Adult Summary Report

Secondary Findings in Adult Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Adult): Passed (Consensus scoring is Complete)
• Curation Status (Adult): Released 1.0.0
• GENE/GENE PANEL: F11
• Condition: Factor XI Deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• F11 ⇔ 612416: Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Bleeding complications with pregnancy, procedures or trauma / Development and implementation of comprehensive management plan based on activity levels and bleeding history by hematology team	2	2C	3E	3	10CE

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of factor XI (FXI) deficiency has been estimated as 1 to 33 per 1,000,000, with the prevalence of the homozygous form estimated at 1 per 1,000,000. The disease is more frequent in the Ashkenazi Jewish population, with heterozygosity in 8-9% and homozygosity in 0.2-0.5%. [1, 2, 3, 4]

Clinical Features

FXI deficiency is a bleeding disorder due to reduced plasma FXI levels. Spontaneous bleeding is rare even with low factor levels, with bleeding usually occurring after circumcision, dental extractions, trauma, or surgery. Hemorrhages are usually moderate and can occur at sites rich in fibrinolytic activity, such as the oral and nasal mucosa, and genitourinary system. Women are at risk for menorrhagia, bleeding during childbirth and miscarriage, as well as post-partum hemorrhage (PPH). Intracranial bleeding is very uncommon. [1, 2, 3, 5, 6]

Natural History

FXI deficiency affects both sexes equally and manifests at any age. Severely low FXI levels are typically seen in homozygotes or compound heterozygotes and partial deficiency in heterozygotes. Most heterozygotes are asymptomatic, but patients with even mild reductions in FXI may have a bleeding tendency. Plasma levels of FXI show poor correlation with bleeding symptoms. The condition is associated with a variable bleeding tendency even in the same individual. The unpredictable nature of FXI deficiency makes management more difficult. The risk of PPH in women is highest in those with a bleeding phenotype and of blood group O (26.4% in blood group O vs 6.3% in non-O group). [2, 3, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

It is likely that other clotting factors, such as VWF and platelet function, play a role in determining the bleeding tendency. Thus, patients with FXI deficiency should be assessed for the presence of other potentially confounding factors, such as low VWF levels and platelet dysfunction. (Tier 2) [1, 2, 5, 7]

As spontaneous bleeding is uncommon in FXI deficiency, management usually comprises treatment of traumatic bleeds and prevention of surgical or obstetric bleeding. Therapeutic options include incrementing FXI levels by administration of fresh frozen plasma (FFP) or the administration of FXI concentrates and through use of antifibrinolytic agents (such as tranexamic acid). Cases with FXI deficiency should be identified as at a higher risk of bleeding if the FXI activity is <0.1 IU/ml or if there is another coagulopathy, a personal history of bleeding or if surgery comprises dental extraction or involves the oropharyngeal or genitourinary mucosa. Consider tranexamic acid for minor bleeds or minor surgery in higher bleeding risk cases, and for all bleeds or surgery in low bleeding risk cases. Consider FXI concentrate without additional tranexamic acid for severe bleeds or major surgery in high bleeding risk cases. (Tier 2) [1, 2, 5, 6, 7]

One study evaluated 86 patients over 242 treatment episodes of FXI concentrate for emergency or elective situations. There were eight (3.3%) episodes of persistent bleeding post-concentrate. (Tier 5) [8]

Dental management in patients with inherited bleeding disorders should involve a liaison between a hemophilia center, hospital dentist, and general dental practice regarding the nature of the disorder, treatment plans, and risk of transfusion-transmitted infection. Each hemophilia follow-up visit should document the oral health status and advice about preventive care. Treatment planning during dental procedures is essential for good outcome. Coagulation factors should be provided for inferior dental block, lingual infiltration, and invasive dental procedures. (Tier 2) [6]

One study evaluated 19 patients with severe factor XI deficiency who had previously bled following dental extractions (14 patients) or other trauma (5 patients). Tranexamic acid was given from 12 h before surgery, until 7 days afterwards. No excessive bleeding was observed following dental extractions. One patient had slight oozing after 3 days which ceased spontaneously. (Tier 5) [9]

