HEMOPHILIA

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Dr Ira Shah
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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 & 200-300mg 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 analogue 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 50ml saline and infused over 15-30 minutes. The drug can also be injected into the subcutaneous tissue. Intranasal spray is also now available. It is the treatment of choice for mild Hemophilia A or type 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 (10mg /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 correct dose may fail to stop the bleed. For every unit/kg of plasma-derived or recombinant factor VIII concentrate, the factor VIII levels increases 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 50U/kg infusion raises the factor IX level by 50%.

Example - Dosage Calculation for Hemophilia A.
Patient - 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.
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 level is inadequate, more factor VIII is infused.
High responders - They are treated with PCC or AICC in 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 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 low dose of FVIII every few days.

C] Hemophilia B :
Primary Prophylaxis - Factor IX concentrate in a dose of 40U/kg given twice weekly to maintain to 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 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-galeal region. Vacuum extraction is contra-indicated. If fetus is large or if labor is difficult, 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 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 dose not change the patent's genotype or his likelihood to transmit the disorder to his offspring.



Contributor Information and Disclosures Dr Ira Shah
Consultant Pediatrician, B.J.Wadia Hospital for Children, Mumbai, India


First Created : 12/20/2000
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