Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released

Condition: Hemophilia A and B
Mode(s) of Inheritance: X-linked
Actionability Assertion
Gene Disease Pairs(s)
Final Assertion
F80010602 (hemophilia a)
Assertion Pending
F90010604 (hemophilia b)
Assertion Pending
Actionability Rationale
This report was generated prior to the implementation of the process for making actionability assertions. An actionability assertion will be made, but may take time due to the substantial backlog of topics that need assertions.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Disease Pairs: F8 0010602 (OMIM:306700) F9 0010604 (OMIM:306900)
Males: Severe/prolonged hemorrhage / Development of comprehensive management plan based on activity levels
Females: Severe/prolonged hemorrhage / Development of comprehensive management plan based on activity levels

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
It is estimated that there are roughly 400,000 individuals worldwide and 17,000 males in the US with hemophilia due to factor VIII (Hemophilia A or HEMA) or factor IX (Hemophilia B or HEMB) deficiency. HEMA is more common than HEMB, representing 80-85% of all patients with hemophilia. Age-adjusted prevalence rates in US males, similar to worldwide rates, have been estimated as 1/10,000 for HEMA and 1/35,000 for HEMB. The incidence of HEMA and HEMB in the US was estimated to be 1/5032 live male births.
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Clinical Features
(Signs / symptoms)
HEMA and HEMB are X-linked disorders that typically affect males while females are most commonly carriers. As many as 1/3 of all cases (depending on hemophilia type) are the result of spontaneous mutation, and thus patients will lack a prior family history. Both disorders are characterized by deficiencies in coagulation factors that promote blood clotting, which results in abnormal bleeding. Signs include easy bruising; spontaneous bleeding or bleeding for no apparent/known reason, particularly in the joints, muscles, and soft tissues; and excessive bleeding following trauma or surgery. Bleeding can be immediate due to impaired clot formation or delayed due to clot instability. Some bleeding can be life-threatening and require immediate treatment.
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Natural History
(Important subgroups & survival / recovery)
Disease severity is correlated with the level of factor VIII or IX clotting activity, with a normal range of about 50-150% for both. In the US, it is estimated that roughly 43%, 26%, and 31% of patients with hemophilia are classified as severe, moderate, and mild:
• Severe (<1% clotting activity): Patients are typically diagnosed prior to age 2. Patients experience prolonged bleeding or excessive pain and swelling from joint bleeds, minor injuries, surgery, and tooth extractions. Without treatment, spontaneous bleeding is common (mostly in the joints and muscles), with an average frequency of 2-5 episodes per month.
• Moderate (1-5% clotting activity): Patients are typically diagnosed prior to age 5 or 6. They seldom have spontaneous bleeding but prolonged or delayed oozing may be triggered by relatively minor trauma if untreated. The frequency of episodes varies from once a month to once a year.
• Mild (6-40% clotting activity): Patients are often diagnosed later in life. They do not have spontaneous bleeding and may not bleed excessively until they experience trauma, tooth extractions, or surgery. The frequency of bleeding varies from once a year to once every ten years.
Female carriers may experience milder symptoms of abnormal bleeding. Roughly 10% of carriers with factor clotting levels <35% for factor VIII and <30% for factor IX are at similar risk for bleeding as males with mild hemophilia. A few carriers may have clotting factor levels in the moderate or severe range due to extremely skewed X-inactivation. In addition, more subtle abnormal bleeding may be seen with clotting factor activity in the ranges of 35-60% for factor VIII and 30-60% for factor IX. Women are at particular risk of bleeding complications during menstruation and, especially for HEMB, during and following childbirth. Menorrhagia is the most common bleeding symptom in women and may be the first or only presenting symptom.
The leading cause of death related to bleeding is intracranial hemorrhage. The major cause of disability from bleeding is from chronic joint disease. Prophylactic treatment with clotting factor concentrates normalizes life expectancy and reduces chronic disease.
