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2176 Part XII: Hemostasis and Thrombosis Chapter 126: von Willebrand Disease 2177

VON WILLEBRAND FACTOR REPLACEMENT plasma-derived VWF replacement product in patients with gyneco-
THERAPY logic bleeding, mucous membrane bleeding, or undergoing dental
procedures. Fibrinolytic inhibitors can be delivered systemically or
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It is important to determine the response to DDAVP for each individual topically and are generally well tolerated, but rarely can cause nausea
so as to avoid the unnecessary use of plasma products. For type 3 VWD or diarrhea and are contraindicated in patients with gross hematuria.
patients and other patients unresponsive to DDAVP, the use of selected Estrogens or oral contraceptives have been used empirically in
virus-inactivated, VWF-containing FVIII concentrates is generally safe treating menorrhagia. In addition to their effects on the ovaries and
150
and effective. Humate-P, Alphanate, Wilate, and Koate are all accept- uterus, some estrogens can increase plasma VWF levels. Patients
able commercial VWF-containing plasma concentrates that have been with VWD frequently normalize their levels of FVIII, VWF:Ag, and
evaluated in VWD replacement therapy in clinical studies, and other VWF:RCo during pregnancy (Chap. 8). Postpartum hemorrhage within
VWF-containing FVIII concentrates may also be effective. A plasma- the first few days after parturition may be related to the relatively rapid
free recombinant VWF–recombinant FVIII combination (rVW- return of FVIII and VWF activities to prepregnancy levels, and post-
F-rFVIII) shows promise in clinical trials and may become available in partum hemorrhage in all forms of VWD may occur as long as 1 month
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the near future. Cryoprecipitate was useful in the past, but because it postpartum. In pregnant patients with type 1 VWD, the FVIII and ris-
is not generally treated to inactivate bloodborne pathogens, is less tar- tocetin cofactor activities usually rise above 50 percent. These patients
geted to correcting the VWD hemostatic defect, and its administration usually do not require any specific therapy at the time of parturition. In
is associated with a large volume load, it is less desirable. It is impor- contrast, individuals who have 30 percent or less FVIII or variant forms
tant to note that most standard FVIII concentrates and all recombinant of VWD are more likely to require prophylactic therapy before deliv-
FVIII products are not effective in VWD because they lack clinically ery. In a recent study, women receiving treatment for VWD postpartum
significant quantities of VWF. Although such products can substantially were unexpectedly found not to have corrected to target levels. There-
353
increase circulating FVIII:C, the infused factor is short-lived in the cir- fore, laboratory testing is recommended at term and should be consid-
culation in the absence of stabilizing VWF. Only preparations that ered in the postpartum period in patients at risk for immediate and/or
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contain large quantities of VWF with well-preserved multimer struc- delayed bleeding complications or receiving therapy.
ture are suitable for use in VWD patients. Recombinant activated factor VII (rFVIIa, or NovoSeven) has
In practice, VWD replacement therapy dosing and timing has also been successfully used in VWD patients with severe hemorrhage
been largely empiric. Recommendations for therapy have been outlined refractory to VWF replacement therapy and in bleeding patients with
based upon the degree and nature of hemorrhage and experience in anti-VWF antibodies (reviewed in Ref. 354). In the case of minor acces-
150
clinical practice. The objective is to elevate FVIII:C and VWF:RCo sible bleeding, topical drugs such as fibrin sealants or topical bovine
until bleeding stops and healing is complete. In general, replacement thrombin may also be considered when standard VWD therapies fail to
goals of FVIII:C and VWF:RCo should be initial replacement to greater provide adequate local hemostasis. 150
than 100 IU/dL and maintenance of greater than 50 IU/dL for 7 to 14
days for major trauma, surgery, or central nervous system hemorrhage; REFERENCES
greater than 30 to 50 IU/dL for 3 to 5 days for minor surgery or bleed-
ing; greater than 50 IU/dL for delivery and continued for at least 3 to 1. von Willebrand EA: Hereditär Pseudohemofili. Fin Lakaresallsk Handl 67:7–112, 1926.
5 days in the postpartum period; greater than 30 to 50 IU/dL for 1 to 2. Hoyer LW: Von Willebrand’s disease. Prog Hemost Thromb 3:231–287, 1976.
