Pediatric Summary Report

Secondary Findings in Pediatric Subjects

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

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 0.0.1
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: F7
• Condition: Factor VII deficiency
• Mode(s) of Inheritance: Autosomal Recessive

Actionability Assertion

• F7 ⇔ 0009211 (congenital factor vii deficiency): Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: F7 ⇔ 0009211 (OMIM:227500)

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 by hematology team based on activity levels and bleeding history	2	3C	2B	3	10CB

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 VII deficiency has been estimated to be 1/300,000-500,000 but may be markedly higher in communities or countries where consanguineous marriages are common. [1, 2, 3, 4, 5, 6]

Clinical Features

Factor VII deficiency is a rare inherited bleeding disorder due to reduced plasma FVII activity. The clinical manifestations include cutaneous/mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by surgery or trauma. Antepartum hemorrhage, post-partum hemorrhage (PPH), and pregnancy loss have been reported in individuals with FVII deficiency. Babies at risk of homozygosity or compound heterozygosity are at significant risk of bleeding following delivery, including intracranial hemorrhage and umbilical bleeding. [1, 2, 3, 4, 5, 6]

Natural History

Clinical expression of factor VII deficiency is highly variable, and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. Individuals can be completely asymptomatic despite a very low FVII level. A bleeding history appears more predictive of further bleeding than the factor VII level. Factor VII levels increase during pregnancy, but levels usually remain insufficient for hemostasis in severely affected cases. Individuals with no history of bleeding do not appear to be at increased risk of PPH. Heterozygotes often have approximately half-normal levels of coagulation factors and are often asymptomatic. However, up to 2% of patients with severe bleeding phenotype are heterozygotes. [1, 2, 3, 4, 5, 6]

2. How effective are interventions for preventing harm?

Patient Management

Therapeutic options include administration of recombinant activated factor VII (rFVIIa), or plasma derived FVII concentrate (if rFVIIa is not available) and through use of antifibrinolytic agents (such as tranexamic acid). Cases with FVII deficiency should be identified as having a higher risk of bleeding if the FVII activity is <0.1 IU/ml or if there is another coagulopathy or a personal history of bleeding. Tranexamic acid may be considered for minor bleeds or minor surgery in higher bleeding risk cases, and for all bleeds or surgery in low bleeding risk cases. Consider rFVIIa for severe bleeds or major surgery in high bleeding risk cases. Data summarized from the Compassionate and Emergency use programs and from independent reports show that rFVIIa provides effective hemostasis in patients of all ages and in a range of bleeding situations, including acute central nervous system/life-threatening bleeding episodes, non-life-threatening bleeding episodes, surgery, and childbirth. In a prospective evaluation of 41 surgical procedures, there were three bleeds after rFVIIa treatment, but all occurred in cases given low treatment doses. A prospective study evaluated 101 spontaneous or traumatic bleeds in individuals with inherited factor VII deficiency. Seventy-nine bleeding episodes were treated with rFVIIa. Most bleeds resolved with a single dose of rFVIIa. Thrombosis was not reported in these studies described above, but FVII inhibitors were identified in three cases. (Tier 2) [1, 4, 7]

Consider prophylaxis using rFVIIa in certain circumstances. Long term prophylaxis should be considered for cases with a personal or family history of severe bleeding or with FVII activity <0.01 IU/ml using rFVIIa, adjusting to maintain clinical response. Short term prophylaxis should be considered for cases for neonates without a personal or family history of severe bleeding but who have FVII activity 0.01-0.05 IU/ml up to 6-12 months of age. (Tier 2) [1, 4]

Pregnancy management should consider both the factor VII level and whether there is a clinical history of bleeding. Recommendations include:
•Modify treatment plans according to the nature of the individual bleeds or procedures, and to the background bleeding phenotype.
• Consider rFVIIa for at least 3-5 days following cesarean section for factor VII activity less than 0.2 IU/ml in the third trimester with prior history of bleeding. For all other women, rFVIIa is recommended only in response to abnormal or severe bleeding. For mild bleeding, tranexamic acid can be used.
In a review of case reports describing 94 live births in women with factor VII deficiency, FVII replacement (usually with rFVIIa) was used before 32% of deliveries, especially before cesarean delivery. PPH occurred in 13% of deliveries without FVII replacement, but also in 10% of deliveries with FVII replacement. Women with no history of bleeding did not experience PPH. (Tier 2) [4, 6]

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, 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]

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

No surveillance recommendations have been provided for the Pediatric context.

