrate, conducted in 13 centres over three years, describes real-world use of the product: 44 patients (30 women), median age 37.5 years (8 months to 91 years), 29 (66%) with severe deficiency (activity below 20 IU/dL) and median baseline activity of 5.5 IU/dL, received 67 treatments — 43 operations including caesarean sections, 10 invasive procedures, 8 vaginal deliveries and 6 bleeding episodes [67]. The median dose per infusion was 18.0 IU/kg (9.3 to 38.7) and the median number of infusions per episode was 1, a single dose sufficing in 37 of the 67 episodes (55.2%); of the 143 infusions, 55 (38.5%) were 15 IU/kg or less, 49 (34.3%) 16 to 20 IU/kg, 30 (21.0%) 21 to 30 IU/kg and nine exceeded 30 IU/kg, because the whole vial content was given or its exact content was not known; in the six obese patients, the median dose was 20.9 IU/kg [67]. The observed recovery was 2.0 IU/dL per IU/kg, consistent with the summary of product characteristics, and the half-life described was 45.5 ± 7.9 hours [22, 67]. Efficacy was rated excellent or good in 63 of the 67 treatments, moderate in two and indeterminate in two; tranexamic acid was combined in eight procedures (18.6%) and enoxaparin 40 mg/day in ten (23.3%) [67]. Of the seven adverse effects, two were serious: acute respiratory distress about 15 hours after infusion and 7 hours after a neurosurgical intervention, fatal, attributed by the local investigator to massive pulmonary embolism — without autopsy, and with the expert committee unable to decide between a thrombotic cause and fat embolism, in a patient with obesity, baseline factor VIII of 180 IU/dL, air travel and extensive varicose veins — and the inhibitor described in section 3.5 [67]. The authors conclude that the product is effective in preventing bleeding, but that it should be used sparingly because of its potential prothrombotic effect and that dosing needs to be adapted in patients with intrinsic or acquired thrombotic risk factors, a conclusion that preceded the revision of the guidance on use [67, 95].

Thrombotic risk defines the use of the product. The first series described thrombosis in about 10% of treated patients, mainly those with cardiovascular disease [20]. The manufacturer's response was to add heparin and antithrombin to the formulation, and that of the scientific societies was to limit the individual dose to a maximum of 30 IU/kg, keep the FXI peak below 0.7 IU/mL and not combine antifibrinolytics [12]. In a British series of 134 procedures with concentrate there were two thrombotic events, and a later report showed that these measures did not eliminate them, which led to the recommendation of more conservative doses and use restricted to situations of high bleeding risk [12]. The experience of two British centres over five years confirmed this pattern: 29 patients (median age 57.1 years), 64 treatment episodes (56 operations, five bleeds and three other indications), 126,000 units administered, with a median baseline FXI of 9 U/dL; six clinically significant bleeds and two thrombotic events — a transient ischaemic attack and a pulmonary embolism — in two patients with severe deficiency, despite cautious use [96]. The 2026 systematic review puts the thrombotic risk of the concentrate at 5% to 7% and notes the unavailability of the product in several countries [21]. The international reference page dedicated to rare coagulopathies recalls that twelve thrombotic events associated with the French concentrate were reported in 2014, with subsequent revision of the guidance on use [95].

The summary of product characteristics of the French product (authorisation of 21 July 1998, updated 29 September 2026) indicates the concentrate in patients with severe congenital FXI deficiency, defined by a baseline level below 20%, for curative treatment of a bleeding event and, as prevention, exclusively for major surgery and in patients without a therapeutic alternative, in particular when volume overload is not tolerated and plasma is therefore contraindicated [22]. Dosing is prescribed by a haemostasis specialist: the maximum recommended initial dose is 15 IU/kg, reassessed according to efficacy and tolerance, doses above 20 IU/kg are rarely justified and the dose not to be exceeded is 30 IU/kg; the calculation aims at a target activity of 30% to 40% and uses the formula dose in IU/kg equal to the difference between target activity and baseline activity divided by individual recovery in per cent per IU/kg, assuming 2% when recovery is unknown (range 1.5% to 2.5%); for a target of 35%, the dose ranges between 14.0 and 23.3 IU/kg if baseline activity is zero and between 8.0 and 13.3 IU/kg if it is 15% [22]. The document requires regular monitoring of FXI activity, especially before readministration, specialist advice and testing for an inhibitor if bleeding persists or the target is not reached, and gives a half-life of about 48 hours (30 to 60 hours) with a peak at 30 to 60 minutes; administration is exclusively intravenous, immediately after reconstitution, at a rate not exceeding 4 mL/min [22]. The contraindications are allergy to any component, hypersensitivity to heparin and derivatives, including low-molecular-weight heparins, and a history of severe type II heparin-induced thrombocytopenia [22]. The warnings detail the postoperative arterial and venous thromboembolic risk, with a list of risk factors that includes major surgery, prolonged immobilisation, age, obesity, cancer, thrombophilia, personal and family history, atherosclerosis, diabetes, arrhythmias and prothrombotic drugs, among them tranexamic acid itself, oral contraception and hormone replacement therapy, and indicate clinical and laboratory monitoring after administration (FXI activity, PT including factor V, fibrinogen, platelets and fibrin degradation products), perioperative venous thromboembolism prophylaxis according to current recommendations and reassessment of risk before each new injection [22]. The non-interventional post-marketing study, with 46 patients and 145 injections, recorded five possibly related effects in five patients (10.9%): neutralising anti-FXI antibodies in one patient (2.2%), thromboembolism in one patient (pulmonary embolism and superficial phlebitis) and increased fibrin degradation products in two (4.4%); through spontaneous reporting, cases of hypersensitivity, stroke and disseminated intravascular coagulation were reported, with serious thromboembolism, sometimes fatal, in patients with risk factors and pulmonary embolism often early, about 24 hours after administration [22]. In pregnancy and breastfeeding, the product should be used only in case of absolute necessity [22]. The concentrate has no authorisation in Portugal, where the Infomed search returned no registration on 27 October 2026, nor an active registration in Brazil [90, 94].

7.5. Recombinant activated factor VII

rFVIIa is the main bypassing therapy, indicated mainly in patients with an alloinhibitor and also in patients with severe deficiency without an inhibitor who wish to avoid plasma-derived products; the thrombotic risk is higher than that of FXI concentrate and the half-life is 2.5 hours, which requires administration every 2 to 6 hours when used in a repeated regimen [3]. The British guideline and the French proposals converge on the low dose of 15 to 30 µg/kg combined with tranexamic acid in patients with an inhibitor [12, 17]. At haemophilia doses, thrombosis occurred in three of twelve patients with FXI deficiency, and a thrombin generation study showed that a concentration of 0.24 µg/mL produces an effect equivalent to 1.9 µg/mL, corresponding to about 80 µg/kg, which underpins the dose reduction [97]. The Israeli protocol applied tranexamic acid from two hours before until 7 to 14 days after surgery, with a single low-dose infusion of rFVIIa, in four patients with an inhibitor or IgA deficiency undergoing five major operations, without excessive bleeding and without thrombosis [97]. A later study in ten patients with severe deficiency and twelve interventions used a single dose of 10 to 15 µg/kg at wound closure, with tranexamic acid started two hours before and 4 g/day for 3 to 5 days: there was no excessive bleeding, no plasma-derived products were used, no thrombosis occurred and thrombin generation at the rFVIIa peak remained below the curve of healthy controls [98]. In the British alloinhibitor series, thirteen operations were managed with rFVIIa, including low doses of 15 to 30 µg/kg, with good haemostasis [6].

