Factor XI deficiency and its management

Factor XI deficiency has a more variable bleeding tendency than haemophilia A or B. Individuals with severe deficiency have only a mild bleeding tendency, which is typically provoked by surgery, but the risk of bleeding is not restricted to individuals with severe deficiency. The bleeding tendency varies between individuals with similar factor XI levels, and sometimes the bleeding tendency of an individual may vary. The reasons for this are not fully understood, although in cases of severe deficiency there is some correlation between phenotype and genotype.
Factor XI is activated by thrombin. The role of factor XI in physiological processes has become clearer since this fact was discovered, and the discovery has contributed to a revised model of blood coagulation. Factor XI deficiency occurs in all racial groups, but is particularly common in Ashkenazi Jews. The factor XI gene is 23 kilobases long. Two mutations are responsible for most factor XI deficiency in the Ashkenazi population, but a number of other mutations have now been reported in other racial groups.
Individuals with factor XI deficiency may need specific therapy for surgery, accidents, and dental extractions. Several therapies are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs, and desmopressin. Each has advantages and risks to be considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.     

Thromboembolism complicating the treatment of lupus anticoagulant hypoprothrombinemia syndrome

Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare disorder characterized by a bleeding tendency due to factor II deficiency associated with the presence of lupus anticoagulant (LAC) autoantibodies. We describe a patient with systemic lupus erythematosus and LAHPS in whom successful treatment of central nervous system bleeding due to severe factor II deficiency was followed by a major thromboembolic complication. Literature review revealed 2 other patients with LAHPS who developed thrombosis resulting from the treatment of factor II deficiency. We suggest that factor II deficiency counterbalances the prothrombotic effect of LAC in LAHPS, and correcting this deficiency may promote thromboembolism.     

Polyphosphate is a cofactor for the activation of factor XI by thrombin

Factor XI deficiency is associated with a bleeding diathesis, but factor XII deficiency is not, indicating that, in normal hemostasis, factor XI must be activated in vivo by a protease other than factor XIIa. Several groups have identified thrombin as the most likely activator of factor XI, although this reaction is slow in solution. Although certain nonphysiologic anionic polymers and surfaces have been shown to enhance factor XI activation by thrombin, the physiologic cofactor for this reaction is uncertain. Activated platelets secrete the highly anionic polymer polyphosphate, and our previous studies have shown that polyphosphate has potent procoagulant activity. We now report that polyphosphate potently accelerates factor XI activation by α-thrombin, β-thrombin, and factor XIa and that these reactions are supported by polyphosphate polymers of the size secreted by activated human platelets. We therefore propose that polyphosphate is a natural cofactor for factor XI activation in plasma that may help explain the role of factor XI in hemostasis and thrombosis.     

An Alu-mediated 31.5-kb deletion as the cause of factor XI deficiency in 2 unrelated patients

Factor XI deficiency (MIM 264900) is an autosomal bleeding disorder of variable severity. Inheritance is not completely recessive as heterozygotes may display a distinct, if mild, bleeding tendency. Recent studies have shown the causative mutations of factor XI deficiency, outside the Ashkenazi Jewish population, to be highly heterogeneous. We studied 39 consecutively referred patients with factor XI deficiency to identify the molecular defect. Conventional mutation screening failed to identify a causative mutation in 4 of the 39 patients. Epstein-Barr virus (EBV)-transformed cells from these 4 patients were converted from a diploid to haploid chromosome complement. Subsequent analysis showed that 2 of the patients had a large deletion, which was masked in the heterozygous state by the presence of a normal allele. We report here the first confirmed whole gene deletion as the causative mutation of factor XI deficiency, the result of unequal homologous recombination between flanking Alu repeat sequences.     

