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 1.3.2
• GENE/GENE PANEL: F5
• Condition: F5: Factor V deficiency (AR)
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• F5 ⇔ 0009210 (congenital factor v deficiency): 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

Gene Condition Pairs: F5 ⇔ 0009210 (OMIM:227400)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Severe or prolonged hemorrhage / Development and implementation of comprehensive management plan based on activity levels	2	3N	3B	2	10NB

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

Prevalence of the Genetic Condition

Factor V (FV) deficiency is a rare inherited bleeding disorder with a prevalence estimate of severe deficiency (homozygous or compound heterozygous) of 1 in 1,000,000. Approximately 200 patients with FV deficiency have been described in the literature. [1, 2, 3, 4, 5]

Clinical Features

Congenital FV deficiency is caused by alterations in the F5 gene resulting in reduced production of plasma coagulation FV; activated FV serves as an essential protein in the coagulation pathway. Common clinical signs include epistaxis, bruising, mucosal bleeding, and soft tissue bleeding. Excessive and prolonged bleeding during or following surgery, delivery or trauma are frequent. Women often present with menorrhagia. Less common are symptoms of joint, muscle, genitourinary, gastrointestinal, and intracranial bleeding. [2, 3, 6]

Natural History

Congenital FV deficiency can manifest at any age, with the most severe forms manifesting in early life. Prognosis is good with early diagnosis and treatment. There is limited correlation between FV activity and severity of bleeding. Patients who come to medical attention are typically symptomatic homozygotes or compound heterozygotes with FV activity levels less than 5%. No clear ethnic predisposition is apparent. Data from registries indicate patients are more likely to have skin and mucocutaneous bleeding rather than hemarthroses. Women are at risk of bleeding complications during menstruation and childbirth. Menorrhagia is the most common bleeding symptom in women and may be the first or only presenting symptom. Heterozygotes often have approximately half-normal levels of coagulation factors and are usually asymptomatic, though there may be an increase in bleeding symptoms in carriers. [1, 2, 3, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

In common with other heritable bleeding disorders, the treatment and prevention of bleeding in rare coagulation disorders requires general measures, such as selecting invasive procedures with minimum bleeding risk and ensuring adequate communication of treatment plans developed by hemophilia centers with appropriate expertise. (Tier 2) [2]

There is currently no FV concentrate. For mild bleeding or minor surgery, consider tranexamic acid. For severe bleeding or major surgery, consider FV replacement with solvent detergent fresh frozen plasma (SD-FFP) and additional platelet transfusion. In an open label study of 41 treatment episodes in FV deficiency, SD-FFP increased FV activity and was effective for the treatment of spontaneous or traumatic bleeds and the prevention of surgical bleeds. Off-label recombinant factor VIIa (rFVIIa) was effective in cases with allergy to FFP or to avoid volume overload. (Tier 2) [2]

Case reports were found for 3 pediatric cases of severe homozygous FV deficiency, totaling 13 surgeries in all that were successfully managed with prophylaxis (FFP, rFVIIa, tranexamic acid) and continued supplementation after surgery with FFP and platelets. (Tier 5) [7]

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. Treatment planning for procedures is essential for a good outcome. (Tier 2) [8]

Pregnancy in women with inherited bleeding disorders may require a multidisciplinary approach. Women with severe bleeding disorders should deliver in a hospital or where there is access to consultants in obstetrics, anesthesiology, and hematology. (Tier 2) [9]

FV deficiency is associated with post-partum hemorrhage (PPH). Cases have been described with patients with FV activity >0.1 IU/ml and severe bleeding; therefore, clinical history should be considered in addition to laboratory levels. Patients should be advised about the possibility of early and late PPH and instructed to report excessive postpartum bleeding immediately. In a case report of 3 pregnancies in 2 homozygous patients, prophylactic and continued treatment with FFP resulted in an uncomplicated Caesarean section in one patient. In the second patient, the condition was discovered due to excessive bleeding at delivery, successfully treated with whole blood and FFP postpartum. The authors also reviewed 18 successful pregnancies reported in the literature, 11 of which were accompanied by heavy bleeding requiring FFP or whole blood transfusion. The other 7 deliveries were uncomplicated due to successful prophylaxis. (Tier 2) [2, 5, 9]

Treatment of menorrhagia in women with inherited bleeding disorders should be individualized and managed with a multidisciplinary approach including a hematologist and gynecologist. In a survey by the Centers for Disease Control and Prevention, 95% (71 of 75) of women receiving care in hemophilia treatment centers reported a strong positive opinion and satisfaction. (Tier 2) [1, 2, 9, 10]

A case report of 4 homozygote women treated with oral contraception reported decrease in menorrhagia without complications. One woman treated for twenty years showed progressive reduction of menstrual cycle, decreased transfusional needs, and a steady increase of hematocrit. (Tier 5) [11]

Surveillance

No surveillance recommendations have been provided for the Adult context.

Circumstances to Avoid

Aspirin and other NSAIDs are contraindicated in patients with inherited bleeding disorders because they can increase bleeding risk and prolong bleeding times. (Tier 2) [8, 9, 10, 12]

Patients with untreated inherited bleeding disorders should not be offered prophylaxis (mechanical or pharmaceutical) for venous thrombotic embolism (VTE), unless the risk of VTE outweighs the risk of bleeding. (Tier 2) [13, 14]

Tranexamic acid is contraindicated for renal tract bleeding and in cases with high thrombotic risk. (Tier 2) [2]

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

Mode of Inheritance

Autosomal Recessive
So-called “severe” FV deficiency is inherited in an autosomal recessive (AR) manner. Compound heterozygous cases have been described, as well as some apparently heterozygous (AD) cases with “mild” FV deficiency and significant bleeding history. [4, 15, 16]

Prevalence of Genetic Variants

No genetic variant prevalence information has been provided for the Adult context.