Pregnancy in women with FXI deficiency requires specialized and individualized care provided collaboratively by an obstetrician, hematologist and anesthetist. Pregnancy management recommendations include:
• Treatment plans around labor and delivery plans should be individualized and made in advance due to the unpredictable nature of bleeding. Factors to consider are: personal history of bleeding, family history of bleeding, mode of delivery, previous obstetric history, blood group, FXI level (if low)
• Delivery should occur at a unit with expertise in the management of this disorder and resources for laboratory testing and clotting factor treatments readily available
• Though FXI levels usually remain constant during pregnancy, they can change; thus, levels should be checked at booking, third trimester, and prior to invasive procedures
• Patients with low FXI levels or a bleeding history should be given prophylaxis to cover invasive procedures
• Central neuraxial anesthesia should not be given to women with low FXI levels with a known bleeding phenotype, where the phenotype is not clear, or when there is a severe reduction in level given the risk of a spinal hematoma with compression of the spinal cord; in those with a nonbleeding phenotype, discussion and counseling should be given regarding the risks and benefits of neuraxial anesthesia with or without factor replacement
• Active management of third stage should be practiced, with prophylactic treatment with tranexamic acid considered post-delivery (Tier 2) [2, 5]

Among 61 pregnancies and 49 live births in 30 women with FXI deficiency there was no significant change in FXI levels during pregnancy. Among women with a history of bleeding, PPH occurred after 3/19 deliveries when prophylaxis was given and after 3/3 deliveries when prophylaxis was not given. Of the 38 pregnancies where the woman was known to have FXI deficiency prior to delivery, intrapartum prophylaxis with FXI concentrate or tranexamic acid was given in 19 deliveries where the mother had a positive bleeding history, with no PPH in 16, primary PPH in 1 case, and secondary PPH in 2. Three cases had a bleeding history, but did not have prophylaxis, and all 3 had a primary PPH. The remaining 16 cases had no bleeding history and prophylaxis was given; PPH occurred after 4/16 of these deliveries. (Tier 5) [10]

Within a retrospective study of 62 women with low FXI levels, PPH occurred in 24% (32/132) not covered by FFP and in 14% (2/14) of vaginal deliveries covered by FFP. In none of the 34 vaginal deliveries associated with bleeding was this complication life-threatening, and in only 12 deliveries (35.5%) was blood transfusion or plasma replacement therapy given. PPH occurred in 16.7% (2/12) of cesarean deliveries not covered by FFP and in none of the six cesarean deliveries covered by FFP. Overall, 43 women (69%) never experienced PPH during 164 deliveries. (Tier 5) [11]

Management of menorrhagia in women with inherited bleeding disorders should be provided by a multidisciplinary team including a hematologist and gynecologist to ensure optimal outcomes. Specific hemostatic therapy will be required in some women to control menorrhagia. Medical treatment of menorrhagia in women with inherited bleeding disorders include tranexamic acid, combined oral contraceptive pills, DDAVP (desmopressin), cyclical 21-days oral progesterone, and the levonorgestrel intrauterine device. The treatment choice depends on the type of bleeding disorder, and patient’s age, childbearing status and preferences in terms of the perceived efficacy and side effects. (Tier 2) [5, 12]

Women with inherited bleeding disorders are more likely to be symptomatic from gynecological problems that are associated with bleeding. Awareness of an underlying bleeding disorder will allow appropriate management. (Tier 2) [5]

Surveillance

Information on surveillance in individuals with FXI deficiency was not available.

Circumstances to Avoid

NSAID (nonsteroidal anti-inflammatory drugs) use is contraindicated in individuals with inherited bleeding disorders due to their anti-aggregation effect on platelet function. (Tier 2) [5, 13]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Recessive
Autosomal Dominant

Prevalence of Genetic Variants

One study performed molecular testing in 25 index cases with FXI plasma levels below 50 IU dL. They identified disease-associated variants in F11 in 24 of the 25 cases. Of these 24 cases with disease-associated variants in F11, 22 patients were heterozygous, and two patients were homozygous. (Tier 5) [14]

These results indicate that pathogenic variants in F11 are likely to have a similar prevalence as that estimated for FXI deficiency, or 1 to 33 per 1,000,000.

Penetrance

In two UK series of 128 cases with FXI deficiency (based on FXI levels and not genotype), approximately 65% were asymptomatic. In the remainder, the most common symptoms were bleeding after surgery and trauma. (Tier 3) [1]

Most studies of heterozygotes suggest that 20-50% of partially FXI deficient individuals bleed excessively. (Tier 3) [15]

Pregnant female patients with FXI levels <15 IU dL have a 16–30% risk of excessive bleeding during delivery. (Tier 3) [5]

The risk of PPH is increased in women with FXI deficiency, in both homozygotes and heterozygotes, with an overall risk of 16-22%. (Tier 3) [2, 5]

Relative Risk

This risk of PPH is increased in those with a bleeding phenotype, with a relative risk of 7.2 (95% CI 1.99 - 25.90). (Tier 3) [2]

