AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Hemophilia B is an inherited, X-linked, recessive disorder resulting in deficiency of functional plasma coagulation factor IX. Spontaneous mutation and acquired immunologic processes can result in this disorder as well.

Morbidity and death are primarily the result of hemorrhage, although infectious diseases (eg, HIV, hepatitis) became prominent, particularly in patients who received blood products prior to 1985.

For related information, see Medscape's Hematology-Oncology Resource Center.

Pathophysiology

Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal intrinsic coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma.

Hemorrhage sites include joints (eg, knee, elbow), muscles, CNS, GI system, genitourinary (GU) system, pulmonary system, and cardiovascular system.

Patients who acquired HIV, hepatitis, or other viruses suffer from maladies associated with those infections.

Frequency

United States

Occurrence in males is estimated to be 1 per 25,000 males.

International

The prevalence of hemophilia B is 1 in 60,000 people.

Mortality/Morbidity

The death rate for those affected with hemophilia B is not reported. The life span approaches that of the healthy population, excluding individuals infected with HIV.

• Severe disease, defined as less than 1% factor IX activity, accounts for 50% of those with hemophilia B.
• Moderate disease, defined as 1-5% factor IX activity, typically presents in children aged 1-2 years and accounts for 30% of those with hemophilia B.
• Mild disease is defined as levels greater than 5% factor IX activity and accounts for 20% of those with hemophilia B.

Race

Rates of hemophilia among whites, African Americans, and Hispanic males in the US are similar.

Sex

• Because hemophilia is an X-linked, recessive condition, it occurs primarily in males.
• Occasionally, cases are reported in females; however, females usually are asymptomatic carriers.

Age

The disease usually presents in infancy or childhood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Hemophilia is suggested by a history of hemorrhage disproportionate to trauma, spontaneous hemorrhage, or familial hemorrhage. Concomitant illness may include chronic inflammatory disorders, autoimmune diseases, hematologic malignancies (acquired form), and allergic drug reactions.

For individuals with documented hemophilia, inquire regarding the type of deficiency (eg, VIII, IX, von Willebrand), percent factor deficiency, known presence of inhibitors, and HIV/hepatitis status. For patients with mild-to-moderate hemophilia A, determine responsiveness to desmopressin acetate (DDAVP).

• Hemorrhage - In infants, bleeding may occur from blood sticks, immunizations, or circumcision. Children may exhibit bleeding with tooth loss, excessive bruising, or spontaneous hemorrhage. With mild disease, hemorrhage is most likely to occur with trauma or surgery.
• • General - Weakness, orthostasis
  • Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)
  • CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes
  • GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain
  • GU - Hematuria, renal colic, and postcircumcision bleeding
  • Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions
• Joint and muscle hemorrhage are the most common manifestations of moderate and severe hemophilia.
• Infectious disease
• • HIV/AIDS-related symptoms
  • Hepatitis-related symptoms

Physical

• General signs of hemorrhage - Tachycardia, tachypnea, hypotension, and orthostasis
• Organ system specific signs of hemorrhage
• • Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, swelling, effusion, and warmth
  • CNS - Abnormal neurologic exam findings, altered mental status, and meningismus
  • GI - Can be painless, hepatic/splenic tenderness, and peritoneal signs
  • GU - Bladder spasm/distension/pain, costovertebral angle pain
  • Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)
• Infectious disease
• • HIV/AIDS-related signs
  • Hepatitis-related signs

Causes

Hemophilia B is caused by an inherited or acquired genetic mutation or an acquired factor IX inhibitor.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

von Willebrand disease
Vitamin K and other factor deficiencies
Afibrinogenemia/dysfibrinogenemia
Fibrinolytic diseases
Platelet disorders

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Never delay indicated coagulation correction pending diagnostic testing.
• Hemoglobin/hematocrit
• • Assess blood loss.
  • Expect normal range or low values.
• Prothrombin time (PT)
• • Extrinsic coagulation pathway screen
  • Normal range expected
• Activated partial thromboplastin time (aPTT)
• • Intrinsic pathway screen
  • Elevated values expected (may be normal range in mild disease)
• Platelet count
• • Assess bleeding.
  • Expect normal range.
• Factor IX level
• • Assess percentage activity.
  • Normal range is 50-150%; severe disease less than 1%; moderate disease 1-5%; mild disease greater than 5%.
• Factor IX inhibitors
• • Assess presence and anamnestic response to factor IX.
  • Expect low titer (0-10 Bethesda U) or high titer (>10 Bethesda U).