Penetrance

Three cohort studies of patients with FV deficiency have been reported from Iran, Korea, and Germany. The Iranian and Korean cohort were defined based on clinical Factor V levels, while the German cohort included genotype information.

In the Iranian cohort (n=35, plasma levels 0-10%), 57% of patients had epistaxis and oral mucosa bleeding, 50% of the women had menorrhagia, 43% had postprocedural or postpartum bleeding, 29% had muscle hematomas, and 26% had hemarthroses. Gastrointestinal, genitourinary, and CNS bleeding episodes were each present in 6% of the patients. (Tier 5) [4]

A North American cohort of 18 presumed homozygotes/compound heterozygotes (defined as FV<20%) with severe FV deficiency all had bleeding symptoms. Bleeding events were predominated by bleeding in skin and mucus membranes (44%), joints and muscles (23%), genitourinary (19%), and gastrointestinal tract (6%). Intracranial hemorrhage represented 8% of bleeding events. In the same North American cohort, 19 patients with a heterozygous FV deficiency (defined as FV≥20%) were also examined, and 50% were reported to be symptomatic with spontaneous bleeding events. Of those, bleeding events were predominated by skin and mucus membranes (62%), followed by musculoskeletal (19%) and genitourinary (19%). (Tier 5) [4]

In the German cohort 9 patients with homozygous F5 pathogenic variants, 3 patients with compound heterozygous pathogenic variants and 1 patient with a pseudo-homozygous pathogenic variant in addition to Factor V Leiden were reported with bleeding phenotype data available. Of those patients who were homozygous or compound heterozygous (n = 12) for F5 pathogenic variants, 67% reported bleeding symptoms, with the remainder having no bleeding phenotype at the time of study. Bleeding symptoms included hematoma (50% of patients), bleedings following invasive procedures (42%), epistaxis (25%), menorrhagia (20% of females, although patient age was not reported), and severe bleedings (8%). The patient with a pseudo-homozygous genotype had no bleeding phenotype. (Tier 5) [16]

In the German cohort, 12 heterozygous patients were also reported with phenotype data available. Of these patients, 75% experienced at least one bleeding symptom, with 50% experiencing bleeding following invasive procedures, 25% experiencing hematoma, 17% experiencing epistaxis, 17% of females experiencing hypermenorrhea (although patient age was not reported), and 8% experiencing hematuria. (Tier 5) [16]

Relative Risk

Information on relative risk was not available for the Adult context.

Expressivity

Patients with identical pathogenic variants or activity levels, including related patients with identical genotypes and equally low (<1%) FV activities, can vary greatly in their bleeding symptoms. (Tier 5) [4]

4. What is the Nature of the Intervention?

Nature of Intervention

The interventions included in this report include treatments with potential risk and side effects. FFP, platelets, and other blood products carry risk of infection transmission. FFP carries risk of volume overload. Tranexamic acid carries risk of thrombosis. [2]

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

Chance to Escape Clinical Detection

Congenital FV deficiency can manifest at any age, with intracranial hemorrhage possible as a first event, indicating a chance to escape clinical detection prior to diagnosis. (Tier 5) [2, 4]

Date of Search: 11.10.2017

Reference List

1. 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.

2. 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.

3. Congenital factor V deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=326

4. Huang JN, Koerper MA. Factor V deficiency: a concise review. Haemophilia. (2008) 14(6):1164-9.

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

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. FACTOR V DEFICIENCY. MIM: 227400: 2016 May 23. World Wide Web URL: http://omim.org.

7. Mathias M, Tunstall O, Khair K, Liesner R. Management of surgical procedures in children with severe FV deficiency: experience of 13 surgeries. Haemophilia. (2013) 19(2):256-8.

8. 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.

9. Demers C, Derzko C, David M, Douglas J. Gynaecological and obstetric management of women with inherited bleeding disorders. J Obstet Gynaecol Can. (2005) 27(7):707-32.

10. 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.

11. Girolami A, Scandellari R, Lombardi AM, Girolami B, Bortoletto E, Zanon E. Pregnancy and oral contraceptives in factor V deficiency: a study of 22 patients (five homozygotes and 17 heterozygotes) and review of the literature. Haemophilia. (2005) 11(1):26-30.

12. Scottish Intercollegiate Guidelines Network (SIGN),. Antithrombotics: indications and management. A national clinical guideline. SIGN publication; no. 129. (2013) Accessed: 2017-11-10. Website: http://www.sign.ac.uk/assets/sign129.pdf

13. National Clinical Guideline Centre for Acute and Chronic Conditions,. Venous thromboembolism in adults admitted to hospital: reducing the risk. Clinical Guideline; No. 92. (2015) Accessed: 2017-11-10. Website: https://www.nice.org.uk/guidance/cg92

14. Scottish Intercollegiate Guidelines Network (SIGN),. Prevention and management of venous thromboembolism. SIGN publication; no. 122. (2014) Accessed: 2017-11-10. Website: http://www.sign.ac.uk/assets/sign122.pdf

15. Acharya SS, Coughlin A, Dimichele DM. Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost. (2004) 2(2):248-56.

16. Delev D, Pavlova A, Heinz S, Seifried E, Oldenburg J. Factor 5 mutation profile in German patients with homozygous and heterozygous factor V deficiency. Haemophilia. (2009) 15(5):1143-53.