Hemophilia

Hemophilia is a coagulation disorder caused by a clotting factor deficiency. The three types of hemophilia classified by deficient clotting factor are hemophilia A (factor VIII), hemophilia B (factor IX), and hemophilia C (factor XI). Hemophilia A and B are the most common types, and they are typically X-linked recessive disorders. Clinical features include spontaneous or trauma-induced bleeding. Disease severity depends on the residual activity of the deficient clotting factor. Diagnosis is based on coagulation studies showing a prolonged activated partial thromboplastin time (aPTT) that is corrected by mixing study, and it is confirmed by measuring factor activity levels. Management focuses on replacing the deficient clotting factor, either as prophylaxis to prevent bleeding or on demand to treat acute bleeding episodes. Desmopressin can be used as an alternative treatment for bleeding in mild hemophilia A. Tranexamic acid and aminocaproic acid (antifibrinolytics) are used to treat minor superficial bleeding. Emicizumab may be used for prophylactic therapy in hemophilia A. Complications include major bleeding events, the development of clotting factor inhibitors, and hemophilic arthropathy.

• Affects ∼ 1/5,000 male births.
• Average age at diagnosis is 1 month for people with severe hemophilia, 8 months for people with moderate hemophilia, and 36 months for people with mild hemophilia. ^[1]

Epidemiological data refers to the US, unless otherwise specified.

Hemophilia is caused by an X-linked recessive defect (inherited or spontaneous mutation) or antibody production against clotting factors.

• Hemophilia A (factor VIII deficiency): ∼ 80% of cases ^[2]
• Hemophilia B (factor IX deficiency): ∼ 20% of cases ^[2]
• Hemophilia C (factor XI deficiency): : very rare (increased frequency in the Ashkenazi Jewish population; ); most commonly caused by an autosomal recessive defect ^[3]

Hemophilia usually affects male individuals, as it is primarily an X-linked recessive disease.

• Spontaneous bleeding or delayed-onset bleeding (joints, muscular and soft tissue, mucosa) in response to different degrees of trauma
  • Repeated hemarthrosis (e.g., knee joint) → hemophilic arthropathy (i.e., destruction of the joint due to repeated hemarthrosis)
    • Typically develops by early adulthood
    • Most commonly involves the knees, ankles, and elbows
  • Recurrent bruising or hematoma formation
  • Oral mucosa bleeding, epistaxis, excessive bleeding following small procedures (e.g., dentist procedures)
  • Hemophilia C does not typically manifest with spontaneous bleeding, hemarthrosis, or deep tissue bleeding. ^[4]
• Further sites/symptoms of hemorrhage:
  • CNS (e.g., headache, neck stiffness)
  • Gastrointestinal tract (e.g., melena, hematemesis)
  • Genitourinary system (e.g., hematuria)
• Female carriers may show mild symptoms.
• The degree of bleeding and, therefore, severity of hemophilia depends on residual factor activity levels; normal reference activity is > 50%

Petechial bleeding is a common sign of platelet disorders, but NOT of coagulation disorders such as hemophilia.

Maintain a high index of suspicion in young children, as signs of joint or muscle bleeding may be subtle (e.g., reluctance to move a limb). ^[2]

Bleeding in hemophilia may be triggered by very minor trauma and manifest days to weeks following the event. ^[6]

This section provides information on the management of bleeding emergencies in patients with known hemophilia. For a general approach to acute bleeding, see "Management of acute bleeding in patients with bleeding disorders."

Approach ^[2][7][8]

• Triage urgently to avoid delays in treatment.
• Consult the patient's treating hematologist (preferred), the hematology consult service, or a hemophilia treatment center. ^[9]
• When available, follow the patient's individual bleeding management plan. ^[7]
• Administer immediate hemostatic treatment (e.g., factor replacement therapy).
• Provide blood product transfusions if needed (see also “Massive transfusion”).
• Consider diagnostics and further interventions as needed once initial treatment has been provided (see "Diagnosis").

Do not delay immediate hemostatic treatment to obtain diagnostic studies. ^[7]

Immediate hemostatic treatment ^[2][7][8]

See "Emergency pharmacological management of hemophilia" for specific indications, dosing, and additional considerations.