FXI deficiency is not an approved indication in any jurisdiction. The US label for NovoSeven® RT (initial approval in 1999, revised November 2022) approves the product in congenital haemophilia with inhibitors, congenital factor VII deficiency, Glanzmann thrombasthenia refractory to platelets and acquired haemophilia, with a boxed warning for serious arterial and venous thrombosis; the dose in the closest analogous condition, congenital factor VII deficiency, is 15 to 30 µg/kg every 4 to 6 hours until haemostasis, with efficacy reported at doses as low as 10 µg/kg, and 15 to 30 µg/kg immediately before surgery and every 4 to 6 hours perioperatively, with no maximum dose defined in the source [99]. The European summary of product characteristics (centralised authorisation of 23 February 1996, renewal of 9 February 2006) approves the same indications and, additionally, severe postpartum haemorrhage when uterotonics are insufficient, with 60 to 90 µg/kg as an intravenous bolus and the possibility of a second dose after 30 minutes; the dose in factor VII deficiency is likewise 15 to 30 µg/kg every 4 to 6 hours, with a mean plasma recovery of about 20% and a half-life of 2.82 to 3.11 hours [100]. The European document states explicitly that, when given outside the approved indications, arterial thromboembolic events are common (at least 1 in 100 and fewer than 1 in 10), with 5.6% versus 3.0% in a meta-analysis of placebo-controlled trials conducted outside the approved indications, and concludes that safety and efficacy have not been established outside the indications and that the product should not be used there [100]. It also recommends avoiding simultaneous administration of prothrombin complex concentrates, activated or not, notes that experience with combination with antifibrinolytics is limited, and advises caution in patients with a history of coronary disease or liver disease, postoperatively, in pregnant women and in the peripartum period, in newborns and in those at risk of thromboembolism or disseminated intravascular coagulation [100]. In pregnancy, it recommends avoiding use as a precaution, and in breastfeeding excretion into human milk is unknown [100]. The RCOG summarises the clinical position: rFVIIa is not licensed for this condition and is generally not recommended, except in the presence of an anti-FXI inhibitor [13]. The product has an active registration in Brazil [90], and eptacog beta activated (Cevenfacta®) has had European authorisation since 15 July 2022, restricted to congenital haemophilia with inhibitors from 12 years of age [100].

7.6. Desmopressin, topical agents and adjunctive measures

Older reviews included desmopressin among the therapeutic options for FXI deficiency, alongside fibrin glue and antifibrinolytics [45]. The current position is different: the effect is inconsistent and the drug is not used in current practice, a position shared by the 2025 laboratory review and by the European patient association, which describes it as having a variable effect and not as routine [3, 19]. No guideline consulted recommends it for this indication and no source read gives a dose for FXI deficiency. Fibrin glue and topical haemostatic agents remain useful in mucosal procedures, in combination with the antifibrinolytic [12, 45]. Dental extraction in patients with severe deficiency can be performed without plasma replacement, with an antifibrinolytic alone, as demonstrated in the 1992 series and reiterated by the reference literature on rare coagulopathies [84, 95].

7.7. Comparative regulatory framework

7.8. Guideline recommendations and divergences between societies

The 2014 UKHCDO guideline, issued on behalf of the British Committee for Standards in Haematology, is the only formal guideline dedicated to rare coagulopathies that includes graded recommendations for FXI deficiency; the search performed up to 27 October 2026 did not locate a later update, and the two most recent reviews confirm this absence [12, 17, 21]. Its seven recommendations for FXI deficiency are all grade 2C, except the second, grade 2B: identification of the factors of higher bleeding risk; screening for inhibitors before surgery or delivery in patients with FXI below 0.1 IU/mL previously exposed to replacement; tranexamic acid 15–20 mg/kg or 1 g four times daily for 5 to 7 days for minor bleeding or surgery in high-risk patients and for any bleeding or surgery in low-risk patients; FXI concentrate 10–15 IU/kg without tranexamic acid, or, alternatively, solvent/detergent-treated plasma 15–25 mL/kg with tranexamic acid, for severe bleeding or major surgery in high-risk patients; concentrate 10–15 IU/kg or plasma 15–25 mL/kg with tranexamic acid 15–20 mg/kg in established labour or before caesarean section in women with FXI below 0.15 IU/mL in the third trimester; tranexamic acid 15 mg/kg or 1 g four times daily for at least three days in women with FXI between 0.15 and 0.70 IU/mL with a bleeding history or without previous challenges; and expectant management, with replacement only if abnormal bleeding occurs, in women with the same activity range who have not bled despite previous challenges [12].

The proposals of the French reference centre, published in 2023 on the basis of the 2021 recommendations, diverge on three points. First, the haemostatic threshold: they consider treatment generally indicated with FXI below 15 IU/dL and place the haemostatic level between 15 and 30 IU/dL, with the note that rare patients with activity up to 30% may bleed and that personal and family history is decisive; the British threshold is 20 IU/dL and the laboratory review refers to a target of about 40 U/dL for major surgery [3, 12, 17]. Second, the explicit therapeutic target: FXI concentrate 10 to 15 IU/kg before and after surgery to keep activity above 30%, until healing, with plasma 15 to 25 mL/kg with or without tranexamic acid if the concentrate is not available or thrombotic risk is high [17]. Third, and most relevant in practice, they recommend thromboprophylaxis whenever replacement is prescribed, a provision that does not appear in the British or the RCOG guideline [17]. At delivery, the divergence is clear: the UKHCDO recommends considering replacement in all women with FXI below 0.15 IU/mL in the third trimester, the French proposals recommend only tranexamic acid in these women when there is no history of surgical or traumatic bleeding, reserving the concentrate for abnormal bleeding, and the RCOG proposes considering prophylactic replacement in homozygous and compound heterozygous women, in women with previous postpartum haemorrhage or a bleeding history, and expectant management with tranexamic acid alone in the others [12, 13, 17]. All sources agree on not combining tranexamic acid with FXI concentrate because of thrombotic risk [12, 13, 17].

The consensus of the European Society of Cardiology Working Group on Thrombosis adds recommendations for the patient with a congenital bleeding disorder and a cardiac indication for antithrombotic therapy, with the degree of agreement among the four experts given in brackets: involve an experienced haematologist (3/4); in coronary angiography and percutaneous intervention, prefer radial access (3/4) and use unfractionated heparin or bivalirudin after factor replacement (3/4); limit dual antiplatelet therapy with acetylsalicylic acid and clopidogrel to one month or less (3/4), giving factor concentrate during that period (2/4) and then moving to single antiplatelet therapy with low-dose acetylsalicylic acid while maintaining the replacement regimen (2/4); in ST-elevation infarction treated by primary intervention without heparin, measure factor levels immediately after the procedure and replace as needed (2/4); in non-ST-elevation infarction and unstable angina, replace before intervention (2/4); give the acetylsalicylic acid loading dose at diagnosis and avoid pre-loading with a P2Y12 receptor inhibitor (3/4); avoid thrombolysis, glycoprotein IIb/IIIa inhibitors, ticagrelor and prasugrel (3/4); combine a proton pump inhibitor with antiplatelet agents (3/4); in cardiac surgery, measure levels and test for inhibitors before the procedure and give concentrate before and after (3/4), preferring minimally invasive surgery (2/4) and mitral repair and an aortic bioprosthesis to a mechanical valve (2/4); in atrial fibrillation, decide case by case and, if anticoagulation is necessary, prefer a direct oral anticoagulant to a vitamin K antagonist (3/4), a statement formulated for congenital bleeding disorders in general [46]. The same document classifies all patients with a rare coagulopathy undergoing percutaneous coronary intervention as being at high bleeding risk [46].

