Page 2001 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 117 Transfusion Therapy for Coagulation Factor Deficiencies 1775

High-purity factor IX products are produced from plasma using that many of these inhibitors are low titer and transient in nature. 42,43
techniques of ligand affinity or immunoaffinity chromatography and Patients with low-titer, transient inhibitors can be managed with
typically have specific activities greater than 150 IU/mg. Three single increased doses of factor VIII. Inhibitors to factor IX occur less fre-
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high-purity recombinant factor IX products have been licensed in the quently; with an estimated incidence of approximately 1% to 3%.
United States (Alphanine, Grifols; Mononine, CSL Behring; and Patients with factor IX antibodies may have anaphylactic reactions
BeneFIX, Wyeth). Because specific products have different recovery when treated with high-purity products. 90,91
results, consulting the package insert and performing recovery studies Patients with high-titer inhibitors to either factor VIII or factor
are recommended; for example, 1 IU BeneFIX/kg will increase the IX do not usually achieve hemostasis after factor replacement and
circulating activity of factor IX by 0.8 ± 0.2 and 0.7 ± 0.3 IU/dL in thus present a treatment challenge. Treatment of patients who develop
adults and pediatric (younger than 15 years old) patients, respec- inhibitors involves two approaches: (1) acute treatment of bleeding
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tively. Also, the initial dose of BeneFIX should be given under direct episodes and (2) immune tolerance induction therapy, whereby the
medical supervision because the potential for an allergic reaction is patient is treated frequently (often daily) with factor VIII or factor
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significant. Thrombotic complications have not been reported with IX in an effort to suppress the production of inhibitors by the
these high-purity products; some thrombotic events have been associ- immune system (similar to allergic desensitization therapy).
ated with continuous administration, which is not an approved Treatment of acute bleeding episodes can be accomplished by two
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method. In patients with a history of allergy and inhibitors, an methods. For patients with low-titer inhibitors (<5 Bethesda units
irreversible nephrotic syndrome has been reported during immune [BU], a laboratory measurement of inhibitor activity), hemostasis can
tolerance induction. 85 be accomplished with large doses of factor VIII or factor IX (e.g., as
In communities where factor IX concentrates are not available, high as 200 IU/kg given at frequent intervals) in an effort to neutral-
plasma may provide a means of replacing factor IX in hemophilia B ize or “override” the circulating inhibitor. A neutralization approach
patients during bleeding episodes. Each unit of FFP derived from a is usually ineffective for patients with high-titer inhibitors (>5–10
450-mL whole blood collection contains approximately 200 IU of BU) and is expensive because of the large amounts of factor required.
factor IX. Replacement to therapeutic levels of factor IX with FFP is These patients and patients with low-titer inhibitors who fail to
difficult because of the complication of volume overload. In some respond to override therapy can be treated using products that act to
areas, S/D plasma provides a virally inactivated alternative to FFP. “bypass” the inhibitor. The only current bypass agents include acti-
The first long-acting recombinant factor IX product, Alprolix, vated prothrombin complex concentrates (FEIBA, Baxter Bioscience)
Biogen Idec, synthesized in a human embryonic kidney cell line and (aPCC), which contain factors VII, X, and prothrombin in addition
purified by nanofiltration was FDA approved in March 2014. This to factor IX that enhance production of thrombin generation by
factor IX is covalently linked to human immunoglobulin G1; this Fc activating the coagulation pathway at points further down than the
fusion protein has extended the half-life of factor IX: in adults, almost factor VIIIa/factor IXa step. FEIBA is used as first-line treatment of
86.5 hours, 12–17-years old about 83.5 hours, 6–11 years old about bleeding episodes in patients with inhibitors by some treaters even
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72 hours and 2–5 years old almost 66.5 hours. Some patients with though the concentrate is derived from human plasma.
