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HEMORRHAGIC DISORDERS | VOLUME 7, SUPPLEMENT 1, 84-87, JULY 2009

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Factor XI deficiency in humans

U. SELIGSOHN   Open Archive • DOI: https://doi.org/10.1111/j.1538-7836.2009.03395.x

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Summary
Factor XI (FXI) deficiency is an autosomal recessive injury-related bleeding tendency, which is
common in Jews particularly of Ashkenazi origin. To date, 152 mutations in the FXI gene have
been reported with four exhibiting founder effects in specific populations, Glu117stop in
Ashkenazi and Iraqi Jews and Arabs, Phe283Leu in Ashkenazi Jews, Cys38Arg in Basques, and
Cys128stop in the United Kingdom. Severe FXI deficiency does not confer protection against
acute myocardial infarction, but is associated with a reduced incidence of ischemic stroke.
Inhibitors to FXI develop in one-third of patients with very severe FXI deficiency following
exposure to blood products. Therapy for prevention of bleeding during surgery in patients with
severe FXI deficiency consists of plasma, factor XI concentrates, fibrin glue and antifibrinolytic
agents. In patients with an inhibitor to FXI, recombinant factor VIIa is useful.

Keywords
coagulation • factor XI • factor XI deficiency • Jews • mutations

History
Inherited factor XI (FXI) deficiency was first described in 1953 as a mild to moderate bleeding
tendency [1]. A seminal study established that the disorder is autosomal recessive and prevalent
in Jews [2]. In the classical ‘waterfall’ or ‘cascade’ scheme of coagulation, FXI was assigned with

a role in the ‘contact phase’ of the intrinsic coagulation system. Negatively charged surfaces 
were shown to activate factor XII (FXII) in the presence of prekallikrein (PK) and high molecular
weight kininogen (HK), and FXIIa was shown to activate FXI. FXIa in turn, activated factor IX
(FIX), which leads through additional reactions to thrombin generation. This sequence of
reactions was hard to reconcile with observations that patients with severe deficiencies of FXII,
   
PK, or HK had no bleeding tendency, whereas patients with FXI deficiency exhibited injury-


related bleeding. In 1991, FXI was shown to be activated by thrombin [3, 4], a finding which led
to a revised coagulation scheme in which FXII, PK, and HK are obsolete, while FXI activated by
thrombin, generated by tissue factor–factor VII pathway, augmented further thrombin generation
[3]. Others dispute this concept and suggest that the contact system does play a role in inducing
thrombosis [5].

Factor XI deficiency and functional defects

Homozygotes or compound heterozygotes have an FXI level of <15 U dL−1and heterozygotes
display levels of 25–70 U dL−1or normal values [6, 7]. Vertical transmission of severe FXI
deficiency in unrelated Ashkenazi Jewish families [8], was shown to stem from matings between
homozygotes and heterozygotes commonly observed in this population. In most patients with
FXI deficiency, FXI activity is concordant with antigenicity [9]. Only few patients were described
with dysfunctional FXI, e.g., 100 U dL−1antigenicity and <1 U dL−1activity [10].
Heterozygotes with particularly low level of FXI were described in whom there was a dominant
negative effect; the mutated protein formed a heterodimer with the product of the normal allele
impairing secretion of FXI from cells [11].

