HAEMOPHILIA

HAEMOPHILIA

THE WORLD HAEMOPHILIA DAY--- 17 APRIL

Hemophilia A—Factor VIII Deficiency

Hemophilia A is the most common hereditary cause of serious bleeding. It is an X-linked recessive disorder caused by reduced factor VIII activity. It primarily affects males. Much less commonly excessive bleeding occurs in heterozygous females, presumably due to preferential inactivation of the X chromosome carrying the normal factor VIII gene (unfavorable lyonization). Approximately 30% of cases are caused by new mutations; in the remainder, there is a positive family history. Severe hemophilia A is observed in people with marked deficiencies of factor VIII (activity levels less than 1% of normal). Milder deficiencies may only become apparent when other predisposing conditions, such as trauma, are also present. The varying degrees of factor VIII deficiency are explained by the existence of many different causative mutations. As in the thalassemias, several types of genetic lesions (e.g., deletions, inversions,splice junction mutations) have been identified. In about 10% of patients, the factor VIII concentration is normal by immunoassay, but the coagulant activity is low because of a mutation in factor VIII that causes a loss of function. In symptomatic cases there is a tendency toward easy bruising and massive hemorrhage after trauma or operative procedures. In addition, “spontaneous” hemorrhages frequently are encountered in tissues that normally are subject to mechanical stress, particularly the joints, where recurrent bleeds (hemarthroses) lead to progressive deformities that can be crippling. Petechiae are characteristically absent. Specific assays for factor VIII are used to confirm the diagnosis of hemophilia A. Typically, patients with hemophilia A have a prolonged PTT that is corrected by mixing the patient’s plasma with normal plasma. Specific factor assays are then used to confirm the deficiency of factor VIII. In approximately 15% of those with severe hemophilia A replacement therapy is complicated by the development of neutralizing antibodies against factor VIII, probably because factor VIII is seen by the immune system as a “foreign” antigen. In these persons, the PTT fails to correct in mixing studies. Hemophilia A is treated with factor VIII infusions. Historically, factor VIII was prepared from human plasma, carrying with it the risk of transmission of viral diseases. Before 1985 thousands of hemophiliacs received factor VIII preparations contaminated with HIV. Subsequently, many became seropositive and developed AIDS. The availability and widespread use of recombinant factor VIII and more highly purified factor VIII concentrates have now eliminated the infectious risk of factor VIII replacement therapy.

Hemophilia B—Factor IX Deficiency

Severe factor IX deficiency is an X-linked disorder that is indistinguishable clinically from hemophilia A but much less common. The PTT is prolonged. The diagnosis is made using specific assays of factor IX. It is treated by infusion of recombinant factor IX. It is clinically similar to hemophilia A.The severity of symptoms can vary. Bleeding is the main symptom. It is often first seen when the an infant is circumcised. Other bleeding problems usually show up when the infant starts crawling and walking. Mild cases may go unnoticed until later in life. Symptoms may first occur after surgery or injury. Internal bleeding may occur anywhere.

Symptoms can include:

• Bleeding into joints with associated pain and swelling
• Blood in urine or stool
• Bruising
• Gastrointestinal tract and urinary tract hemorrhage
• Nosebleeds
• Prolonged bleeding from cuts, tooth extraction, and surgery
• Spontaneous Bleeding

MNEMONICS:-

Hemophilia C- Factor XI deficiency

Low levels of factor XI (FXI) cause hemophilia C. FXI plays an important role in tissue factor-dependent thrombin generation on the surface of activated platelets.The formation of the initiating complex, TF-FVIIa-FXa, results in the generation of a small amount of thrombin. This is insufficient to produce a stable fibrin clot but stimulates a number of reactions in the amplification loop, including the activation of FXI. Subsequent formation of the tenase complex (FIXa-FVIIIa), followed by the prothrombinase complex (FXa-FVa), leads to a large burst of thrombin. For a schematic of these processes, Hemophilia C is also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome. Like the other hemophilias, hemophilia C is associated with bleeding, but it differs from hemophilia A and B in some ways.