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2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with hemophilia, the following evaluations are recommended:
• A personal and family history of bleeding to help predict disease severity
• A joint and muscle evaluation, particularly if the individual describes a history of hemarthrosis or deep-muscle hematomas
• Baseline CBC and platelet count, especially if there is a history of nose bleeds, GI bleeding, mouth bleeding; or in women, menorrhagia or postpartum hemorrhage
• Medical genetics consultation, particularly if a new diagnosis in the family and for females of childbearing years. (Tier 4)
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Prophylaxis with factor replacement is the main form of therapy in young patients with severe disease and prevents bleeding and joint destruction. Prophylaxis is not recommended for mild disease. (Tier 2)
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All patients should be taught to self-administer at home under supervision and monitoring by a hemophilia specialist. Patients should treat acute bleeding episodes as quickly as possible, preferably within 2 hours. Treatment consists of factor IX concentrate for HEMB and desmopressin for mild to possibly moderate cases of HEMA, in responsive patients, or factor VIII concentrate. (Tier 2)
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To facilitate appropriate management in emergency situations, all patients should carry easily accessible identification indicating the diagnosis, severity of the bleeding disorder, inhibitor status, type of treatment product used, initial dosage for treatment of severe, moderate, and mild bleeding, and contact information of the treating physician/clinic. (Tier 2)
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A hemophilia patient requiring surgery is best managed at or in consultation with a comprehensive hemophilia treatment center to ensure care by healthcare professionals with experience treating patients with bleeding disorders. (Tier 2)
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Infusion of factor concentrates/hemostatic agents may be necessary before invasive diagnostic procedures, endoscopy with biopsy, surgery, and during the post-operative period. (Tier 2)
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Good oral hygiene is essential to prevent periodontal disease and dental caries, which predispose to gum bleeding. Patients should undergo an enhanced regimen of preventive dental care (brushing, flossing, and fluoride treatment) as well as regular dental exams with a general dental practitioner. Oral injections, deep dental cleanings, tooth extraction, and oral surgery should be done in consultation with hemophilia specialists. (Tier 2)
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Regular exercise and other activities to stimulate psychomotor development should be encouraged to promote strong muscles, develop balance and coordination, improve fitness, and maintain a healthy body weight. Non-contact and low-impact sports are encouraged. An active lifestyle improves muscle tone and balance to prevent falls and improve range of joint movement. Two small studies have also shown a reduction in bleeding tendency with exercise. A study of 11 hemophiliac boys showed a decrease in mean prothrombin time across all patients, while 4 mild cases had increased factor VIII activity. A separate study of 8 patients indicated that 7 showed significantly reduced muscle bleeds after 13 months on a home exercise program. (Tier 2)
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Patients with hemophilia should be vaccinated. Immunization to hepatitis A and B is especially important for all persons with hemophilia. (Tier 2)
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In females known to be carriers, it is important to assay their factor VII or factor IX levels to establish whether they are at increased risk of bleeding. (Tier 2)
Pregnancy in carriers of hemophilia should be managed by a multidisciplinary team including an obstetrician, hematologist, and anesthetist. A pregnancy and delivery plan should be formulated to meet the needs of the patient. Pregnancy management should include:
• Assessment of family and personal bleeding history.
• Knowledge of fetal gender enables appropriate management of labor and delivery to reduce the risk of bleeding in a potentially affected infant. Invasive fetal monitoring techniques (e.g., fetal scalp electrodes and blood sampling), vacuum extractions, mid-cavity or difficult forceps deliveries, and prolonged labor should be avoided for an affected male fetus or when the fetal sex or coagulation status of the male fetus is unknown. Delivery should be achieved by the least traumatic method and early recourse to cesarean section should be considered.
• Cord blood should be collected from all male neonates to assess clotting factor levels for identification and early management. In addition, until the affected status is known, intramuscular injections and venipunctures should be avoided, vitamin K should be given orally, routine immunizations should be given intradermally or subcutaneously, heel pricks should be avoided, and circumcision should be delayed.
• Clotting factor levels should be assessed at booking and at 28 and 34 weeks gestation to allow appropriate management of labor and delivery and to assess the need for prophylactic treatment.