Mutations
Three mutations in the FXI gene, termed types I, II, and III, were first described in six Ashkenazi
Jews who had severe FXI deficiency [12]: type I mutation at a splice site of the last intron, type II
– a Glu117stop mutation, and type III – a Phe283Leu substitution. Homozygotes for type II
mutation have a mean FXI activity of 1.2 U dL−1, homozygotes for type III mutation have a
mean FXI activity of 9.7 U dL−1, and compound heterozygotes for types II and III mutations
have a mean activity of 3.3 U dL−1[7]. Types II and III mutations predominate in Ashkenazi
Jews [7, 13]; among 295 Jewish patients of various ethnic origins with severe FXI deficiency,
52% of the alleles harbored type II mutation, 46%– type III mutation, 1%– type I mutation, and
1%– other mutations. Databases listing 152 published mutations are available
(http://www.med.unc.edu/isth/and http://www.hgmd.organd http://www.factorxi.com). Seven of
the listed mutations encode for dysfunctional FXI, i.e., Arg184Gly, Ser248Asp, Val371Ile,
Arg378Cys, Pro520Leu, Glu555Gly, and Thr575Met.  
Ethnic distribution
The highest incidence of FXI deficiency has been observed in Ashkenazi Jews [8]; among 531
individuals, the allele frequencies of type II and type III mutations were 0.0217 and 0.0254,
   
respectively [14]. These data indicate that 1:11 Ashkenazi Jews are heterozygotes for either 
mutation and predictably, 1:450 individuals (0.22%) has severe FXI deficiency. Iraqi Jews, who
represent the ancient gene pool of Jews from Babylonian times (2500 B.C.) only harbor type II
mutation. Among 507 Iraqi Jews, an allele frequency of 0.0167 was found, predicting
heterozygosity in 1:30 individuals and homozygosity in 1:3600 individuals [14]. Among 382
Arabs, type II mutation was detected with an allele frequency of 0.0065. Haplotype analysis
disclosed distinct founder effects for type II and type III mutations [15]. Type II mutation occurred
more than 120 generations ago when all Jews resided in the Middle East, while type III mutation
confined to Ashkenazi Jews occurred more recently [16]. Three other clusters of patients with
FXI deficiency have been observed: one in Basques in whom the predominant mutation is
Cys38Arg, with an allele frequency of 0.005 [17], another in Caucasians from the United
Kingdom in whom the predominant mutation is Cys128X with an allele frequency of 0.009 [18],
and another mutation, Gln88stop, in four families residing in west France [19]. For each
mutation, haplotype analysis was consistent with a founder effect. All other cases of FXI
deficiency from around the world are sporadic.

Bleeding manifestations
Spontaneous bleeding, except for menorrhagia, is rare in patients with severe FXI deficiency.
Bleeding is usually injury related particularly when it afflicts tissues containing activators of the
fibrinolysis, such as oral cavity, nose, tonsils, and urinary tract [7, 20]. At other sites of trauma
like during orthopedic surgery, appendicectomy, circumcision, or cuts in the skin, bleeding is less
common. Postpartum hemorrhage only occurs in approximately 20% of affected women [21, 22].
Some patients with very low level of FXI may not bleed at all following trauma [2], while in others,
bleeding varies in the same patient over time even when provoked by similar hemostatic
challenges [7, 21]. Bleeding can occur at the time of injury and persists unless treated, or can
begin several hours following trauma.

Heterozygotes for FXI deficiency bleed less frequently than homozygotes or compound
heterozygotes. In one study, bleeding was observed in 9:94 (9.6%) heterozygotes who
underwent surgical procedures, including tooth extractions, tonsillectomy, and nasal operation
[2]. Assessment of the risk of bleeding in a cohort of patients with severe and partial FXI
deficiency yielded an odds ratio of 13 [95% confidence interval (CI) 3.8–45] for patients with


severe FXI deficiency and an odds ratio of 2.6 (CI 0.8–9.0) for patients with partial deficiency