The stepwise approach emerging from the 2026 systematic review summarises practice: an antifibrinolytic alone for minor procedures in territories of high fibrinolysis in patients without a significant bleeding history; plasma replacement mainly in major cardiac and abdominal surgery; low-dose rFVIIa with an antifibrinolytic as an alternative in patients with null variants or an inhibitor; and genotyping with inhibitor screening in severe deficiency, especially when the response to plasma is inadequate [21].

7.9. Evidence of efficacy: available studies

There are no randomised trials in FXI deficiency; the evidence comes from guidelines and observational data, with case reports, small series and retrospective cohorts, and heterogeneous practices [8, 21]. The table brings together the intervention studies and perioperative cohorts.

These results are not comparable with one another. The populations differ in the proportion of severe deficiency (from 12% in the New York cohort to 100% in the Israeli series), in the definition of bleeding and in the spectrum of procedures, and most are retrospective, without a control group and subject to publication bias, a limitation the systematic review explicitly notes, together with heterogeneity and the absence of data for the 10 to 20 IU/dL range in territories of high fibrinolysis [21]. The bleeding rates observed in contemporary cohorts reflect treated populations, not the natural history; comparison with the older series without prophylaxis should take this into account. In the series in which replacement was associated with less bleeding, such as the North American cohort of 256 procedures in patients with severe deficiency, the effect was observational and subject to confounding by indication, and adverse events of haemostatic therapy reached 16% [21]. The absolute numbers remain low: 33 complications in 252 procedures, no major bleeding [43].

The North American cohort from a New York haemophilia treatment centre, with 38 adults with severe deficiency (64% women; mean age 56 ± 21 years; median FXI activity 3%, interquartile range 1%–8%) followed between 2017 and 2022, recorded 256 operations and procedures: the mean ISTH-BAT score was 3.1 ± 2.4 and 52% of patients had no bleeding history; bleeding was lower when there was preventive or reactive treatment, arterial but not venous thrombotic complications were observed, plasma was used mainly in procedures with higher bleeding risk and antifibrinolytics in procedures in territories of high fibrinolysis [104]. The authors conclude that current strategies represent a care burden, manifested in non-bleeding adverse effects and changes in management, and that research on the prediction and treatment of bleeding in this group is needed [104]. Only the abstract and the conclusions published in open access could be read for this study, so the denominators by procedure type are not reproduced here.

7.10. Pregnancy, delivery and neuraxial analgesia

FXI activity does not reliably increase in pregnancy. The RCOG recommends measuring FXI at the booking visit, in the third trimester and before any invasive procedure (grade C) [13]; the French proposals record conflicting data on the course of the level and recommend monitoring at the end of pregnancy [17]; the New York cohort documented stability in 81 women with two measurements (49.7 versus 48.3 U/dL; p=0.3), suggesting that repeated measurements may not be necessary [43]. Studies cited by ClinGen likewise describe no significant change in 61 pregnancies in 30 women [15].

Neuraxial analgesia is the point of greatest divergence. The RCOG recommends not giving central neuraxial blockade to women with low FXI and a known bleeding phenotype, an uncertain phenotype or a severe reduction, and discussing risks and benefits, with or without replacement, in women with an established non-bleeding phenotype, in whom the balance may favour the procedure, especially single-shot spinal anaesthesia [13]. The French proposals and the French multicentre study advocate a quantitative criterion: a haemostatic level of 30 IU/dL at the time of the procedure and of catheter removal [17, 56]. The accumulated experience supports the safety of this practice. In the French study, 199 of the 314 pregnancies had neuraxial analgesia (137 epidurals, 61 spinals and one combined), with median FXI of 46 to 46.5 IU/dL; 118 procedures were performed with activity below 50 IU/dL and thirteen with activity below 30 IU/dL (17 to 29 IU/dL), and there was no complication, either at the procedure or at catheter removal; of the 115 women without neuraxial analgesia, 105 had a medical contraindication, and median FXI in that group was 27.5 IU/dL versus 46.5 IU/dL in the epidural group (p<0.0005) [56]. A 2018 French survey of 32 centres revealed thresholds in use between 30 and 60 IU/dL [56]. In the New York cohort, 174 procedures (70%) were performed under neuraxial anaesthesia, with mean FXI of 50 U/dL (3 to 118), without any epidural or spinal haematoma, and five patients without a bleeding history despite previous challenges received a block with FXI below 10 U/dL, only one with plasma [43]. Smaller series cited in these works describe 66 and 51 neuraxial procedures without haematomas [56].

In the management of delivery, the three guidelines converge on individualising the plan, having laboratory support and products available in the unit where delivery takes place, practising active management of the third stage and considering prophylactic tranexamic acid postpartum [13, 15]. The RCOG risk annex classifies FXI deficiency with a clinical bleeding phenotype as medium risk at delivery, with adequate replacement after the onset of established labour, avoiding neuraxial analgesia unless adequate replacement has been confirmed, and maintenance of normal levels for at least three days after vaginal delivery or five days after caesarean section; it classifies a rare coagulopathy without a bleeding phenotype, including FXI heterozygosity, as unlikely to be at risk, needing no replacement and able to receive neuraxial analgesia [13]. Excessive bleeding after miscarriage or termination of pregnancy is described, especially in women with a bleeding phenotype, without an increased risk of miscarriage or antenatal bleeding [13]. When replacement is given, the French proposals add the need for thromboprophylaxis [17]. In the treatment of established postpartum haemorrhage, the French study recorded tranexamic acid in at least 16 cases, plasma in 11 and transfusion in 10, without any thrombotic event [56].

The New York experience adds data on therapeutic parsimony: in the 64 pregnancies of 28 women, antifibrinolytics and plasma were used only in women with severe deficiency — in 42% of those with a bleeding phenotype and in 17% of those without — and neuraxial anaesthesia was successfully given in 32 of the 54 deliveries (59%), 75% in partial deficiency and 28% in severe deficiency, with no complications described; the authors conclude that most women have an uncomplicated pregnancy and delivery with minimal haemostatic support [59]. The Dutch data point in the opposite direction regarding prophylaxis: blood loss was significantly greater in deliveries without haemostatic prophylaxis and, in the FXI deficiency subgroup, postpartum haemorrhage occurred only in women who did not receive it [53, 58]. The divergence reflects different populations and criteria — the definition of postpartum haemorrhage as a loss of 500 mL or more is more sensitive than that used in the Israeli series — and supports the individualisation by bleeding history that the three guidelines recommend [13, 58, 59].