• The risk of postpartum hemorrhage (PPH) can be reduced by active monitoring of factor levels during the third stage of labor. In addition, factor levels should be monitored and adjusted appropriately post-delivery for at least 3 days, or 5 days for a cesarean delivery. In carriers, the incidence of primary (<24 hours) and secondary (>24 hours) PPH is 22% and 11%, respectively, compared to 5-8% and 0.8% in the general population, respectively. Evidence that active monitoring improves outcomes was not available. (Tier 2)
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Patients with hemophilia are best managed in a comprehensive care setting with a multidisciplinary team of healthcare professionals with experience in treating bleeding disorders. Patients should meet with their team regularly for a complete hematologic, serologic, musculoskeletal, and psychosocial assessment and to develop, audit, and refine their comprehensive management plan. The frequency of assessments depends on the severity of hemophilia. Analysis of a cohort of 2950 patients with hemophilia indicated that treatment via a hemophilia treatment center that provided comprehensive care was associated with reduced mortality (RR=0.6, 95% CI=0.5-0.8). (Tier 2)
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Circumstances to Avoid
Drugs that affect platelet function, such as aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), should be avoided. Paracetamol/acetaminophen, cyclo-oxygenase-2 (COX-2) inhibitors, or opioids are recommended alternatives for analgesia. (Tier 2)
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Avoid all intramuscular injections (administer vaccines subcutaneously). (Tier 2)
Never cut down into a vein, except in an emergency, and venous access devices should be avoided whenever possible. (Tier 2)
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High contact and collision sports (e.g., hockey, wrestling) as well as high-velocity activities (e.g., skiing) should be avoided. (Tier 2)
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3. What is the chance that this threat will materialize?
Mode of Inheritance
Prevalence of Genetic Variants
Information on the prevalence of genetic mutations associated with HEMA and HEMB in the general population was not available. However, given that virtually all males with mutations associated with hemophilia are affected, the prevalence of mutations in F8 and F9 in males is likely similar to the prevalence rates of HEMA (1/10,000) and HEMB (1/35,000), respectively. In addition, carrier prevalence can be estimated for HEMA (1/5000) and HEMB (1/17,500) based on the prevalence in males. (Tier 3)
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(Include any high risk racial or ethnic subgroups)
All males with pathogenic F8 and F9 variants are affected. Approximately 10% of carrier females will be affected due to factor VIII clotting activity <30% or factor IX clotting activity <35%. In addition, mild bleeding can occur in carriers with low-normal factor activity. (Tier 4)
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Relative Risk
(Include any high risk racial or ethnic subgroups)
Information on relative risk was not available.
The nature of hemophilia is consistent among family members with the same mutation. However, other genetic and environmental effects may modify the clinical severity to some extent. (Tier 4)
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4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified for HEMA and HEMB include increased surveillance, particularly during surgical or other invasive procedures and childbirth, with the potential for administration of prophylactic agents, such as factor concentrates, to prevent bleeding. Patients often respond variably to the administration of coagulation agents and may develop complications such as alloimmune inhibitors (antibodies) to the clotting factor or allergic reactions. Inhibitors to F8 or, far less often, F9 proteins can severely impede the effectiveness of treatment. Inhibitor development likely affects only a small proportion of mild/moderate HEMA cases.
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5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Though patients with moderate or severe hemophilia will likely be detected and diagnosed prior to adulthood, patients with mild hemophilia are often not diagnosed until later in life when they undergo surgery or tooth extraction or experience major trauma. (Tier 4)
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Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Disease Associations
Disease Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. 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.
2. Mahlangu JN, Gilham A. Guideline for the treatment of haemophilia in South Africa. S Afr Med J. (2008) 98(2 Pt 2):126-40.
3. WFH Guidelines for the Management of Hemophilia. (2013) Website:
4. BA Konkle, NC Josephson, S Nakaya Fletcher. Hemophilia B. 2000 Oct 02 [Updated 2014 Jun 05]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
5. BA Konkle, NC Josephson, S Nakaya Fletcher. Hemophilia A. 2000 Sep 21 [Updated 2014 Jun 05]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
6. Protocols for the Treatment of Hemophilia and von Willebrand Disease. (2015) Website:
7. Negrier C, Seuser A, Forsyth A, Lobet S, Llinas A, Rosas M, Heijnen L. The benefits of exercise for patients with haemophilia and recommendations for safe and effective physical activity. Haemophilia. (2013) 19(4):487-98.
8. 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.
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