Introduction

What is hemophilia?

Hemophilia is an inherited disorder in which there is an inability to form an effective clot and hence causes prolonged bleeding in a patient. It is seen exclusively in males. A person with hemophilia does not bleed faster, only longer.

How common is hemophilia?

Hemophilia affects approximately 1 in 5,000 live male births.

How does Hemophilia occur?

The normal clotting system consists of

Vascular Spasm

Platelet plug formation

Coagulation: Fibrin production

The normal coagulation of blood depends on the following clotting factors:
The factor I - Fibrinogen

Factor II - Prothrombin

Factor III - Tissue thromboplastin

Factor IV - Calcium ions

Factor - V - Labile Factor

Factor - VII - Stable Factor

Factor VIII - Antihemophilic Factor

Factor IX - Christmas Factor

Factor X - Stuart-Prower Factor

Factor XI - Plasma Thromboplastin Antecedent (PTA)

Factor XII - Hageman Factor

Factor XIII - Fibrin stabilizing factor

The coagulation cascade consists of two pathways - the intrinsic and extrinsic pathways. It is the deficiency of factor VIII or IX in the intrinsic pathway that causes hemophilia.

Presentation

Hemophilia is divided into severe, moderate, and mild diseases depending on the level of functional factor VIII or factor IX. (normal levels are between 50% and 150%)

Mild hemophilia patients (factor levels >5% and <50%) bleed only after injury, invasive procedure, or surgery. Carriers of hemophilia are also sometimes found to have factor levels in the Mild range.

Moderate hemophiliacs (factor levels - 2to5%) experience more bleeds, about once a month, usually after trauma, surgery, or extreme exertion. They usually bleed in the muscles and joints. Once bleeding occurs in a particular area, these patients may continue to have bleeding episodes in those areas.

Severe hemophiliacs (factor level<1%) bleed spontaneously usually in joints, muscles, and soft tissues.

Joint and muscle bleeding may cause pain, tingling, heat, swelling, limited range of motion, etc. It commonly occurs in the ankles, elbows and knees but can also affect any joint in the body.

Rarely, bleeding can occur in mucous membranes such as the mouth, tongue, throat, nose, etc. Hematuria may also occur. Central nervous system bleeds such as intracranial or spinal cord bleeds are life-threatening and may present as stiff neck or back, headache, vomiting, confusion, change in behavior, slurred speech, focal deficits or unequal pupils. Other sites where major bleeds may occur is neck, throat, eye, GI system, hip, testes, retroperitoneum, and following severe injury.

Hemophilia Inheritance

There are two types of hemophilia - Hemophilia A and Hemophilia B. Hemophilia A results from deficiency or abnormality of factor VIII. Hemophilia B results from deficiency or abnormality of factor IX. Both are inherited as a sex-linked recessive disorder as the genes responsible for factor VIII & IX are located on the X chromosome. Females are usually carriers as they have two X-chromosome and can pass on the defective gene to her offspring. In a rare event, if the female inherits two defective genes, then clinical hemophilia may result. Female carriers of hemophilia may be symptomatic due to lower than normal clotting factor levels.

The following permutations-combinations can occur while inheriting hemophilia:-

Normal Mother + Father with hemophilia:
During each pregnancy, the female offspring has a 100% chance of being a carrier and the male offspring is always normal. Hence, the sons of hemophiliac fathers and normal mothers are normal.

Carrier Mother + Normal Father:
During each pregnancy, there is a 25% chance of a normal female, 25% chance of a carrier female, 25% chance of a normal male, and 25% chance of an affected male.

Carrier Mother + Father with hemophilia:
Each pregnancy has a 25% chance of a female carrier, a 25% chance of a female with hemophilia, a 25% chance of a normal male, and a 25% chance of an affected male.

Mother with hemophilia + Father with hemophilia:
During each pregnancy, there is a 50% chance of an affected female and a 50% chance of an affected male (actual occurrence is rare).

Mother with Hemophilia + Normal Father:
During each pregnancy, there is a 50% chance of a carrier female and a 50% chance of an affected male though the actual occurrence is rare.

How Is Hemophilia Diagnosed?

Prolonged PTT (Prothrombin thromboplastin time) with a normal PT (Prothrombin Time) and normal bleeding time is suggestive of hemophilia. It is confirmed by doing the factor assay.

Prenatal Diagnosis

Chorionic villus biopsy at 8 weeks gestation on amniocentesis at 12-14 weeks can be used for prenatal diagnosis by DNA analysis if the mother's carrier state is demonstrated either by mutation analysis or Restriction Fragment Length polymorphism study. If DNA analysis is not available, fetal blood can be aspirated at 18-20 weeks gestation. If pure fetal blood is obtained, factor VIII activity can be assayed. If fetal blood mixed with amniotic fluid is obtained, factor VIII: Ag can be measured.

