Factor XI (eleven) deficiency

INTRODUCTION — Factor XI (eleven) is a plasma glycoprotein that acts in the contact phase of blood coagulation (the intrinsic pathway). Unlike the other contact factors (high molecular weight kininogen [HMWK], factor XII, and prekallikrein), factor XI is important for normal hemostasis in vivo.

This topic discusses the diagnosis and management of inherited factor XI deficiency (also called Rosenthal syndrome or hemophilia C).

Separate topic reviews discuss other inherited and acquired factor deficiencies and a general approach to the patient with unexplained bleeding or abnormal coagulation testing:

●Unexplained bleeding – (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

●Abnormal coagulation testing – (See "Clinical use of coagulation tests".)

●Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) – (See "Clinical manifestations and diagnosis of hemophilia".)

●Rare factor deficiencies – (See "Rare inherited coagulation disorders".)

●Acquired factor inhibitors – (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

A separate topic review discusses F11 genetic testing. (See "Gene test interpretation: F11 (gene for coagulation factor XI)".)

PATHOPHYSIOLOGY

Factor XI function — Factor XI (factor eleven; F11; FXI) circulates in the inactive form (as a zymogen) and becomes activated to factor XIa, a serine protease (figure 1). Unlike other coagulation factors, factor XI circulates as a homodimer (with subunits stabilized by disulfide bonds) (figure 2); it is bound noncovalently to high molecular weight kininogen (HMWK) in the circulation [1].

Activators of factor XI include thrombin (factor IIa), factor XIIa, and itself (ie, autoactivation by factor XIa) [2,3]. These proteases activate factor XI by cleavage at Arg369-Ile370, inducing a conformational change that moves the active sites of the factor XI catalytic region closer together [4]. FXI activation is markedly enhanced by the presence of polyanions such as phosphate polymers released from dense granules of activated platelets [5,6].

Factor XI activity is unaffected by vitamin K deficiency or vitamin K antagonist anticoagulants (warfarin), since it does not contain gamma-carboxyglutamic acid ("Gla") residues that are present in some of the other coagulation factors and regulatory proteins (factors II, VII, IX, and X; proteins C and S). Gla residues require vitamin K for their synthesis. Gla domain proteins bind to phospholipids via the Gla domain in the presence of calcium, and this binding is important for their activity in vivo. Despite the absence of Gla domains, factor XI and factor XIa bind to activated platelets in a specific and saturable manner. (See "Vitamin K-dependent clotting factors: Gamma carboxylation and functions of Gla", section on 'Function of Gla in clotting proteins'.)

It was first reported in 1953 that individuals with factor XI deficiency can have a bleeding phenotype [7]. However, the precise role of factor XI in coagulation and mechanisms of the bleeding risk in factor XI deficiency are not fully understood. The hemostatic role of factor XI is thought to involve amplification of the clotting cascade (via a positive feedback mechanism to generate additional thrombin after clotting is initiated), as well as stabilization of new clots by inhibiting fibrinolysis and other roles related to the immune system [4,8]:

●Thrombin generation – Factor XI does not participate in the initiation of clotting; the initial burst of thrombin comes from circulating factor VIIa and tissue factor (TF, which is usually exposed on injured endothelium). Factor VIIa and TF activate factor X to factor Xa, as well as factor IX to factor IXa, which in turn convert prothrombin to thrombin (figure 3). The initial burst of thrombin is small, kept in check by tissue factor pathway inhibitor (TFPI). Factor XI is activated by this initial burst of thrombin when it encounters thrombin.

After factor XI is activated to factor XIa, it activates factor IX to IXa, which activates factor X and amplifies thrombin generation in a positive feedback loop [9]. This is thought to be the clinically important role of factor XI in clot formation [10].

Glycoprotein Ib (GPIb) of the GPIb-IX-V complex is the main receptor for factor XI on the platelet surface. Homodimers of factor XI bind to activated platelets (together with HMWK and zinc) via platelet GPIb [3,11-14]. The binding of HMWK exposes the GPIb-binding site in factor XI, allowing one of the factor XI monomers to bind to the platelet surface and leaving the other factor XI monomer free for activation by thrombin, which also binds to the platelet surface in an orientation that allows it to cleave factor XI. The apolipoprotein E receptor 2 (ApoER2) has also been identified as a platelet receptor for factor XI [14,15].

In clotting assays in vitro, factor XI is activated by factor XIIa on negatively charged surfaces such as glass (silica) or clay (kaolin), in a process referred to as contact activation (the basis for the activated partial thromboplastin time [aPTT] assay) (figure 1). Polyphosphates, released at sites of cellular damage, appear to provide the negatively charged surface and are the in vivo homolog of silica. This is why individuals with severe factor XI deficiency have a prolonged aPTT. The physiologic role of this activation step in vivo is unclear [16]. (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

●Downregulating fibrinolysis – A second role for factor XI is in downregulating fibrinolysis. Supplemental thrombin formation at the site of the clot is critical for the activation of thrombin-activatable fibrinolysis inhibitor (TAFI; also called carboxypeptidase B2) [4]. TAFI stabilizes the clot by increasing its resistance to fibrinolysis [17-20]. Animal studies and in vitro assays have demonstrated that activated factor XI can dramatically inhibit fibrinolysis via TAFI [17,21,22]. (See "Overview of hemostasis", section on 'CPB2/TAFI'.)

●Other roles – Factor XI has been proposed to play a role in the response to inflammation and/or bacterial infection. The mechanism may involve direct or indirect effects via activation of factor XI on bacterial surfaces, interactions with the kallikrein-kinin system, or activation of TAFI by factor XIa and other enzymes [8,14,20,23].

These observations provide an explanation for the observation that factor XI-deficient patients generally do not have spontaneous bleeding (because factor XI is not required for the initial thrombin generation step) but are prone to bleeding provoked by trauma or surgery, particularly when involving tissues with high intrinsic fibrinolytic activity such as the oral cavity, nose, and genitourinary tract (table 1).

Once activated, factor XIa activity can be inactivated by two classes of inhibitors:

●Serine protease inhibitors (serpins) such as antithrombin (AT), alpha-1 protease inhibitor, C1 esterase inhibitor, and alpha-2 antiplasmin [24-27]

●Kunitz-type inhibitors such as protease nexin-2 (PN2), which is secreted from platelet alpha granules following platelet activation [28]

Factor XIa that is not bound to platelets is inhibited by PN2 secreted by activated platelets [29-31]. When factor XI is bound to the platelet surface, it is protected from inactivation by PN2; this regulation ensures that production of thrombin is localized to the surface of activated platelets at the site of initial injury [32].

Control of factor XI levels — Factor XI levels are low at birth and correlate with gestational age; adult levels are reached by six months of age [33]. The primary site of synthesis is the liver. Secretion from hepatic cells requires homodimerization of the factor XI protein. Patients with severe liver disease may therefore have decreased factor XI levels. A small population of factor XI (<1 percent) is found in platelets and other cell types [34,35]. The source of platelet factor XI and its contribution to hemostasis are unclear [36,37].

Causes of reduced factor XI

F11 gene variants — Inherited factor XI deficiency (F11D; also called Rosenthal syndrome or hemophilia C; MIM #612416) is due to homozygosity, compound heterozygosity, or heterozygosity for a pathogenic variant (disease-causing mutation) in the F11 gene. Heterozygosity tends to produce less severe disease, but certain variants have a dominant negative effect in which the abnormal protein interferes with secretion of the normal protein, leading to more severe deficiency [4,38,39]. Thus, factor XI deficiency may have an autosomal dominant or autosomal recessive transmission pattern, depending on the specific variant.

There is a weak correlation between factor XI levels and bleeding, and genotype-phenotype relationships have been difficult to define [40,41]. (See 'Bleeding' below.)

The F11 gene is located on the long arm of chromosome 4 (4q34-35). The gene consists of 15 exons and 14 introns and encodes a 607 amino acid protein with a number of distinctive structural and functional features [4,8]:

●The heavy chain contains four apple domains (A1 to A4; tandem repeat sequences shared with other proteins such as prekallikrein) that confer substrate and ligand binding as well as homodimerization (figure 2). These domains create a circular platform for the catalytic domain (like a saucer under a cup) [4,8]. A1 contains the binding site for thrombin; A2 binds high molecular weight kininogen (HMWK); and A3 has binding sites for factor IX, heparin, and GPIb [14]. A4 mediates homodimerization, which is essential for the secretion of factor XI from hepatic cells.