Expressivity

There is intra- and inter-individual variation in bleeding phenotype. Clinical phenotypes vary even among individuals with the same factor level, and the bleeding tendency can also be variable in the same individual in response to different hemostatic challenges. (Tier 3) [2, 5]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified for FXI include treatment for bleeding episodes or prophylactic coverage for surgery using FXI concentrate, FFP, and antifibrinolytic agents (such as tranexamic acid). Issues with FXI concentrate are the risk of thrombosis and (rarely) inhibitor development in patients with very low FXI levels. There is also a very rare risk of transfusion-transmitted infection or allergic reactions. Tranexamic acid is generally well tolerated, with nausea and diarrhea as the most common side effects. [1, 2, 5]

One study evaluated 86 patients over 242 treatment episodes of FXI concentrate for emergency or elective situations. There were 4 (1.7%) non-bleeding adverse events: two recorded inhibitors, one thrombotic event (central retinal artery occlusion), and one transfusion reaction. No patient suffering an adverse event had long-term morbidity. [8]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Bleeding episodes in patients with FXI are unpredictable and vary in response to different hemostatic challenges. Undiagnosed and untreated patients with FXI deficiency can develop significant hematomas after a surgical procedure. (Tier 4) [3, 5]

Reference List

1. Mumford AD, Ackroyd S, Alikhan R, Bowles L, Chowdary P, Grainger J, Mainwaring J, Mathias M, O'Connell N. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol. (2014) 167(3):304-26.

2. Management of Inherited Bleeding Disorders in Pregnancy: Green-top Guideline No. 71 (joint with UKHCDO). BJOG. (2017) 124(8):e193-e263.

3. Congenital factor XI deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=329

4. Qu Y, Nie X, Yang Z, Yin H, Pang Y, Dong P, Zhan S. The prevalence of hemophilia in mainland China: a systematic review and meta-analysis. Southeast Asian J Trop Med Public Health. (2014) 45(2):455-66.

5. Lee CA, Chi C, Pavord SR, Bolton-Maggs PH, Pollard D, Hinchcliffe-Wood A, Kadir RA. The obstetric and gynaecological management of women with inherited bleeding disorders--review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors' Organization. Haemophilia. (2006) 12(4):301-36.

6. Anderson JA, Brewer A, Creagh D, Hook S, Mainwaring J, McKernan A, Yee TT, Yeung CA. Guidance on the dental management of patients with haemophilia and congenital bleeding disorders. Br Dent J. (2013) 215(10):497-504.

7. Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. A United Kingdom Haemophilia Center Doctors' Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology. Haemophilia. (2008) 14(4):671-84.

8. Ling G, Kagdi H, Subel B, Chowdary P, Gomez K. Safety and efficacy of factor XI (FXI) concentrate use in patients with FXI deficiency: a single-centre experience of 19 years. Haemophilia. (2016) 22(3):411-8.

9. Berliner S, Horowitz I, Martinowitz U, Brenner B, Seligsohn U. Dental surgery in patients with severe factor XI deficiency without plasma replacement. Blood Coagul Fibrinolysis. (1992) 3(4):465-8.

10. Chi C, Kulkarni A, Lee CA, Kadir RA. The obstetric experience of women with factor XI deficiency. Acta Obstet Gynecol Scand. (2009) 88(10):1095-100.

11. Salomon O, Steinberg DM, Tamarin I, Zivelin A, Seligsohn U. Plasma replacement therapy during labor is not mandatory for women with severe factor XI deficiency. Blood Coagul Fibrinolysis. (2005) 16(1):37-41.

12. Singh S, Best C, Dunn S, Leyland N, Wolfman WL. Abnormal uterine bleeding in pre-menopausal women. J Obstet Gynaecol Can. (2013) 35(5):473-475.

13. Scottish Intercollegiate Guidelines Network (SIGN). Antithrombotics: indications and management. A national clinical guideline. SIGN publication; no. 129. (2013) Accessed: 2018-07-19. Website: https://www.sign.ac.uk/assets/sign129.pdf

14. Gueguen P, Chauvin A, Quemener-Redon S, Pan-Petesch B, Ferec C, Abgrall JF, Le Marechal C. Revisiting the molecular epidemiology of factor XI deficiency: nine new mutations and an original large 4qTer deletion in western Brittany (France). Thromb Haemost. (2012) 107(1):44-50.

15. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. FACTOR XI DEFICIENCY. MIM: 612416: 2016 Oct 21. World Wide Web URL: http://omim.org.