A case published in 2025 illustrates the use of thromboelastometry in the anaesthetic decision: in a 28-year-old primigravida with incidentally discovered moderate deficiency (FXI 52.6%) and an ISTH-BAT score of 1, the INTEM trace showed slightly prolonged clotting time (236 seconds) and slightly reduced early clot firmness (A5 of 42 mm), with preserved maximum firmness (68 mm); the multidisciplinary decision, based on the activity, the trace and the absence of symptoms, allowed spinal anaesthesia under prophylactic tranexamic acid, with an uncomplicated elective caesarean section and an estimated loss of 450 mL [70]. The authors emphasise that thromboelastometry is not diagnostic in itself, that the postoperative improvement of the trace is multifactorial, including the procoagulant state of the puerperium and the antifibrinolytic, and that prospective studies and standardised thresholds are lacking [70]. The management described is not routine, and the quantitative threshold of 30 IU/dL in the French proposals remains the published reference for neuraxial analgesia [17, 56].

7.11. Paediatric age, transition and agents to avoid

In the newborn and infant, diagnosis requires specific reference ranges and confirmation at six months, and there is no indication for prophylaxis [12, 13]. For religious circumcision on the eighth day, tranexamic acid alone suffices in most cases, although some centres avoid the drug at this age and prefer plasma [12]. The British guideline recorded in 2014 that tranexamic acid was not licensed in children in the United Kingdom [12]; the Portuguese summary of product characteristics indicates the drug in adults, with no experience below 15 years for the oral form, with a described paediatric dose of 25 mg/kg per administration, and allows the injectable form above one year at about 20 mg/kg/day [88, 89]; the Brazilian package insert provides for paediatric use at 10 mg/kg per administration, two to three times daily, with no paediatric maximum dose defined in the sources [91]. The laboratory review considers the drug safe in childhood [3]. Transition to adult care should ensure that the patient keeps the written plan from the haemophilia centre, knowledge of their genotype and inhibitor status, and information about the procedures that require prior coordination, notably dental surgery, for which ClinGen recommends coordination between the haemophilia centre, hospital oral surgery and the dentist, with replacement for inferior alveolar nerve block, lingual infiltration and invasive procedures [12, 15].

The agents to avoid are non-steroidal anti-inflammatory drugs, because of their antiplatelet effect [15], the combination of tranexamic acid with FXI concentrate [12, 17], the combination of rFVIIa with prothrombin complex concentrates [100] and, in the cardiological setting, thrombolysis, glycoprotein IIb/IIIa inhibitors, ticagrelor and prasugrel [46]. A letter published in 2025, based on data from an Israeli health system, specifically addresses the risk of major bleeding with antiplatelet agents and anticoagulants in inherited FXI deficiency; access was limited to the introduction, which recalls the cardiovascular protection documented in the same cohort and poses the question of whether these drugs increase bleeding risk at reduced FXI levels, without the results having been readable [105].

The question of anticoagulation in these patients now has its own data. In the Spanish cohort of 269 individuals with FXI deficiency, 13 (4.8%; 95% confidence interval 2.8%–8.1%) had a cardiovascular event (eight myocardial infarctions, three strokes and two transient ischaemic attacks) and only one (0.3%) venous thrombosis; 15 patients required anticoagulation, all with mild to moderate deficiency (median FXI:C 40%, interquartile range 33%–48.5%), median age 70 years, with atrial fibrillation as the main indication (12 of 15) [51]. Fourteen started acenocoumarol and four switched to a direct oral anti-factor Xa anticoagulant (rivaroxaban, apixaban or edoxaban); over 1020 cumulative months of treatment, only two bleeding episodes were recorded, both World Health Organization grade 1, without any major or fatal bleeding, including in four patients simultaneously taking antiplatelet agents and two who received therapeutic-dose heparin before the oral anticoagulant [51]. The median acenocoumarol dose was 10.75 mg per week and the median time in therapeutic range was 70%, no different from usual, indicating that mild to moderate deficiency does not alter dosing or monitoring [51]. The 2026 review summarises these data by stating that practically no bleeding complications were observed in patients with mild deficiency on antithrombotics [53]. The numbers are small, no patient with severe deficiency received anticoagulation and follow-up is retrospective, so the decision remains individual and coordinated with the haematologist, as the European cardiology consensus recommends [46, 51].

7.12. Developments in the last twelve months

The dominant development is not a treatment for FXI deficiency but its pharmacological reversal: anticoagulants that inhibit FXI or FXIa were designed on the basis of the observation that congenital deficiency protects against thrombosis without causing spontaneous bleeding [37, 61, 64]. The phase 3 OCEANIC-STROKE trial (NCT05686070), published in 2026, randomised 12,327 patients (6162 versus 6165) within 72 hours of non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack to asundexian 50 mg once daily or placebo, on top of antiplatelet therapy: ischaemic stroke occurred in 6.2% versus 8.4% (cause-specific hazard ratio 0.74; 0.65–0.84; p<0.001), with major bleeding according to ISTH criteria in 1.9% versus 1.7% (1.10; 0.85–1.44) [106]. The bleeding analysis of the same trial, with 12,254 patients, showed major or clinically relevant non-major bleeding in 5.5% versus 5.0% (1.12; 0.96–1.30), symptomatic intracranial haemorrhage in 0.7% versus 0.6% and gastrointestinal bleeding in 3.0% versus 2.4% (1.28; 1.03–1.59), with the excess concentrated in lower gastrointestinal bleeding, mainly rectal (1.7% versus 1.0%; 1.75; 1.27–2.41), with no difference in procedural or mucosal bleeding [107]. This positive result coexists with negative trials on the same target: OCEANIC-AF (NCT05643573), which compared asundexian with apixaban in 14,830 patients with atrial fibrillation, was terminated on the recommendation of the independent data monitoring committee for insufficient efficacy [108]; LIBREXIA-ACS (NCT05754957), with milvexian 25 mg twice daily versus placebo in 14,194 patients after acute coronary syndrome, was terminated for futility, with the composite of cardiovascular death, infarction and ischaemic stroke in 5.4% versus 5.1% (1.05; 0.91–1.21; p=0.50) and BARC 3c/5 bleeding in 0.3% in both groups [109]; the ASTER and MAGNOLIA trials, with abelacimab in cancer-associated thromboembolism, were terminated by sponsor decision in 2026 [110]. LIBREXIA-AF (NCT05757869, 20,284 patients) and LIBREXIA-STROKE (NCT05702034, 12,523 patients) remain ongoing, with primary completion expected on 8 December 2026 and 15 October 2026, as do LILAC-TIMI 76 with abelacimab and several phase 3 trials of anti-FXI antibodies that are recruiting [110].

The regulatory status, checked on 27 October 2026, is that of an accepted application and not of an authorisation: the FDA and the Japanese health ministry accepted the asundexian applications on 19 May 2026, the FDA with priority review, and the Chinese authority likewise accepted with priority review [101]; the EMA validated the application and began its assessment on 10 June 2026 [102]; neither the FDA nor the EMA approved medicines database contained the drug on that date, and the expected decision date was not disclosed in the press releases consulted [100–102]. The practical consequence for this article is laboratory and clinical: patients on these drugs pharmacologically reproduce FXI deficiency, which interferes with coagulation assays and requires the drug to be excluded before interpreting a reduced FXI activity, and the French guidance on procedures in patients on anti-FXI(a) agents rests on individual assessment of procedural risk [3, 21].