●The carboxy-terminal light chain contains the enzymatic (catalytic) site (figure 2).

Over 400 distinct pathogenic variants in the F11 gene have been reported [42]. These are distributed throughout the gene, with most located in the apple domains or the catalytic site [4]. These variants may impair production, secretion, or dimerization of the factor XI protein or to heterodimer trapping. Many F11 mutations are listed in the European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases and University College London [43,44]. Interpretation of genetic testing of F11 is discussed separately. (See "Gene test interpretation: F11 (gene for coagulation factor XI)".)

There appear to be two founder mutations in a large proportion of factor XI-deficient individuals of Ashkenazi (Eastern or Central European) Jewish ancestry. One of the most common is a Phe283Leu missense mutation in exon 9 (in the A4 domain) that interferes with dimerization and impairs secretion of factor XI; this is referred to as a "type III mutation" [4,45,46]. Another common mutation is a premature stop codon (Glu117stop) in exon 5 that leads to complete absence of expression; this is referred to as a "type II mutation" and is associated with more severe bleeding phenotypes (and inhibitor development) in homozygous individuals [46]. Most people of Ashkenazi Jewish descent with severe factor XI deficiency have either the II/II, III/III, or II/III genotype [47]. Other pathogenic variants have been identified in groups of individuals from various countries. (See "Gene test interpretation: F11 (gene for coagulation factor XI)".)

Other apparent founder mutations have been identified in France and England. A Cys38Arg variant was identified in 8 of 12 families from the Basque region of France, and a common ancestral mutation (Cys128stop) was reported in 11 non-Jewish families from the United Kingdom (UK) [48,49]. In a series of 116 index cases in a UK population, 55 (39 percent) were due to one of the three most commonly described mutations (Phe283Leu and Glu117stop, seen in Ashkenazi Jewish individuals; and Cys128stop) [50].

Acquired factor XI inhibitors — Acquired factor XI inhibitors (auto- and alloantibodies) are rare:

●Severe hereditary factor XI deficiency and undetectable baseline factor XI activity (≤1 percent) can be complicated by factor XI alloantibodies following exposure to exogenous factor XI. (See 'Inhibitor development' below.)

●Cancer or autoimmune diseases such as systemic lupus erythematosus (SLE) may be associated with factor XI autoantibodies. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)", section on 'Factor XI inhibitors'.)

These inhibitors may be detected as an incidental finding during preoperative screening, in the evaluation of unexplained bleeding, or during management of an individual with known factor XI deficiency when plasma or factor XI concentrates fail to raise the factor XI level or if the bleeding pattern worsens.

Although some individuals present with bleeding, most people with a factor XI inhibitor do not experience spontaneous bleeding.

Other causes — Other conditions may also lead to reduced factor XI levels along with reduced levels of other coagulation factors:

●DIC – Factor XI deficiency can occur along with other factor deficiencies in consumptive coagulopathies such as acute disseminated intravascular coagulation (DIC). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

●Liver disease – Factor XI is produced in the liver, and factor XI deficiency can occur along with other factor deficiencies in severe liver disease. A case report described acquired factor XI deficiency following liver transplantation from a factor XI-deficient donor [51]. A separate case report described correction of factor XI deficiency in an individual who received a liver transplant from an unaffected donor (to treat hepatocellular cancer) [52]. (See "Hemostatic abnormalities in patients with liver disease", section on 'Coagulation factor deficiencies'.)

Factor XI levels are not affected by warfarin or vitamin K deficiency. (See 'Factor XI function' above.)

Role of factor XI in thrombosis — High circulating factor XI levels appear to be a risk factor for thrombosis. A case-control study involving 948 individuals in the Leiden Thrombophilia Study found that individuals with deep vein thrombosis (DVT) were twice as likely to have high factor XI levels than controls (proportion with factor XI levels above the 90^th percentile [established to be 120 percent] 19 versus 10 percent; odds ratio [OR] 2.2, 95% CI 1.5-3.2) [53]. Subgroup analysis suggested a continuous dose-response effect that was unaffected by other DVT risk factors. Subsequent observational studies with larger numbers of patients have found similar associations [54-56].

High levels of factor XI were associated with an increased risk of ischemic stroke in one study, although the number of patients evaluated was small [56]. Low levels of factor XI appear to be protective against DVT and stroke, as discussed below. (See 'Possible protection from cardiovascular events and DVT' below.)

EPIDEMIOLOGY — Severe inherited factor XI deficiency (factor activity <20 percent) is rare, with a global prevalence of approximately 1 in 1 million in the general population [57]. However, this may represent an underestimate, as some individuals with factor XI deficiency may not come to medical attention, especially heterozygous individuals with milder deficiencies. In a study in which 3879 healthy Italian individuals underwent F11 genotyping, the prevalence of common pathogenic F11 variants was closer to 1 in 1000 [58].

Both males and females are affected because the disorder is autosomal.

Although the prevalence of factor XI deficiency is low, these individuals account for approximately one-fourth of rare bleeding disorders [59]. In a series of 112 consecutive patients referred for heavy menstrual bleeding, four (4 percent) had factor XI deficiency, which was only slightly lower than the rate of von Willebrand disease (VWD; seen in 5 percent) [60]. In another series of 150 patients with heavy menstrual bleeding, five (3 percent) had factor XI deficiency, in one case in combination with VWD and factor X deficiency [61].

Inherited factor XI deficiency appears to be more common in certain groups, possibly due to founder effects (see 'F11 gene variants' above):

●Ashkenazi Jewish individuals – Factor XI deficiency is relatively common in individuals of Ashkenazi (Eastern and Central European) Jewish and Iraqi Jewish ancestry, with a rate of heterozygosity as high as 8 to 9 percent (approximately 1 in 11 individuals) [57,62]. Approximately 0.2 to 0.5 percent of Ashkenazi and Iraqi Jews (1 in 450) are homozygous or compound heterozygous for pathogenic F11 variants [62-64].

●UK and Ireland – A survey from the World Federation of Haemophilia (WFH) across multiple countries found the highest prevalence in the United Kingdom (UK) and Ireland, at 56 and 55 per million [65].

CLINICAL MANIFESTATIONS

Bleeding — Bleeding in factor XI deficiency is highly variable in site and severity. Unlike hemophilia A and B, most individuals with factor XI deficiency do not have spontaneous bleeding, hemarthrosis (joint bleeding), or muscle hematomas. This is thought to be because the initial steps in hemostasis occur normally in individuals with factor XI deficiency, and only the subsequent amplification of the thrombin response and resistance of the clot to fibrinolysis are affected by lack of factor XI. (See 'Factor XI function' above.)

Bleeding is most likely in individuals with factor XI levels <20 percent; however, the correlation between factor XI activity and bleeding is weak. Some individuals with very low factor XI levels do not have bleeding, whereas others with factor XI activity levels >50 percent can have excessive surgical bleeding [40,66].

●A report from the European Network of Rare Bleeding Disorders found that of all the rare coagulation factor deficiencies, factor XI had the least correlation between factor levels and bleeding manifestations [67].

●A review of 24 kindreds (169 patients) found that even individuals within the same family, who presumably have the same F11 variant, have different bleeding phenotypes; one-third of the individuals with factor XI levels >20 percent had excessive surgical bleeding [68].

●Sometimes patients report a history of minor bleeding during childhood (bruising, epistaxis) that is only deemed clinically significant in retrospect. A 58-year-old man with severe factor XI deficiency (factor XI activity 3 to 6 percent) reported minor epistaxis during childhood, tonsillectomy at age four years without serious bleeding, and appendectomy at age 19 with life-threatening hemorrhage [69].

When bleeding occurs, it is often in the setting of trauma or surgery, especially in tissues with high fibrinolytic activity (table 1). This bleeding pattern has led to the characterization of factor XI deficiency as an "injury-related bleeding disorder" [35].

