von Willebrand Disease (vWD)
von Willebrand disease is a common inherited bleeding disorder characterized by abnormal platelet function secondary to a defect of von Willebrand factor (vWF) activity. The abnormality may be either a quantatative defect of vWF or a qualatative defect of vWF or platelet receptors. The diagnosis should be suspected in any patient with mucocutaneous bleeding (especially epistaxsis) who does not suffer from thrombocytopenia. Acquired vWD may occur secondary to conditions which result in the production of antibodies against vWF, conformational changes of vWF secondary to high shear forces, marked thrombocytosis, removal of vWF from the circulation via binding to tumor cells, decreased vWF production, and medication side effects.
von Willebrand factor is a large multimeric plasma glycoprotein synthesized in both megakaryocytes and endothelial cells. von Willebrand factor serves to provide an adhesive link between platelets and the wall of blood vessels at sites of injury and as a carrier of clotting factor VIII in addition to stabilizing and localizing the clotting factor to the site of injury. Therefore, when there is a deficiency of von Willebrand factor, platelet adhesion is ineffective and there is a low level of factor VIII in conjunction with deficient levels of von Willebrand factor. This is the opposite of hemophilia A, in which there are deficient levels of factor VIII with normal levels of von Willebrand factor. However, both manifest clinically as bleeding.
Laboratory abnormalities may vary depending on the type and severity of disease. The diagnosis should not be made in persons who are critically ill, pregnant or suffering from acute inflammatory illnesses as these conditions can falsely affect vWF levels. The initial evaluation should include a platelet count, PT, aPTT and PFA-100 (platelet function analyzer). The aPTT may be prolonged in patients suffering from severe disease. PFA-100 testing will display both epinephrine and adenosine prolonged closure times. Further evaluation should include measurements of factor VIII coagulant activity (VIII:C), vWF antigen (vWF:Ag), vWF activity (ristocetin activity), and agarose gel electrophoresis to determine vWF multimer size. The ristocetin activity test measures the binding of vWF to platelet GpIb in the presence of ristocetin with normal activity in the range of 50 to 150 U/dL or 50 to 150%. vWF:Ag is measured by electroimmunoassay or ELISA testing. The range for normal levels is 50 to 200 U/dL. If acquired vWD is suspected, then vWF multimer analysis is necessary to establish the diagnosis by demonstrating a lack of high-molcular-weight .
Type 1 disease:
This is the most common variant of vWD occuring in 80% of cases. Persons with blood type O often demonstrate low normal vWF levels without having vWD, and caution should be used when trying to establish the diagnosis of mild type I disease in persons with type O blood.. This type of disease represents an autosomal dominant inheritance of a quantatative defect of vWF levels which manifests clinically as a mild to moderate bleeding diathesis. The level of vWF may be reduced in both plasma and platelets, plasma reduced only with normal platelet levels, or platelet reduced with normal plasma levels. The diagnosis is established when there is a normal multimer pattern on agarose gel electrophoresis in the presence of decreased vWF antigen (vWF:Ag) and activity measurements (ristocetin activity)..
Type 2 disease:
This is characterized by a qualatative defect of vWF. Type 2A disease is the most common qualatative variant with patients suffering an absence of high and intermediate molecular weight multimers. Persons with type 2A disease suffer from a moderately severe bleeding diathesis. On laboratory evaluation these patients exhibit a reduction in ristocetin cofactor activity greater than the reduction in vWF:Ag. Patients with 2B disease have abnormal vWF which displays an increased propensity for binding to platlet GPIb/IX receptors thus resulting in deficient levels of circulating free vWF. 2B patients also have increased platelet aggregation as a result of their defect which manifests clinically as an increased bleeding tendency and biochemically as thrombocytopenia. There is also a form of type 2 disease known as platelet-type vWD which is similar to 2B disease in that there is an increased propensity for binding of vWF to platelet GP1b receptor; however, in platelet type disease, the defect is with the platelet receptor and not vWF. Type 2M disease is the result of an abnormal vWF molecule which suffers a decreased affinity for platelet GP1b/IX receptor. Type 2N disease is secondary to a defect in the binding of factor VIII to vWF. Laboratory evaluation of type 2N disease shows normal vWF activity and antigen along with normal multimer analysis on electrophoresis in the presence of decreased factor VIII activity levels. Type 2N disease should be considered in female patients and when female members of a patient’s family are involved.
