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2122 Part XII: Hemostasis and Thrombosis Chapter 123: Hemophilia A and Hemophilia B 2123

cryoprecipitate both contain factor VIII and once were the only prod- the patient’s plasma volume (approximately 5 percent of body weight
ucts available for treatment. A disadvantage of plasma is that large vol- in kilograms) and the level to which factor VIII is to be raised. Thus,
umes must be infused to achieve and maintain even minimal factor VIII the plasma volume of a 70 kg adult is approximately equivalent to
levels. The highest factor VIII level that can be achieved with plasma 3500 mL (5 percent × 70 kg = 3.5 kg = 3500 g, approximately equivalent
is approximately 20 percent of normal, which is not always attainable to 3500 mL). To achieve normal factor VIII levels of 1 U/mL (100 percent),
or sufficient for hemostasis. Cryoprecipitate, containing approximately 3500 U of factor VIII should be given. This scenario assumes a 100
80 U of factor VIII in 10 mL of solution, can be used to attain nor- percent recovery of the administered dose. Recovery has approached
mal factor VIII levels, but individual bags of cryoprecipitate must be 100 percent in studies, but depends upon the method of assay and the
pooled; the factor VIII dose can only be estimated; and the product factor VIII standard used for comparison. After the initial dose of
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must be stored frozen. Several commercial lyophilized factor VIII con- factor VIII, further doses of factor VIII are based on a half-life of 8 to
centrates, using cryoprecipitate of pooled normal human plasmas as 12 hours. Thus, after a loading dose of 3500 U of factor VIII, a dose of
starting material (2000 to 20,000 donors), are available and do not have 1750 U could be given in 12 hours. However, for practical purposes, the
the disadvantages of plasma and cryoprecipitate (Table 123–2). Factor dose of factor VIII is based on the knowledge that 1 U of factor VIII
VIII concentrates have been sterilized by heating in solution, by super- per kilogram of body weight raises the circulating factor VIII level by
heating to 80°C after lyophilization, and by exposure to organic sol- approximately 0.02 U/mL. Thus, to raise the factor VIII level to 100 per-
vent-detergents that inactivate lipid-enveloped viruses, including HIV cent, that is, 1 U/mL, the dose of factor VIII required is approximately
and hepatitides B and C viruses, but do not inactivate parvovirus or 50 U per kilogram of body weight, assuming the patient’s baseline factor
hepatitis A. 46,47 Parvovirus infection does not occur frequently in hemo- VIII level is less than 1 percent of normal. The site and severity of hem-
philia A patients because parvovirus is transmitted by cellular elements orrhage determine the frequency and dose of factor VIII to be infused.
of the blood. Nevertheless, seroconversion to B19 parvovirus has been Table 123–3 summarizes the recommended doses of factor VIII
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observed in patients receiving plasma-derived concentrates undergoing for various types of hemorrhage. These doses are not based on rigor-
solvent-detergent extraction or pasteurization. ous randomized studies, and recommendations vary among hemophilia
Some of these products contain significant amounts of VWF (see centers. Given the high cost of factor VIII, some physicians prefer to use
Table 123–2). Plasma-derived factor VIII concentrates prepared by lower doses.
monoclonal antibody techniques, and subjected to viral inactivation Factor VIII can be given as a constant infusion to hospitalized
techniques, are highly purified and, barring breakdown in manufactur- patients. Following a loading dose to raise factor VIII to the desired
ing procedures, are considered to be safe in terms of transmission of level, 150 to 300 U of factor VIII per hour can be infused. Factor VIII
viral diseases. levels can be conveniently monitored in blood obtained from veins
Factor VIII produced by recombinant DNA techniques is avail- other than the vein into which factor VIII was infused intravenously.
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able, safe, and effective. There are new “third-generation” factor VIII In selected patients, factor VIII can be given outside the hospital in a
products that are manufactured without exposure to animal or human continuous infusion using pump devices. 50
protein. Although all factor VIII products, both recombinant and
plasma-derived, are currently safe and effective, some physicians and DDAVP (Desmopressin)
patients prefer products that are not exposed to human or animal pro- During the 1970s, 1-desamino-8-d-arginine vasopressin (DDAVP;
teins during the manufacturing process. desmopressin) was found to cause a transient increase in factor VIII
The dose of factor VIII can be determined as follows. If 1 U of in normal subjects and in patients with mild to moderate hemophilia.
factor VIII per milliliter of plasma is considered 100 percent of nor- After a dose of DDAVP (0.3 mcg per kilogram body weight), given
mal, the dose required to raise the level to a given value depends upon intravenously or subcutaneously, factor VIII levels increase two- to

TABLE 123–3. Doses of Factor VIII for Treatment of Hemorrhage*
Desired Factor VIII Level Factor VIII Dose (U/kg Frequency of Dose
‡
†
Site of Hemorrhage (% of Normal) Body Weight) (Every No. of Hours) Duration (Days)
Hemarthroses 30–50 ~25 12–24 1–2
Superficial intramuscular 30–50 ~25 12–24 1–2
hematoma
Gastrointestinal tract 50–100 50 12 7–10
Epistaxis 30–50 ~25 12 Until resolved
Oral mucosa 30–50 ~25 12 Until resolved
Hematuria 30–100 ~25–50 12 Until resolved
Central nervous system 50–100 50 12 At least 7–10 days
Retropharyngeal 50–100 50 12 At least 7–10 days
Retroperitoneal 50–100 50 12 At least 7–10 days
*Mild or moderately affected patients may respond to 1-deamino-8-d-arginine vasopressin (DDAVP), which should be used in lieu of blood or
blood products whenever possible.
† Factor VIII may be administered in a continuous infusion if the patient is hospitalized. After initial bolus, approximately 2 to 5 U/kg/h of factor
VIII usually are sufficient in an average-size adult. Bolus doses are given every 12 to 24 hours.
‡ The frequency of dosing and duration of therapy can be adjusted, depending on the severity and duration of the patient’s bleeding episode.

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