Hemophilia is the most common inherited bleeding disorder. Conventionally, hemophilia refers to deficiencies of the coagulation proteins, factor VIII (FVIII) and factor IX (FIX).
• FVIII deficiency is known as hemophilia A or classic hemophilia.
• FIX deficiency is known as hemophilia B or Christmas disease.
Both FVIII and FIX are synthesized in the liver. They participate in the intrinsic pathway of blood coagulation. The primary function of the intrinsic pathway is to amplify thrombin generation and facilitate formation of a strong fibrin clot at the site of vascular injury and arrest the bleeding
FVIII circulates in plasma non – covalently bound to von Willebrand factor (VWF). Upon activation by thrombin, it dissociates from VWF and acts as a cofactor for FIXa to activate factor X (FX) to FXa. The assembly of FVIIIa, FIXa and FX on the phospholipid surface constitutes the intrinsic tenase complex.
FXa generated from the intrinsic tenase complex is critical for amplifying the conversion of prothrombin to thrombin in the presence of its cofactor, factor Va, within the prothrombinase complex.
Deficiency of FVIII or FIX leads to a significant reduction in thrombin generation resulting in reduced fibrin clot formation that manifests as severe bleeding even after minor trauma and an increased tendency to re – bleed during physiologic clotlysis.
The genes for both factor VIII ( F8 ) and factor IX ( F9 ) are located near the terminus of the long arm of the X – chromosome, Xq28 and Xq27.1 respectively. F8 gene is 186 Kb and consists of 26 exons while F9 spans 33 Kb and contains 8 exons. The type of mutations within the F8 or F9 gene predicts the disease severity. Typically deletions, insertions and nonsense mutations result in severe disease while missense mutations are more often found in mild to moderate disease.
Hemophilia A and B are transmitted as X – linked recessive disorders, hence males are typically affected and females are carriers of the disease. All the daughters of an affected male are “obligate carriers” of hemophilia while all his sons are unaffected. A carrier female has a 50% risk of transmitting her affected X – chromosome with each pregnancy; therefore half of her sons can be affected with hemophilia and half of her daughters can be carriers of hemophilia.
Hemophilia is classified as mild, moderate and severe on the basis of the patient’s residual FVIII and FIX blood concentrations (1 IU/dL = 1%).
• Severe hemophilia: less than 1%.
• Moderate hemophilia: greater than or equal 1 to 5%.
• Mild hemophilia: greater than or equal 6 – 40 %.
Principles of management of hemophilia
1. Primary prophylaxis: The regular and long – term administration of clotting factor concentrates in order to prevent bleeding. It is typically started before the age of 2 years and after no more than one joint bleed.
2. Secondary prophylaxis: Regular continuous (long – term) treatment started after two or more joint bleeds or at an age above 2 year.
3. Episodic prophylaxis: Regular infusion of factor concentrates for a short period of time related to activity, follow up after an injury or a procedure.
4. On – demand therapy: Infusion of factor concentrates during an episode of an acute bleed.
■ Minor bleeding episodes: it is recommended to raise the factor level up to 30 to 50%. Usually one or two doses are enough to control minor bleeding events.
■ Major bleeding episodes (e.g., CNS bleeds): factor levels should be raised up to 80 to 100% until the bleeding is arrested. Subsequent maintenance of hemostatic levels will depend upon the severity of bleeding episode and its response to treatment and may be achieved by continued bolus injections or a continuous infusion.
Desmopressin (DDAVP) is a synthetic peptide that causes release of VWF from storage sites within endothelial cells. DDAVP also results in a parallel increase in plasma FVIII levels. This agent is particularly useful in patients with mild hemophilia and may obviate the need for factor replacement therapy with minor bleeds such as epistaxis or gum bleeding.
Other adjuvant therapies such as antifibrinolytic medications (aminocaproic acid and tranexamic acid) and topical hemostatic agents (thrombin, fibrin sealant) may also be used even in severe hemophilia along with specific factor replacement therapy.