von Willebrand's

Von Willebrandís Disease: Disorders associated with Multiple Hemostatic Defects

Von Willebrandís disease is a group of bleeding disorders involving the production of von Willebrand factor (vWF). There are three major subtypes based on clinical features and laboratory studies. Type 1 and 3 are quantitative deficiencies of the vWF protein antigen and function. Type 1 is a partial deficiency of the vWF protein antigen (vWF:Ag) with proportionally low activity (vWF:RCo), while type 3 vWF:Ag and vWF:RCo are absent along with a markedly reduced level of factor VIII due to its association with vWF. Type 2 variants are characterized by qualitative defects in vWF function.

Epidemiology

Approximately 80% of cases are classified as type 1 disease, 15-20% are type 2 disease, and type 3 disease is a rare autosomal recessive disorder characterized by absence of vWF and severe bleeding. Incidence is 10/100,000 per year. The overall worldwide prevalence is approximately 1%, but the number of clinically significant cases is mush lower. There is no racial or gender predilection.

Biology

Von Willebrandís disease is transmitted in an autosomal dominant fashion. It has an estimated prevalence of 1% in the United States. Von Willebrand factor is synthesized by  megakaryocytes and is stored in platelet alpha granules. It is also produced by and stored in endothelial cells and present as large glycoprotein multimers in the circulation. Deficiency of vWF causes a reduction in platelet adherence to damaged subendothelium and also in platelet-platelet aggregation time. In addition, the level of factor VIII, which is carried and stabilized by vWF, is often reduced.  The vWF gene is located on chromosome 12.

Clinical presentation

Bleeding symptoms in vWD usually involve mucocutaneous tissues, dental work or surgery. Other common complaints are easy bruising, epistaxis, and menorrhagia.

Symptoms which are most predictive of vWD are excessive bleeding with minor lacerations, frequent bruising without known injury, having a large hematomas after venipuncture, frequent nosebleeds, and frequent gum bleeding. Many adolescent girls who have vWD initially present with menorrhagia. The exception to the above pattern of bleeding occurs in type 2N and type 3 vWD. In type 2N vWD there is a qualitative defect in vWF that affects its binding site for factor VIII. This leads to impaired binding of factor VIII and therefore rapid clearance of factor VIII. In these patients, bleeding is due to a low factor VIII, as in hemophilia A, and mimics the findings seen in hemophilia A such as soft tissue, joint, and urinary bleeding, in addition to delayed bleeding after invasive procedures.  Type 2N vWD disease is inherited in an autosomal recessive trait as opposed to X-linked pattern for hemophilia A. Type 2N vWD should be suspected in females who present with isolated factor VIII deficiency with normal levels of vWF activity and antigen and in families where an autosomal inheritance pattern for factor VIII deficiency is suggested. Type 3 vWD is distinguished from hemophilia A because its bleeding show patterns characteristic for vWD and hemophilia, since there is no functional vWF and therefore reduced factor VIII due to is shorter half-life when not bound to vWF. Because vWF is an acute-phase protein, stress will increase its level. Therefore, patients may not bleed with procedures that incur major stress, but may bleed excessively at the time of cosmetic surgery or dental work. In patients with mild vWD, antiplatelet medications can precipitate bleeding that may not have occurred otherwise.

Evaluation/diagnosis

Screening patients for vWD is difficult because of the multiple subtypes and broad spectrum of severity. There is also a wide range of vWF concentrations, which do not always correlate with disease severity. Initial screening tests include a CBC to rule out anemia and thrombocytopenia, PT/PTT, and measure of bleeding time. In general it is taught that patients with vWD have long bleeding times and a prolonged PTT. However, these test are frequently normal in patients with type 1 vWD. If history is strongly suggestive of a bleeding disorder, vWD testing should be pursued. A typical panel, which is necessary to make a definitive diagnosis, includes the measurement of vWF antigen concentrations, ristocetin cofactor for functional testing of vWF, and factor VIII values.

Treatment

Treatment of vWD depends on the severity of bleeding. The goal of treatment is directed toward increasing the plasma levels of vWF and factor VII. Because the gene for factor VIII is normal in patients with vWD, normalizing the concentration of vWF will normalize factor VIII. Desmopressin acetate (DDVAP) is a synthetic analogue of vasopressin that increased the level of vWF and factor VIII by mobilizing the platelet and endothelial stores of vWF and stabilizing factor VIII. A patient who has type 1 or type 2A may use DDVAP, however a DDVAP challenge should be performed to determine responsiveness. If vWF rise into the normal range after administration, DDVAP can be used to treat or prevent bleeding. DDVAP is not used in type 2B due to its association with thrombocytopenia.

If DDVAP is not an option, such as in patients with type 3 vWD or those who fail to respond to DDVAP, replacement therapy must be used. Current replacement therapy used plasma-derived vWF containing concentrates that also contain factor VIII.

Patients with vWD should never take aspirin or clopidrogrel since it will markedly increase bruising.

Long-term effects

If undiagnosed or if proper prophylactic measures have not been taken, there is always the risk of severe hemorrhage.

Follow-up

Patients should be under the care of a hematologist especially for more severe subtypes of vWD and should be followed regularly.

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