Imaging Studies

• Early and aggressive imaging is indicated after coagulation therapy is initiated, even when suspicion is low for hemorrhage.
• CT scan
• • Head (noncontrast): Assess for spontaneous or traumatic hemorrhage.
  • Body (with or without intravenous [IV] and/or oral contrast): Assess spontaneous or traumatic hemorrhage as indicated by clinical suspicion and anatomic location.
• MRI
• • Head and spinal column
  • Further assessment of spontaneous or traumatic hemorrhage
• Joint x-ray
• • Of limited value in the acute setting of hemarthrosis
  • Chronic degenerative joint disease often present
• Special studies (as clinically indicated)
• • Angiography
  • Nucleotide bleeding scan

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

• Prehospital providers should address the ABCs while rapidly transporting the patient to a definitive care facility.
• In the prehospital setting, providers should do the following:
• • Apply aggressive hemostatic techniques.
  • Assist patients capable of self-administered factor therapy.
  • Gather focused historical data if the patient is unable to communicate.

Emergency Department Care

• Use aggressive hemostatic techniques.
• Correct coagulopathy immediately. Never delay indicated coagulation correction pending diagnostic testing. However, in cases of previously undiagnosed coagulopathy, collecting blood specimens prior to treatment is important.
• Perform a diagnostic workup for hemorrhage.
• If possible, draw blood for the studies listed in Lab Studies, including 2 blue top tubes to be spun and frozen for factor and inhibitor assays.

Consultations

• Hematologist/blood bank/pathologist
• Others as indicated by hemorrhagic complications

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the preferred source for replacement therapy. The factor IX activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, CNS, trauma related, GI, GU, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular). One unit of factor IX is the amount of factor IX in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor IX is approximately 100 mL/kg. The difference between the desired factor IX activity level and the patient's native factor IX activity level can be calculated by simple subtraction and expressed as a fraction.

To find the number of units of factor IX needed to correct the factor IX activity level, use the following:

As an example, an 80-kg person with hemophilia with known 1% factor IX activity level presents to the ED with a serious upper GI bleed. The correct dose of factor IX to administer to the patient would be calculated as follows:

The next dose should be administered 24 hours after the first and is one half of the initial calculated dose. Minor hemorrhage requires 1-3 doses of factor IX. Major hemorrhage requires many doses and continued factor IX activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be considered for major hemorrhage.

Drug Category: Factor Ix-containing Products

These agents are used to correct the patient's native deficiency, with the goals of achieving a normal hematologic response to hemorrhage or preventing hemorrhage.

Drug Category: Coagulation Factor VIIa (Recombinant)

These agents can activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa.

Drug Category: Antifibrinolytics

These agents are used in addition to factor IX replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Continue further hemostatic (eg, splenectomy, posttrauma) and supportive care, as indicated.
• The patient's disposition (ICU vs floor) is based on the severity of hemorrhage and potential for morbidity and death.
• Choose attending service based on etiology of hemorrhage.
• Hematology/blood bank/pathology consultation is mandatory.
• Continue factor replacement and monitoring.
• Administer epsilon aminocaproic acid, as indicated.
• Consider inhibitor screening.

Further Outpatient Care

• Minor hemorrhage (not life threatening): Continue hemostatic measures (eg, brief joint immobilization, bandage).
• Hematologist or primary care physician follow-up care is indicated.
• Continue factor replacement and monitoring.
• Administer epsilon aminocaproic acid, as indicated.
• Hepatitis A and B immunizations are recommended.

Transfer

• The preference is to bring factor IX to the patient.
• Transfer to a tertiary care center when indicated specialists are not available.
• Transfer to a hemophilia treatment center for optimal hematologic management.

Deterrence/Prevention

• Consider prophylactic or scheduled factor IX.
• Optimize physical conditioning.
• Avoid high-risk activities.
• Gene therapy may be available in the future.

Complications

• Ongoing hemorrhage with resulting morbidity and death
• Inhibitor development
• Exposure/infection from blood products (eg, HIV; hepatitis A, B, C; unknown viruses)

Prognosis

• With appropriate education and treatment, patients with hemophilia can live full and productive lives.
• Life expectancy was approaching age 60 years prior to HIV epidemic in the 1980s.
• HIV-infected individuals are likely to succumb to HIV/AIDS-related complications.