The cause of variability in bleeding phenotype is not completely understood. One case report described spontaneous intracerebral hemorrhage in the setting of concomitant hypertension [70]. In some cases, use of an antiplatelet agent such as aspirin or another inherited bleeding predisposition (eg, von Willebrand disease [VWD], fibrinogen deficiency) may contribute [71-78]. Avoidance of antiplatelet medications and testing for other bleeding disorders are discussed below. (See 'Overview of management' below.)

Menses and pregnancy — Factor XI levels are unaffected by hormonal changes or pregnancy. Females with factor XI deficiency are more likely to have heavy menstrual bleeding, but pregnancy is generally well tolerated [35].

The rate of postpartum hemorrhage (PPH) is greater than in the general population, although the risk is not well characterized and predictors of PPH have been difficult to define. Small case series have reported PPH rates of approximately 16 to 31 percent that typically respond to therapy with factor XI replacement or antifibrinolytic therapy [79-82]. PPH was somewhat more common in individuals who reported a bleeding phenotype and did not correlate well with baseline factor XI levels or mode of delivery. Neonates born to factor XI-deficient mothers generally do not have bleeding, and the presence of factor XI deficiency in the mother generally does not affect decisions about the mode of delivery [35].

Management of heavy menstrual bleeding and obstetric concerns are discussed below. (See 'Obstetric/gynecologic considerations' below.)

Inhibitor development — Individuals with inherited factor XI deficiency can develop inhibitors (antibodies directed against factor XI) if exposed to exogenous factor XI from factor XI concentrates or plasma [35]. If an inhibitor is present, a mixing study on the activated partial thromboplastin time (aPTT) assay will not show correction.

The prevalence and risk factors for inhibitor development after exposure to exogenous factor XI are not well described; they appear to be most common in individuals with severe deficiency or undetectable levels of factor XI, especially in individuals with the Glu117stop mutation or other nonsense (premature stop codon) mutation, in whom it can be as high as one-third; these individuals may choose to use a bypassing agent such as recombinant factor VIIa (rFVIIa) rather than factor XI replacement in some settings to reduce the risk of inhibitor development. (See 'rFVIIa' below.)

●In a series of 118 Israeli patients with factor XI deficiency, seven (6 percent) had a detectable inhibitor [83]. All seven were homozygous for a type II mutation (see 'F11 gene variants' above) with factor XI levels ≤1 percent, and all had received plasma. These seven individuals accounted for one-third of the patients who were homozygous for a premature stop codon and had been exposed to plasma. This observation provides the rationale for avoiding exposure to exogenous factor XI in individuals with severe deficiency. (See 'Planning for surgery and dental procedures' below.)

●A factor XI inhibitor was reported in an individual with severe factor XI deficiency who received anti-D immune globulin (Rho[D] immune globulin) during pregnancy [84]. Analysis of batches of anti-D revealed factor XI in preparations from three different suppliers, in concentrations ranging from 20 nanograms to 6.5 micrograms per dose.

Testing for inhibitors is appropriate when planning for elective surgery, especially for individuals with severe factor XI deficiency who have been exposed to exogenous factor XI. (See 'Planning for surgery and dental procedures' below.)

Individuals who develop a factor XI inhibitor generally do not develop spontaneous bleeding [35]. However, their factor XI levels may not increase in response to factor XI administration, they may develop an amnestic response when exposed to factor XI, and they may require a bypassing product such as recombinant activated factor VII (rFVIIa) for treatment of bleeding or surgical bleeding prophylaxis. (See 'rFVIIa' below.)

Possible protection from cardiovascular events and DVT — The rates of cardiovascular events and venous thromboembolism (VTE) have not been extensively studied in individuals with factor XI deficiency. However, retrospective cohort and case-control studies have suggested that the risks of stroke and deep vein thrombosis (DVT) appear to be reduced [85-87].

●A retrospective study involving 10,193 individuals within a large health care system in Israel in whom factor XI levels were obtained over a 12-year period, identified low factor XI activity (<50 percent) in 12 percent [85]. Factor XI deficiency was associated with a reduced risk of VTE (adjusted hazard ratio [HR] 0.26, 95% CI 0.08-0.84). None of the people with factor XI activity <30 percent developed VTE. Similarly, factor XI deficiency was associated with a reduced risk of cardiovascular events (composite of stroke, transient ischemic attack, and myocardial infarction; HR for individuals with factor XI <30 percent 0.57, 95% CI, 0.35-0.93; for factor XI activity 30 to 50 percent, HR 0.52, 95% CI, 0.31-0.87).

●In a smaller study, rates of myocardial infarction appear to be similar to the general population [86].

●In a clinical trial involving 300 patients undergoing elective knee surgery who were assigned to VTE prophylaxis using an antisense oligonucleotide (ASO) to reduce the factor XI level (to a mean of 20 percent) or to daily enoxaparin, the incidence of postoperative VTE was 4 percent with the factor XI ASO versus 30 percent with enoxaparin [88]. There was no increased bleeding risk with the factor XI ASO. These observations have generated enthusiasm about therapeutic reduction of factor XI levels as a form of thromboprophylaxis, as discussed separately. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene silencing' and "Investigational anticoagulants", section on 'Inhibitors of factor XI or factor XIa'.)

DIAGNOSTIC EVALUATION

When to suspect — Factor XI deficiency may be suspected in:

●Individuals with a known family history of factor XI deficiency, especially if they are of Ashkenazi Jewish ancestry. (See 'Epidemiology' above.)

●Individuals with excessive bleeding whose initial evaluation shows an isolated prolonged activated partial thromboplastin time (aPTT), no evidence of an inhibitor (no heparin; correction in an aPTT mixing study), and normal factor VIII and IX levels. (See 'Initial testing (PT, aPTT)' below and "Approach to the adult with a suspected bleeding disorder".)

●Individuals with excessive bleeding and normal prothrombin time (PT) and aPTT may require determination of specific factor activity levels of intrinsic pathway factors (factor VIII, factor IX, factor XI) to rule out a partial deficiency of factor XI.

●Asymptomatic individuals for whom coagulation testing shows an isolated prolonged aPTT, with no evidence of an inhibitor and normal factor VIII and IX levels. (See 'Initial testing (PT, aPTT)' below and "Clinical use of coagulation tests", section on 'Prolonged PT and/or aPTT without bleeding or thrombosis'.)

Because bleeding generally only occurs during trauma, surgery, or childbirth, many individuals with factor XI deficiency are not diagnosed until late childhood or adulthood. Heavy menstrual bleeding may be the initial manifestation in females.

Some experts have suggested screening for factor XI deficiency (with aPTT testing) in pregnant individuals of Ashkenazi Jewish descent and those with a known family history of factor XI deficiency, although a benefit of such an approach has not been demonstrated [35]. Prenatal testing is not done, due to the lack of spontaneous bleeding in factor XI deficiency. However, testing before circumcision is advisable in Ashkenazi Jewish newborns. (See 'Genetic testing and counseling' below and 'Obstetric/gynecologic considerations' below.)

Testing for factor XI deficiency often is not included in standard genetic carrier testing panels for individuals of Ashkenazi Jewish ancestry. However, screening family members of affected individuals with an aPTT and factor XI level may be appropriate before an elective procedure or if bleeding symptoms occur. (See "Preconception and prenatal carrier screening for genetic disorders more common in people of Ashkenazi Jewish descent and others with a family history of these disorders" and 'Genetic testing and counseling' below.)

Testing for factor XI variants is included in certain direct-to-consumer genetic carrier screening tests. Detection of a variant warrants further testing of the factor XI activity level. (See 'Confirmation by factor XI activity' below.)

Initial testing (PT, aPTT) — The typical evaluation for suspected factor XI deficiency begins with a prothrombin time [(PT), aPTT, and platelet count.

Factor XI deficiency causes isolated prolongation of the aPTT, although a normal aPTT does not exclude mild deficiency; typically, the aPTT becomes prolonged when the factor XI level is <40 to 50 percent [89]. If the aPTT is prolonged in an individual with factor XI deficiency, the abnormality will correct in a mixing study (aPTT performed with a 1:1 mix of patient plasma with pooled normal plasma).

Factor XI deficiency does not cause a prolonged PT, prolonged thrombin time (TT), or platelet abnormalities. If present, these abnormalities should prompt evaluation for other conditions. (See "Clinical use of coagulation tests", section on 'Evaluation of abnormal results'.)

