Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ von Willebrand disease (VWD) is a result of quantitative and qualitative abnormalities in von Willebrand factor (VWF), a plasma protein serving as a carrier for factor VIII and as an adhesive link between platelets and damaged blood vessel walls. Table 80–1 presents the nomenclature used in discussing the functions of VWF. ++Table Graphic Jump LocationTABLE 80–1von WILLEBRAND FACTOR AND FACTOR VIII TERMINOLOGYView Table||Download (.pdf) TABLE 80–1 von WILLEBRAND FACTOR AND FACTOR VIII TERMINOLOGY Factor VIII Antihemophilic factor, the protein that is reduced in plasma of patients with classic hemophilia A and VWD and is measured in standard coagulation assays Factor VIII activity (factor VIII:C) The coagulant property of the factor VIII protein (this term is sometimes used interchangeably with factor VIII) Factor VIII antigen (VIII:Ag) The antigenic determinant(s) on factor VIII measured by immunoassays, which may employ polyclonal or monoclonal antibodies von Willebrand factor (VWF) The large multimeric glycoprotein that is necessary for normal platelet adhesion, a normal bleeding time, and stabilizing factor VIII von Willebrand factor antigen (VWF:Ag) The antigenic determinant(s) on VWF measured by immunoassays, which may employ polyclonal or monoclonal antibodies; inaccurate designations of historical interest only include factor VIII-related antigen (VIIIR:Ag), factor VIII antigen, AHF antigen, and AHF-like antigen Ristocetin cofactor activity (or: von Willebrand factor activity; VWF:act) The property of VWF that supports ristocetin-induced agglutination of washed or fixed normal platelets Source: Williams Hematology, 8th ed, Chap. 127, Table 127–1, p. 2070. + ETIOLOGY AND PATHOGENESIS Download Section PDF Listen +++ ++ VWF is synthesized in endothelial cells and megakaryocytes. Posttranslational modification of the molecule involves glycosylation, sulfation, and multimer formation through extensive disulfide bond formation. VWF is stored in platelets and in Weibel-Palade bodies in endothelial cells. Secretion of VWF from Weibel-Palade bodies is both constitutive and regulated. High-molecular-weight multimers with the greatest activity are released in response to agents such as thrombin in vitro or desmopressin (DDAVP) in vivo. A specific VWF processing protease can reduce the size of high-molecular-weight multimers in plasma. VWF plays an important role in platelet aggregation at sites of vessel injury. VWF stabilizes factor VIII through formation of a noncovalent complex between the two proteins. A large number of mutations of the VWF gene have been discovered and more than 20 distinct subtypes of VWD have been described. Table 80–2 presents a simplified classification of VWD. Types 1 and 3 are deficiencies of normal VWF, either partial (type 1) or complete (type 3). Type 2 includes the qualitative abnormalities of VWF structure and/or function. The quantity of VWF (VWF antigen) in type 2 disease may be normal but is usually reduced. Platelet-type VWD is an inherited platelet abnormality due to a mutation in glycoprotein Ib (CD42b, c). It is discussed in Chap. 76. ++Table Graphic Jump LocationTABLE 80–2CLASSIFICATION OF VON WILLEBRAND DISEASEView Table||Download (.pdf) TABLE 80–2 CLASSIFICATION OF VON WILLEBRAND DISEASE Type Inheritance Frequency Factor VIII Activity VWF Antigen Ristocetin Cofactor Activity RIPA Plasma VWF Multimer Structure Previous Nomenclature Type I Autosomal dominant 1–30:1000j most common (>70% of VWD) Decreased Decreased Decreased Decreased or normal Normal Type I Type 3 Autosomal recessive (or codominant) 1–5:106 Markedly decreased Very low or absent Very low or absent Absent Usually absent Type III Type 2A Usually autosomal dominant ≈10–15% of clinically significant VWD Decreased to normal Usually low Markedly decreased Decreased Largest and intermediate multimers absent Type IIA, IB, I "platelet discordant," IIC-H Type 2B Autosomal dominant Uncommon variant (< 5% of clinical VWD) Decreased to normal Usually low Decreased to normal Increased to low concentrations of ristocetin Largest multimers absent Type IIB Type 2M Usually autosomal dominant Rare (case reports) Variably decreased Variably decreased Decreased Variably decreased Normal Type B, IC, ID, Vicenza Type 2N Autosomal recessive Uncommon: heterozygotes may be prevalent in some populations Decreased Normal Normal Normal Normal VWD Normandy Platelet-type (pseudo-) Autosomal dominant Rare Decreased to normal Decreased to normal Decreased Increased to low concentrations of ristocetin Largest