[23]. However, studies from the United Kingdom and Iran, described injury-related bleeding in
48–60% of heterozygotes, as well as spontaneous bleeding manifestations [6, 21, 24]. The
reason for this discrepancy has not been clarified, but is conceivably related to variable
definitions of ‘bleeding’ and to concomitant acquired or inherited hemostatic disorder.
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Thrombosis
The effect of FXI in augmenting coagulation by thrombin generation and inhibiting fibrinolysis
through activation of thrombin activatable fibrinolysis inhibitor [25] could hypothetically predict
that in patients with severe FXI deficiency, thrombosis would occur infrequently. However, unlike
patients with severe hemophilia A or hemophilia B, in whom the incidence of acute myocardial
infarction is significantly reduced, patients with severe FXI deficiency are not protected against
such events. Of 96 adult patients with severe FXI deficiency, 16 (17%) had an acute myocardial
infarction at median ages of 64.5 and 58 years in women and men, respectively [26]. The
incidence of acute myocardial infarction was not significantly different from the incidence in the
general population. In contrast, a reduced incidence of ischemic stroke was observed in severe
FXI deficiency. A cohort of 115 patients over 45 years of age with severe FXI deficiency was
compared with an Israeli health survey of 9509 individuals. After correction for common risk
factors, the expected incidence of stroke was 8.56 compared to only one observed [27].

Venous thromboembolism has been observed in anecdotal cases [28]. Conceivably, some
protection against venous thromboembolism is conferred by severe FXI deficiency because high
levels of FXI constitute a risk factor for venous thrombosis [29].

Inhibitors to factor XI
Inhibitors to FXI have been described in patients with severe FXI deficiency. Such patients do
not usually present with spontaneous bleeding. However, trauma or surgery can be
accompanied by excessive bleeding that cannot be managed by FXI concentrate or plasma.
Among 118 unrelated patients with severe FXI deficiency, seven harbored an inhibitor [30]. All
seven patients had received plasma replacement therapy and all were homozygous for the type
II null allele. Of 45 patients with other genotypes, i.e., type III homozygotes or type II and type III
compound heterozygotes who had received plasma, none had an inhibitor to FXI. Thus, only
homozygotes or compound heterozygotes for two null alleles are at risk of developing an
inhibitor following exposure to exogenous FXI. The seven patients who developed an inhibitor
were among 21 homozygotes for the type II mutation who had received plasma, which suggests
that 33% of patients with FXI levels of 1 U 
dL−1or less are prone to develop an inhibitor. 
Immunoglobulin G isolated from patients with an inhibitor display impaired FXI activation by
thrombin or by FXIIa, inhibition of binding of FXI to HK, or diminished activation of FIX by FXIa
[30].

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Diagnosis
The common modes of presentation of FXI deficiency are excessive bleeding following injury,
e.g., tooth extraction, tonsillectomy, nose surgery, urologic procedures, or an incidental finding of
prolonged activated partial thromboplastin time (APTT). All patients with severe FXI deficiency
(activity of <15 U dL−1) exhibit an APTT value more than two standard deviations above the
normal mean [31]. Heterozygotes may have a slightly prolonged APTT or values within the
normal range. Similarly, FXI levels are partially decreased but can be in the normal range [6, 8,
21].

Because severe FXI deficiency can remain asymptomatic until injury is inflicted, it is essential for
all Ashkenazi Jews in need of surgery to be tested by an APTT assay. If a prolonged APTT is
obtained, FXI activity should be measured by a specific assay.

Therapy
Spontaneous bleeding manifestations except for menorrhagia are rare in patients with severe
FXI deficiency, and if they occur, they usually abate without therapy. Oral antifibrinolytic drugs
are useful for ameliorating menorrhagia. Deliveries are infrequently complicated by excessive
bleeding and thus, on-demand, rather than preventive therapy with factor XI concentrate or
plasma therapy is advocated [22].