In congenital FXI deficiency itself, there is no active specific therapeutic trial on ClinicalTrials.gov, and the only record associated with a product is an expanded access programme for the French concentrate, now closed [110]. The non-replacement therapies developed for haemophilia are discussed as a future option in rare coagulopathies, but none has clinical data in FXI deficiency in the sources consulted, and the preclinical research identified is limited to thrombin generation work [37, 60]. The publications of the last year relevant to practice are therefore observational: the perioperative systematic review, the German genetic cohort, the Italian cohort, the Israeli urological series and the oncology study [7, 21, 41, 65, 85].

The proposals of the French perioperative haemostasis group (GIHP) and the French Society of Thrombosis and Haemostasis, published in 2025, transpose the experience of congenital deficiency to patients on anti-FXI(a) anticoagulants, and were built from the recommendations for inherited deficiency, adapted with pharmacological data and phase I and II trial data until consensus was reached between the two groups [111]. Four points are of direct interest for this article. First, FXI activity assay is proposed only in patients treated with antisense oligonucleotides, with the same limitations it has in inherited deficiency; with monoclonal antibodies and small molecules, FXI measurement is of little use and may be misleading because of assay interference [111]. Second, the pharmacological scheme for controlling bleeding risk is that of inherited deficiency: tranexamic acid first, adjusted in renal impairment, at doses of 15 to 20 mg/kg or 1 g four times daily for 5 to 7 days, the antifibrinolytic alone generally sufficing; in high-risk procedures, rFVIIa or FXI concentrate, with plasma 15 to 20 mL/kg as an alternative when the concentrate is not available [111]. Third, FXI concentrate makes sense only when the drug reduces the FXI level, that is, with antisense oligonucleotides, and is ineffective when the target is FXI(a) or when inhibition is saturating; tranexamic acid and rFVIIa, which do not act on FXI, may be effective with all classes [111]. Fourth, there is no specific antidote and its development is at an early stage; preoperative discontinuation is possible only with small molecules (half-life of 11 to 18 hours for milvexian and 16 to 18 hours for asundexian, with concentrations below 10% of maximum 48 hours after the last dose, which supports discontinuation three days before), whereas antibodies and oligonucleotides maintain their effect for weeks and most procedures are performed under anticoagulation [111]. The authors further recommend not giving rFVIIa or FXI concentrate systematically before the procedure, reserving them for situations in which bleeding would have severe functional consequences or would not be surgically controllable, such as neurosurgery and complex surgery, and, in patients treated with oligonucleotides, monitoring FXI before and after administration, without repeating the dose in the first 24 hours given the 48-hour half-life [111]. In the absence of concentrate, rFVIIa and plasma, prothrombin complex concentrate is preferred to the activated concentrate, although there are no data beyond case reports, and there are no data on desmopressin in this indication [111]. Pharmacological thromboprophylaxis after the procedure or bleeding remains undefined, with low-molecular-weight heparin as a considered option, especially when the small molecule has been stopped and rFVIIa or FXI concentrate has been given [111].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by scenario

Counselling requires prior identification of the mechanism in each family, because the two inheritance patterns coexist in the same disease [12, 13]. In the recessive scenario, a couple in which both members are heterozygous has, in each pregnancy, a 25% probability of having a child with severe deficiency, 50% of having a heterozygous child with partial deficiency and 25% of having a child without variants. A patient with severe deficiency, homozygous or compound heterozygous, necessarily transmits an altered allele, so all their children will be at least heterozygous, and will have severe deficiency if the other parent is heterozygous. In the dominant scenario, with a variant with a dominant-negative effect, each child of a carrier has a 50% probability of inheriting the variant and presenting partial deficiency, sometimes with activity below that expected for a heterozygote, down to values below 0.25 IU/mL, and with a possible mild bleeding tendency [3, 12].

The carrier frequency in the consultand's population determines the partner's risk. In the expanded screening data, the carrier frequency was 1 in 92 across all populations studied and 1 in 12.6 in the Ashkenazi group, a value that earlier literature placed at 1 in 8 [69]; the denominators of that study were 15,724 individuals of diverse origins and 1501 individuals of Ashkenazi origin [4]. The Israeli series estimate heterozygosity at 9.0% in Ashkenazi Jews and 3.3% in Iraqi Jews, with a risk of severe deficiency of 0.22% and 0.03%, respectively [34]; the RCOG gives heterozygosity of 8% to 9% and homozygosity of 0.2% to 0.5% in the Ashkenazi group, compared with an incidence of 1 in 1,000,000 in non-Jewish populations [13]. The British guideline also gives a heterozygosity of 1 in 11 and a frequency of homozygotes and compound heterozygotes of 1 in 450 for the two common variants in that population [12]. In populations with cousin marriages, rare factor deficiencies are overall more frequent, a point to consider in counselling about consanguinity [2]. Consanguinity also generates pseudodominance: in an Arab family from East Jerusalem, an 8-year-old girl, one of her brothers and her father had severe deficiency due to homozygosity for Thr386Asn, and both the proband's parents and the father's parents were first cousins, so that transmission over two generations mimicked dominant inheritance [11].

8.2. Cascade testing and carrier identification

Screening relatives of an index case is desirable and has a direct practical consequence: it allows the relative to know the diagnosis before a procedure, which is when the deficiency becomes clinically relevant [3, 15]. When the familial variant is known, targeted testing for that variant may be sufficient, as the European consensus recommends for mild to moderate bleeding disorders in general; alternatively, specific factor assay identifies most carriers [68]. The two approaches are not equivalent: the assay may be normal in symptomatic heterozygotes, a situation in which only genetic testing establishes the diagnosis [3], and genetic testing may be negative in patients with biochemical deficiency, with a variant detection rate of only 14% above 60 IU/dL of activity [7]. Assessment of the carrier should include an objective bleeding history, because it is this, and not the level, that best predicts risk [3, 43].

Testing for large deletions adds value in counselling. One case from the German cohort was initially classified as homozygous for a missense variant and turned out to carry a large deletion on the other allele, a pseudohomozygosity that would completely alter the probabilities conveyed to relatives; in four other cases, the deletion also encompassed KLKB1, with combined FXI and prekallikrein deficiency [7]. Genetic information also identifies null alleles, which signal a risk of alloinhibitor after exposure to plasma or concentrate, with a prevalence of 30% in homozygotes for the type II variant and a 50% risk after plasma exposure [6, 8].

8.3. Mosaicism, prenatal diagnosis and preimplantation testing

There is no description of relevant germline or somatic mosaicism in F11 in the sources consulted. Prenatal diagnosis is technically possible when the familial variants have been characterised, but the RCOG considers it unnecessary, because of the low morbidity of the disease, the absence of described spontaneous or intracranial neonatal bleeding and the existence of effective treatment; it recommends only avoiding cranial trauma in a newborn at risk of homozygosity and, in the case of a boy with planned circumcision, collecting a sample for assay [13]. The sources read do not describe series of preimplantation genetic testing in this condition. The reproductive decision, when it arises, should weigh the variability of the phenotype, which ranges from lifelong absence of symptoms to potentially fatal bleeding after surgery, and the availability of effective and simple treatment in most situations [3, 12].

