What is the definition, pathophysiology, signs, symptoms, and management of Hemophilia, including its types, Hemophilia A (Factor VIII deficiency) and Hemophilia B (Factor IX deficiency)?

From the Guidelines

Hemophilia is an inherited bleeding disorder where the blood doesn't clot properly due to a deficiency in specific clotting factors, and management focuses on replacing the missing clotting factors through regular infusions of factor concentrates, either on-demand for bleeding episodes or as prophylaxis to prevent bleeds, with a strong recommendation for prophylaxis over episodic treatment for individuals with severe and moderately severe hemophilia A and B 1.

Pathophysiology

There are three main types of hemophilia: Hemophilia A (the most common) results from factor VIII deficiency, Hemophilia B (Christmas disease) is caused by factor IX deficiency, and Hemophilia C (rare) involves factor XI deficiency. In these conditions, the blood clotting cascade is disrupted, preventing the formation of stable clots after injury.

• Hemophilia A is more common than hemophilia B, accounting for about 80% to 85% of all hemophilia cases 1.
• Hemophilia A and B are classified as severe, moderate, or mild based on factor levels <1 international unit (IU)/dL, 1 to 5 IU/dL, or >5 to 40 IU/dL, respectively 1.

Signs and Symptoms

Symptoms of hemophilia include:

• Prolonged bleeding after injuries or surgery
• Easy bruising
• Spontaneous bleeding into joints and muscles causing pain and swelling
• Blood in urine or stool
• Potentially life-threatening internal bleeding

Management

Prophylaxis with clotting factor concentrates is the mainstay of care for severe hemophilia, and emicizumab is a new therapy approved for prophylaxis of bleeding in individuals with hemophilia A with and without inhibitors 1.

• For mild Hemophilia A, desmopressin (DDAVP) may temporarily increase factor VIII levels.
• Antifibrinolytic medications like tranexamic acid help stabilize clots.
• Newer treatments include extended half-life factor products requiring less frequent infusions.
• Gene therapy shows promise as a potential cure.
• Patients should avoid activities with high bleeding risk, maintain good dental hygiene, and carry medical identification.
• A comprehensive care approach involving hematologists, physical therapists, and other specialists is essential for optimal management.

Recommendations

• Prophylaxis is recommended over episodic treatment for individuals with severe and moderately severe hemophilia A and B 1.
• The choice of prophylaxis agent should be guided by availability, resources, costs, values, and preferences 1.
• Initial prophylaxis with plasma-derived FVIII is suggested over standard half-life recombinant FVIII for previously untreated individuals with severe hemophilia A 1.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Definition and Pathophysiology

• Hemophilia A and hemophilia B are rare congenital, recessive X-linked disorders caused by a lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively 2.
• The severity of the disease depends on the reduction of coagulation FVIII or FIX activity levels, which is determined by the type of the pathogenic variants in the genes encoding the two factors (F8 and F9, respectively) 2.
• Hemophilia A is caused by a deficiency in factor VIII, while hemophilia B is caused by a deficiency in factor IX.

Signs and Symptoms

• Hemophilia A and B are traditionally considered clinically indistinguishable, but differences in bleeding frequency, clinical scores, use of prophylaxis, and need for orthopedic surgery have been reported 3.
• The bleeding tendency associated with factor IX deficiency may be less severe, with consequent better outcomes in the long term 3.
• The type of factor VIII/IX mutation is a major determinant of the bleeding tendency as well as of the risk of inhibitor formation 3.

Management

• Molecular genetic analysis is widely applied in inherited bleeding disorders and allows genetic counseling of affected families 2.
• Genetic analysis in hemophilia has tremendously improved in the last decades, with many new techniques and modifications as well as analysis software becoming available 2.
• Advances in genetic variant detection strategies facilitate identification of the causal variants in up to 97% of patients, which is important for genetic counseling and interpretation of the clinical presentation of hemophilia patients 2.
• The distinction of various bleeding phenotypes in hemophilia has considerable therapeutic implications, and further research in this field is required to optimize treatment regimens 3.