Patient Education

• Local hemophilia treatment centers
• The National Hemophilia Foundation
  116 West 32nd Street 11th Floor
  New York, New York 10001
  Phone: (212) 328-3700, (800) 42-HANDI (information service)
• Medic-Alert bracelets
• For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Hemophilia.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Delay of indicated coagulation correction pending diagnostic testing
• Failure to monitor the results of treatments administered
• Failure to administer prophylactic factor IX replacement, which is indicated prior to invasive procedures (eg, lumbar puncture [LP], tooth extraction)
• Failure to recognize the remote risk of viral infection from blood products
• Failure to consider the presence of inhibitors and treat accordingly.

Special Concerns

• Inhibitors
• • Inhibitors are antibodies that neutralize factor IX and can render replacement therapy ineffective.
  • They are less common than factor VIII inhibitors and are found in only 3% of those with severe disease.
  • Low-titer inhibitors and, occasionally, high-titer inhibitors can be overcome with high doses of factor IX.
  • The relatively low frequency of this problem has lead to a dearth of experience in its treatment.
  • Recombinant human coagulation factor VIIa (rFVIIa) is indicated for the treatment of patients with bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with hemophilia A or B with inhibitors to factor VIII or factor IX.
  • Recent treatments with the anti-inhibitor coagulant complex factor VIII inhibitor bypassing activity (FEIBA) have shown promise.
  • Immune-tolerance strategies in those with identified inhibitors have been successful as well.
  • Early hematology consultation for these patients is essential.
• Cryoprecipitate contains no factor IX and is not appropriate for factor IX therapy.
• DDAVP is not a treatment for factor IX deficiency.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Coagulation Factor VII a (Recombinant) [package insert]. Denmark: Novo Nordisk; 2006. [Full Text].
2. Adamson S, Charlebois T, O'Connell B, Foster W. Viral safety of recombinant factor IX. Semin Hematol. Apr 1998;35(2 Suppl 2):22-7. [Medline].
3. Bell B, Canty D, Audet M. Hemophilia: an updated review. Pediatr Rev. Aug 1995;16(8):290-8. [Medline].
4. Bolan CD, Alving BM. Pharmacologic agents in the management of bleeding disorders. Transfusion. Jul-Aug 1990;30(6):541-51. [Medline].
5. Brettler DB, Levine PH. Clinical manifestations and therapy of inherited coagulation factor deficiencies. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice, Third Edition. 1994:169-83.
6. Brinkhous KM, Sigman JL, Read MS, et al. Recombinant human factor IX: replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B. Blood. Oct 1 1996;88(7):2603-10. [Medline].
7. DiMichele D, Neufeld EJ. Hemophilia. A new approach to an old disease. Hematol Oncol Clin North Am. Dec 1998;12(6):1315-44. [Medline].
8. Dunn AL, Abshire TC. Recent advances in the management of the child who has hemophilia. Hematol Oncol Clin North Am. Dec 2004;18(6):1249-76, viii. [Medline].
9. Furie B, Limentani SA, Rosenfield CG. A practical guide to the evaluation and treatment of hemophilia. Blood. Jul 1 1994;84(1):3-9. [Medline].
10. Goldsmith JC. Hemophilia: Current Medical Management. The National Hemophilia Foundation; 1994:1-30.
11. Ludlam CA. Treatment of haemophilia. Br J Haematol. May 1998;101 Suppl 1:13-4. [Medline].
12. Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Found. Recommendations concerning prophylaxis. Medical Bulletin #193. 1994;1-3.
13. Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Found. Recommendations regarding the use of recombinant factor VIII in the treatment of hemophilia A. Medical Bulletin # 232. 1995;1-2.
14. Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Found. Revised recommendations regarding hepatitis A vaccination in individuals with hemophilia and other congenital bleeding disorders. Medical Advisory # 277. 1997;1-2.
15. Soucie JM, Evatt B, Jackson D. Occurrence of hemophilia in the United States. The Hemophilia Surveillance System Project Investigators. Am J Hematol. Dec 1998;59(4):288-94. [Medline].
16. Thompson A. Recombinant factor IX for the treatment of hemophilia B. Introduction. Semin Hematol. Apr 1998;35(2 Suppl 2):1-3. [Medline].
17. White G, Shapiro A, Ragni M. Clinical evaluation of recombinant factor IX. Semin Hematol. Apr 1998;35(2 Suppl 2):33-8. [Medline].

Article Last Updated: Oct 6, 2008