factor IX deficiency may only need factor IX three times a month Recombinant activated factor VII (rFVIIa) (NovoSeven, Novo
with this product. It should be noted that kaolin-based assays may Nordisk) product was licensed in Europe and the United States with
underestimate the factor IX level. 86 an indication for use as a bypass agent in the treatment of inhibitors
in patients with hemophilia A and hemophilia B, as well as for
Other Useful Adjuncts for Treatment of Bleeding in bleeding and perioperative management in Glanzmann thrombasthe-
Hemophilia A and B nia, who are refractory to platelet transfusion. Another recombinant
The antifibrinolytic agents tranexamic acid and ε-aminocaproic acid VII product, AryoSeven (Aryogen), which is biosimilar to NovoSeven
(EACA) (Amicar, Xanodyne Pharmaceuticals) are sometimes used in is available and was shown to be as effective in the management of
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conjunction with clotting factor replacement therapy or DDAVP in acute bleeding episodes. The dose of rFVIIa is 90 µg/kg. Recombi-
the treatment of bleeding that occurs with hemophilia and other nant activated factor VIIa is administered every 2 hours compared
bleeding disorders. These agents interact with the lysine-binding site with every 8–12 hours for PCCs or aPCCs. Thrombosis has also been
of plasminogen and enhance its activation. The more important effect reported with the use of rFVIIa 93,94 and PCCs. 95
of lysine analogs is that their occupancy of this site inhibits binding Despite the success achieved with immune tolerance induction
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of the zymogen, plasminogen, to fibrin, which is necessary for full regimens (80%–90%), “bypass” agents are still needed in patients
fibrinolytic activity. Antifibrinolytics are useful in the setting of undergoing tolerization because an interval potentially as long as 2–3
mucosal bleeding and may substantially reduce the need for clotting years exists between the time that induction is initiated and the
factor concentrates in the setting of oral mucosal bleeding with tooth inhibitor is suppressed. Bleeding episodes that occur before achieve-
extractions. These agents are administered preoperatively and contin- ment of tolerance usually require treatment with one or other of the
ued postoperatively until wound healing occurs. Although tranexamic bypassing agents.
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acid is more potent, it is less readily absorbed when given orally. Recently, Leissinger et al demonstrated in hemophilia A patients
Tranexamic acid is administered at 25 mg/kg orally or 10 mg/kg IV with high-titer inhibitors the superiority of prophylactic thrice-weekly
preoperatively, and therapy can be continued postoperatively using FEIBA (Baxter) at 85 U/kg over on-demand therapy. In a prospec-
oral rinses with a 5% solution. EACA is used at a dose of 100 mg/ tive, randomized, crossover study with a 3-month washout between
kg preoperatively followed by 100 mg/kg every 6 hours either orally the two arms, which were each 6 months, the prophylaxis regimen
or IV (maximum dose, 24 g/day). Dosing of EACA should be prevented progression of joint disease in high-titer inhibitor patients;
reduced in patients with renal insufficiency. and is now recommended for prophylaxis in high-titer inhibitor
patients (see box Treatment of Life-Threatening Bleeding Episodes in
Patients With Inhibitors Against Factor VIII or Factor IX).
INHIBITORS OF FACTOR VIII AND FACTOR IX Treatment of life-threatening bleeds in the context of a high-titer
inhibitor represents a significant challenge. The effect of nonfac-
A major complication in the treatment of patients with hemophilia tor VIII concentrates (bypass agents), when the inhibitor titer is
is the development of inhibitory antibodies against the infused factors greater than 10 BU (precluding the use of factor VIII), is difficult to
that interfere with factor activity. Rarely, antibodies may develop that monitor in the laboratory because plasma factor levels do not reflect
do not affect activity but increase clearance of factor VIII or factor hemostasis. Adjunctive therapies are frequently used in this setting to
IX. The incidence of factor VIII inhibitors is approximately 30%, lower the titer of the antibody to allow for treatment of the patient
and inhibitors typically develop within the first 20 exposures to with factor VIII concentrates. Aggressive regimens are used in which
replacement therapy. 87,88 Well-designed prospective studies of the use circulating antibodies are depleted using plasmapheresis or staphy-
of recombinant factor VIII in previously untreated patients revealed lococcal protein A immunoadsorption, and reduction of antibody