Intrinsic pathway of coagulation and arterial thrombosis

Formation of a fibrin clot is mediated by a group of tightly regulated plasma proteases and cofactors. While this system is essential for minimizing blood loss from an injured blood vessel (hemostasis), it also contributes to pathologic fibrin formation and platelet activation that may occlude vessels (thrombosis). Many antithrombotic drugs target key elements of the plasma coagulation mechanism such as thrombin and factor Xa, based on the premise that plasma elements contributing to thrombosis are primarily those involved in hemostasis. Recent studies with genetically altered mice raise questions about this paradigm. Deficiencies of the intrinsic pathway proteases factor XII and factor XI are not associated with abnormal hemostasis in mice, but impair formation of occlusive thrombi in arterial injury models, indicating that pathways not essential for hemostasis participate in arterial thrombosis. If factor XII or factor XI make similar contributions to thrombosis in humans, these proteases could be ideal targets for drugs to treat or prevent thromboembolic disease with minimal risk of therapy-associated bleeding.     

The management of factor XI deficiency

Summary. Factor XI deficiency leads to a more variable bleeding tendency than haemophilia A or B. Although severely deficient individuals are likely to bleed excessively especially after surgery in areas of the body with increased fibrinolysis, there is evidence that some partially deficient individuals are at risk of excessive bleeding. This will entail careful planning for surgery. Several therapeutic modalities are available which include fresh frozen plasma, factor XI concentrates, fibrin glue, antifibrinolytic drugs and desmopressin. The advantages and risks of these are considered. Factor XI concentrate may be indicated for procedures with a significant risk of bleeding especially in younger patients with severe deficiency, but its use in older patients has been associated with thrombotic phenomena. If fresh frozen plasma is to be used, it is preferable to obtain one of the virally inactivated products. Fibrin glue is a useful treatment which deserves further study.     

Deficiency of protein C in patients with portal vein thrombosis

Portal vein thrombosis has been considered idiopathic in 50% of cases reported in adults. Protein C deficiency is a recently described disorder characterized by a predisposition to develop thromboembolic disease. We report the findings in two patients with portal hypertension and bleeding varices due to portal vein thrombosis in whom a deficiency of protein C was present. Both cases were very similar, with a history of recurrent episodes of systemic thromboembolic disease, mesenteric venous thrombosis that required intestinal resection and upper gastrointestinal bleeding from gastroesophageal varices. Portal hypertension as well as portal vein thrombosis were demonstrated. The hematologic work-up revealed a deficiency of protein C. Both patients were subjected to the Sugiura procedure, and anticoagulation was instituted thereafter. At the time of surgery, a liver biopsy was performed, which was reported as "normal." Two years and 3 months, respectively, after surgery both patients are in good condition. We conclude that protein C deficiency should be investigated in all cases of portal vein thrombosis, especially in those with a history of thromboembolic disease elsewhere.     

Factor XI activity and factor XI antigen in homozygous and heterozygous factor XI deficiency

A relatively potent antiserum against highly purified, unactivated human factor XI antigen was raised in a rabbit. This antiserum, after concentration, neutralized 50% of the factor XI clotting activity of a standard normal plasma at an antiserum dilution of 1/900. The antiserum was used in a neutralization-inhibition assay to study the relation between factor XI clotting activity and factor XI antigen in plasma from ten unrelated patients with homozygous factor XI deficiency and from 12 heterozygous family members of these patients. No evidence of factor XI antigen significantly in excess of factor XI activity was found in either group. All data to date have been consistent with the hypothesis that hereditary factor XI deficiency represents a genetic disorder resulting from the absence of factor XI molecule. Severity of bleeding in factor XI deficiency could not be correlated with the level of factor XI activity or factor XI antigen.     