• Minor superficial bleeding
  • Apply localized pressure and topical hemostatic agents (e.g., topical tranexamic acid)
  • If bleeding continues, consider desmopressin (in mild hemophilia A) and/or antifibrinolytic therapy.
• All other bleeding
  • Mainstay of treatment: Administer emergency factor replacement therapy.
    • Hemophilia A; without inhibitor: factor VIII replacement
    • Hemophilia B; without inhibitor: factor IX replacement
    • Hemophilia C; without inhibitor: factor XI replacement
    • Hemophilia A or B with inhibitor: Consider bypass agent (e.g., recombinant factor VIIa).
  • Mucocutaneous bleeding: Consider antifibrinolytic therapy in addition to factor replacement therapy.
  • Mild hemophilia A; with non-life-threatening and non-limb-threatening bleed: Consider desmopressin as an alternative to factor replacement therapy.

Signs of bleeding may be subtle or absent. Initiate hemostatic treatment promptly based on clinician, patient, or caregiver concern, even without objective findings. ^[2][7]

Adjunctive care ^[2][7]

• Bleeding prevention
  • Avoid tight tourniquets.
  • Minimize traumatic or repeated needle sticks.
  • In patients not requiring volume replacement, use the smallest gauge needles for IV access.
  • Avoid intramuscular injections whenever possible; if unavoidable, administer factor replacement therapy first.
  • Administer factor replacement therapy to a goal factor activity level of 100% before invasive procedures. ^[7]
  • Avoid antithrombotic agents except for critical indications. ^[10]
• Pain control
  • Acetaminophen and opioids are preferred.
  • Avoid NSAIDs. ^[2]
• Joint and muscle bleeds
  • Manage according to the POLICE principles in addition to factor replacement therapy.
  • Refer to physiotherapy for supervised gradual reinitiation of physical activity.

Disposition ^[6][7]

• Hospital admission: Consider for any significant bleeding.
• Transfer: Consider if local hemophilia expertise is not available; initiate factor replacement therapy before transport.

Emergency factor replacement therapy

Emergency factor replacement therapy is used on demand to treat or prevent bleeding.

Indications ^[2][7]

• Suspected musculoskeletal or soft tissue bleeding, including severe pain or swelling at any location
• Any significant head and neck injury or bleeding
• Any new or atypical headache, especially following head injury
• Traumatic injuries or any trauma with potential for internal bleeding
• Heavy or persistent bleeding from any site
• Any wounds requiring closure
• Any invasive procedure (e.g., arterial stick, lumbar puncture, surgery)

Agents and initial dosing

• Hemophilia A without inhibitors
  • Major bleeding or invasive procedure: high-dose replacement with recombinant or plasma-derived factor VIII concentrate (off-label) ^[6][7][8]
  • Minor bleeding: low-dose replacement with recombinant or plasma-derived factor VIII concentrate ^[6][8]
• Hemophilia B without inhibitors
  • Major bleeding or invasive procedure: high-dose replacement with recombinant or plasma-derived factor IX concentrate (off-label) ^[6][7][8]
  • Minor bleeding: low-dose replacement with recombinant or plasma-derived factor IX concentrate (off-label) ^[6][8]
• Hemophilia A or B with inhibitors ^[2]
  • Urgent discussion with hematology is advised if feasible because treatment decisions may be complicated.
  • For limb-threatening or life-threatening bleeding, consider immediate treatment with a bypass agent.
    • Options: recombinant factor VIIa (RFVIIa) or activated prothrombin complex concentrate (aPCC) ^[6][7][8]
    • Patients receiving emicizumab: RFVIIa is preferred to aPCC, which increases the risk of thrombosis or thrombotic microangiopathy.
    • Patients with hemophilia B: RFVIIa is preferred because of the high risk of anaphylactic reaction to aPCC.

Closely monitor patients with hemophilia B with inhibitor during administration of factor IX concentrate (e.g., in aPCC), as anaphylactic reactions occur in up to 50% of patients. ^[2]

Additional considerations

• Factor replacement is administered as an IV push over 1–2 minutes.
• In a bleeding emergency, the patient's baseline clotting factor level is assumed to be 0%.
• Peak factor levels are measured 15–30 minutes after administration to assess the rise in factor activity. ^[2]
• Target factor activity levels
  • Minor bleed: 40–50%
  • Major bleed: 80–100%
  • Invasive procedures: 100%
• Subsequent dosing is determined by hematology based on trough and peak factor levels.

