Hemophilia

Hemophilia is the most common, severe inherited bleeding disorder recognized in humans.

A. Overview

Hemophilia A (factor VIII:C deficiency) and hemophilia B (factor IX deficiency) are the two most commonly inherited deficiencies of coagulation proteins, occurring with an annual incidence of approximately 1 per 5000 male births and 1 per 30,000 female births. The mild hemophilia(clotting factor activities >5% of normal) are not associated with spontaneous bleeding and often remain undiagnosed until adulthood, when patients undergo a major surgical procedure.

Although because of the X-linked recessive inheritance of the disease, the significant majority of affected subjects are male, there are also significant numbers of carrier women who manifest clinical symptoms of bleeding because of low clotting factor levels.

Hemophilia A and hemophilia B overwhelmingly affect males, although their mothers or sisters may manifest excessive bruising and bleeding tendencies as carriers if their factor activity levels exceed 50% of normal.

The clinical severity of the hemophiliac patient is inversely proportional to the level of plasma coagulant factor activity.

Hemophilia Clinical Severity

B. Signs and Symptoms

The major signs and symptoms of hemophilia are excessive bleeding and easy bruising.

Excessive bleeding

The extent of bleeding depends on how severe the hemophilia is.
Bleeding can occur on the body’s surface (external bleeding) or inside the body (internal bleeding).

Signs of external bleeding may include:

• Bleeding in the mouth from a cut or bite or from cutting or losing a tooth
• Nosebleeds for no obvious reason
• Heavy bleeding from a minor cut
• Bleeding from a cut that resumes after stopping for a short time

Signs of internal bleeding may include:

• Blood in the urine (from bleeding in the kidneys or bladder)
• Blood in the stool (from bleeding in the intestines or stomach)
• Large bruises (from bleeding into the large muscles of the body)

Bleeding in the Joints

Bleeding in the knees, elbows, or other joints is another common form of internal bleeding in people who have hemophilia. This bleeding can occur without obvious injury.

At first, the bleeding causes tightness in the joint with no real pain or any visible signs of bleeding. The joint then becomes swollen, hot to touch, and painful to bend.

Swelling continues as bleeding continues. Eventually, movement in the joint is temporarily lost. Pain can be severe. Joint bleeding that isn’t treated quickly can damage the joint.

Bleeding in the Brain

Internal bleeding in the brain is a very serious complication of hemophilia. It can happen after a simple bump on the head or a more serious injury. The signs and symptoms of bleeding in the brain include:

• Long-lasting, painful headaches or neck pain or stiffness
• Repeated vomiting
• Sleepiness or changes in behavior
• Sudden weakness or clumsiness of the arms or legs or problems walking
• Double vision
• Convulsions or seizures

C. Laboratory findings
Following tests are abnormal:
Activated partial thromboplastin time (APTT)
Factor VIII clotting assay.
The bleeding and clotting tests are normal.

Carrier detection and antenatal diagnosis

• Till recently, carrier detection and antenatal diagnosis were limited to measuring plasma levels of factor VIII and von willebrand factor.
• Carriers are now better detected with DNA probe. Chorionic biopsies at 8 – 10 weeks’ gestation provide sufficient fetal DNA for analysis.
• Antenatal diagnosis is also possible following demonstration of low levels of factor VIII in fetal blood at 16-20 weeks’ gestation from the umbilical vein by ultrasound guided needle aspiration.

D. Clinical Management

The key aspects of hemophilia management are preventive therapy, treatment of bleeds, and care of the complications of hemophilic bleeding

Factor VIII replacement therapy

In severe haemophilia A, bleeding episodes should be treated by raising the factor VIII level, usually by intravenous infusion of factor VIII concentrate. Factor VIII concentrate is prepared from blood donor plasma. However, factor VIII concentrates prepared by recombinant technology are now widely available and, although more expensive, are perceived as being safer than those derived from human plasma. In addition to treatment ‘on demand’ for bleeding, factor VIII can be administered 2 or 3 times per week as ‘prophylaxis’ to prevent bleeding in severe haemophilia. This is most appropriate in children, but its widespread use is limited by the high cost of factor VIII preparations.

Complications of replacement therapy include:

• Developing antibodies (proteins) that attack the clotting factor
• Developing viral infections from human clotting factors
• Damage to joints, muscles, or other parts of the body resulting from delays in treatment.

One of the most serious complications of hemophilia is development of antibodies(inhibitors) to infused factor VIII which occurs in 5-10 percent of patients. This makes the patient refractory to further replacement therapy so that tremendous doses have to be given to achieve a significant rise in plasma factor VIII activity.

Immunosuppression and immune tolerance regimens have been used in an attempt to eradicate the antibody.

Other Types of Treatment

• Desmopressin: Desmopressin (DDAVP) is a man-made hormone used to treat people who have mild hemophilia A.
• Gene therapy: Various viral vectors (retro-viral, adeno-associated) as well as non-viral vectors are being explored.
  Phase 1 trials have been carried out for both haemophilia A and B.