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Factor XI Deficiency

Hemophilia C

Factor XI is part of the intrinsic pathway of blood coagulation. Factor XI deficiency leads to hemophilia C, which is a rare and relatively mild disorder with unpredictable bleeding tendencies. The function of the factor, and the pathology of the disease are incompletely understood.


Presentation

Factor XI functions as a serine protease and activates factor IX, which, together with factor VIII activates factor X. Factor XI also acts to decrease fibrinolysis [1], and may have a role in inflammatory processes. The protein circulates as a homodimer, and dimerization is required for secretion into the bloodstream.

Deficiency of factor XI has a high incidence of occurrence in people of Ashkenazi Jewish heritage. In this population, there are two prevalent mutations, one substituting for an amino acid, and another resulting in premature chain termination. As may be expected, people homozygous for the nonsense mutation tend to bleed more extensively than those with the missense mutation. However, in most other cases the severity of the disease is not well correlated with genotype or with residual amount or activity of the protein [2] [3] [4], possibly owing to aberrant interactions between factor XI and other coagulation factors when those are at suboptimal levels [5]. For example, members of the same family with similar factor XI deficiency were found with incongruous symptoms [6]. The disease is normally inherited in a recessive manner. However, some mutant proteins can bind normal monomers in heterodimer structures that cannot be secreted. In a situation like this, the secretion of the normal protein is prevented in a heterozygote, and the inheritance becomes dominant [7].

Spontaneous bleeding in factor XI deficiency is very rare, as is bruising or hemarthrosis. Unusual bleeding usually follows trauma, such as circumcision, dental work, tonsillectomy or other surgeries, but there is a tendency for it to occur mainly in the mouth and genitourinary systems, where fibrinolytic activity is high. This may be explained by the role of factor XI in inhibiting fibrinolysis. Menorrhagia and postpartum bleeding are frequent signs of factor XI deficiency. In some cases, a family history of a mild bleeding disorder may be a sign of the deficiency. In other cases, factor XI deficiency may be discovered during follow-up of an incidental finding of prolonged activated partial thromboplastin time (aPTT), which is measured routinely before surgeries. Factor XI deficiency may be acquired as a consequence of systemic lupus erythematosus. The levels of factor XI will decrease, together with many other proteins, when liver function is compromised.

Workup

A suspicion of coagulopathy calls for the usual coagulation tests, which comprise the prothrombin time (PT), (APTT), and fibrinogen level. If a prolonged APTT result is obtained, mixing studies with normal plasma are usually performed to determine whether the anomaly is due to deficiency of a factor, or to the presence of an inhibitor. This determination has obvious implications for therapy. More than a quarter of the patients with a severe factor XI deficiency harbor an inhibitor to the factor [8], and very small amounts of factor XI in blood-derived preparations have been shown to trigger formation of the inhibitor [9]. In interpreting the APTT test results, the variability of different testing agents should be kept in mind. On the one hand, some reagents are oversensitive to lupus anticoagulant antibodies, and therefore may show false positive results. On the other hand, the sensitivity of some test reagents may be too low so that false negative results will be observed [2]. People with bleeding abnormalities should undergo tests with individual clotting factors.

Homozygotes, or people with two differently affected alleles (compound heterozygotes), usually have less than 10% of normal factor XI levels, whereas heterozygotes have about 50%.

Treatment

  • Both treatment types improved thrombin generation and clot formation.[ncbi.nlm.nih.gov]
  • Fresh frozen plasma of 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.[ncbi.nlm.nih.gov]
  • INTERVENTION: Cataract extraction without prophylactic treatment for the FXI deficiency. MAIN OUTCOME MEASURES: Assessment of intraoperative and postoperative ocular bleeding and other related complications.[ncbi.nlm.nih.gov]
  • Beclère, Clamart, France. 4 Haematology Department, CHU Nantes, Nantes, France. 5 Haemophilia Treatment Center, CHU Angers, Angers, France. 6 Haemophilia Treatment Center, Haematology Department, Hautepierre Hospital, Strasbourg, France. 7 Haemostasis[ncbi.nlm.nih.gov]
  • Management and treatment Patients may require treatment when dental extraction or surgery is planned. Factor XI concentrates or fresh frozen plasma is usually used.[orpha.net]

Prognosis

  • Prognosis Prognosis is good, as bleeding symptoms are usually moderate. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • FFP transfusion prior to surgery may help patients’ coagulation, and proper anesthetic management, including peripheral nerve block, may contribute to improved prognosis.[jaclinicalreports.springeropen.com]