Individuals without a known family history of factor XI deficiency who are being evaluated for an isolated prolonged aPTT are usually tested for more common causes such as heparin in the sample or hemophilia A or B before testing factor XI levels (table 2). If mixing studies on the aPTT correct and factor VIII and IX levels are normal, we proceed to measuring factor XI activity. An exception may be an individual of known Ashkenazi Jewish ancestry, in whom factor XI activity testing may be done first or simultaneously with factor VIII and factor IX levels, or an individual with a known family history of factor XI deficiency, in whom the aPTT and factor XI activity level may be measured simultaneously or sequentially. (See "Clinical use of coagulation tests", section on 'Causes of prolonged aPTT' and 'Confirmation by factor XI activity' below.)

For individuals with a known family history or strong suspicion of factor XI deficiency (Ashkenazi Jewish ancestry and typical bleeding history), factor XI activity should be determined regardless of aPTT result because individuals with partial deficiency can develop significant bleeding that requires treatment.

Confirmation by factor XI activity — Factor XI deficiency is diagnosed (or the diagnosis confirmed) by the finding of reduced factor XI activity; this is assayed in an aPTT-based test. Results are reported as percent activity, which is equivalent to units per deciliter. Testing is available onsite in most tertiary hospitals and may be a send-out test in smaller community hospitals.

The lower limit of normal for factor XI activity is approximately 60 to 70 percent (60 to 70 units/dL) [4,68]. The typical normal range is from approximately 65 to 130 percent (mean, approximately 100 percent). The reference range from the testing laboratory should be used when available. Measurement of factor XI activity becomes less accurate at levels below 10 percent, and in such cases, genetic testing may be used to determine if the individual is truly homozygous for a null mutation, which greatly increases the risk for inhibitor development.

Factor XI levels are lower in neonates than older children, and age-specific reference ranges should be used. Children with apparent factor XI deficiency should be retested at age six months or older to establish the true factor XI level [4]. (See 'Factor XI function' above.)

Testing should be performed when the individual is not receiving an anticoagulant, some of which can cause spurious results. If this is not possible, the anticoagulant may be diluted; close discussion with the testing laboratory is prudent in such cases. Lupus anticoagulants can also interfere with testing.

Deficiency can be categorized as severe or partial based on the factor XI activity:

●Severe deficiency (factor XI activity <20 percent) – Unlike hemophilia A and B, in which severe deficiency refers to factor levels <1 percent, severe deficiency of factor XI is typically defined as levels below 20 percent [4,35]. These individuals are usually homozygotes or compound heterozygotes for a pathogenic F11 variant. Some heterozygous individuals with F11 variants that affect secretion of the normal factor XI may have levels in the severely deficient range. Even with severe deficiency, bleeding manifestations may be mild [4].

●Partial deficiency (factor XI activity 20 to 60 percent [or upper limit of normal for a laboratory-specific assay]) – These individuals are usually heterozygous for a pathogenic F11 variant. Bleeding is highly variable, with some individuals having serious bleeding and others having none (see 'Bleeding' above). Some heterozygotes may have factor XI activity levels within the normal range.

Genetic testing — Genetic testing is not required for diagnosis. However, it may be pursued in selected cases, especially in individuals of Ashkenazi Jewish descent, for whom the mutations are well characterized, allowing accurate identification of those with a null mutation, which confers a greater risk of inhibitor development and might affect management decisions. (See 'Genetic testing and counseling' below and 'Hemostatic therapies' below.)

Some individuals may receive genetic test results that include information about variants in F11 as an incidental finding (secondary finding). (See "Gene test interpretation: F11 (gene for coagulation factor XI)".)

Differential diagnosis — The differential diagnosis of factor XI deficiency includes other causes of bleeding and/or a prolonged aPTT.

Bleeding disorders:

●Hemophilia A or B – Hemophilia A and B are congenital bleeding disorders due to deficiencies of factor VIII (F8) and factor IX (F9), respectively. Like factor XI deficiency, there is often a positive family history (although up to one-third of cases of hemophilia A result from de novo mutations). Unlike factor XI deficiency, hemophilia A and B are both X-linked, and severe disease is typically restricted to males; females are typically unaffected carriers. Like hemophilia A and B, severe factor XI deficiency causes an isolated prolonged aPTT. These conditions are readily distinguished by determining factor levels. (See "Clinical manifestations and diagnosis of hemophilia".)

●Von Willebrand disease – Von Willebrand disease (VWD) is an inherited bleeding disorder due to deficiency of von Willebrand factor (VWF). Acquired von Willebrand syndrome (AVWS) occurs in the setting of other conditions that affect production or stability of VWF. Like factor XI deficiency, VWD is an inherited autosomal bleeding disorder that can present at any age. As with some individuals with mild factor XI deficiency, the aPTT may be normal in some individuals with mild VWD and AVWS. Unlike factor XI deficiency, VWD and AVWS have abnormal testing for VWF function and normal factor XI levels. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Acquired von Willebrand syndrome".)

●Acquired factor inhibitors – Acquired inhibitors (autoantibodies) can develop against any of the coagulation factors; inhibitors of factor VIII are the most common. Like factor XI deficiency, inhibitors affecting the intrinsic pathway may present with bleeding and prolongation of the aPTT. Unlike factor XI deficiency, acquired factor inhibitors often present with severe spontaneous bleeding, the aPTT will not correct in a mixing study, and the activity of the implicated factor will be low. (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

Prolonged aPTT without bleeding:

●Antiphospholipid antibodies/lupus anticoagulant – Antiphospholipid antibodies (aPL) are autoantibodies directed against phospholipid-protein complexes; they can cause the lupus anticoagulant phenomenon, with prolongation of clotting times (typically the aPTT) in vitro, but they do not cause clinical bleeding. Like factor XI deficiency, the patient may present with an incidental finding of a prolonged aPTT. Unlike factor XI deficiency, mixing studies will fail to correct in the presence of an aPL, especially at later time points, and aPL may cause the appearance of multiple factor deficiencies (including factor XI), although these are actually laboratory artifacts [90]. Unlike factor XI deficiency, these individuals are not at risk for bleeding; they may be at risk for thrombosis if they have the antiphospholipid syndrome (APS). (See "Diagnosis of antiphospholipid syndrome".)

●Deficiency of other contact factors – Other contact factor deficiencies (factor XII, prekallikrein, high molecular weight kininogen [HMWK]) are rare. These deficiencies can present as an incidental finding of a prolonged aPTT. Unlike factor XI deficiency, these individuals have normal factor XI levels and do not have an increased risk of bleeding. (See "Overview of hemostasis", section on 'Deficiencies of intrinsic contact pathway proteins' and "Overview of the causes of venous thrombosis", section on 'Factor XII deficiency'.)

MANAGEMENT

Overview of management — Management of factor XI deficiency is challenging because the correlation between the factor XI level and the bleeding phenotype is poor, and available therapies have potential adverse effects that may be serious [4]. Randomized trials comparing different approaches are lacking.

Our general approach is summarized here and discussed in more detail below.

●Bleeding history – Bleeding history is critical for management (see 'Bleeding' above). We thoroughly review all prior bleeding challenges to determine the bleeding phenotype. In a 2014 guideline from the British Society for Haematology, the factors most predictive of bleeding with surgery or childbirth include a positive personal bleeding history, presence of an additional coagulopathy, factor XI level ≤1 percent, and surgery involving an area of high fibrinolytic activity (table 1) [57]. If a patient has been documented to tolerate a particular procedure (or type of procedure) well in the past without bleeding, we are more likely to reserve factor XI replacement for bleeding instead of using it prophylactically.

In some cases, individuals with factor XI deficiency may be screened for other hemostatic defects such as von Willebrand disease (VWD) or platelet disorders, although this approach may not apply to all individuals [4,35]. Most individuals with heavy menstrual bleeding will be screened for VWD and thrombocytopenia. (See "Approach to the adult with a suspected bleeding disorder", section on 'Positive bleeding history and normal initial testing'.)

