Page 2002 - Hematology_ Basic Principles and Practice ( PDFDrive )

1776 Part XI Transfusion Medicine

parameters. These factors, particularly the subtype of vWD and the
Treatment of Life-Threatening Bleeding Episodes in Patients With
Inhibitors Against Factor VIII or Factor IX patient’s response to DDAVP, influence the recommended treatment
for acute bleeding episodes or for prophylaxis against bleeding.
Concentrates Although the disease had been described in the 1920s, the primary
1. Factor VIII containing concentrates in high doses (as high as defect had earlier been attributed to either platelets or the vessel wall.
150–200 IU/kg) if inhibitor titer is low (<5–10 BU). High-dose An understanding of the missing protein in vWD and its relationship
continuous infusion of factor VIII (≈10 IU/kg/hour) after a to factor VIII was not appreciated until the 1950s. Correction of the
high-dose bolus may be useful. defect with transfusion of plasma, but not with platelet concentrates
2. Recombinant factor VIIa. Dose is 90 µg/kg (or a dose up to alone, defined the disease as one involving a missing plasma protein
320 µg/kg) administered every 2 hours. Risk of thrombosis exists factor (vWF), not a platelet or vessel wall defect. A correlation
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with this product. between vWD and factor VIII activity had previously been observed—
3. Activated PCCs at a dose of 50–75 IU/kg every 8–12 hours. Risk the observation that a plasma fraction from patients lacking factor
of thrombosis exists with this product.
VIII (hemophilia A) could correct the defect in vWD in addition to
Immunomodulation the autosomal inheritance pattern, which helped further differentiate
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1. Antibody depletion hemophilia A from vWD. A more detailed discussion of clinical
a. Plasmapheresis features and pathophysiology of vWD and the molecular biology of
b. Extracorporeal immunoadsorption of plasma (staphylococcal vWF can be found in Chapter 138.
protein A column therapy and other methods)
2. Suppression of antibody production
a. High-dose steroids (equivalent of prednisone 80 mg/day) Transfusion Therapy for von Willebrand Disease
b. Cyclophosphamide (10–15 mg/kg load and 2–3 mg/kg/day)
c. Intravenous immunoglobulin (1 g/kg daily for 2 days)
d. More aggressive regimens that may include vincristine, The specific treatment for vWD varies with the bleeding symptoms
azathioprine, cyclosporine, or interferon-γ and signs and with the individual diagnostic subtype of vWD (see
Chapter 138). Treatment is guided further by laboratory results
Conservative Measures indicating the potential success of increasing vWF with DDAVP and
1. Immobilization the clinical experience with a particular patient and his or her natural
2. Compression biologic family members who have vWD. When possible, attempts
3. Local application of hemostatic agents
4. Antifibrinolytics should be made to treat the patient without exposing him or her to
5. Avoid venipunctures, intramuscular injections, arterial puncture, plasma-derived products.
and lumbar punctures
6. Avoid use of medications that inhibit platelet function (ASA,
NSAIDs) Nonprotein-Based Treatment
7. DDAVP may be effective in some patients with low-titer inhibitors
DDAVP is a synthetic octapeptide homolog of vasopressin that
ASA, aspirin; BU, Bethesda unit; NSAIDs, nonsteroidal antiinflammatory drugs;
PCC, prothrombin complex concentrate. results in the release of stored vWF from Weibel Palade bodies of
the endothelium (see section on treatment of hemophilia A). DDAVP
is often effective for type 1 disease and may be useful in certain
patients with type 2 disease. It is not appropriate for use in patients
production is attempted using immunomodulatory agents such as with type 3 disease in whom no stores of vWF exist. Before the use
steroids, cyclophosphamide, and IV infusion of immunoglobulin of DDAVP, a DDAVP trial should be conducted to document its
G (IgG). 98–101 These strategies for acutely reducing antibody titers efficacy in an individual patient. The trial is performed as described
are also used by some hemophilia treaters at the outset of immune for hemophilia A. The phenomenon of tachyphylaxis is also observed
tolerance induction. In a phase II trial, Leissinger et al evaluated when DDAVP is used to treat vWD. For bleeding that does not
the safety and efficacy of rituximab, without concurrent immune respond to DDAVP or in patients in whom a poor response is
tolerance induction (ITI), to reduce high-titer inhibitor levels in observed with DDAVP, other modalities (typically protein based) must
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hemophilia A patients, although the study was designed to enroll be used.
43 patients, only 23 were enrolled and the Data Safety Monitoring As described for hemophilia A, the antifibrinolytic agent EACA or
Board closed the study because of poor accrual over 4 years. Three tranexamic acid are often administered in the setting of dental surgery
of 16 (18.8%) had a major response (inhibitor titer <5 BU) and one to inhibit fibrinolysis. Care should be taken when these agents are
with a minor response (initial inhibitor titer <5 BU but increased administered in patients with a predisposition to thrombosis.
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after factor VIII exposure). Several case reports or series of patients Estrogens upregulate vWF synthesis and may be useful especially
with severe hemophilia have demonstrated a greater advantage from in women. Therapy with estrogens should also help ameliorate
rituximab when used in conjunction with ITI. 104,105 In a recent review menorrhagia in affected symptomatic patients.
of inhibitor eradication with rituximab, Franchini and Mannucci
concluded that the combination of ITI with rituximab in mild to
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moderate hemophilia is likely to be more beneficial than when Plasma-Protein–Based Therapy
used without simultaneous factor VIII. Also, rituximab has been
used successfully in the setting of acquired hemophilia A, mostly with Factor VIII Concentrates
concurrent immunosuppression. 105 Some intermediate-purity factor VIII concentrates are manufactured
from plasma using methods that copurify significant amounts of
vWF. Many of the products listed in Table 117.4 contain vWF.
VON WILLEBRAND DISEASE Humate-P (ZLB Behring), Alphanate (Grifols USA), and Wilate
(Octapharma), which is 1 : 1 vWF:RCo/factor VIII, are currently
vWD is an autosomal dominant bleeding disorder first described by licensed for the treatment of vWD. Others, including Koate-DVI
Erik von Willebrand in 1926, who named this bleeding diathesis (Talecris Biotherapeutics), have been tested in vitro and in vivo for
pseudohemophilia. vWD is relatively common, with a prevalence of their potential use in therapy for vWD. 109–111 The multimeric pattern
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up to 2% of the general population. The penetrance and severity of VWF in these concentrates varies, and no product has the pattern
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of the disease vary depending on the type of vWD (type 1, 2, or 3); of multimers that is present in normal plasma. Because many of
the specific mutation; the number of affected genes; the patient’s these products are effective clinically, the importance of these differ-
blood type; and numerous drug, hormonal, and stress-related ences in multimer pattern remains to be determined. In addition,