ANGELES UNIVERSITY FOUNDATION

Angeles City
COLLEGE OF ALLIED MEDICAL PROFESSIONS

Hematology 2 LABORATORY

VON WILLEBRAND DISEASE

Submitted by:
Group 9
BS MT 3-C
Group Leader: David, Kyla Denise
Members: De Jesus, Kim Paula
Leongson, Shirlene Anne
Malaban, Kelvin
Submitted to:
Maam Genevieve Dizon
Sir Jeshua Caleb Miole
CC02 Laboratory Professors

December 29, 2016

CASE SUMMARY

A 56-year old male patient had come to the outpatient department with complaint of bleeding
gums. The patient narrated that his problem had been persistent and recurrent since childhood but
from the last three months, it has been more severe. He also had episodes of melena which were
recurrent and relieved on its own. On general examination, anemia and pallor were noted.
Further examination revealed gingival bleeding. The rest of the oral mucosa including the palate
and tongue were normal on inspection and palpation. Refer to the following for the patients
diagnostic examination results:
-

Dukes Method: 17 minutes (NV: 1-3 minutes)

Lee and White: 5 minutes (7-15 minutes)
PT: 12 seconds (10-13 seconds)
APTT: 37 seconds (<35 seconds)
RIPA: decreased

GUIDE QUESTIONS
1. What is the most probable diagnosis of the case?
The most probable diagnosis would be von Willebrand Disease.
VWD is a common mucocutaneous bleeding disorder first described by Finnish Professor Erik
von Willebrand in 1926. VWD is caused by any one of dozens of germline mutations that result
in quantitative or structural abnormalities of VWF. Both quantitative and structural abnormalities
lead to decreased adhesion by platelets to injured vessel walls, causing impaired primary
hemostasis.
2. Discuss the pathophysiology and the different types of the disease.
This disease is characterized by abnormal platelet function, expressed as a prolonged bleeding
time. This is a consistent finding and may be accompanied by decreased factor VIII procoagulant
activity. vWF circulates in the blood in two distinct compartments, with two types of cells being
responsible for vWF production.
Vascular endothelium is the primary source of the synthesis and release of plasma vWF; the
other type of cell that synthesizes vWF is the megakaryocyte. Approximately 15% of circulating
vWF is produced in the megakaryocyte. vWF circulates in platelets, being stored primarily in the
alpha granules. vWF is a large, adhesive, multimeric GP present in plasma, platelets, and
subendothelium. It is synthesized as a large precursor which has two main functions: regulating
coagulant activity and aiding in adhesion of platelets to subendothelial cell walls following
vessel damage.
vWF is essential in providing the basis for formation of a normal platelet thrombus. vWF binds
to specifi c sites on the platelet, namely GP Ib and GP IIb/IIIa, while concurrently binding to the
subendothelium of damaged vessel walls, forming a bridge. Patients with decreased levels of
vWF,especially the larger multimeric forms, will lack adequate bridging action that produces

prolonged bleeding times. Qualitative or quantitative abnormalities of vWF result in decreased

adhesion and are responsible for the bleeding associated with von Willebrand disease.
There are various types of von Willebrand Disease.
Type 1 von Willebrand Disease.
Type 1 VWD is a quantitative VWF deficiency caused by one of several autosomal dominant
frameshifts, nonsense mutations, or deletions. Type 1 is seen in approximately 75% of VWD
patients. The plasma concentrations of VWF and factor VIII are variably, although
proportionally, reduced. There is mild to moderate bleeding, usually following a hemostatic
challenge such as dental extraction or surgery. In women, menorrhagia is a common complaint
that leads to the diagnosis of VWD.
Type 2 von Willebrand Disease.
Type 2 VWD comprises a variety of qualitative VWF abnormalities. VWF levels may be normal
or moderately decreased, but VWF function is consistently reduced.
Subtype 2A von Willebrand Disease.
Ten percent to 20% of VWD patients have subtype 2A, which arises from well-characterized
autosomal dominant point mutations in the A2 structural domain of the VWF molecule. These
mutations render VWF more susceptible to proteolysis, which leads to a predominance of smallmolecular-weight multimers in the
plasma. The smaller multimers support less platelet adhesion activity than the normal high- or
intermediate-molecular weight multimers. Patients with subtype 2A VWD have normal or
slightly reduced VWF: Ag levels with markedly reduced VWF activity as a result of the loss of
the high-molecular-weight and intermediate-molecular-weight multimers essential for platelet
adhesion.
Subtype 2B von Willebrand Disease.
In subtype 2B VWD, rare mutations within the A1 domain raise the affinity
of VWF for platelet glycoprotein Ib/V/IX, its customary binding site; these are thus gain of
function mutations. Large
VWF multimers spontaneously bind resting platelets and are unavailable for normal platelet
adhesion. Consequently,
the electrophoretic multimer pattern is characterized by lack of high-molecular-weight multimers
but presence of intermediate-molecular-weight multimers. There also may be moderate
thrombocytopenia caused by chronic platelet activation, because multimer-coated platelets
indiscriminately bind the endothelium.
Subtype 2M von Willebrand Disease.