8.4. Content of counselling and counselling of minors

Counselling should convey five points. First, the autosomal nature of the disease, which affects both sexes equally, although women are more frequently symptomatic: in the British registry 50% more women than men are registered, owing to menstrual and obstetric manifestations [3]. Second, the unpredictability of the phenotype: the level does not predict bleeding, which varies between individuals with the same activity, within the same family and in the same individual over time [3, 13]. Third, the importance of disclosing the diagnosis before any procedure, in particular dental, oropharyngeal, urological or obstetric, and of having the written plan from the haemophilia centre [12, 15]. Fourth, the significance of inhibitor status for those with a null allele who have already received plasma products [6]. Fifth, the existence of partial protection against thrombotic events, which does not dispense with conventional cardiovascular prevention or exclude myocardial infarction [46, 63, 64].

In a minor, diagnosis has immediate clinical usefulness when a procedure is planned or when there is a bleeding history, and its predictive value is limited by the scarcity of haemostatic challenges at that age [3]. Laboratory assessment before six months requires neonatal reference ranges [12]. Incidental detection in expanded carrier screening panels raises a particular issue: the frequency table documenting FXI as the most common condition in the Ashkenazi group does not flag it as recommended screening, and information obtained in that context should be interpreted together with the factor assay and the bleeding history, not in isolation [69]. Coordination with a specialised haemophilia centre is recommended for all families with a rare coagulopathy [2, 17].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What each figure measures

Estimates of the frequency of FXI deficiency differ by an order of magnitude because they measure different realities: different severities, different populations and different modes of detection.

The contrast between 1 in 1,000,000 and 1 in 17,000 is the most instructive. The British registry, with nearly 4000 cases, establishes that FXI deficiency is more frequent than haemophilia B, whose incidence is 1 in 25,000 male births in the same database, and the laboratory review attributes the historical underestimation to two causes: mild or asymptomatic patients who never face a haemostatic challenge and the limited availability of the assay [3]. The German cohort reaches the same conclusion by another route, noting that the frequency observed in several studies, the breadth of the variant spectrum and the low bleeding risk of many patients suggest underdiagnosis [7]. Conversely, prevalence estimated from allele frequencies, such as that of ExAC, measures the severe deficiency expected from population genetics and not the number of diagnosed patients, and recent studies indicate that the deficiency may occur 2 to 20 times more frequently than expected in several groups [7, 16].

The 2026 international review maintains the classical estimate of about 1 per 1,000,000 for severe deficiency in the world population and defines severe deficiency by activity below 15 to 20 IU/dL with a biallelic genotype, in contrast to mild deficiency of 20 to 65 IU/dL, generally monoallelic [53]. The Italian review of rare coagulopathies presents the same condition with two distinct estimates by inheritance pattern, 1 in 1,000,000 for homozygosity and 1 in 30,000 for heterozygosity, and notes that the specific concentrate is available in some European countries and not in the United States [112]. Contemporary national registries allow proportions to be compared: in the Dutch study, 26 of the 106 patients with a coagulation factor deficiency studied by thrombin generation had FXI deficiency, the second largest group after factor VII deficiency [50]; in the Spanish cohort, only 15 of 269 individuals identified with FXI deficiency had severe deficiency, that is, 5.6% [51]. These figures measure the composition of populations referred to specialised centres and not population prevalence.

The two reviews converge on the research agenda. The 2026 review concludes that the impossibility of linking the laboratory phenotype to bleeding outcome requires international collaboration, with unification of national registries and uniform sample collection protocols before new laboratory techniques can be evaluated [53]. The Italian review adds that, in rare coagulopathies, rarity is the main obstacle to licensing new products and describes haemostatic rebalancing as an experimental line: the anti-TFPI antibody marstacimab increased thrombin generation in plasma from patients with factor V, factor VII and FXI deficiencies, with a positive result in FXI deficiency, and in vitro and animal model work has shown that reducing antithrombin increases thrombin generation in several deficiencies; none of these agents is authorised or available for prophylaxis in rare coagulopathies, except for individual compassionate use [112].

9.2. Geographical distribution and founder effects

In the United States, the available epidemiology is hospital-based and reflects the composition of the population served: in the cohort of a New York health system, with 198 patients, 77% of the 177 with recorded ethnicity were Ashkenazi Jews, eight were Hispanic and two African American, with a mean age of 36 years and 94% women [43]. No specific recommendation from the US reference body for bleeding disorders was identified, and no FDA-approved FXI concentrate was identified; the negative search does not demonstrate non-existence [93, 99].

In Europe, the series document distinct realities. The United Kingdom has the largest registry, with 2079 individuals identified in 2015 and about 4000 in 2022, and the British literature describes FXI deficiency as the most common of the rare coagulopathies in that country [3, 96]. The German cohort of 316 index cases, collected between 2009 and 2023 in a reference laboratory, had a mean FXI activity of 37 IU/dL (1 to 60), 58.6% women, 24% with severe deficiency and a mean age of 26.6 years, with diagnosis below 30 years of age in 67% of severe cases [7]. The southern Italian cohort, with 93 individuals from 39 families, had activities between 1% and 69%, a majority of heterozygotes with moderate deficiency, 12 patients with severe deficiency and bleeding symptoms in 31% [41]. France has a network of reference centres that gathered 314 pregnancies in 20 haemostasis centres [56]. Israel concentrates research on severe deficiency, with cohorts of 96 to 219 patients and population studies of tens of thousands of tested individuals [62–64, 66].

Founder effects explain the distribution. The two common variants in the Ashkenazi group give a combined allele frequency of about 1 in 24, with partial deficiency in about 1 in 20 individuals and severe deficiency in 0.2% to 0.5% [3, 13]; the older variant is shared by several Middle Eastern communities and by Arab populations [35]. There is a regional founder in the French Basque Country, with an allele frequency of 0.005 in 206 controls [36]; in that region a cluster of 39 individuals with the deficiency was identified, and Cys38Arg explained the disease in 8 of 12 unrelated families, with intragenic haplotypes compatible with a common ancestor [11]. Another founder has been described in the United Kingdom [3]. In the Ashkenazi group, the two common variants accounted for 49% and 47% of 86 patient alleles, and in a survey of 53 Ashkenazi individuals without known disease two were heterozygous for type III and none for the other two [11]. In East Asian populations there are distinct recurrent variants, and in a Chinese series of 27 unrelated patients, with a median activity of 4%, 21 had severe deficiency, 20 were asymptomatic and seven had minor bleeding, with 19 compound heterozygotes [16, 42]. In Africans and Latinos, the ExAC analysis likewise identified distinct recurrent variants [16].

The sources consulted contain no epidemiological data from Portugal or Brazil on FXI deficiency, and no targeted geographical search was performed. The absence of data in these sources does not demonstrate the absence of published data.

9.3. Special populations

Women of reproductive age constitute the group with the greatest burden of morbidity, owing to heavy menstrual bleeding and postpartum haemorrhage, and are the most represented in the registries [3, 60]. Newborns require specific reference ranges and have no described spontaneous bleeding [12, 13]. Older people accumulate bleeding risk and thrombotic risk, the latter aggravated by replacement, so the British guideline and the French proposals restrict the concentrate in patients with cardiovascular disease [12, 17, 60]. Oncology patients have a particular profile, with less venous thromboembolism and more surgical bleeding than controls [65]. Patients with a null allele previously exposed to plasma products constitute the group at risk of alloinhibitor [6]. Patients with a cardiological indication for antithrombotic therapy are the subject of a dedicated consensus document [46].