Prevalence,causes, and characterization of factor XI inhibitors in patients with inherited factor XI deficiency

Factor XI deficiency, an injury-related bleeding disorder, is rare worldwide but common in Jews in whom 2 mutations, Glu117Stop (type II) and Phe283Leu (type III), prevail. Mean factor XI activities in homozygotes for Glu117Stop and for Phe283Leu are 1 and 10 U/dL, respectively. Inhibitors to factor XI in patients with severe factor XI deficiency have been reported in a small number of instances. This study was undertaken to determine the prevalence of acquired inhibitors against factor XI in patients with severe factor XI deficiency, discern whether these inhibitors are related to specific mutations, and characterize their activity. Clinical information was obtained from unrelated patients with severe factor XI deficiency, and blood was analyzed for factor XI activity, inhibitor to factor XI, and causative mutations. Immunoglobulin G purified from patients with an inhibitory activity was tested for binding to factor XI, effects on activation of factor XI by factor XIIa and thrombin, and activation of factor IX by exogenous factor XIa. Of 118 Israeli patients, 7 had an inhibitor; all belonged to a subgroup of 21 homozygotes for Glu117Stop who had a history of plasma replacement therapy. Three additional patients with inhibitors from the United Kingdom and the United States also had this genotype and were exposed to plasma. The inhibitors affected factor XI activation by thrombin or factor XIIa, and activation of factor IX by factor XIa. The results imply that patients with a very low factor XI level are susceptible to development of an inhibitor following plasma replacement.     

Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review

A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty-two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.     

Role of blood coagulation factor XI in downregulation of fibrinolysis

Factor XI is a component of the intrinsic pathway of coagulation. A deficiency of factor XI is associated with a mild to moderate bleeding disorder especially from tissues with a high local fibrinolytic activity. In contrast, high levels of factor XI are a risk factor for venous thrombosis. The recent finding that factor XI can be activated by thrombin led to a revised model of coagulation. In this model the primary thrombin generation that results in fibrin formation takes place via the extrinsic pathway. Additional thrombin generation takes place inside the fibrin clot via the intrinsic pathway after the activation of factor XI by thrombin. High concentrations of thrombin are formed that are necessary for the activation of thrombin activatable fibrinolysis inhibitor (TAFI). Activated TAFI protects the fibrin clot against lysis. The role of factor XI in hemostasis can therefore be seen as a combination of procoagulant and antifibrinolytic actions. The new insights in the role of factor XI in coagulation and fibrinolysis may lead to new strategies for the treatment of thrombotic disorders.     

Four novel FXI gene mutations in three factor XI- deficient patients.

Hereditary factor XI deficiency is a mild bleeding disorder, which is highly prevalent among Ashkenazi Jews, but has been reported in all populations. In Ashkenazi Jews, two factor XI gene mutations Glu 117X (type II) and Phe283Leu (type III) are particularly common. In other ethnic groups, factor XI deficiency is a rare bleeding disorder and is related to a variety of mutations throughout the factor XI gene. Three cases of quantitative factor XI deficiency in relation with four novel missense mutations are reported: a compound heterozygosity for two novel mutations (Ala 181 Val and Ala 412 Thr) with a severe factor XI deficiency and two missense mutations (His 388 Pro and Trp 407 Cys) in heterozygous patients with partial factor XI deficiency.     

One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews [see comments]

In recent years four mutations causing factor XI deficiency have been identified in Jews of Ashkenazi (European) origin. Two of them, type II (a nonsense mutation) and type III (a missense mutation), were found to prevail among 125 unrelated Ashkenazi Jews with severe factor XI deficiency. A finding of type II mutation in four unrelated Iraqi- Jewish families raised the possibility that this mutation is also common in Iraqi Jews, who represent the ancient gene pool of the Jews. A molecular-based analysis performed in 1,040 consecutively hospitalized patients disclosed the following results: Among 531 Ashkenazi-Jewish patients, the type II allele frequency was 0.0217 and among 509 Iraqi-Jewish patients, 0.0167 (P = .50). The type III allele frequency in the Ashkenazi-Jewish patients was 0.0254, whereas none of 502 Iraqi-Jewish patients examined had this mutation. These data suggest that the type II mutation was present in Jews already 2.5 millenia ago. The data also indicate that the estimated risk for severe factor XI deficiency in Ashkenazi Jews (due to either genotype) is 0.22% and in Iraqi Jews, 0.03%, and that the estimated risk of heterozygosity in Ashkenazi Jews is 9.0% and in Iraqi Jews, 3.3%. As patients with severe factor XI deficiency are prone to bleeding after injury and patients with partial deficiency may have similar bleeding complications when an additional hemostatic derangement is present, the observed high frequencies should be borne in mind when surgery is planned for individuals belonging to these populations.     