●Surgical planning – Advance planning for elective surgery is key to reducing the bleeding risk and avoiding unnecessary exposure to plasma or factor XI concentrates. For most major procedures in individuals with severe factor XI deficiency or a significant bleeding history, we suggest factor XI replacement. Some individuals may reasonably choose expectant management (if bleeding risk is acceptable) or recombinant activated factor VII (rFVIIa) if a factor XI inhibitor is present or likely to develop. For most minor and dental procedures, we suggest an antifibrinolytic agent or expectant management (ie, a "watch and wait" approach, with factor XI replacement given for clinically significant bleeding). (See 'Planning for surgery and dental procedures' below.)

●Inhibitor screening – Screening for a factor XI inhibitor is appropriate in individuals with severe deficiency (especially with a factor XI level below 1 to 2 percent), in those with a prior history of an inhibitor, and in those who are planning for elective surgery (especially if they have ever received a factor XI-containing product in the past [eg, plasma, factor XI concentrate, immunoglobulin preparation]) [35]. As noted above, factor XI activity testing may be inaccurate in some laboratories that are not calibrated for measuring very low levels, and inhibitor testing may be done if there are questions about the factor XI level. (See 'Confirmation by factor XI activity' above.)

Inhibitor screening may also be performed if the bleeding phenotype changes; however, in contrast with hemophilia A and B, routine inhibitor screening is not performed as most individuals are not routinely exposed to factor XI products.

●Routine care – We do not use prophylaxis for routine daily activities. We advise individuals with factor XI deficiency to avoid aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and other antiplatelet agents due to concerns about increased bleeding risk unless there is a cardiovascular indication. Acetaminophen and opioid pain medications may be used for pain.

●Heavy menstrual bleeding and obstetric care – For heavy menstrual bleeding, hormonal therapy (birth control pill, intrauterine device) or an antifibrinolytic agent are good options, provided that anatomic causes of bleeding have been eliminated. Management of labor and delivery depends on the bleeding history, factor XI level, type of delivery, and use of neuraxial anesthesia. (See 'Obstetric/gynecologic considerations' below.)

●VTE prophylaxis – The risk and benefit of thromboprophylaxis during hospitalization should be individualized. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

Prophylaxis may be administered if indicated. Case reports have demonstrated prophylactic-dose anticoagulation can be well tolerated and effective [69,91]. However, as noted above, factor XI deficiency may be protective against deep vein thrombosis (DVT). (See 'Possible protection from cardiovascular events and DVT' above.)

Pharmacologic prophylaxis is likely not needed for those with severe factor XI deficiency (factor XI activity <20 percent).

Management of acute bleeding — Serious acute bleeding should be treated with factor XI replacement, with or without an antifibrinolytic agent, to raise the factor XI activity level to 30 to 45 percent. Lower levels may be appropriate depending on the tissue or area involved. Often, co-administration of an antifibrinolytic agent is appropriate, as this may improve hemostasis in areas of high fibrinolytic activity with a low risk of adverse events. Dosing is discussed below. (See 'Factor XI replacement products (FFP and factor XI concentrate)' below and 'Antifibrinolytic agents' below.)

Individuals with inhibitors (or presumed inhibitors based on failure of the factor XI level to increase as expected with factor XI replacement) may use rFVIIa. (See 'rFVIIa' below.)

Minor bleeding can be managed with an antifibrinolytic agent alone, especially when involving areas of high fibrinolysis (table 3).

Planning for surgery and dental procedures — Key decisions include whether to use antifibrinolytic therapy and/or factor XI prophylaxis (and, if so, what product and what target factor XI level), inhibitor status, need for VTE prophylaxis, and pain control that avoids antiplatelet agents.

Preoperative assessment includes the following:

●Bleeding history – Obtain a thorough bleeding history, with additional testing as needed (eg, for other hemostatic defects).

●Laboratory testing – Measure the factor XI activity level to help assess bleeding risk (highest with severe deficiency) and as a baseline if replacement is used.

A reliable test to predict bleeding is not available, and data are limited and conflicting on the use of global tests of hemostasis to predict bleeding risk. One report found thrombin generation time predictive, but a subsequent report found the sensitivity to be too low [92,93]. Developing an accessible global test that could discriminate individuals with factor XI deficiency and a bleeding phenotype from those with factor XI deficiency without a bleeding phenotype remains an area of research.

Rule out a factor XI inhibitor in patients with low baseline factor XI (done simultaneously with factor activity testing). Inhibitors can generally develop in individuals with undetectable factor XI or very low factor XI levels (<2 percent) who have been exposed to exogenous factor XI. However, in practical terms, measurement of factor XI activity can be inaccurate in the low ranges (eg, in laboratories not calibrated to detect levels below 7 to 8 percent). (See 'Confirmation by factor XI activity' above.)

●Medications – Discontinue aspirin at least seven days before surgery.

Determine whether an antifibrinolytic agent is appropriate (applies to surgeries involving areas with high fibrinolytic activity). Antifibrinolytic agents are especially useful for dental extractions and other procedures in areas of high fibrinolytic activity (table 1) [35,57,94]. These agents may be used together with plasma replacement or alone. Caution should be used if administered concurrently with factor XI concentrates due to the risk of thrombosis. This concern and information about dosing are discussed below. (See 'Antifibrinolytic agents' below.)

Determine whether factor XI replacement is appropriate. Prophylactic factor XI replacement is generally required for individuals undergoing major surgery if they have a significant bleeding history, or if their bleeding history is unknown and their factor XI level is <20 percent. Additional individuals may choose to receive prophylactic factor XI if they place a higher value on avoiding bleeding than on avoiding adverse effects from exposure to plasma or factor XI concentrate. For others (eg, those who have undergone bleeding challenges without significant bleeding or who have factor XI levels above 20 percent), it may be reasonable to reserve factor XI supplementation for severe or uncontrolled bleeding. If this approach is used, a factor XI replacement product (and information about dosing) should be readily available if needed. (See 'Factor XI replacement products (FFP and factor XI concentrate)' below.)

•For those who will require treatment with a plasma product such as Fresh Frozen Plasma (FFP), assess the risk of fluid overload. Large volumes of FFP may be required for hemostasis; this can be more easily administered with plasma exchange if available.

•If replacement will be used, ensure the ability to obtain factor XI activity levels in a timely manner.

Another option for individuals who wish to avoid exposure to plasma or a factor XI concentrate is use of rFVIIa at low doses. Although data on the efficacy and safety of rFVIIa are very limited in this population, the doses used are significantly lower than the doses commonly associated with an increased risk of thrombosis, and rFVIIa avoids the risk of inhibitor development, which is known to be quite high following plasma exposure in individuals with very low or undetectable factor XI levels. Some experts do not use rFVIIa in patients with factor XI deficiency unless they have a factor XI inhibitor (autoantibody). (See 'rFVIIa' below and 'Inhibitor development' above.)

●Local hemostasis should be maximized. This may include topical products such as fibrin sealant or others, depending on the expertise and preference of the surgeon. (See "Overview of topical hemostatic agents and tissue adhesives" and "Fibrin sealants".)

Anticoagulation or antiplatelet therapy — Antithrombotic therapy may be indicated in individuals with factor XI deficiency despite the possibility that factor XI deficiency provides partial protection from stroke and DVT. (See 'Possible protection from cardiovascular events and DVT' above.)

These decisions must be individualized based on the bleeding phenotype and the consequences of withholding antithrombotic therapy.

Evidence regarding bleeding risks with antithrombotic therapy include the following:

●Anticoagulation – A retrospective review of 269 people with factor XI deficiency identified 15 mildly deficient individuals who required therapeutic anticoagulation, mostly using a vitamin K antagonist for atrial fibrillation [95]. None had major bleeding. During >1000 months of follow-up, there were two mild bleeding episodes. The severity and location of bleeding before and after anticoagulation were not appreciably different (two had a history of bleeding prior to using anticoagulation). This suggests that standard dose anticoagulation can be used in individuals with factor XI deficiency if needed, although only small numbers have been evaluated.

●Antiplatelet therapy – A retrospective review of antithrombotic therapy at one institution identified 16 patients with factor XI deficiency, including six patients with severe deficiency, who received some type of antithrombotic therapy [96]. Two patients with severe deficiency treated with dual antiplatelet therapy required discontinuation of clopidogrel due to epistaxis. No other patients receiving dual antiplatelet therapy were reported. This suggests that dual antiplatelet therapy should be used very cautiously, although data are limited. Low-dose aspirin as a single agent appears to be tolerated in most patients.