9.4. Reference networks, registries and patient associations

The relevant European reference network is EuroBloodNet, dedicated to rare haematological diseases, which include the coagulopathies [23]. EAHAD maintains the F11 variant database, with 403 unique variants recorded, a reference tool for variant interpretation [3, 38]. In the United Kingdom, the network of haemophilia centres is coordinated by the UKHCDO, which issues protocols and guidelines and maintains the national database [2, 3]. In France, the network of reference centres for haemophilia and constitutional deficiencies of coagulation proteins published the proposals for the management of rare coagulopathies [17]. The international rare coagulopathies registry maintains a documentary resource with pages dedicated to FXI deficiency, including preoperative considerations [95]. Referral of all patients with a bleeding disorder to a haemophilia centre, for registration, counselling and treatment, is recommended practice [2].

Among patient associations, the European Haemophilia Consortium maintains a specific information page on FXI deficiency, with clinical content aligned with the guidelines [19]; the World Federation of Hemophilia is the international reference organisation, although its 2020 guidelines cover haemophilia and not FXI deficiency [27]. In Portugal there is the Associação Portuguesa de Hemofilia e de outras Coagulopatias Congénitas, which runs activities aimed at women with coagulopathies [24]; in Brazil, the Federação Brasileira de Hemofilia [25]; in the United Kingdom, The Haemophilia Society [26]. Product availability differs between countries: FXI concentrate is authorised in France and used on a named-patient basis in the United Kingdom, has no authorisation in Portugal or active registration in Brazil, and no approved product was identified in the United States, so replacement is with solvent/detergent-treated plasma, authorised in Portugal with an indication that expressly names isolated factor deficiency [12, 22, 90, 94].

10. Illustrative Clinical Case

10.1. Family with compound heterozygosity and a novel variant

Cai and colleagues described, in 2026, a three-generation family studied from an 80-year-old woman of Chinese ethnicity, admitted for intermittent stabbing chest pain and tightness of one year's duration, worsened by syncope on the day before admission; she had arterial hypertension, had no history of severe bleeding after trauma, dental extraction or obstetric procedures, and there was no family history of bleeding, thrombosis or liver or kidney disease [113]. The diagnosis was incidental, from the preoperative work-up: aPTT 81.6 seconds (reference 29.0 to 43.0), PT 13.1 seconds, FXI activity 2.0% and FXI antigen 3.1% (references 82.0 to 118.0 and 90.0 to 110.0), with factor VIII 151%, factor IX 116% and factor XII 87% [113].

The family study, with six relatives assessed, showed segregation of the two variants and the discordance between level and aPTT in heterozygotes [113].

Sanger sequencing of all exons and exon–intron boundaries identified compound heterozygosity for NM_000128.4:c.599G>T, p.(Cys200Phe), a novel variant, absent from ClinVar, gnomAD, dbSNP, HGMD and LOVD on the date the authors consulted them and classified as likely pathogenic by ACMG and AMP criteria, and for c.738G>A, p.(Trp246Ter), described in 2003 and identified as the most prevalent variant in Chinese series; both lie in exon 7, in the Apple 3 domain [113]. The notations were validated in VariantValidator: c.599G>T corresponds to NC_000004.12:g.186276234G>T and c.738G>A to NC_000004.12:g.186276373G>A [10, 113]. Structural modelling indicated that the Cys200Phe substitution eliminates the disulphide bridge between residues 200 and 283, whereas the nonsense variant generates a truncated protein, probably subject to nonsense-mediated mRNA decay [113]. All affected members had quantitative deficiency, with activity and antigen reduced in parallel [113].

The global tests were discordant with one another. Thrombin generation with tissue factor at 5 pM was preserved in the proband (peak 183.0 nM, endogenous thrombin potential 1098.32 nM·min and lag time 3.1 minutes, versus 191.28 nM, 1182.88 nM·min and 3.0 minutes in the control), a result consistent with the recommendation to use tissue factor concentrations below 1 pM in FXI deficiency [3, 113]. Kaolin thromboelastography, by contrast, was clearly abnormal in the proband (R time 35.22 minutes, reference 5.0 to 8.0; K time 6.34 minutes; α angle 35.5°; maximum amplitude 76.9 mm, versus 5.68 minutes, 1.94 minutes, 63.4° and 54.0 mm in the control), whereas her children had results similar to the control [113].

The authors declared several limitations: they did not perform a mixing study or test for lupus anticoagulant, used a single control, did not carry out in vitro functional studies and acknowledge that the allelic imbalance observed on Sanger sequencing does not exclude copy number variation [113]. The first limitation is relevant: the mixing study is mandatory in the recommended approach, even without previous exposure to plasma [3, 12].

10.2. Clinical reading of the case

The case illustrates four points of this article. First, incidental diagnosis in the preoperative work-up, one of the three usual routes of detection, here at 80 years of age, in someone who went through her whole life, including pregnancies, without severe bleeding [3, 113]. Second, the dissociation between laboratory and clinical findings: an activity of 2% with an absent bleeding phenotype, at the lower end of the severity spectrum, illustrates incomplete penetrance and why the guidelines favour personal history over level [12, 113]. Third, the insensitivity of the aPTT to partial deficiency: three heterozygotes with activities between 34.2% and 41.0% had an aPTT within the reference range, exactly the phenomenon that justifies the British recommendation to assay FXI even with a normal aPTT in patients with bleeding [3, 12, 113]. Fourth, the usefulness and limits of global tests, discordant in the same patient, consistent with the conclusion that none is validated for predicting bleeding [71, 113].

The management in the report is not routine. The study was conducted for molecular and functional characterisation, and the authors describe no haemostatic treatment, as there was no bleeding; had the patient undergone a procedure, guideline management would be tranexamic acid, with replacement only if the procedure or history justified it, and, as she was an 80-year-old with cardiac complaints, FXI concentrate would be specifically contraindicated because of thrombotic risk [12, 17, 22]. Inhibitor testing would not be indicated as there had been no exposure to plasma [12].

The figures of the original article, whose legends were read in the full text, are available on the PubMed Central page: family pedigree (Figure 1), sequencing chromatograms (Figure 2), thrombin generation curves (Figure 3), thromboelastography traces (Figure 4), conservation of residues across species (Figure 5) and structural models of the protein (Figure 6) [113].