5 days for dental extractions and minor surgery; and greater than 20 3. Nilsson IM: Von Willebrand’s disease—Fifty years old. Acta Med Scand 201:497–508,
1977.
to 50 IU/dL for mucous membrane bleeding or menorrhagia. Labora- 4. Zimmerman TS, Ratnoff OD, Powell AE: Immunologic differentiation of classic hemo-
tory monitoring of posttreatment FVIII:C and VWF levels is impor- philia (Factor VIII deficiency) and von Willebrand disease. J Clin Invest 50:244–254,
1971.
tant in guiding therapy and avoidance of supratherapeutic replacement 5. Howard MA, Firkin BG: Ristocetin—A new tool in the investigation of platelet aggre-
doses (>200 IU/dL VWF:RCo, >250 IU/dL FVIII), which are associated gation. Thromb Diath Haemorrh 76:362–369, 1971.
with an increased risk of thrombosis. 150,350,351 Although thrombosis is 6. Weiss HJ, Rogers J, Brand H: Defective ristocetin-induced platelet aggregation in von
rare overall, VWD patients on prolonged therapy or with central access Willebrand’s disease and its correction by Factor VIII. J Clin Invest 52:2697–2707,
1973.
catheters appear to be at higher risk. 352 7. Weiss HJ, Hoyer LW: Von Willebrand factor: Dissociation from antihemophilic factor
In patients who have concomitant thrombocytopenia associated procoagulant activity. Science 182:1149–1151, 1973.
with or in addition to VWD, it may be necessary to transfuse plate- 8. Zimmerman TS, Edgington TS: Factor VIII coagulant activity and factor VIII-like anti-
gen: Independent molecular entities. J Exp Med 138:1015–1020, 1973.
lets in addition to factor concentrates. If clinical bleeding continues, 9. Gitschier J, Wood WI, Goralka TM, et al: Characterization of the human factor VIII
additional replacement therapy must be given and searches undertaken gene. Nature 312:326–330, 1984.
for other hemostatic defects. Type 3 VWD patients receiving multiple 10. Toole JJ, Knopf JL, Wozney JM, et al: Molecular cloning of a cDNA encoding human
antihaemophilic factor. Nature 312:342–347, 1984.
transfusions can develop antibodies directed against VWF (reviewed 11. Ginsburg D, Handin RI, Bonthron DT, et al: Human von Willebrand factor (vWF):
in Ref. 277). Continued replacement with VWF-containing concen- Isolation of complementary DNA (cDNA) clones and chromosomal localization.
trates is contraindicated because of the risk of anaphylaxis. A variety Science 228:1401–1406, 1985.
of approaches to the management of VWD inhibitors, similar to the 12. Lynch DC, Zimmerman TS, Collins CJ, et al: Molecular cloning of cDNA for human
von Willebrand factor: Authentication by a new method. Cell 41:49–56, 1985.
treatment of FVIII inhibitors in hemophilia A (Chap. 123), have been 13. Sadler JE, Shelton-Inloes BB, Sorace JM, et al: Cloning and characterization of
attempted. Immunosuppression, recombinant FVIII, and recombinant two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A 82:
factor VIIa have been reported to be useful in patients with type 3 VWD 6394–6398, 1985.
who have developed anti-VWF antibodies. 14. Verweij CL, de Vries CJM, Distel B, et al: Construction of cDNA coding for human
von Willebrand factor using antibody probes for colony-screening and mapping of the
chromosomal gene. Nucleic Acids Res 13:4699–4717, 1985.
15. Sadler JE, Budde U, Eikenboom JC, et al: Update on the pathophysiology and classi-
OTHER NONREPLACEMENT THERAPIES fication of von Willebrand disease: A report of the Subcommittee on von Willebrand
Factor. J Thromb Haemost Thromb Haemost 4:2103–2114, 2006.
Fibrinolytic inhibitors, such as ε-aminocaproic acid or tranexamic 16. Titani K, Kumar S, Takio K, et al: Amino acid sequence of human von Willebrand
factor. Biochemistry 25:3171–3184, 1986.
acid, have been used effectively in some VWD patients. Antifibrino- 17. Fay PJ, Kawai Y, Wagner DD, et al: Propolypeptide of von Willebrand factor circulates
lytics are commonly used alone or in conjunction with DDAVP or a in blood and is identical to von Willebrand antigen II. Science 232:995–998, 1986.

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