Obstetric/gynecologic considerations

Heavy menstrual bleeding — Individuals with heavy menstrual bleeding should be evaluated for other causes of abnormal uterine bleeding (eg, cervical polyp). Options for therapy may include an oral contraceptive or other medical or surgical interventions to reduce the frequency or severity of menses. These options are discussed in more detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

Heavy menstrual bleeding may also be treated with an oral antifibrinolytic agent. (See 'Antifibrinolytic agents' below.)

Attention should be paid to the possibility of iron deficiency (eg, monitoring of complete blood count and/or ferritin level). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

Pregnancy — Individuals with factor XI deficiency can have a successful pregnancy. There is no increased risk of spontaneous miscarriage.

Antenatal bleeding is rare unless associated with a surgical procedure or a miscarriage. Factor XI levels during pregnancy can vary, but changes are usually not clinically significant. We check the factor XI level during the third trimester in preparation for delivery and prior to any invasive procedures.

Amniocentesis and chorionic villus sampling can be complicated by excessive bleeding; for individuals undergoing these procedures, the risks and benefits should be assessed and potential alternatives reviewed. Factor XI levels should be checked; a source of prophylactic factor XI may be indicated depending on the maternal bleeding history [97]. Testing the fetus for factor XI deficiency before birth is not required [57].

Labor and delivery — Factor XI deficiency confers an increased risk of postpartum hemorrhage (PPH). The lack of a good correlation between factor XI level and bleeding manifestations contributes to the uncertainty when trying to determine who needs factor replacement in the peripartum setting. Still, all individuals should have a factor XI activity level obtained during the third trimester.

A positive history of bleeding is the strongest predictor of obstetric hemorrhage. In the absence of prophylactic measures, approximately 20 percent of individuals with severe factor XI deficiency experience excessive bleeding after delivery [80]. Two systematic reviews reported PPH in 85 of 490 (17 percent) and 90 of 490 (18 percent) deliveries [98,99] A 2023 single institution retrospective review reported a rate of PPH of 11 percent in 206 deliveries, at least twice as high as in the general obstetric population (risk estimate of 2 to 6 percent) [100]. In a case-control study of 71 deliveries in individuals with mild factor XI deficiency (20 to 70 percent activity), the rate of PPH was significantly higher among the 26 cesarean deliveries (odds ratio [OR] 2.73, 95% CI 1.02-7.26) [101]. The majority of patients with PPH had a positive bleeding history. In contrast, there were no episodes of PPH among 45 vaginal deliveries. Factor XI levels were not predictive for the development of PPH [101].

Advance planning is critical. Discussions should incorporate risks; patient values and preferences; and input from the obstetrician, anesthesiologist, hematologist or clinician with expertise in rare bleeding disorders, and/or a local hemophilia treatment center [97]. Active management of the third stage of labor should be practiced [97]. We base decisions for labor and delivery on the individual's prior bleeding history, the factor XI activity level obtained during the third trimester, the mode of delivery, and whether neuraxial anesthesia is desired. Our approach based on factor XI activity and bleeding history is illustrated in the algorithm (algorithm 1) and summarized here:

●Factor XI >40 percent – People with a factor XI level >40 percent can generally be managed using routine obstetric care. Most anesthesiologists are comfortable providing neuraxial anesthesia if the factor XI level is above 40 percent.

●Factor XI ≤40 percent – For people with a factor XI level ≤40 percent, decisions about factor XI supplementation (via factor XI concentrate or plasma) depend on the bleeding history. For all patients, we suggest prophylactic administration of an antifibrinolytic agent to reduce postpartum blood loss [102].This is especially relevant if there is concern about bleeding (due to a history of bleeding with prior bleeding challenges, an unknown bleeding history, or severe deficiency). If the bleeding history is negative, intravenous tranexamic acid should also be considered at time of neuraxial anesthesia or delivery, or it should be readily available if needed [102]. An antifibrinolytic agent can be given concomitantly with a plasma product or with rFVIIa, but caution is required if a factor XI concentrate is also being used. (See 'Antifibrinolytic agents' below.)

●Factor XI <20 percent – For people with severe factor XI deficiency (factor XI level <20 percent) who have a prior bleeding history, we prefer elective induction of labor to allow for factor replacement. When replacing with FFP, we suggest starting FFP 15 to 20 mL/kg the evening before elective induction of labor or prior to elective cesarean delivery and continued for 24 to 48 hours (typically, one to two doses), in combination with an antifibrinolytic agent for three to five days. Exceptions may include those who place a very high value on avoiding plasma (eg, due to prior allergic reaction) and who do not have access to a factor XI concentrate. These individuals may be treated with low-dose rFVIIa (not a licensed indication) or managed with antifibrinolytic therapy alone, with a source of factor XI reserved for treatment of severe bleeding [80]. (See 'Factor XI replacement products (FFP and factor XI concentrate)' below and 'rFVIIa' below.)

●Anesthesia – People who desire neuraxial anesthesia should speak with the anesthesiologist during the third trimester, prior to labor and birth, to understand the risks and benefits of different approaches, to determine what factor XI level is considered acceptable and what interventions will be required to increase the factor XI level, and to ensure that sufficient time will be available to document that the factor XI level is sufficient (based on the turnaround time of factor XI assays at their institution). The typical approach by obstetric anesthesia is not to transfuse plasma or platelets solely for the purpose of placing an epidural or spinal catheter. (See "Anesthesia for cesarean delivery", section on 'General versus neuraxial anesthesia'.)

Evidence to guide hematologic care during delivery and neuraxial anesthesia is limited to small observational studies.

●Delivery – One of the largest series involved 62 individuals with severe factor XI deficiency who had 164 deliveries (146 vaginal and 18 cesarean) [80]. The decision of whether to administer an antifibrinolytic agent and/or prophylactic factor XI or to reserve therapy for bleeding was made by the treating obstetrician. A typical course of FFP was 15 to 20 mL/kg for one to two doses. PPH occurred less frequently in those treated with FFP (2 of 14 vaginal deliveries and none of six cesarean deliveries [total, 10 percent]) compared with those managed expectantly (32 of 132 vaginal deliveries and 2 of 12 cesarean deliveries [total, 24 percent]). Of those managed expectantly who had bleeding, approximately one-third were treated with plasma; the remainder were clinically mild and did not require therapy. There were no clinical features besides a positive prior bleeding history that reliably predicted who was likely to have postpartum bleeding.

●Neuraxial anesthesia – The incidence of epidural hematoma in the general obstetric population is rare, reported at 0.6 per 100,000 deliveries [103]. There is no general consensus on a safe factor XI level for regional anesthesia. The target level is generally determined by the anesthesiologist; in most cases, levels of approximately 40 percent or greater are considered adequate, and lower levels may be acceptable in selected patients.

Single center studies suggest that epidural anesthesia can probably be performed safely in people with nonsevere factor XI deficiency. One study estimated that at least 2150 individuals with unknown partial factor XI deficiency underwent neuroaxial anesthesia without bleeding complications [104]. Another study noted that 86 percent of individuals with factor XI activity >30 percent underwent neuraxial anesthesia without complications [100]. Neuraxial anesthesia is usually avoided with severe deficiency [102].

Care of the neonate — Neonatal bleeding is very rare, including in those with severe deficiency. However, invasive procedures such as circumcision and intramuscular injections are avoided until the factor XI level is known. Vitamin K can be given orally. A cord blood sample can be obtained for factor XI activity testing if the neonate is at risk of homozygosity or compound heterozygosity [102]. Care should be taken to avoid unnecessary trauma to the neonate.

The British Society for Haematology guidelines recommend tranexamic acid (TXA) for all infants with low factor XI levels when planning for circumcision [57]. Factor XI levels are lower in neonates (approximately 50 percent of adult levels) and do not reach adult levels until approximately six months of age. Thus, age-appropriate reference values should be used.

