Hemophilia A
Hemophilia A is a bleeding disorder caused by Factor VIII deficiency. Characteristic laboratory findings include prolonged aPTT, normal PT, and normal fibrinogen. The prolonged aPTT is due to the Factor VIII deficiency. One unit of Factor VIII activity is defined as the Factor VIII content of 1 mL of fresh, citrated, pooled, normal plasma. Disease severity correlates with factor VIII activity. Patients with factor VIII levels less than 1% are classified as severe, 1-5% as moderate and >5% as mild hemophilia A.
Treatment Guidelines
Desmopressin (1-deamino-8-d-arginine vasopressin, DDAVP) results in a transient fourfold increase in plasma Factor VIII levels by stimulating the release of Factor VIII and vonWillebrand’s factor from storage sites. Most mild hemophiliacs with factor VIII levels greater than 8% will respond to DDAVP. Therefore, it provides an alternative therapy for minor bleeding in most patients with mild hemophilia A. DDAVP is administered either intranasally or intravenously.. Repeat doses can be given at 12 to 24 hour intervals, but 2-3 consecutive daily doses may cause side effects.
Patients with moderate or severe hemophilia A usually require treatment with Factor VIII concentrate. The patient’s Factor VIII level should be measured prior to the loading dose to calculate dosage and after the loading dose to determine adequacy of the dose. Trough levels should be measured prior to each maintenance dose. Doses are usually scheduled at 12- hour intervals because the circulating half-life of Factor VIII is 8 to 12 hours. One unit of infused Factor VIII should raise the plasma level by approximately 2%. The following formula is used to calculate Factor VIII dosage:
# Factor VIII Units = wt(kg) x desired % increase
2
When bleeding is severe, the appropriate loading dose of Factor VIII concentrate is 50 units/kg, which should result in a factor level of 80 –100%. Control of serious bleeding requires hospitalization and factor VIII boluses every 8 to 12 hours to maintain trough levels above 50%. A plasma level of 30-50% is usually sufficient for less severe bleeding. One to three doses are usually sufficient to control mild bleeding, prevent secondary hemorrhage, and initiate tissue healing.The following general treatment recommendations are for individuals without Factor VIII inhibitors.
Factor VIII Dosing Recommendations
|
Bleeding Site |
Loading Dose Units/Kg |
Desired Plasma FVIII Level % |
Maintenance Dose—Units/Kg |
|
Oral mucosa |
20 |
30-50 |
20 q 12 hours |
|
Epistaxis |
40-50 |
80-100 initial, then 30 |
30-40 |
|
Joint |
20-40 |
30-50 |
20 q 12 hours |
|
Muscle |
20-30 |
>50 |
20 q 12 hours |
|
CSN |
50 |
100 initial, then 50-100 |
25 q 12 hours |
|
Abdominal pain |
20-40 |
>50 |
20-40 q 12 hours |
|
Gastrointestinal |
40-50 |
100 initial, then 30 |
30-40 q 12 hours |
|
Genitourinary |
40-50 |
100 initial, then 30 |
30-40 q 12 hours |
|
Neck hemorrhage |
50 |
100 |
25-30 q 12 hours |
|
Major trauma |
50 |
100 initial, then 50 |
25-30 q 12 hours |
|
Surgery prophylaxis |
50 |
100 initial, then 50 |
25-30 q 12 hours |
|
Dental procedure |
20 |
30-50 |
20 q 12 hours |
Inhibitors to Factor VIII
Approximately 20-30% of patients with severe hemophilia A develop antibodies to Factor VIII that neutralize or inhibit coagulant activity, making replacement therapy ineffective. These antibodies are referred to as inhibitors and occur almost exclusively in patient with severe hemophilia A. The presence of an inhibitor does not increase the frequency of bleeding, but does increase morbidity and mortality, including less well controlled hemorrhage, more joint damage, and increased hospitalization. The strength of an inhibitor is measured with the Bethesda assay which determines the dilution of patient plasma that decreases normal plasma Factor VIII activity by 50%. The result is expressed as Bethesda units and classified as low (<10 BU), intermediate (10-20 BU), and high (>20 BU) titers.
Treatment of Patients with Inhibitors
Treatment of bleeding in patients with inhibitors is challenging. One reatment strategy involves bypassing Factor VIII in the coagulation cascade. Recombinant Factor VIIa (NovoSeven) received FDA approval and became commercially available in 1999. NovoSeven is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX. Recombinant Factor VIIa is supplied in three sizes: 1200 ?g/vial, 2400 ?g/vial and 4800 ?g/vial The recommended dose is 90 ?g/kg by IV bolus given every two hours for 24 hours or until hemostasis is achieved. Once the patient is stabilized, the interval between treatments can be lengthened to 3-6 hours. This dosage schedule can be used for patients undergoing major surgery or treatment of serious CNS, intraperitoneal, retroperitoneal, or intramuscular bleeding. The goal of therapy should be to increase peak levels of FVII functional clotting activity (FVII: C) measured immediately after the initial dose, to above 30% and preferably between 60 and 90 %. The protime shortens significantly and often plateaus around 7 seconds; the aPTT may shorten as much as 15 to 20, but usually does not completely normalize.