Surgery or trauma can be associated with excessive bleeding unless treated properly. Careful
evaluation of patients with severe FXI deficiency prior to surgery is necessary, as well as
meticulous planning of hemostasis during and following surgery. Several considerations should
be reckoned with: surgery should be absolutely indicated; previous bleeding episodes should be
taken into account; presence of an inhibitor to FXI should be ruled out; prothrombin time and
platelet count should be normal; use of antiplatelet drugs should be discontinued 1 week
before surgery; sites of surgery that include tissues with increased fibrinolytic activity are
expected to bleed more than sites with low fibrinolytic activity; assessment of the cardiovascular
status of the patient is essential for two reasons: (i) when use of fresh-frozen plasma is planned,
volume overload might be a problem if cardiovascular function is compromised, (ii) compromised
cardiovascular function confers a risk of thrombosis when FXI concentrate is used; patients who
 
need tooth extraction can be safely treated by tranexamic acid without replacement therapy [32];
on demand replacement therapy can be used in patients during or following delivery [22]; fibrin
glue can be used for enhancing hemostasis; and replacement therapy should be started prior to
surgery and carefully monitored thereafter by assays of FXI level.
    

Replacement therapy is usually by fresh frozen plasma (FFP). The main disadvantages of this
therapy are potential transmission of infectious agents, allergic reactions, and volume overload.
Processing FFP by solvent/detergent or by pasteurization has increased its safety without
compromising FXI activity [33]. Two FXI concentrates produced in the United Kingdom and in
France are safe regarding transmission of infectious agents. However, approximately 10% of
patients treated by these products developed arterial thrombosis or venous thromboembolism.
Because almost all patients who developed these unfortunate complications were elderly and
had pre-existing cardiovascular disease [33], these products should be avoided in such patients
or used with extreme caution. Notwithstanding these limitations, FXI concentrates have been
successfully used in many patients. The relatively small volume that needs to be infused, the
excellent in vivorecovery of FXI (90%), and the long half-life of FXI (52 h) substantially facilitate
therapy. For prostatectomy and other lower urinary tract surgery, blood component therapy and
flushing the bladder by saline containing tranexamic are useful; for nasal surgery and
tonsillectomy, replacement therapy and parenteral tranexamic acid administration are advisable;
for major surgery, plasma or FXI concentrate infusions should be targeted to reach trough FXI
levels of 45 U dL−1for approximately 7 days; for minor surgery, a trough level of 30 U
dL−1during approximately 5 days is usually sufficient.

For tooth extractions and skin biopsy, there is no need for replacement therapy
therapy. In 19 patients
with severe FXI deficiency who have had a history of bleeding following tooth extractions or
trauma, tooth extractions were uneventfully performed under treatment with tranexamic acid
alone started 12 h prior to surgery and continued for 7 days after surgery [32]. Fibrin glue can
also be used in such cases and in patients undergoing resection of skin lesions.

The approach to patients with partial FXI deficiency who need surgery varies among centers.
Excessive bleeding following surgery observed in some patients with FXI levels of approximately
50 U dL−1is used as an argument for replacement therapy during surgery [6]. Other
observations of patients who underwent uneventful prostatectomy with a level of 30 U
dL−1support the view that replacement therapy is unnecessary during most surgical procedures
in patients with partial FXI deficiency [34]. Albeit these inconsistencies, a reasonable approach in
patients with partial FXI deficiency can be: to obtain a detailed history of bleeding; if a clear
history of bleeding tendency is revealed, a thorough investigation of other potential inherited or
acquired hemostatic disorders should be performed and reckoned with during planning surgery;
to use tranexamic acid and/or fibrin glue when there is a bleeding history or when high-risk
 
surgery such as prostatectomy is planned; to use replacement therapy in patients with an
unequivocal bleeding tendency (after ruling out other hemostatic defects) aiming at a trough FXI
level of 45 U dL−1for 5 days after surgery.

    
Surgery in patients who have developed an inhibitor to FXI presents a challenge. When the titer
of the inhibitor is very low, use of an FXI concentrate can suffice, but an anamnestic reaction is
to be expected. A one time low dose of recombinant factor VIIa (rFVIIa) given during surgery and
prolonged therapy by tranexamic acid were successfully used in two such patients who
underwent major surgery [35].

Disclosure of Conflict of Interests

The author states that he has no conflict of interest.

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DOI: https://doi.org/10.1111/j.1538-7836.2009.03395.x

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© 2009 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc.

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