When available, follow the patient's individual bleeding management plan and use their own clotting factor product as prescribed by the treating hematologist. ^[7]

Other hemostatic agents

Desmopressin

• Mechanism of action
  • Releases endothelial von Willebrand factor and factor VIII into the circulation
  • Can raise factor VIII activity levels threefold to sixfold
• Indications
  • Alternative to factor replacement therapy in patients with mild hemophilia A if bleeding is non-life-threatening and non-limb threatening
  • Only use in patients with a previously documented hemostatic response to desmopressin.
  • Avoid in children < 2 years of age. ^[2]
• Route of administration and initial dosing
  • IV desmopressin ^[2][7][8]
  • Subcutaneous desmopressin (off-label) ^[2][7][8]
  • Intranasal desmopressin ^[2][7][8]

Desmopressin may cause hyponatremia, hypotension, tachycardia, and/or tachyphylaxis, especially with repeated use; consult hematology for repeat dosing. ^[2]

Antifibrinolytic therapy

• Mechanism of action: promotes clot stabilization by blocking fibrinolysis
• Indications
  • Superficial or mucocutaneous bleeding: Consider alone or in addition to emergency factor replacement therapy. ^[2]
  • Avoid in patients receiving prothrombin complex concentrates because of the increased risk of thromboembolism. ^[2]
  • Avoid in patients with hematuria because of the increased risk of obstructive uropathy. ^[2]
• Agents and initial dosing
  • Tranexamic acid
    • Oral tranexamic acid (off-label) ^[2][8]
    • IV tranexamic acid (off-label) ^[2][8]
    • Tranexamic acid oral rinse
  • Aminocaproic acid
    • Oral aminocaproic acid (off-label) ^[2][8]
    • IV aminocaproic acid ^[2][8]
    • Aminocaproic acid oral rinse

Consult hematology for continued management, as repeat dosing of antifibrinolytic agents is often required due to their short half-life. ^[2]

See "Diagnostic workup of suspected bleeding disorders" for details on comprehensive evaluation.

Diagnostics in patients with known hemophilia and bleeding ^[2][7][8]

Do not delay factor replacement therapy to obtain diagnostics. ^[7]

• Laboratory studies
  • CBC, type and cross
  • Coagulation studies
    • Not routinely indicated unless requested by the treating hematologist
    • PT, aPTT, factor levels ^[2]
• Imaging studies: Consider after initial treatment and stabilization to evaluate suspected bleeding sites.

Diagnosis of hemophilia

Screening ^[2][5]

• Indications
  • Family history of hemophilia or unexplained bleeding affecting siblings or maternal male relatives
  • Bruising tendency
  • Spontaneous bleeding
  • Excessive bleeding after trauma or medical procedures
• Testing
  • Platelet count: normal
  • Prothrombin time: normal
  • aPTT: typically prolonged
  • Mixing study: Prolonged aPTT is typically corrected. ^[11]

Maintain a low threshold to screen for hemophilia, as over half of individuals with newly diagnosed severe hemophilia have no known family history. ^[2]

A normal aPTT does not rule out mild hemophilia. ^[2]

Confirmatory testing ^[2][5]

• Indications
  • Prolonged aPTT that is corrected with a mixing study
  • Strong clinical suspicion (e.g., based on family history) despite a normal aPTT
• Testing: : confirmation of low factor activity level by quantitative assessment (e.g., factor VIII, factor IX assays)

Obtain von Willebrand factor antigen levels and activity testing in all patients with low factor VIII to rule out von Willebrand disease. ^[2]

Genetic testing ^[2][5]

Testing for hemophilia genetic variants is indicated for all of the following people:

• Individuals with hemophilia
• Obligate carriers and potential carriers
• Female individuals with low levels of factor VIII or factor IX

Beyond establishing carrier status, genetic testing and variant analysis help predict disease severity and the development of clotting factor inhibitors. ^[5]

Testing for clotting factor inhibitors ^[2][5][12]

Clotting factor inhibitors are tested in patients with an established diagnosis of hemophilia to assess for the development of hemophilia with inhibitors.

• Indications
  • Routine screening every 6–12 months after initiation of factor replacement therapy
  • Inadequate clinical or laboratory response to factor replacement therapy
  • Prior to surgery
  • After treatment with factor concentrate for more than 5 days
  • Allergic or anaphylactic response to factor IX concentrate
• Testing: antibody titer quantification

Long-term care of patients with hemophilia is guided by specialists, and is centered around preventing complications.

• Expert care: management in a hemophilia treatment center or by a hematologist with hemophilia expertise
• Prophylactic factor replacement therapy ^[2][13]
  • Severe hemophilia, moderate hemophilia, or life-threatening bleed: continuous prophylaxis
  • Mild hemophilia: episodic prophylaxis as needed (e.g., trauma or surgery)
• Emicizumab
  • Description: a humanized monoclonal bispecific antibody
  • Therapeutic use: bleeding prophylaxis in hemophilia A
  • Mechanism of action: replaces the action of the deficient factor VIIIa by bridging activated factor IX and factor X → activation of factor X → restoration of the clotting cascade ^[5]
• Gene therapy: may be considered with specialist guidance ^[15]