Factor XI deficiency in humans
U. Seligsohn, Amalia Biron Research Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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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.
Inherited factor XI (FXI) deficiency was first described in 1953 as a mild to moderate bleeding tendency . A seminal study established that the disorder is autosomal recessive and prevalent in Jews . 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 . Others dispute this concept and suggest that the contact system does play a role in inducing thrombosis .
Factor XI deficiency and functional defects
Homozygotes or compound heterozygotes have an FXI level of <15 U dL−1 and heterozygotes display levels of 25–70 U dL−1 or normal values [6,7]. Vertical transmission of severe FXI deficiency in unrelated Ashkenazi Jewish families , 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 . Only few patients were described with dysfunctional FXI, e.g., 100 U dL−1 antigenicity and <1 U dL−1 activity . 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 .
Three mutations in the FXI gene, termed types I, II, and III, were first described in six Ashkenazi Jews who had severe FXI deficiency : 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 . 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.org and http://www.factorxi.com). Seven of the listed mutations encode for dysfunctional FXI, i.e., Arg184Gly, Ser248Asp, Val371Ile, Arg378Cys, Pro520Leu, Glu555Gly, and Thr575Met.
The highest incidence of FXI deficiency has been observed in Ashkenazi Jews ; among 531 individuals, the allele frequencies of type II and type III mutations were 0.0217 and 0.0254, respectively . 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 . 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 . 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 . 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 , another in Caucasians from the United Kingdom in whom the predominant mutation is Cys128X with an allele frequency of 0.009 , and another mutation, Gln88stop, in four families residing in west France . For each mutation, haplotype analysis was consistent with a founder effect. All other cases of FXI deficiency from around the world are sporadic.
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 , 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 . 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 . 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.
The effect of FXI in augmenting coagulation by thrombin generation and inhibiting fibrinolysis through activation of thrombin activatable fibrinolysis inhibitor  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 . 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 .
Venous thromboembolism has been observed in anecdotal cases . Conceivably, some protection against venous thromboembolism is conferred by severe FXI deficiency because high levels of FXI constitute a risk factor for venous thrombosis .
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 . 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−1 or 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 .
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 . 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.
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 .
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 ; on demand replacement therapy can be used in patients during or following delivery ; 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 . 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 , 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 vivo recovery 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−1 for approximately 7 days; for minor surgery, a trough level of 30 U dL−1 during approximately 5 days is usually sufficient.
For tooth extractions and skin biopsy, there is no need for replacement 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 . 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−1 is used as an argument for replacement therapy during surgery . Other observations of patients who underwent uneventful prostatectomy with a level of 30 U dL−1 support the view that replacement therapy is unnecessary during most surgical procedures in patients with partial FXI deficiency . 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−1 for 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 .
Disclosure of Conflict of Interests
The author states that he has no conflict of interest.