Hemostatic therapies

Antifibrinolytic agents — Use of an antifibrinolytic agent, given alone or together with factor XI replacement therapy, has been applied extensively in individuals with factor XI deficiency. These agents are effective in reducing bleeding risk and in treating bleeding, especially in sites of fibrinolytic activity (table 1) and for dental extractions, treatment of heavy menstrual bleeding, and delivery, including in patients with very low factor XI levels [102].

Typical doses are as follows:

●Tranexamic acid (TXA) – 1 gram four times daily (orally, 15 to 25 mg/kg every six to eight hours; or intravenously, 10 mg/kg every six to eight hours). The oral formulation available in the United States is 650 mg tablets; in other countries, the oral formulation is 500 mg tablets. For dental procedures, TXA can be administered as a 5 percent mouthwash.

●Epsilon aminocaproic acid (EACA) – 5 to 6 grams four times daily (or 50 to 60 mg/kg four times daily), given orally. For dental procedures, EACA can be given as an oral rinse (15 mL of a solution containing 1.25 g/5 mL), used for two minutes.

Therapy is started approximately 2 to 12 hours before surgery and continued for approximately seven days. For dental procedures, an antifibrinolytic agent is the treatment of choice, even in severe deficiency; it can be given as a mouth wash, orally, or intravenously [94]. (See 'Planning for surgery and dental procedures' above.)

For labor and delivery, the antifibrinolytic agent is given at the time of neuraxial anesthesia, at delivery, or prior to elective cesarean delivery. TXA is used, at a dose of 1 gram intravenously. The duration of therapy is discussed above. (See 'Labor and delivery' above.)

For heavy menstrual bleeding, an antifibrinolytic agent is given orally on days of heavy bleeding. (See 'Obstetric/gynecologic considerations' above.)

Antifibrinolytic agents can be given concurrently with a plasma product or with low-dose recombinant activated factor VII (see 'rFVIIa' below). While they are considered safe in this setting, their efficacy and safety have not been evaluated in randomized trials in factor XI deficiency; use in individuals with cardiovascular disease should be avoided or approached with caution [35].

Concurrent use of an antifibrinolytic agent with a factor XI concentrate should generally be avoided due to the potential thrombotic risk. If the patient has received a factor XI concentrate, a period of approximately 24 hours should elapse before an antifibrinolytic agent is given. If the patient has received an antifibrinolytic agent and requires a source of factor XI, it may be prudent to use a plasma product rather than a factor XI concentrate.

Antifibrinolytic agents are generally avoided if hematuria is present.

Factor XI replacement products (FFP and factor XI concentrate) — Most surgical procedures do not require prophylaxis with a source of factor XI, particularly if not involving areas of fibrinolysis (table 3). When needed, options include a plasma product such as Fresh Frozen Plasma (FFP) or a high-purity factor XI concentrate derived from human plasma. The purified factor XI concentrates are available in Australia, Canada (through a special access program), and some countries in Europe; thus, many individuals will not have access to these products. A factor XI concentrate was provided through an expanded access program in the United States but is no longer available [69,105]. There are no recombinant factor XI products for clinical use.

Factor XI is not present in Cryoprecipitate or prothrombin complex concentrates (PCCs); these products have no value in the treatment of isolated factor XI deficiency.

Evidence for efficacy and safety — There are no large trials that compare prophylactic versus expectant administration of factor XI in individuals with severe factor XI deficiency and no randomized trials comparing different sources of factor XI (factor XI concentrate versus FFP or antifibrinolytic agents).

●A prospective study reviewed outcomes in 44 patients with factor XI deficiency treated in 13 centers in France over a three-year period (2006 to 2009); 29 had severe deficiency (factor XI level <20 percent) [91]. Most of the patients (71 percent) had a history of hemorrhage; approximately one-half had factor XI activity <20 percent. Factor XI concentrate was administered 67 times (before 43 surgeries, before 10 invasive procedures, before eight vaginal deliveries, and after six bleeds). Hemostasis was judged to be good or excellent in 65 cases (97 percent). Four individuals (9 percent) received a red blood cell transfusion. Adverse events included one fatal episode of respiratory distress that was attributed to pulmonary embolism (no autopsy was performed) and one case of factor XI inhibitor development.

●A retrospective analysis found a higher rate of bleeding complications in 120 patients with severe factor XI deficiency (factor XI levels <15 percent) who had undergone surgical procedures without replacement therapy [106]. Procedures performed on tissues exhibiting fibrinolytic activity were associated with bleeding in 49 to 67 percent, while those involving sites with no local fibrinolytic activity were associated with bleeding in 2 to 40 percent. The incidence of bleeding following circumcision was 1.5 percent.

Adverse effects differ between plasma products and factor XI concentrates:

●The main safety concerns with FFP are volume overload (transfusion-associated circulatory overload [TACO]), transfusion-related acute lung injury (TRALI), allergic reactions, and transfusion-transmitted infections. Pathogen-inactivated products such as solvent/detergent-treated plasma have a theoretical advantage of reducing exposure to enveloped viruses without any increase in adverse events. However, the cost of these products is higher, they do not reduce the risks of TACO or TRALI, and they have not been demonstrated to improve outcomes. (See "Clinical use of plasma components", section on 'Risks' and "Pathogen inactivation of blood products".)

●Purified factor XI concentrates have been reported to cause thrombotic complications (arterial and venous) in up to 10 percent of individuals [107-109]. Antithrombin and heparin have been added to reduce this risk [110]. A summary of experience with these products suggests that the risk is greatest in individuals over the age of 60 years with underlying cardiovascular disease. In a series involving 161 patients, 19 had adverse events, 12 of which were considered thrombotic [110]. Transient changes in coagulation testing suggestive of disseminated intravascular coagulation (DIC) have been observed, but these patients have not developed clinical DIC [111-113].

Patients at high risk for bleeding should have an evaluation for the specific risks of the procedure, and it may be appropriate to use a lower dose of factor XI concentrate or an alternative source of factor XI such as FFP. Revised guidelines have recommended lower initial doses of Hemoleven (the factor XI concentrate available in the United Kingdom [UK] and France) of no more than 10 to 15 units/kg with a goal factor XI of 30 to 40 percent (30 to 40 units/dL) [108]. The risk of thrombotic complications associated with a different factor XI concentrate used in the UK appears lower [109]. The reason for this difference in observed thrombotic risk is unclear; it may be related to potency.

Concomitant administration of factor XI concentrates and antifibrinolytic agents within 24 hours should be avoided due to the potential risk of thrombotic complications. (See 'Administration' below.)

Administration

●FFP – By definition, the amount of factor XI in plasma is equivalent to 1 unit/mL. Thus, a dose of Fresh Frozen Plasma (FFP) or a related product such as Plasma Frozen Within 24 Hours After Phlebotomy (PF24) given at a dose of 10 to 20 mL/kg is usually sufficient to raise the factor XI level to 10 to 20 percent above the baseline level. This amount of plasma may represent a significant volume load for some individuals (eg, those with underlying heart disease or renal insufficiency) and administration may take several hours; in cases requiring significant plasma administration, plasma exchange may be needed. A case report has described successful treatment of an individual undergoing hip arthroplasty using a single course of preoperative plasma exchange followed by postoperative plasma administration [114]. Subsequent doses of 5 to 10 mL/kg can be given every 24 to 48 hours, depending on the required duration of therapy.

●Factor XI concentrates – There are two virally inactivated factor XI concentrates available for clinical use (Hemoleven in France and the UK; factor XI concentrate in the UK). Hemoleven contains factor XI, antithrombin, C1 esterase inhibitor, and a small amount of heparin; factor XI concentrate contains factor XI, antithrombin, and heparin. The patient's factor XI level typically increases by 2 units/dL (2 percent) for every unit/kg administered. Thus, a dose of approximately 15 units/kg is usually sufficient to raise the factor XI level to >30 percent.

A dose calculation may be used for other factor XI targets:

The dose is repeated every 48 to 72 hours depending on measured factor XI levels.

The optimal target factor XI level is unknown. Most experts suggest a level of approximately 30 to 45 percent [4]. Selected individuals with partial factor XI deficiency may have bleeding at this level and may require higher levels; this decision is individualized based on the bleeding history and clinical course of that patient. In general, the factor XI level should not be raised above 70 percent due to concerns about thrombotic complications, especially when using factor XI concentrates.

