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 A is an inherited, X-linked, recessive disorder resulting in deficiency of functional plasma coagulation factor VIII. Significant rates of 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 VIII deficiency, dysfunctional factor VIII, or factor VIII inhibitors lead to the 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 system, pulmonary system, and cardiovascular system. Intracranial hemorrhage is most common in patients younger than 18 years and can be a fatal event.

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

Frequency

United States

An estimated 17,000 people were affected with hemophilia A in the United States in 2003.

Approximately 1 per 5,000-10,000 males are born with hemophilia A.

Mortality/Morbidity

The death rate for those affected with hemophilia A 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 VIII activity, presents in children younger than 1 year and accounts for 43-70% of those with hemophilia A.
• Moderate disease, defined as 1-5% factor VIII activity, presents in children aged 1-2 years and accounts for 15-26% of those with hemophilia A.
• Mild disease, defined as greater than 5% factor VIII activity, presents in children older than 2 years and accounts for 15-31% of those with hemophilia A.

Race

Hemophilia occurs in all races and ethnic groups. 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 predominantly in males.
• Occasionally, cases are reported in females; however, females usually are asymptomatic carriers.

Age

Patients often present in infancy or childhood.

CLINICAL

Section 3 of 10  

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

History

For patients in whom hemophilia is suspected, ascertain the history of hemorrhage disproportionate to trauma, spontaneous hemorrhage, familial hemorrhage, concomitant illness (eg, chronic inflammatory disorders, autoimmune diseases, hematologic malignancies [acquired form], allergic drug reactions), and pregnancy.

For individuals with documented hemophilia, ascertain 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 disease, determine responsiveness to desmopressin acetate (DDAVP).

• Hemorrhage
• • General - Weakness and 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
  • Genitourinary - Hematuria, renal colic, and postcircumcision bleeding
  • Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions; excessive bleeding with routine dental procedures
• Infectious disease
• • HIV/AIDS-related symptoms
  • Hepatitis-related symptoms

Physical

• General signs of hemorrhage
• • Tachycardia
  • Tachypnea
  • Hypotension
  • Orthostasis
• Organ system–specific signs of hemorrhage
• • Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, effusion, and warmth
  • CNS - Abnormal neurologic exam findings, altered mental status, and meningismus
  • GI - Can be painless, hepatic/splenic tenderness, and peritoneal signs
  • Genitourinary - Bladder spasm/distension/pain and 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 A is caused by an inherited or acquired genetic mutation or an acquired factor VIII 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 defects
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 VIII level
• • Assess percentage activity (normal 50-150%).
  • Expect severe disease with less than 1%, moderate disease with 1-5%, and mild disease with greater than 5%.
• Factor VIII inhibitors
• • Assess presence.
  • Assess anamnestic response to factor VIII.
  • Expect low titer (0-10 Bethesda U) or high titer (>10 Bethesda U).

Imaging Studies

• Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated.
• Head CT scan (noncontrast): Assess spontaneous or traumatic hemorrhage.
• Body CT scan
• • Perform with or without intravenous (IV) and/or oral contrast.
  • Perform as indicated by clinical suspicion and anatomical location.
  • Assess spontaneous or traumatic hemorrhage.
• MRI
• • Head and spinal column
  • Further assessment of spontaneous or traumatic hemorrhage
• X-ray for joint assessment
• • Of limited value in 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

• Rapid transport to definitive care is the mainstay of prehospital care.
• Prehospital care 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.
• Include a diagnostic workup for hemorrhage.
• If possible, draw blood for the studies listed above, 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 VIII is the treatment of choice for acute or potential hemorrhage. Recombinant factor VIII concentrate is the preferred source of factor VIII. The factor VIII activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, CNS, trauma related, GI, genitourinary [GU], epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular). One unit of factor VIII is the amount of factor VIII in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor VIII is that of plasma, approximately 50 mL/kg. The difference between the desired factor VIII activity level and the patient's native factor VIII activity level can be calculated by simple subtraction and expressed as a fraction (eg, 100% - 5% = 95% or 0.95).

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

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

The next dose should be administered 12 hours after the initial dose and is one half the initial calculated dose. Minor hemorrhage requires 1-3 doses of factor VIII. Major hemorrhage requires many doses and continued factor VIII activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor VIII may be considered for major hemorrhage.