Type 3 disease:
This is characterized by an absence or marked reduction of vWF:Ag and low levels of factor VIII:C (<1 to 10%). Also, the bleeding times of these patients are very prolonged. Clinically, these patients manifest severe bleeding with hemarthroses and muscle hematomas.
Acquired vWD is a disorder associated with underlying conditions such as myeloproliferative disorders (PCV, ET, primary myelofibrosis, etc), hypothyroidism, benign or malignant B-cell disorders, monoclonal gammopathies (multiple myeloma, smouldering myeloma, MGUS, amyloidosis, CLL), systemic lupus erythematosus, Wilm tumor, ventricular septal defect, patent ductus arteriosus, aortic stenosis, hypertrophic obstructive cardiomyopathy, left ventricular assist devices, primary pulmonary hypertension, and medications (ciprofloxacin, valproic acid, hydroxyethyl starch, and griseofulvin). Acquired vWD is diagnosed by electrophoresis analysis of vWF multimers which will reveal an absence of high molecular weight multimers.
Type 1 disease is distinguished from type 2 by the evaluation of vWF multimers. In type 1 disease there is a normal distribution of multimers with a decrease in the overall number of multimers. Also, in type 1 disease there is the vWF:Ag and ristocetin cofactor activity are proportionately decreased. In contrast, type 2A and 2B demonstrate an abnormal multimer pattern on electrophoresis with large and sometimes intermediate multimers missing. Another clue to distinguish type 2 disease from type 1 is that with type 2A, 2B and 2M disease the vWF activity (ristocetin cofactor activity) is much more depressed than the vWF:Ag level. If there is associated thrombocytopenia, then type 2B disease should be suspected, and the diagnosis may be confirmed by demonstrating platelet aggregation at low ristocetin concentrations. Type 2N disease is diagnosed by demonstrating a disproportionately low factor VIII as compared to vWF:Ag and ristocetin cofactor activity. For definitive diagnosis of type 2N disease, a specialized test (vWF/factor VIII binding assay) which is available only in specialized laboratories is necessary.
Therapy for vWD varies on the type of disease due to the varied underlying pathophysiology associated with the different types. If vWD is suspected during an acute condition (such as in critically ill patients or in association with surgical complications), then immediate treatment should be broad and empiric to include discontinuing medications with platelet inhibiting side effects, vWF supplementation, and if needed, platelet transfusion. In-patients with an established diagnosis, they should be counseled to wear an identification bracelet and to avoid medications that interfere with platelet function. For mild type 1 disease, DDAVP (desmopressin) serves as an effective therapy and is administered at a dose of 0.2 to 0.4 micrograms/kg intravenously over 15 to 30 minutes. Intranasal DDAVP is also effective for mild type 1 disease patients. DDAVP is contraindicated in patients with type 2B and the platelet-type variant of type 2 disease. vWF replacement can be achieved with transfusion therapy using either plasma or cryoprecipitate. Another method to replace vWF is with concentrates. Both Humate P and Alphanate are available concentrates and should be administered at a dose of 50 factor VIII Units/kg. When using concentrates in persons with type 3 disease, it is important to be aware of the possibility of an anaphalactoid reaction with repeated dosages. Estrogens are an effective alternative therapy which may be offered to females afflicted with this disorder especially those who suffer from menorrhagia. Epsilon aminocaproic acid (3 to 4 grams every 4 to 6 hours either IV or PO) is another potential therapy to be offered. Treatment of the underlying disease state may result in resolution of acquired vWD especially with disorders associated with high shear stress induced disease. Septal myectomy for hypertrophic obstructive cardiomyopathy or valvular replacement for aortic stenosis appeas to reverse acquired vWD.