Carrier Detection

Most carriers have a factor VIII level between 30-70 U/dl. Factor VIII levels should be assayed in all females who might be carriers to identify those with levels below 30 U/dL. These women should be treated the same way as male hemophiliac with similar factor levels.

Assays of factor VIII activity and VWF: Ag can be used to predict whether a given woman is a carrier. If the factor VIII level is below normal, then she is designated as a true carrier. If her factor VIII level is in the normal range, but her VWF: Ag is higher, then she is a true carrier.

When a definite diagnosis of the carrier state can not be made, the probability of being a carrier is calculated from family tree analysis.

Recently, carrier identification can be done by examination of factor VIII gene and DNA analysis and Restriction fragment length polymorphisms

How Is Hemophilia Treated?

Replacement of the deficient factor in the blood is the mainstay of the therapy. Factor concentrates are available in nominal values of 250, 500, and 1000 IU. Factor concentrates available are:

Human factor VIII concentrates - They are plasma-derived Factor VIII concentrates made from pooled plasma from thousands of donors.

Recombinant Factor VIII concentrates - They are made by recombinant technique and also contain albumin.

Porcine Factor VIII concentrates - They are used in patients with inhibitors of Human Factor VIII. They do not transmit Hepatitis or HIV. Recipients may have occasional allergic reactions.

Prothrombin Complex Concentrate (PCC, Factor IX Complex) - It contains a concentrate of Prothrombin, Factor IX, and X. Activated forms of factor VII, IX, and X are also present. PCC is widely used to treat bleeding in patients with inhibitors to factor VIII. It is also in therapy for Hemophilia B. However, it may cause thrombosis and there is a risk of myocardial infarction.

Coagulation Factor IX concentrates - It is the product of choice for patients with Hemophilia B. It is a human plasma-derived factor.

Anti- inhibitor Coagulant complex (AICC) - Used for patients with inhibitors to factor VIII.

Recombinant factor IX concentrate - It is still in clinical trial.

Cryoprecipitate - One bag consists of 80 U of factor VIII and VWF & 200-300 mg of fibrinogen. However, factor VIII content varies from bag to bag and no infant should be treated with less than 2-3 bags. It is used to treat Von-Willebrand disease, Hemophilia A, or fibrinogen deficiencies if there is no alternative.

Other agents used to increase the factor levels in the blood are:
Desmopressin (DDAVP) - It is a synthetic analog of natural vasopressin, which causes immediate release of factor VIII, von-Willebrand Factor, and Plasminogen activator from endothelial cells. It is given intravenously in a dose of 0.3 mg/kg diluted in 50 ml saline and infused over 15-30 minutes. The drug can also be injected into the subcutaneous tissue. The intranasal spray is also now available. It is the treatment of choice for mild Hemophilia A or types 1 VWD. Its side-effects are mild and transient and include facial flushing during the infusion, light-heartedness, etc. It does not cause water retention.

Estrogen-Progesterone - In high doses (10 mg/day), they may raise plasma levels of factor VIII and IX after several weeks and also reduce endometrial proliferation. They are given to women with VWD/factor VIII or IX deficiency to treat menorrhagia or to raise factor levels before surgery.

Various Treatment Regimes

Demand therapy - Infusion of a factor at the time of a bleed.

Prophylaxis - Instead of receiving the factor on demand, the patient receives infusions at regular intervals to maintain a functional level of factor in the blood at all times.

Continuous infusion - It is usually given before or after elective surgery or after major trauma.

Choice of Treatment:

A] Hemophilia A without inhibitor:

For primary prophylaxis - It is given in young children with severe hemophilia who do not have joint damage. It is given as a dose of 20 U/kg three times a week to keep the trough plasma level above 1 U/dl. If prophylaxis is initiated after some joint damage has occurred, higher or more frequent doses may be needed to prevent bleeding.

Demand therapy - It is usually not necessary to raise the factor levels to 100% except in cases of major trauma, head bleeds, or surgery. There is little risk of clinical harm by giving moderately excessive dosage, however, less than the correct dose may fail to stop the bleed. For every unit/kg of plasma-derived or recombinant factor VIII concentrate, the factor VIII levels increase by 2%. Therefore, a 50 U/kg infusion raises the factor VIII level to 100%. Similarly, every unit/kg of plasma-derived factor IX concentrate increases the factor IX level by 1%. Therefore, a 50 U/kg infusion raises the factor IX level by 50%.

Example - Dosage Calculation for Hemophilia A.

Patient - a 14-year-old boy with a bleed.

Weight - 50 kg.

Goal - To raise Factor VIII level to 30% of normal

Calculate - 50 kg X 30% X 0.5 = 750 Units Total dose.

