What is the primary treatment for a patient with Factor VIII (8) deficiency?

Treatment of Factor VIII Deficiency (Hemophilia A)

The primary treatment for Factor VIII deficiency is replacement therapy with Factor VIII concentrates—either plasma-derived or recombinant (standard or extended half-life)—administered episodically for bleeding episodes or prophylactically to prevent spontaneous bleeding, with the choice depending on disease severity and inhibitor status. 1

Treatment Algorithm Based on Clinical Scenario

For Congenital Hemophilia A Without Inhibitors

Factor VIII replacement is the cornerstone of therapy:

• Plasma-derived FVIII concentrates or recombinant FVIII concentrates (including standard half-life and extended half-life formulations) are the primary treatment options 1
• These concentrates can be manufactured from human plasma (plasma-derived) or using mammalian cell culture systems (recombinant), with extended half-life molecules modified for improved pharmacokinetics 1
• Prophylactic replacement is recommended for severe hemophilia (FVIII <1 IU/dL) to prevent spontaneous joint and muscle bleeding that occurs without prophylaxis 1
• Episodic (on-demand) treatment can be used for bleeding episodes in patients not on prophylaxis or for breakthrough bleeding 1

For mild hemophilia A with minor bleeding:

• Desmopressin (DDAVP) 0.3 mcg/kg may be used for minor bleeding episodes in patients with mild hemophilia A who have very low inhibitor titers (<5 BU), but only after confirming response with a prior test dose 2
• DDAVP should not be used for massive bleeding as it is ineffective in this setting 2
• Fluid restriction is essential when using DDAVP to prevent hyponatremia, particularly in elderly patients 2

For Hemophilia A With Inhibitors (Neutralizing Antibodies)

The treatment approach changes fundamentally when inhibitors develop (cumulative incidence 20-35% in severe hemophilia A) 1:

First-line bypassing agents:

• Recombinant activated Factor VII (rFVIIa) 90 μg/kg every 2-3 hours until hemostasis is achieved 1
• Activated prothrombin complex concentrates (aPCCs) 50-100 IU/kg every 8-12 hours to a maximum of 200 IU/kg/day 1
• These bypassing agents are used when bleeding does not respond to replacement of the deficient factor 1
• rFVIIa demonstrates 86-100% efficacy as first-line therapy for moderate to severe bleeding episodes requiring immediate hemostatic control 2

Alternative approaches when bypassing therapy unavailable:

• Recombinant or plasma-derived human FVIII concentrates or desmopressin may be considered only if bypassing therapy is unavailable 1
• Alternative treatment strategies should be considered after failure of appropriate first-line treatment 1

Emicizumab as prophylaxis:

• Emicizumab (a bispecific antibody) is approved as an alternative to FVIII concentrates and bypassing agents for prophylactic treatment of patients with severe hemophilia A with and without inhibitors 1
• This represents the first approved non-replacement therapy for hemophilia A 1

Inhibitor eradication:

• Immune tolerance induction (ITI) with regular infusions of FVIII concentrate has been the standard treatment to eradicate FVIII inhibitors for over 30 years 1
• However, ITI is burdensome and unsuccessful in approximately 30% of individuals with hemophilia A with inhibitors 1

For Acquired Hemophilia A (AHA)

This is a distinct entity requiring different management:

Bleeding management:

• Anti-hemorrhagic treatment should be initiated in patients with AHA and active severe bleeding symptoms irrespective of inhibitor titer and residual FVIII activity 1
• rFVIIa or aPCCs are recommended for treatment of severe bleeding in patients with AHA, with rFVIIa showing 86.6% efficacy 1, 2
• rFVIIa is particularly appropriate given the typical elderly population with AHA is vulnerable to DDAVP's adverse effects 2
• DDAVP should only be used when inhibitor titer is very low, bleeding is minor, and no bypassing agent is available 2
• Prophylactic use of bypassing agents is recommended prior to minor or major invasive procedures 1

Inhibitor eradication:

• All patients diagnosed with AHA should receive immunosuppressive therapy immediately following diagnosis 1
• Corticosteroids alone (1 mg/kg/day PO for 4-6 weeks) or in combination with cyclophosphamide (1.5-2 mg/kg/day for maximum six weeks) are recommended as first-line therapy 1
• Rituximab is suggested as second-line therapy if first-line immunosuppressive therapy fails or is contraindicated 1

Critical Pitfalls to Avoid

Do not combine rFVIIa with aPCC except for life- or limb-threatening bleeds due to thrombotic risk 2

Do not rely on DDAVP without a prior test dose to confirm response, as efficacy is unpredictable 2

Do not use tranexamic acid as monotherapy when hemostatic thresholds must be met (factor levels ≥50 IU/dL required for major surgery or neuraxial procedures); it only inhibits fibrinolysis and does not raise factor levels 2

Monitor for inhibitor development as this fundamentally changes treatment strategy, with main risk factors being hemophilia severity, F8 genotype, and cumulative exposure to FVIII concentrates 1

Adjunctive Therapy

Tranexamic acid can be used as adjunctive therapy to desmopressin or factor concentrates for minor surgical procedures, but cannot be used as sole therapy for moderate-to-severe bleeding requiring immediate hemostatic control 2