The specific factor product which patients use is often part of their individualized treatment plan.  Patient's will usually be well educated on their dosing/products.  This information also can be found on institutional treatment center/blood bank data bases.

Prophylactic administration of factor VIII is often recommended for pediatric patients with severe disease.

Other medicinal adjuncts to factor VIII (eg, DDAVP, antifibrinolytics) often are useful in achieving hemostasis and can lessen the need for factor VIII infusion.

Drug Category: Factor VIII 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: Antifibrinolytics

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

Drug Category: Antihemophilic Agent

These agents raise plasma levels of factor VIII.

Drug Category: Coagulation Factor VIIa (recombinant)

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

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.
• Disposition (ICU vs floor) should be based on 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 DDAVP/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 DDAVP/epsilon aminocaproic acid as indicated.
• Hepatitis A and B immunizations are recommended.

Transfer

• The preference is to bring factor VIII to the patient.
• Transfer to a tertiary care center when indicated specialists (eg, neurosurgery) are not available.
• Transfer to a hemophilia treatment center for optimal hematologic management.

Deterrence/Prevention

• Consider prophylactic or scheduled factor VIII.
• Optimize physical conditioning.
• Avoid high-risk activities.
• Gene therapy is a possibility 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 60 years prior to HIV epidemic in the 1980s.
• HIV-infected individuals are likely to die of that disease than from hemophilia.

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

• Failure to administer indicated coagulation correction promptly pending diagnostic testing
• Failure to monitor the results of treatments administered
• Failure to administer prophylactic factor VIII 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 VIII and can render replacement therapy ineffective.
  • They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy.
  • Inhibitors can rarely develop in individuals without hemophilia (eg, elderly persons, pregnant women) and occasionally are responsive to immunosuppressive therapy (eg, prednisone).
  • Immune tolerance strategies in those with identified inhibitors also have been successful.
  • Assuming no anamnestic response, low-titer inhibitors occasionally can be overcome with high doses of factor VIII.
  • 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.
  • High-titer inhibitors have been treated with variable success using porcine factor VIII, factor IX complex concentrates, recombinant factor VIII, and exchange plasma pheresis.
  • Early hematology consultation for management of this type of patient is essential.

REFERENCES

Section 10 of 10

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

1. Coagulation Factor VIIa Recombinant [package insert]. Denmark: Novo Nordisk; 2006. [Full Text].
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3. Bolan CD, Alving BM. Pharmacologic agents in the management of bleeding disorders. Transfusion. Jul-Aug 1990;30(6):541-51. [Medline].
4. Brettler DB, Levine PH. Clinical manifestations and therapy of inherited coagulation factor deficiencies. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3^rd ed. 1994:169-83.
5. DiMichele D, Neufeld EJ. Hemophilia. A new approach to an old disease. Hematol Oncol Clin North Am. Dec 1998;12(6):1315-44. [Medline].
6. Furie B, Limentani SA, Rosenfield CG. A practical guide to the evaluation and treatment of hemophilia. Blood. Jul 1 1994;therapeutic use(1):3-9. [Medline].
7. Goldsmith JC. Hemophilia: Current Medical Management. The National Hemophilia Foundation; 1994:1-30.
8. Luck JV, Silva M, Rodriguez-Merchan EC, et al. Hemophilic arthropathy. J Am Acad Orthop Surg. Jul-Aug 2004;12(4):234-45. [Medline].
9. Ludlam CA. Treatment of haemophilia. Br J Haematol. May 1998;101 Suppl 1:13-4. [Medline].
10. Manco-Johnson M. Hemophilia management: optimizing treatment based on patient needs. Curr Opin Pediatr. Feb 2005;17(1):3-6. [Medline].
11. Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Found. Recommendations concerning prophylaxis. Medical Bulletin #193. 1994;1-3.
12. 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.
13. 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.
14. Mudad R, Kane WH. DDAVP in acquired hemophilia A: case report and review of the literature. Am J Hematol. Aug 1993;43(4):295-9. [Medline].
15. Schneiderman J, Nugent DJ, Young G. Sequential therapy with activated prothrombin complex concentrate and recombinant factor VIIa in patients with severe haemophilia and inhibitors. Haemophilia. Jul 2004;10(4):347-51. [Medline].
16. 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].
17. von Depka M. Immune tolerance therapy in patients with acquired hemophilia. Hematology. Aug 2004;9(4):245-57. [Medline].

Article Last Updated: Oct 6, 2008