Circumstances to Avoid

Aspirin and other NSAIDs (nonsteroidal anti-inflammatory drugs) are contraindicated in individuals with inherited bleeding disorders due to their anti-aggregation effect on platelet function. (Tier 2) [5, 6, 8]

Central neuraxial anesthesia and postpartum pharmacological thromboprophylaxis should usually be avoided in women with severe deficiencies as it may be difficult to guarantee consistent normalization of hemostasis even after treatment. They may be used after individual assessment if adequate replacement therapy is confirmed. (Tier 2) [6]

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

Mode of Inheritance

Autosomal Recessive [1, 2, 3, 4, 5, 6]

Prevalence of Genetic Variants

Information about prevalence of pathogenic variants in the F7 gene was not identified.

Penetrance

One study analyzed genotype and phenotype data of 717 individuals from a FVII deficiency registry. Fifty-two out of 73 (71%) individuals homozygous for F7 pathogenic variants were symptomatic. Seventy-two out of 145 (50%) of compound heterozygotes were symptomatic. Homozygous and compound heterozygous individuals showed a similar profile of bleeding symptoms and pattern of clinical symptoms. Clinical manifestations of the individuals homozygous for F7 pathogenic variants were characterized by the following:
•menorrhagia (19 of 26 females; 73%)
•epistaxis (58%)
•gum bleeding (38%)
•easy bruising (37%)
•gastrointestinal bleeding (17%)
•hematoma (15%)
•hemarthrosis (13%)
•hematuria (10%)
•intracranial hemorrhage (2%). (Tier 3) [4]

Relative Risk

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

Expressivity

Factor VII deficiency shows variable severity. In a large registry study, the variability in clinical manifestation among homozygous persons with identical variants ranged from asymptomatic to highly symptomatic. Severe bleeding was more likely in registry cases with FVII activity <0.01 IU/ml than those with FVII activity >0.01 IU/ml who typically had mild mucocutaneous bleeding or were asymptomatic. However, severe bleeding is reported in some rare cases with FVII activity >0.2 IU/ml, indicating a weak association between clinical and laboratory phenotype. (Tier 3) [3, 4, 6]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified for factor VII deficiency include treatment for bleeding episodes or prophylactic coverage for using rFVIIa and antifibrinolytic agents (such as tranexamic acid). Risks of rFVIIa include thrombosis and rarely inhibitor development. Studies that evaluated 41 surgical procedures and 93 spontaneous or traumatic bleeds in individuals with factor VII deficiency did not identify any reported cases of thrombosis, but FVII inhibitors were identified in three cases. Oral tranexamic acid is generally well tolerated, with nausea and diarrhea as the most common side effects. [1, 4, 5, 6]

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

Chance to Escape Clinical Detection

Undiagnosed and untreated patients with FVII deficiency can experience hemorrhages provoked by surgery or trauma, indicating a chance to escape clinical detection prior to diagnosis. (Tier 3) [4, 6]

Date of Search: 05.29.2021

Reference List

1. Australian Haemophilia Centre Directors’ Organisation. Guidelines for Management of Factor VII Deficiency. (2010) Website: https://www.ahcdo.org.au/documents/item/10

2. Congenital factor VII deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=327

3. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. FACTOR VII DEFICIENCY. MIM: 227500: 2016 May 23. World Wide Web URL: http://omim.org.

4. 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.

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

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. Scottish Intercollegiate Guidelines Network (SIGN). Antithrombotics: indications and management. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (). (2013) Website: https://www.sign.ac.uk/media/1067/sign129.pdf