Subtype 2M VWD is caused by a qualitative variant of VWF that has decreased platelet receptor
binding but a normal multimeric pattern in electrophoresis. The distinguishing feature of subtype
2M that separates it from type 1 is a discrepancy between the concentration of VWF: Ag and its
activity as measured using the VWF: RCo assay.
Subtype 2N von Willebrand Disease (Normandy Variant or Autosomal Hemophilia).
A rare autosomal VWF missense mutation impairs its factor VIII binding site. This condition
results in factor VIII deficiency despite normal VWF: Ag concentration and activity and a
normal multimeric pattern. The disorder is also known as autosomal hemophilia because its
clinical symptoms are indistinguishable from the symptoms of hemophilia except that it affects
both males and females. Subtype 2N is suspected when a girl or woman is diagnosed with
hemophilia after soft tissue bleeding symptoms. In boys or men, subtype 2N is suspected when a
patient misdiagnosed with hemophilia A fails to respond to factor VIII concentrate therapy. The
poor response occurs because the factor has a plasma half-life of mere minutes when it cannot be
bound by VWF. The diagnosis of VWD subtype 2N is made by a molecular assay that detects the
specific mutation responsible for the abnormal factor VIII binding to VWF.
Type 3 von Willebrand Disease.
Autosomal recessive VWF gene translation or deletion mutations produce severe mucocutaneous
and anatomic hemorrhage in compound heterozygotes or, in consanguinity, homozygotes. In this
rare disorder, VWF is absent or nearly absent from plasma. Factor VIII is also proportionally
diminished or absent, and primary and secondary hemostasis is impaired.

3. Enumerate other hematology tests that may be performed with this disorder and give the
expected results.
The standard VWD test panel includes three assays: a quantitative VWF test (VWF : Ag assay)
employing an enzyme immunoassay or automated latex immunoassay technique, such as the
Liatest (Diagnostica Stago, Asnires-sur-Seine, France); the VWF activity test, which determines
the factors ability to bind to platelets, also known as the VWF : RCo assay; and a factor VIII
activity assay. The VWF : RCo assay employs preserved reagent platelets. The agonist ristocetin
supports platelet agglutination in the presence of VWF.

Other tests:

Von Willebrand factor antigen. This test determines the level of von Willebrand factor
in your blood by measuring a particular protein.
Ristocetin cofactor activity. This test measures how well the von Willebrand factor
works in your clotting process. Ristocetin, which is an antibiotic, is used in this
laboratory testing.
Factor VIII clotting activity. This test shows whether you have abnormally low levels
and activity of factor VIII.
Von Willebrand factor multimers. This test evaluates the specific structure of von
Willebrand factor in your blood, its protein complexes (multimers) and how its molecules
break down. This information helps identify the type of von Willebrand disease you have.

4. What kind of treatment is given with this kind of disorder?

Mild bleeding may resolve with the use of local measures, such as limb elevation, pressure, and
application of ice packs (the athletes acronym is RICE for rest, ice, compression, and elevation).
Moderate bleeding may respond to estrogen and desmopressin acetate, which trigger the release
of VWF from storage organelles.
Therapeutic dosages are monitored when necessary using serial VWF: Ag concentration assays.
Desmopressin acetate (1-desamino-8-D arginine vasopressin) is an antidiuretic hormone
analogue used to control incontinence in diabetes mellitus and bedwetting; release of VWF from
storage organelles is a side-effect. Desmopressin acetate in its oral form, DDAVP, or nasal spray
form, Stimate (both from CSL Behring, King of Prussia, Pa.), is consistently effective for type 1
VWD and generally useful for subtype 2A. It is contraindicated for subtype 2B, however,
because it causes the release of abnormal VWF with increased affinity for platelet receptors,

which may intensify thrombocytopenia and lead to increased platelet activation and thrombosis.
Because of its antidiuretic property, repeated doses may lead to hyponatremia (low serum
sodium). For this reason, it is necessary to monitor and regulate electrolytes during desmopressin
acetate therapy.
-Aminocaproic acid (EACA; Amicar) or tranexamic acid (Cyklokapron) inhibits fibrinolysis
and may help control bleeding when used alone or in conjunction with desmopressin acetate.
Therapy using nonbiologic preparations is preferred over human plasmaderived biologic
therapy, because nonbiologicals eliminate the risk of viral disease transmission and circumvent
religious objections to receipt of human blood products.
For treatment of severe VWD (type 3) and subtype 2B, three commercially prepared human
plasmaderived high-purity preparations are available that provide a mixture of VWF and
coagulation factor VIII. These are Humate-P, Alphanate, and Wilate.

REFERENCES:
Steininger, et al., Clinical Hematology: Principles, Procedures, Correlations
Turgeon, Clinical Hematology: Theory and Procedures (Fifth Edition)
Rodak, Clinical Hematology: Clinical Principles and Applications (Fourth Edition)