multimers absent Source: Williams Hematology, 8th ed, Chap. 127, Table 127–2, p. 2071. + CLINICAL FEATURES Download Section PDF Listen +++ +++ Type 1 ++ Type 1 accounts for 70 percent of cases. It is usually transmitted as an autosomal dominant trait with variable expression and incomplete penetrance (heterozygous defect). Symptoms vary considerably in families. In two families, only 65 percent of individuals with both an affected parent and descendent had significant symptoms. Symptoms may vary in the same patient over time. The most common bleeding problems are epistaxis (60%), easy bruising and hematomas (40%), menorrhagia (35%), gingival bleeding (35%), and gastrointestinal bleeding (10%). In some families, there may be an association with hereditary hemorrhagic telangiectasia. Bleeding after trauma is common. Hemarthroses are rare except in association with trauma. In patients with mild to moderate disease, symptoms may ameliorate by the second or third decade of life. During pregnancy in patients with type 1 VWD, levels of factor VIII and ristocetin cofactor activities usually rise above 50 percent. +++ Type 2 ++ Types 2A and 2B are the most common qualitative VWF disorders. In type 2A, VWF function is impaired. In type 2B, the interaction between VWF and platelets is dysfunctional. Type 2 variants are usually transmitted as autosomal dominant traits. They account for 20 to 30 percent of cases. Thrombocytopenia occurs in type 2B but is usually not sufficiently severe to contribute to clinical bleeding. Infants with type 2B may have neonatal thrombocytopenia. Type 2N patients (with impaired factor VIII binding to VWF) usually have moderately decreased levels of factor VIII but may have low levels compatible with severe hemophilia A. +++ Type 3 ++ Inheritance may be autosomal recessive (homozygous or compound heterozygous defect). Major clinical bleeding, including hemarthroses and muscle hematomas, occurs as in severe hemophilia. + LABORATORY FEATURES Download Section PDF Listen +++ ++ In a patient suspected of having VWD, initial laboratory tests should include assay of VWF activity, VWF antigen, and factor VIII activity. Additional tests commonly performed are bleeding time, ristocetin-induced platelet agglutination, and VWF multimer analysis (Fig. 80–1). Great care must be exercised in interpreting these laboratory results. The bleeding time may be prolonged in normal people by drugs, such as aspirin or other nonsteroidal antiinflammatory agents. Factor VIII activity, VWF antigen, and ristocetin cofactor activity may all be increased to normal by many minor illnesses. VWF levels may vary with blood group. Carriers of blood group O typically have lower VWF levels. Wide variation is found in the results of repeated assays for VWF or ristocetin cofactor activity in the same subjects. Repeated studies are usually necessary, and the diagnosis or exclusion of VWD usually requires more than one set of laboratory data. ++ FIGURE 80–1 Agarose gel electrophoresis of plasma VWF. VWF multimers from plasma of patients with various subtypes of VWD are shown. The brackets to the left encompass three individual multimer subunits, including the main band and its associate satellite bands. N indicates normal control lanes. Lanes 5 through 7 are rare variants of type 2A VWD. The former designations for these variants are indicated in parentheses below the lanes (IIC through IIE). (Reproduced with permission from Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH: Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). J Clin Invest Mar;77(3):947–51, 1986.) (Source: Williams Hematology, 8th ed, Chap. 127, Fig. 127–4, p. 2075.) Graphic Jump LocationView Full Size||Download Slide (.ppt) + DIFFERENTIAL DIAGNOSIS Download Section PDF Listen +++ +++ Prenatal Diagnosis ++ In most instances, the clinical phenotype of VWD is mild and prenatal diagnosis is rarely sought. Prenatal diagnosis has been successful using DNA techniques in families with type 3 VWD. +++ Platelet-Type (Pseudo-) VWD ++ This is a platelet defect discussed in Chap. 76. It can be differentiated from VWD by special laboratory tests. +++ Acquired VWD ++ Acquired VWD usually appears later in life in a patient with no personal or family history of abnormal bleeding. Another disease is usually present, such as essential thrombocythemia, hypothyroidism, a benign or malignant B-cell disorder, a solid tumor, or a cardiac or vascular defect. Several drugs, including ciprofloxacin and valproic acid, have been associated with acquired VWD. The patients have decreased levels of factor VIII, VWF