Clinical experience of factor XI deficiency: the role of fresh frozen plasma and factor XI concentrate

Summary. Factor XI deficiency is a rare autosomally transmitted coagulopathy that is associated with a variable bleeding tendency. Recently there have been reports of thrombotic events following the administration of a virally inactivated factor XI concentrate (BPL) to factor XI deficient patients. We have therefore reviewed a single centre's experience of the use of factor XI concentrate over a 6-year period and compared this to our previous experience of either no treatment or treatment with fresh frozen plasma (FFP) in 103 patients.
There were 156 procedures performed without haemo- static cover. The incidence of bleeding was greatest following tonsillectomy (71%) and dental extraction (Sl'h). There was a trend for bleeding complications to be associated with lower levels of factor XI but patients with all levels of factor XI suffered bleeding complica- tions. There were 38 procedures carried out under FFP cover, with only one patient suffering excessive bleeding and no serious complications.
Factor XI concentrate was given to 25 patients to cover 45 episodes. There were no bleeding complications. Three patients suffered serious complications. One patient, with a previous history of cardiovascular disease, died of a myocardial infarction and a second had an ischaemic episode resulting in a %day hospital admission. These episodes both occurred on the same day as the factor XI infusion. A third patient suffered bilateral pulmonary emboli 7 weeks after a prolonged course of factor XI concentrate.
These finding suggest that factor XI concentrate should be contraindicated in patients with a history of cardiovascular disease, when FFP should be used. Guide- lines for the use of factor XI concentrates should be revised, and work performed to establish the mechanism of these thrombotic events.     

Clinical usefulness of desmopressin for prevention of surgical bleeding in patients with symptomatic heterozygous factor XI deficiency

Heterozygous factor XI (FXI) deficiency is sometimes associated with a significant bleeding tendency. Fresh frozen plasma or FXI concentrates are the mainstay of treatment in patients with a clear bleeding history, especially prior to surgery. However, these treatments are not completely free of risk. Furthermore, thrombosis has been reported in patients with FXI deficiency infused with FXI concentrate. No data are available on the possible efficacy of desmopressin in these patients.   Two patients with a clear bleeding history associated with FXI deficiency and no additional haemostatic defects agreed to be treated with desmopressin before carpal tunnel surgery and dental extraction. The reduced basal FXI activity and antigen levels slightly increased after infusion, reaching borderline values. No bleeding was observed after surgical procedures.   Desmopressin treatment seems a reasonable and useful choice in symptomatic, heterozygous FXI-deficient patients, thus reducing the cost of treatment, the risk of transmission of blood-borne viruses, and of thrombosis.     

A novel factor XI gene mutation associated with mild factor XI deficiency in a symptomatic patient.

Congenital factor XI deficiency is a rare condition, in which plasma factor XI levels correlate poorly with the severity of haemorrhage. The condition is typically characterized by post-traumatic bleeding. The factor XI gene is located on chromosome 4 and contains 15 exons. More than 80 mutations have so far been described. We describe a novel mutation in the factor XI gene associated with mild factor XI deficiency. The patient, who is of Irish descent, has a history of post-traumatic bleeding and was found to have a borderline factor XI deficiency. DNA sequence analysis of the factor XI gene revealed a novel T to A mutation at nucleotide 168 resulting in the substitution of the cysteine residue at codon 38 with a stop codon (Cys38STOP). The mutation predicts the premature termination of translation of factor XI mRNA resulting in a truncated, and probably unstable, factor XI protein. The presence of the mutation is consistent with the patient's borderline factor XI deficiency.     

