Site of bleed
Level desired (%)
Hemophilia A (rFVIII) (U/kg)
Hemophilia B (rFIX) (U/kg)
Oral mucosa
>30
20
40
Epistaxis
>30
20
40
Joint or muscle
>50
30
50
Gastrointestinal
>50
30
50
Genitourinary
>50
50
75
Central nervous system
>100
75
125
Trauma or surgery
>100
75
125
How Much FVIII and FIX Is Present in Fresh Frozen Plasma, Cryoprecipitate, and Prothrombin Complex Concentrate [PCC]? How Is Factor VIII or FIX Replenished?
Fresh frozen plasma (FFP) typically contains 0.7–0.9 U/ml of FVIII clotting activity [11]. FVIII is most labile, and its activity falls by approximately 40% in 5 days after thawing [12]. Cryoprecipitate contains 5–13 U/ml of FVIII clotting activity. Generally, cryoprecipitate is only be used to treat Hemophilia A when Factor VIII concentrate is unavailable. Cryoprecipitate also contains vWF, Factor XIII, and fibrinogen [11]. Cryoprecipitate does not contain FIX, thus should not be used to treat hemophilia B. On the other hand, three and four factor prothrombin complex concentrate (PCC) have 20–30 IU/ml of FIX, but do not contain factor VIII, thus should not be used to treat hemophilia A [12].
A typical bleeding episode is treated with FVIII replacement therapy especially if it is within 2 h of the injury. Spontaneous bleeding is typically controlled if FVIII levels are raised to >50% of normal levels. However, for major surgery, spontaneous bleeding in critical sites (enclosed spaces, central nervous system) or severe posttraumatic bleeding, FVIII levels need to be elevated to 100%, (or >125% for FIX, see Table 42.1) and normal levels are maintained until healing occurs. After a major bleed or surgery, FVIII levels need to be maintained for 10–14 days. This can be achieved by bolus dosing or infusion. A bolus dose that achieves 100% of the desired level, then is followed by half the initial dose every 8–12 h, with close monitoring of the factor levels, with the aim of keeping the factor levels above 50% in the postoperative period. Alternatively, replacement therapy is administered by continuous infusion at the rate of 3 U/kg/h after an initial bolus dose [1].
Administration of 1 U/kg of FVIII should increase the plasma concentration by 2% relative to the normal level. Similarly, administration of 1 U/kg of FIX should increase its concentration by 1%. Therefore, in patients with severe hemophilia A, to achieve a desired level 100% of normal, FVIII should be administered at 50 U/kg. The desired concentration of FVIII and FIX in different clinical situations is shown in Table 42.1.
What Is the Half-Life of FVIII? FIX?
All plasma-derived factors have similar pharmacokinetics. The half-life of FVIII is the shortest. The half-life of FVIII (recombinant or plasma derived) is 12 h, while for FIX is 24 h.
Preoperative Management
What Specific Information Would You Like to Know or Prepare for Before Elective Surgery?
Many patients (30%) with severe hemophilia A, who are treated with FVIII, develop alloantibodies to FVIII at some stage in their lives. It is important to know about the presence of these antibodies, since their presence can render a patient refractory to replacement with exogenous FVIII. Autoantibodies against factor IX are extremely rare [1]. If a patient has a low titer, additional FVIII infusion can potentially overcome the antibody effect temporarily. If a patient has a high titer, administration of rFVIIa may be necessary to control bleeding. This bypasses the defect in the clotting cascade. Before the advent of rFVIIa and aPCC, elective surgery was contraindicated in these patients.
Factor supplementation is required for many days after surgery. It is important to confirm availability of specific factor concentrates, not only for the immediate postoperative period, but also for the period until wound healing is complete [13].
What Other Diseases Should Be Considered in Patients with History of Hemophilia?
Until the late 1980s, the only sources for factor replacement products were FFP or cryoprecipitate. Many hemophilia patients were inadvertently infected with viral diseases like HIV, and hepatitis B and C. Thus, older hemophilia patients are at higher risk for acquired immunodeficiency syndrome (AIDS), chronic hepatitis, cirrhosis, or hepatoma. Liver disease may lead to thrombocytopenia which can exacerbate bleeding episodes [2]. Fortunately, recognition of these potential complications lead to the development of a safer blood product supply chain. Donors are screened and every unit is tested. Protocols for viral inactivation have been developed. Some recombinant replacement products are now available (rFVIII, rFIX, and rFVIIa).
To What Extent Should the Patient’s Coagulation Status Be Corrected Before Surgery?
Excessive bleeding is almost inevitable in patients with severe or moderate hemophilia who undergo surgery. Bleeding causes pain that leads to poor wound healing and increases risk of infection. Correction by administration of specific replacement therapy is mandatory before surgery. With appropriate multidisciplinary management intra- and postoperative hemorrhages can be prevented.
The exact factor level required for hemostasis and the duration of clotting factor replacement after surgery is not known. A calculated dose of the required factor concentrate (FVIII or FIX), which will bring the factor levels to 100% of the normal, should be administered within 10–20 min of starting the procedure. Trough levels should be maintained at 80–100% level for the first 3 days after surgery. Between day 4 and 6, trough level should be between 60 and 80%, and after day 7 it should be maintained at 40–60% range [13].
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