antigen, and ristocetin cofactor activity. Large multimers of VWF are relatively depleted from the plasma. The bleeding time is usually prolonged. Autoantibodies to VWF appear to be responsible for the disease in most instances, usually by causing rapid clearance of VWF from the circulation but sometimes by interfering with VWF function. Reduced levels of VWF may also be caused by decreased synthesis (e.g., hypothyroidism), increased destruction (e.g., heart disease, some drugs), or selective adsorption to tumor cells. Laboratory confirmation of acquired VWD can be very difficult, and the diagnosis may depend on the late onset, absence of personal or family bleeding history, and identification of the underlying disease. Management is usually directed to the underlying disorder. Refractory patients have been treated with glucocorticoids, plasma exchange, or intravenous immunoglobulin (IVIG). Bleeding in patients with acquired VWD can be managed by (high dose) VWF concentrate, DDAVP, or by recombinant factor VIIa. + THERAPY, COURSE, PROGNOSIS Download Section PDF Listen +++ ++ The goals of therapy are to correct the VWF deficiency and shorten or correct the bleeding time. +++ Desmopressin ++ Patients with type 1 VWD release unusually high-molecular-weight multimers of VWF into the circulation for 1 to 3 hours after infusion of DDAVP. Therapy with DDAVP increases the baseline levels of factor VIII activity, VWF antigen, and ristocetin cofactor activity two- to five-fold in patients with type 1 VWD, and in many instances also corrects the abnormal bleeding time. Approximately 80 percent of type 1 patients have excellent responses to DDAVP. Many type 2 patients and nearly all type 3 do not respond adequately. DDAVP is regularly used in patients with type 1 VWD to treat mild to moderate bleeding, or as prophylaxis prior to surgery. Patients being considered for DDAVP therapy should, if possible, have factor VIII and ristocetin cofactor levels determined 1 to 2 hours following a preliminary dose. For patients undergoing surgery, DDAVP can be given 1 hour prior to the operation and repeated every 12 hours. The usual dose is 0.3 μg/kg in 100 mL saline over 30 to 45 minutes intravenously. Mild cutaneous vasodilatation is common, leading to facial flushing, tingling, warmth, and headaches. Fluid restriction may be necessary because of the potential for dilutional hyponatremia, in particular in children and perioperative patients. There have been isolated reports of arterial thrombosis (including myocardial infarction and unstable angina) with DDAVP therapy. Response to DDAVP may be reduced in patients receiving doses more frequently than every 24 to 48 hours (tachyphylaxis). The response of factor VIII level and ristocetin cofactor activity should be measured regularly in patients receiving frequent doses of DDAVP. VWF-containing concentrates and/or cryoprecipitate should be available for use in the event that DDAVP becomes ineffective. DDAVP has been successfully used to treat type 2B patients, but there is concern that the release of high-molecular-weight multimers could cause platelet aggregation and worsening thrombocytopenia in some patients. An intranasal form of DDAVP is available and appears to be effective, but with greater variability of response. +++ VWF Replacement ++ Patients unresponsive to DDAVP may be treated with virus-inactivated, VWF-containing factor VIII concentrates, such as Humate P. Replacement therapy is largely empiric, with the initial goal normalization of factor VIII levels and shortening or normalization of the bleeding time. If clinical bleeding continues, additional replacement should be given and the patient evaluated for other causes of bleeding that may require additional intervention. Patients should be treated for 7 to 10 days after major surgical procedures and 3 to 5 days after minor. Postpartum bleeding may occur for more than a month after delivery, and may require prolonged treatment in some severe cases. Patients with type 3 VWD may develop an autoantibody against VWF, requiring treatment similar to that of factor VIII inhibitors in hemophilia A. +++ Other Therapies ++ Estrogens or oral contraceptives have been used empirically for menorrhagia. Fibrinolytic inhibitors, such as ε-aminocaproic acid and tranexamic acid, may be useful adjuncts to prophylactic therapy for dental procedures, and have also been used empirically in menorrhagia or recurrent epistaxis. ++ For a more detailed discussion, see Jill Johnsen and David Ginsburg: von Willebrand Disease. Chap. 127, p. 2069 in Williams Hematology, 8th ed.