Combined dys-form of homozygous factor XI deficiency and heterozygous factor XII deficiency

A 12-year-old girl with lifelong hemorrhagic episodes was found to have both a dys-form of homozygous factor XI deficiency and heterozygous factor XII deficiency. The heredity of the coagulation defects was confirmed by family studies. Severe bleeding after dental surgery occurred in spite of replacement therapy and local measures including fibrin glue. Our findings suggest that the risk of bleeding in patients with homozygous factor XI deficiency must not be underestimated and that the most effective measure is the transfusion of sufficient amounts of fresh frozen plasma until at least the 5th postoperative day.     

Percutaneous coronary intervention in a patient with congenital factor XI deficiency and acquired inhibitor

BACKGROUND: Factor XI deficiency has been associated with bleeding diathesis mostly secondary to trauma and post-operatively depending on the severity of deficiency. Cases with factor XI deficiency having undergone cardiac surgery and coronary intervention after appropriate replacement therapy have been reported in the past. The presence of inhibitor in factor XI deficiency poses a hematological challenge and literature regarding coronary intervention in such patients is limited. Immunosuppressive therapy, plasma exchange and factor VII product transfusions have been used prior to cardiac interventions in few such reported cases. METHOD: We report our approach in such a case of Percutaneous Transluminal Coronary Angioplasty in a 72-year-old male of Jewish origin who has congenital factor XI deficiency complicated with acquired inhibitor. RESULTS: In some cases, the acuity of the coronary syndrome may mandate immediate coronary intervention. However, patient's history of factor XI deficiency and acquired inhibitor pose a major dilemma of further course of action. We performed percutaneous balloon angioplasty in this case with no anti-coagulant and with favorable outcome. CONCLUSION: Under these circumstances of significant coagulation disorder and based on the case report, we recommend that balloon angioplasty be undertaken with no additional anti-coagulation other than Aspirin.     

Management options for thrombophilias

Thrombophilias may be inherited or acquired, continuing or transient, and may contribute strongly or weakly to thrombosis. They may predispose to venous thromboembolism alone or also to artery occlusion. Advice on management must recognize these variations. The presence of an inherited thrombophilia should not alter the intensity of anticoagulant therapy, given that antithrombin, protein C, or protein S deficiency, factor V Leiden, and the prothrombin G20210A mutation are not unusually anticoagulant resistant. However, they can increase the optimal treatment duration after a first thromboembolic event. Optimal duration depends on the balance between thrombosis risk off treatment and bleeding risk during extended anticoagulant therapy, and needs to be separately estimated for each individual with thrombosis and thrombophilia. The higher the thrombosis risk and the lower the bleeding risk, the longer the optimal treatment duration. This balance favors continued (but perhaps not indefinite) therapy in antithrombin, protein C, and protein S deficiency, and perhaps also in patients with the factor V Leiden or prothrombin mutations if their bleeding risk is low. Thrombosis that complicates active malignancy, the antiphospholipid syndrome, or heparin-induced thrombocytopenia needs special consideration: recent clinical trials suggest that low molecular weight heparins are more effective than warfarin in thrombosis with cancer, and that a more intense warfarin effect is not needed for patients with antiphospholipid syndrome and thrombosis. Debate continues about the place of screening for presymptomatic but affected relatives of patients with thrombosis and an inherited predisposition. It is essential that any family testing be done only with the informed consent of all concerned. Given consent, there is general support for family testing in antithrombin, protein C, or protein S deficiency and where the factor V Leiden or prothrombin mutation is strongly penetrant and expressed. There is, however, a strong argument that any testing in families in which clotting factor polymorphisms are weakly expressed should be restricted to young women when they consider hormonal contraception or pregnancy, given that these acquired factors multiply the risk.