10.3. Complementary paediatric case

A second report, from 2025, documents the other end of the spectrum. A 6-year-old child of consanguineous parents, with FXI deficiency diagnosed at 2 years (activity below 15%), developed a 12 by 8 centimetre subgaleal haematoma after a fall from a swing of about half a metre in height, with aPTT 71.2 seconds, PT 17.4 seconds and international normalised ratio 1.28 [55]. Initial treatment with fresh frozen plasma at 10 mL/kg per day was followed by expansion of the haematoma, a 2 g/dL fall in haemoglobin and cellulitis, requiring paediatric intensive care; intensification to 10 mL/kg every eight hours, a single dose of rFVIIa of 30 µg/kg and antibiotics allowed stabilisation, with FXI activity of 18% during that admission, and there was a recurrence two days after discharge; activity varied between values below 15% and 52% between episodes and the child had coexisting reduced von Willebrand factor activity [55]. The case illustrates modulation of the phenotype by a second coagulopathy, identified by the British guideline as an independent predictor of bleeding, and documents that the rFVIIa dose used (30 µg/kg) is at the upper limit of the range recommended by the guidelines for this condition [12, 55].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis is good overall, a position stated by the European patient association and consistent with the quantitative data [19]. The disease is silent for most of life: about 65% of patients in two British series were asymptomatic, and in a cohort of 316 index cases most had partial deficiency without spontaneous bleeding [7, 12]. The excess bleeding risk is real but modest in absolute terms: in the matched cohort of an Israeli health system, the 10-year risk of major bleeding was 1.90% in patients with FXI below 50% versus 0.90% in the general population, with an adjusted risk of 2.56 (1.13–5.81), and that of clinically relevant non-major bleeding 11.60% versus 9.20%, with an adjusted risk of 1.45 (1.08–1.97) [66]. Spontaneous bleeding is rare, intracranial haemorrhage very rare and no spontaneous neonatal bleeding has been described [12, 13].

The determinant of prognosis is prior knowledge of the diagnosis. Morbidity is concentrated in invasive procedures, the moment at which recognition of the condition and application of a simple measure — usually tranexamic acid — prevent most complications; this is why ClinGen classifies the condition as strongly actionable in adults, noting that an undiagnosed patient may develop significant haematomas after surgery [15]. In contemporary cohorts, in which most risk procedures are managed with an antifibrinolytic or plasma, there was no major bleeding in 252 procedures at one centre and rates of major bleeding remained below 7% in more than 590 procedures reviewed [21, 43].

The cardiovascular prognosis has two sides. There is partial protection against ischaemic stroke and venous thromboembolism, with adjusted risks of 0.52 to 0.57 for cardiovascular events and 0.26 for venous thromboembolism in a cohort of 10,193 adults [61, 62, 64]. There is no protection against acute myocardial infarction, and patients with severe deficiency who had an infarction had, in 81.3% of cases, at least one classical atherosclerotic risk factor, so conventional cardiovascular prevention remains fully applicable [46, 63]. Iatrogenic thrombotic events, associated mainly with FXI concentrate and rFVIIa, are the main preventable cause of serious morbidity in this disease [22, 96, 100].

11.2. Surveillance

None of the sources consulted defines a programme of periodic surveillance with intervals for FXI deficiency: the ClinGen actionability report expressly states that information on surveillance is not available [15]. The absence of periodic surveillance is consistent with the nature of the disease, whose risk is concentrated in discrete and predictable events. The table brings together the assessments recommended by the guidelines, whose trigger is the clinical event and not the calendar.

The intervals in this table match those given in section 7: measurement of FXI at the first antenatal visit, in the third trimester and before invasive procedures; inhibitor screening before surgery or delivery in patients with a null allele exposed to plasma; monitoring of activity before each readministration of concentrate; and maintenance of adequate levels for at least three days after vaginal delivery or five days after caesarean section in women with a bleeding phenotype [12, 13, 22].

12. Summary and Concluding Remarks

Factor XI deficiency is an autosomal coagulopathy caused by F11 variants, with two transmission patterns: recessive in the severe deficiency of homozygotes and compound heterozygotes, and dominant in variants with a dominant-negative effect, in which the mixed dimer is retained in the cell. Factor XI amplifies thrombin generation and, through thrombin-activatable fibrinolysis inhibitor, protects the clot from lysis; the deficiency therefore produces provoked bleeding in tissues rich in plasminogen activators — oral cavity, nasopharynx and urogenital tract — and rarely spontaneous bleeding. The disease is more frequent than the historical estimate of one case per million suggested: the British national registry corresponds to about one case per 17,000 inhabitants and genomic data indicate underdiagnosis, with marked concentration in populations with a founder effect.

The feature that dominates clinical practice is the dissociation between laboratory and phenotype. Factor XI activity does not predict bleeding, nor does genotype, antigen or any validated global assay: in the best available series, the area under the curve of activity for predicting perioperative bleeding was 0.62, and the strongest predictor was personal bleeding history, with an odds ratio close to 6. Three consequences follow. Diagnosis is biochemical, rests on an isolated prolonged activated partial thromboplastin time with correction on mixing and a specific assay, and requires attention to reagent sensitivity, because a normal result does not exclude partial deficiency in a patient with bleeding. Molecular study adds value for counselling, cascade screening and identification of null alleles that signal alloinhibitor risk, with a variant detection rate that falls from 96% in severe deficiency to 14% above 60 IU/dL of activity, which should not be confused with clinical sensitivity. And the therapeutic decision is organised around personal history and the territory of the procedure, not the laboratory value.

Treatment is directed at the procedure and follows a scale. Tranexamic acid, at the guideline dose of 15 to 20 mg/kg or 1 g four times daily, is sufficient in most situations, including in patients with severe deficiency undergoing dental extraction, and has a favourable safety profile, with the caveat of renal tract bleeding. Replacement is with solvent/detergent-treated plasma, 15 to 25 mL/kg, or with factor XI concentrate where available, at an initial dose of 10 to 15 IU/kg, never above 30 IU/kg, targeting 30% to 40% activity and without combination with an antifibrinolytic, because of the thrombotic risk that prompted the reformulation of the product and the limitation of doses. Low-dose, single-dose recombinant activated factor VII, with an antifibrinolytic, is the solution in patients with an alloinhibitor, a condition affecting about 30% of homozygotes for the null allele exposed to plasma, which does not worsen bleeding but nullifies the efficacy of replacement. None of these products has factor XI deficiency as an approved indication in the United States; in Portugal, solvent/detergent-treated plasma is the exception, with an indication naming isolated factor deficiency.

In pregnancy and delivery, the three main guidelines diverge on when to give replacement and on the criterion for neuraxial analgesia, and practice has evolved towards parsimony: most women with severe deficiency do not have postpartum haemorrhage, replacement is not mandatory for vaginal delivery, and series with hundreds of neuraxial procedures, many with activity below 50 IU/dL and some below 30 IU/dL, recorded no haematoma. The partial protection against ischaemic stroke and venous thromboembolism, documented in population cohorts, does not extend to acute myocardial infarction and does not dispense with cardiovascular prevention; it was this observation that gave rise to factor XI and factor XIa inhibitors, whose first positive phase 3 result in secondary stroke prevention was published in 2026 and whose marketing applications were under assessment, without a decision, at the update date of this article. For the patient with congenital deficiency, the practical legacy of this drug class is twofold: pathophysiological confirmation of the role of factor XI and the need to exclude these drugs before interpreting a reduced factor XI activity.

Three gaps remain. There is no randomised trial in this disease, and all therapy rests on small series and retrospective cohorts. There is no validated laboratory assay for predicting perioperative bleeding, despite the interest of global assays. And there is no published recommendation for periodic surveillance, a gap that ClinGen explicitly notes and that is consistent with a disease whose risk is concentrated in identifiable events, manageable with a written plan and with coordination between the patient, the haemophilia centre and the team performing the procedure.

13. References

1. Orphanet. Congenital factor XI deficiency (ORPHA:329). https://www.orpha.net/en/disease/detail/329
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