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von WILLEBRAND'S DISEASE:
The "Other" Bleeding Disorder
von Willebrand's Disease (vWD) is the most common inherited bleeding
disorder in humans occurring in approximately 1% of the population1,2.
Unlike hemophilia which is a sex-linked trait, vWD may be discovered at
any age and in either sex. While hemophilia is usually associated with
bleeding into joints and muscles, vWD is more commonly associated with
easy bruising, recurrent nosebleeds, prolonged postoperative or posttraumatic
bleeding, excessive bleeding from the gums or mouth and menorrhagia1.
vWD is a complex hemostatic defect with multiple variations. Diagnosis
may require correlation of clinical observations with laboratory testing
and family studies especially in mild forms of the disease. The disease
process is mediated by a qualitative or quantitative deficiency of a large
glycoprotein called von Willebrand Factor (vWF). vWF is synthesized in
the endothelial cells where it is stored in the Weibel-Palade bodies and
in megakaryocytes where it is stored in the -granules of platelets2.
The mature vWF subunit is assembled into multimers which are required for
biological function. vWF functions in hemostasis by permitting adhesion
of platelets to exposed endothelium and by forming a non-covalent complex
with Factor VIII, thus stabilizing and protecting it from rapid removal
from the circulation2.
Diagnosis of von Willebrand's Disease (vWD) can be complicated by the
fact that von Willebrand Factor (vWF) is an acute phase reactant which
increases when a patient is under stress, has recently had surgery, is
a newborn, is pregnant, post partum, using birth control pills, or has
had a recent blood transfusion3. Tests
for vWD are necessary not only for diagnosis but also for classification
of disease type for the purposes of clinical management and genetic counseling1.
For correct classification, tests should include bleeding time, Factor
VIII activity, vWF antigen (vWF:Ag), vWF activity (vWF:RCo), vWF multimers,
and platelet aggregations3. The most recent
classification of vWD endorsed by the von Willebrand subcommittee of the
International Society of Thrombosis and Hemostasis is based on quantitative
and/or functional alterations in the von Willebrand molecule4.
Type 1 disease, present in over 70% of cases, is characterized
by mild to moderately reduced levels of vWF and often reduced Factor VIII
activity, but no functional abnormalities. The levels of Factor III, vWF:Ag
and vWF:RCo are often decreased to the same relative degree. The normal
levels of vWF antigen are significantly different in the population based
on ABO blood group with type "O" having the lowest normal concentration5.
Type 1 disease is inherited as an autosomal dominant trait1,5,
Type 2: 15 - 30% of individuals with vWF disease have
an abnormality in the vWF molecule which results in abnormal structure
and function. Four main categories have been identified in the classification
scheme endorsed by the ISTH4,5.
Type 2A disease is characterized by decreased
platelet dependent function due to the absence of high molecular weight
multimers of vWF. The vWF:RCo result is often disproportionately low compared
to the vWF:Ag.
Type 2B is characterized by a qualitative defect of the
vWF molecule resulting in an increased affinity for platelet glycoprotein
GPIb. This defect is demonstrated by an enhanced platelet response to ristocetin
and the absence of large vWF multimers. VWF:Ag, vWF:RCo, and Factor VIII
are variable, and may be within normal limits. Some patients with this
defect have chronic thrombocytopenia and circulating platelet aggregates
due to spontaneous aggregation.
Type 2M is characterized by a qualitative defect of the
vWF molecule resulting in decreased vWF-dependent platelet function not
caused by the absence of the high molecular weight multimers. The
vWF:RCo level may be disproportionately low compared to the vWF:Ag level.
Type 2N is a qualitative defect characterized by an abnormally
low affinity of vWF for Factor VIII. Most patients described have both
Type 1 vWD and the Factor VIII binding defect resulting in decreased vWF:Ag
and vWF:RCo, normal multimers, and a disproportionately low Factor VIII
level compared to the vWF level. Those patients with the type 2N defect
alone may resemble patients with hemophilia A with normal vWF:Ag, vWF:RCo,
and multimers and reduced Factor VIII levels. These patients are distinguished
from true hemophiliacs by an autosomal pattern of inheritance.
Type 3 disease is a severe form of vWD in which levels
of vWF are severely reduced or absent, Factor VIII is markedly decreased,
and all multimers are absent4. Type 3 disease
is inherited as an autosomal recessive trait5.
Most patients with vWD are most appropriately treated with DDAVP (desmopressin),
given either intravenously or by highly concentrated nasal spray. DDAVP
causes a release of vWF from storage sites and a temporary rise in the
circulating amount of vWF and Factor VIII1,5,6.
Viral inactivated Factor VIII concentrates rich in vWF are recommended
when necessary for treatment of patients with Type 1 vWD who have become
transiently unresponsive to DDAVP, Type 2B vWD, and Type 3vWD6.
Platelet-type pseudo vWD is actually a defect in platelet GPIb, the receptor for vWF, causing the spontaneous binding of high molecular weight multimers, rapid platelet turnover, and mild thrombocytopenia. Phenotypically these patients are indistinguishable from patients with type 2B vWD but must be treated with platelet concentrates.
In addition to the inherited forms of von Willebrand's Disease, alterations
in the amount and function of vWF have been found in association with a
large number of immunological, malignant, and drug related conditions1,2,3,5.
HEMEX Laboratories offers a complete panel of tests for the diagnosis
and differentiation of von Willebrand Disease types. Please call (602)997-9161
or 1-800-999-CLOT(2568) for additional information on von Willebrand's
testing.
SPECIMEN REQUIREMENTS:
von Willebrand Screen (Factor VIII, vWF:Ag, vWF:RCo, PT, APTT): 4 ml
frozen citrated plasma.; 1 ml aliquots submitted in 4 separate plastic
vials.
von Willebrand Panel (PT, APTT, Factor VIII, vWF:Ag, vWF:RCo, Platelet Aggregations x 3):
4 ml citrated plasma; 1 ml aliquots submitted in 4 separate plastic
vials. Call HEMEX for directions for collection of platelet aggregations.
vWF Multimers: 2 ml frozen citrated plasma, 1 ml aliquots submitted
in 2 separate plastic vials.
Do not filter plasma as high molecular weight multimers
of vWF may adhere to the filter7.
REFERENCES:
1. La Fon J. Exploring Von Willebrand Disease. The National Hemophilia Foundation. 1995.
2. Hathaway W A., Goodnight S H. Hereditary von Willebrand Disease. In: Disorders of Hemostasis and Thrombosis: A Clinical Guide. McGraw-Hill, Inc. 1993.
3. Roher S. The "Other" bleeding disorder. Hemalog October 1994:12-15.
4. Sadler J E. A revised classification of von Willebrand disease. Thrombosis anD Haemostasis 1994;71(4):520-525.
5. Ruggeri Z M. Von Willebrand Disease and the Mechanisms of Platelet Function. Presented at Thrombosis and Hemostasis Update, April 25-27, 1996. Temple University School of Medicine. Philadelphia, PA.
6. Recommendations concerning HIV infection, hepatitis, and other transmissible agents in the treatment of hemophilia. The National Hemophilia Foundation Medical & Scientific Advisory Council. March 1995.
7. Favalaro EJ, Facey D, Grispo L. Laboratory Assessment
of von Willebrand factor. Amer J Clin Pathol 1995;104:264-271.