If bleeding is in a dangerous area, factor VIII may be given intermittently (for eg. half the loading dose every 6-12 hours) or by continuous infusion to maintain a minimum plasma Factor VIII of 30 to 50 U/dl.

For surgical operation, the FVIII level should be maintained near 100 U/dl during the procedure and at a minimum level of about 40-50 U/dl for the next 10-14 days.

The level of FVIII for tooth extraction should be between 20 to 50 U/dl depending on the difficulty of the procedure.

Factor VIII should be 20-40 U/dl to prevent bleeding during vigorous exercise.

B] Hemophilia A with inhibitor:

Hemophiliacs may develop inhibitors to the human-derived factor VIII concentrates. They may be low responders (have inhibitor level <5 Bethesda units, 'BU') or high responders (have inhibitor level>20BU)

Low responders - Hemorrhages can be treated with 2-3 times the normal factor VIII dose. Post-infusion-plasma factor VIII levels should be assayed and if the level is inadequate, more factor VIII is infused.

High responders - They are treated with PCC or AICC in a dose of 75-100 U/kg, repeated once or twice at 8-12 hour interval if needed. Most inhibitors respond better to porcine FVIII. Porcine FVIII is usually the treatment of choice for serious hemorrhages in high responders.

Eradication of an inhibitor is the most effective treatment. Immune tolerance can be induced by a daily infusion of 50 to 300 FVIII U/kg for a few months. Inhibitor levels peak in the first month or two, then fall abruptly and eventually become undetectable. Immune tolerance can be maintained by giving a low dose of FVIII every few days.

C] Hemophilia B:

Primary Prophylaxis - Factor IX concentrate in a dose of 40 U/kg given twice weekly to maintain to a trough level of 10/dL of factor IX level in plasma is useful. More frequent doses may be needed in patients with pre-existing joint damage.

Demand therapy- is similar to Hemophilia A. However, since the half-life of factor VIII concentrate is longer, it has to be given less frequently.

General Measures

Newborns with hemophilia rarely bleeding. If bleeding occurs, it may be in the CNS or sub-general region. Vacuum extraction is contra-indicated. If the fetus is large or if labor is difficult, the Caesarian section should be considered. Newborns with hemophilia should not be circumcised. Femoral or jugular venipuncture should not be attempted. Venipuncture in superficial veins can be done. Also, routine intramuscular injections may be given. Immunization against Hepatitis A and B is also advisable.

For babies with hemophilia, the home environment should be protected. The floor should be carpeted. Trouser and long-sleeved shirts should be padded internally at the levels of the knees and elbows to protect from falls and bumps.

For children, contact sports should be avoided. Good dental care should be advised. Physical exercise is advised as strong muscles support joints and may prevent profuse bleeding.

Gene Therapy

Gene therapy for hemophilia A and B is being tried in animal studies. Gene therapy does not change the patent's genotype or his likelihood to transmit the disorder to his offspring.

Other Complications

Most hemophiliacs treated with concentrates before 1986 have been tested to be HIV positive. Factor concentrates are now subjected to screening and viral inactivation to eliminate HIV transmission. With proper viral inactivation methods, the risk of Hepatitis B and C has already decreased. Immunization with the Hepatitis B vaccine has eliminated the risk of hepatitis B.

Joint Protection In Hemophiliacs

In hemophiliacs, joint bleeding and re-bleeding are common. Bleeding into joints causes inflammation of the synovium. With repeated hemorrhages, chronic synovitis may ensue leading to the proliferation of the inflamed vascular synovial membrane causing rebleeding. Thus, a vicious cycle is created. Cartilage is gradually destroyed and bone is reabsorbed causing degenerative arthritis. Joint bleeding during growing years may cause excess growth at the ends of long bones leading to limb-length discrepancies. Hemorrhage into muscles may lead to atrophy and contracture.

Chronic synovitis - It presents with effusion commonly in the knee causing a swollen, boggy, and warm joint. Concentrate prophylaxis for 2-4 weeks plus 1-2 weeks course of oral prednisone (0.5 mg/kg/d) should be tried. While concentrate is being given, the strength of the adjacent muscles should be improved with isometric and other exercises. Posterior splints should be worn at night to avoid injury during sleep.

It the above measures fail, synovectomy should be considered.

Flexion contractures - it is commonly seen at the elbow and the knee. At the elbow, an enlarged radial head often impedes forearm rotation. Excision of the radial head may prove to be beneficial. Knee flexion contractures can be treated with cylinder casts around the thigh and calf.

Degenerative Arthritis - It is seen adults with severe hemophilia. They benefit from the use of NSAIDS and weight reduction. If chronic disabling pain persists in the shoulder, ankle, or subtalar joint, joint fusion may give relief. Prosthetic knee, hip, or shoulder replacement may be useful.