The half-life of factor XI is long (approximately 46 to 62 hours), and maintenance doses are administered approximately once every 48 to 72 hours [69,91]. Smaller doses of plasma may be given more frequently (eg, 5 mL/kg every 24 hours) to reduce the volume load of each dose. Factor XI activity should be monitored regularly (eg, daily).

The duration of therapy is also not well established and is individualized according to the bleeding history, surgical procedure or type of delivery, and postoperative course. A limited course of factor XI replacement therapy (including preoperative dose) followed by a longer course of antifibrinolytic therapy is often sufficient to prevent bleeding. It may be reasonable to treat for 48 to 72 hours for minor procedures or vaginal delivery; five to seven days for major procedures, cesarean delivery, or postpartum bleeding; and up to 10 days to two weeks for major surgery and/or procedures in which bleeding would be catastrophic (eg, central nervous system surgery).

rFVIIa — Individuals with severe factor XI deficiency who have developed a factor XI inhibitor (alloantibody) may not have an increase in factor XI with factor XI replacement products and may require treatment with a bypassing agent such as recombinant activated factor VII (rFVIIa) [115].

There are many reports of successful use of rFVIIa combined with tranexamic acid in individuals with factor XI deficiency who have developed an inhibitor and are undergoing surgery or a procedure with concern about bleeding [35,115-122]. A lower dose of rFVIIa is often effective (typical dose, 15 to 30 mcg/kg, rounded to the nearest vial size), in contrast with other settings in which much higher doses are used. The half-life of factor VII is very short. Dosing can be repeated at intervals of approximately two to six hours, or a continuous infusion may be used (eg, 1.8 to 3.6 mcg/kg per hour); in some cases, a single dose of rFVIIa is sufficient [118,123]. There is no laboratory parameter that can be measured to guide changes in dosing; clinical assessment of bleeding is the best means of evaluating efficacy. Antifibrinolytic agents can be co-administered with rFVIIa.

Some individuals who do not have a factor XI inhibitor but are at high risk of inhibitor development (eg, those with undetectable factor XI levels due to a null mutation [type II mutation]) may prefer to use rFVIIa to avoid inhibitor development. In two small case series, low-dose rFVIIa 15 to 30 mcg/kg in combination with tranexamic acid was safe and effective for managing delivery with severe factor XI deficiency (<7 percent) without an inhibitor, prior to neuraxial anesthesia and cesarean section [93,116]. More safety data are needed to confirm these findings.

Administration of rFVIIa may be associated with thrombotic complications, although these are often described in the setting of much higher doses (eg, 90 mcg/kg) [117]. These adverse events as well as other aspects of administration are discussed in more detail separately. (See "Recombinant factor VIIa: Administration and adverse effects".)

Desmopressin — A few case series have suggested that use of desmopressin (DDAVP; dose, 0.3 mcg/kg given subcutaneously or intravenously) could prevent clinical bleeding when used for surgery in individuals heterozygous for factor XI deficiency [124-126]. However, it is possible that the efficacy of DDAVP, if any, is mediated through increases in factor VIII and/or von Willebrand factor (VWF) rather than effects on factor XI. We do not use DDAVP in the management of factor XI deficiency, although it might be a useful nonspecific hemostatic option when the perceived risk of bleeding is low, especially in the presence of low VWF levels.

Genetic testing and counseling — Genetic testing for factor XI gene variants is not required as part of the routine diagnostic evaluation. However, testing in high-prevalence populations with well-characterized mutations (eg, individuals of Ashkenazi Jewish ancestry) may be appropriate in certain settings such as the following [35,97]:

●Borderline factor XI levels and severe bleeding phenotype or other strong suspicion of factor XI deficiency

●Suspected test interference (eg, from a lupus anticoagulant or therapeutic anticoagulation that should not be discontinued)

●Factor XI levels ≤1 percent, in cases in which the presence of a null mutation (homozygosity for type II mutation) would alter management (eg, use of rFVIIa rather than factor XI replacement)

Prenatal counseling may be offered to those with concerns about severe factor XI deficiency in the infant.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rare inherited bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

●Mechanisms and prevalence – Factor XI is the precursor to a serine protease (factor XIa) important for clot propagation and maintenance. Inherited factor XI deficiency is an autosomal dominant or recessive bleeding disorder that is rare in the general population but common among individuals of Ashkenazi Jewish heritage (carrier rate, 8 to 9 percent). (See 'Pathophysiology' above and 'Epidemiology' above.)

●Clinical features – Factor XI deficiency is a trauma-associated bleeding disorder; spontaneous bleeding is rare. Bleeding can occur with surgery or trauma. Heavy menstrual bleeding can occur. Factor XI levels do not easily predict the likelihood of bleeding. (See 'Clinical manifestations' above.)

●Evaluation and diagnosis – Factor XI deficiency may be suspected due to family history, excessive bleeding, or a prolonged activated partial thromboplastin time (aPTT). Coagulation testing is typically done first, followed by factor XI activity. Severe disease is defined by factor XI <20 percent (<20 units/dL); partial disease is defined by factor XI level 20 percent to the lower limit of normal (typically, 60 to 70 percent). Genetic testing is not required but may be done in selected cases. The differential diagnosis includes other bleeding disorders and causes of a prolonged aPTT. (See 'Diagnostic evaluation' above and "Gene test interpretation: F11 (gene for coagulation factor XI)".)

●Bleed treatment – Serious acute bleeding (from trauma) should be treated with a plasma product such as Fresh Frozen Plasma (FFP) or a purified factor XI concentrate (available in Australia, Canada, and some European countries), with or without an antifibrinolytic agent. A target factor XI level of 30 to 45 percent is generally sufficient. (See 'Management of acute bleeding' above and 'Hemostatic therapies' above.)

●Bleed prevention – Routine prophylaxis is not required. Antiplatelet therapy should generally be avoided unless there is a cardiovascular indication. Testing for factor XI inhibitors may be appropriate in some individuals. (See 'Overview of management' above.)

●Surgery – Prior to elective surgery, assess for indication of antifibrinolytic therapy and/or factor XI prophylactic replacement, inhibitor status, possible use of venous thromboembolism (VTE) prophylaxis, and a pain control plan that avoids antiplatelet agents. Early discussions among the surgeon, anesthesiologist, hematologist, and/or a hemophilia treatment center are advised. (See 'Planning for surgery and dental procedures' above.)

•Factor XI (major surgery) – For major surgery with factor XI <20 percent or significant bleeding history, we suggest factor XI replacement (using FFP or factor XI concentrates if available) rather than expectant management or antifibrinolytic therapy alone (Grade 2C). Antifibrinolytic therapy may be used concomitantly. Individuals with a significant bleeding history are more likely to choose factor XI prophylaxis if they place a high value on avoiding bleeding, especially with major surgery. Those without a significant bleeding phenotype may be more concerned about avoiding adverse effects of exposure to plasma and they reasonably choose expectant management, especially for lower bleed risk surgeries. (See 'Factor XI replacement products (FFP and factor XI concentrate)' above.)

•Antifibrinolytic agents (dental, nasal, or genitourinary procedures) – Tranexamic acid or epsilon aminocaproic acid are especially useful for dental extractions and other procedures in areas of high fibrinolytic activity and can be used alone or concomitantly with plasma products or low-dose recombinant activated factor VII (rFVIIa, off-label). (See 'Antifibrinolytic agents' above.)

•Expectant management (minor procedures) – For minor procedures (skin biopsy, dental extractions) or vaginal delivery (table 3), we suggest expectant management (reserving a source of factor XI for bleeding) rather than prophylactic factor XI administration (Grade 2C).

•rFVIIa (inhibitors) – Individuals with factor XI inhibitors undergoing major procedures can be treated with low-dose rFVIIa (15 to 30 mcg/kg). (See 'rFVIIa' above.)

●Labor and delivery – Considerations include the prior bleeding history, factor XI activity level, and whether neuraxial anesthesia is desired, as summarized in the algorithm (algorithm 1). (See 'Obstetric/gynecologic considerations' above.)

●Genetic testing and counseling – Genetic testing is not used routinely but may be appropriate in selected individuals. Reproductive counseling can be offered, but prenatal testing is not required. (See 'Genetic testing and counseling' above.)