Etiology

  • Etiology Congenital FXI deficiency is caused by mutations in the F11 gene (4q35) controlling the production of plasma FXI. Unlike in most factor deficiencies, the severity of the bleeding manifestations is poorly correlated with the FXI level.[orpha.net]
  • […] pathway It is activated by factor XIIa, thrombin or autoactivated, and activates factor IX, which in turn activates factor X to convert prothrombin to thrombin Its biologic half-life is 60 - 80 hrs Images hosted on other servers: Coagulation cascade Etiology[pathologyoutlines.com]
  • The only suggested bleeding diathesis that may be linked to low level of factor XII is chronic subdural hematoma but the etiology is related to increased vascular permeability rather than a coagulation deficit [ 7 ].[omicsonline.org]

Epidemiology

  • Summary Epidemiology Prevalence of homozygous forms is estimated at 1/1,000,000. The disease is more frequent in the Jewish population. The frequency of partial deficiency among Ashkenazy Jews is 8%.[orpha.net]
  • Epidemiologic data has shown that high levels of FXI are associated with an increased risk of venous thrombosis. Deficiency of FXI does not protect from myocardial infarction. It is not known if low levels of FXI protect from venous thrombosis.[emedicine.medscape.com]
Sex distribution
Age distribution

Pathophysiology

  • First in this review, we give an overview of the basic pathophysiology, clinical manifestations, and management of FXI deficiency.[ncbi.nlm.nih.gov]
  • LEARNING OBJECTIVES: After participating in this activity, physicians should be better able to identify the pathophysiology of factor XI deficiency.[ncbi.nlm.nih.gov]
  • Understanding the pathophysiology and clinical significance of this disease entity can help avoid potentially hazardous sequelae.[ncbi.nlm.nih.gov]
  • This review gives an overview of the basic pathophysiology, clinical manifestations, and management of FXI deficiency.[ncbi.nlm.nih.gov]
  • 3 Centro di Riferimento Emofilia e Trombosi Angelo Bianchi Bonomi, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 4 Luigi Villa Foundation, Milan, Italy. 5 Department of Pathophysiology[ncbi.nlm.nih.gov]

Prevention

  • A multidisciplinary approach along with an individual care plan is recommended to prevent bleeding complications.[ncbi.nlm.nih.gov]
  • In animal models, targeting FXI by knocking out the gene or by using FXI-neutralizing antibodies, antisense oligonucleotides, and peptidomimetic inhibitors, prevents arterial and vein thrombosis.[ncbi.nlm.nih.gov]
  • A careful evaluation of the bleeding and thrombotic risk was performed before surgery, and despite all preventive measures, this tragic event occurred.[ncbi.nlm.nih.gov]
  • Adequate preoperative assessment and perioperative management are necessary to prevent bleeding complications in these patients.[ncbi.nlm.nih.gov]
  • 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.[ncbi.nlm.nih.gov]

References

Article

  1. Von dem Borne PA, Bajzar L, Meijers JC, et al. Thrombin-mediated activation of factor XI results in a thrombin-activatable fibrinolysis inhibitor-dependent inhibition of fibrinolysis. J Clin Invest. 1997 May 15;99(10):2323-2327.
  2. Bolton-Maggs PH. Factor XI deficiency--resolving the enigma? Hematology Am Soc Hematol Educ Program. 2009:97-105.
  3. Guéguen P, Galinat H, Blouch MT, et al. Biological determinants of bleeding in patients with heterozygous factor XI deficiency. Br J Haematol. 2012 Jan;156(2):245-51
  4. Saunders RE, Shiltagh N, Gomez K, et al. Structural analysis of eight novel and 112 previously reported missense mutations in the interactive FXI mutation database reveals new insight on FXI deficiency. Thromb Haemost. 2009 Aug;102(2):287-301.
  5. Franchini M, Mannucci PM. Interactions between genotype and phenotype in bleeding and thrombosis. Haematologica. 2008 May;93(5):649-652.
  6. Bolton-Maggs PH, Young Wan-Yin B, McCraw AH, et al. Inheritance and bleeding in factor XI deficiency. Br J Haematol. 1988 Aug;69(4):521-528.
  7. Kravtsov DV, Monahan PE, Gailani D. A classification system for cross-reactive material-negative factor XI deficiency. Blood. 2005 Jun 15;105(12):4671-4673.
  8. Salomon O, Zivelin A, Livnat T, Seligsohn U. Inhibitors to Factor XI in patients with severe Factor XI deficiency. Semin Hematol. 2006 Jan;43(1 Suppl 1): S10-1.2
  9. Zucker M, Zivelin A, Teitel J, Seligsohn U. Induction of an inhibitor antibody to factor XI in a patient with severe inherited factor XI deficiency by Rh immune globulin. Blood. 2008 Feb 1;111(3):1306-1308.

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Last updated: 2019-07-11 21:07