Hereditary von Willebrand Disease and Acquired von Willebrand Syndrome: Clinical Manifestations, Diagnosis, and Management

This issue of Seminars in Thrombosis and Hemostasis addresses the clinical aspects of von Willebrand disease (vWD), both congenital and acquired. Difficulties and problems with establishing the correct diagnosis are discussed, and special emphasis is placed on the management of these patients.

In the first article Frederici provides an overview of the diagnosis of vWD. It is the most frequently encountered bleeding disorder that, in many patients, may present clinically with a rather mild hemorrhagic tendency. Three criteria must be fulfilled for a proper diagnosis: a bleeding history since early childhood, decreased plasma levels of von Willebrand factor (vWF), and an autosomal dominant or recessive inheritance pattern. The diagnosis must entail one of the three types of vWD (type 1, 2, or 3). Patients with type 3 vWD should be investigated for deletions in the von Willebrand factor gene.

Favaloro discusses the laboratory monitoring of therapy for vWD with either desmopressin (DDAVP) or with vWF-containing concentrates. Of all assays available in specialized laboratories, the author finds the combination of Platelet Function Analyser (PFA-100) values with the data from the collagen-binding assay as the most efficient and accurate parameters. The collagen-binding assay is especially useful for factor replacement with concentrates because this test also assesses the presence of the hemostatically important high molecular weight multimers of vWF.

Michiels and coworkers review acquired von Willebrand syndrome (AvWS), which may be found in patients with a variety of nonimmune or immune-mediated diseases. Hypothyroidism, thrombocythemia, Wilms' tumor, congenital cardiac defects, and a variety of medications are examples of nonimmune-mediated AvWS. AvWS associated with hypothyroidism and Wilms' tumor is commonly of the type 1, whereas myeloproliferative disorders and congenital heart defects present usually with type 2 AvWS. Removal of the underlying disease will eliminate the AvWS. Immune-mediated AvWS is associated with systemic lupus erythematosus or with immunoglobulin G benign monoclonal gammopathy. The features are commonly type 2 vWD. The authors elaborate on the clinical and laboratory aspects of AvWS in these patients.

In the following article, Michiels et al report on the role of vWF in the etiology of bleedings or thromboses in patients with essential thrombocythemia and polycythemia vera. The bleedings are caused by AvWS type 2. The syndrome improves when the elevated platelet counts are reduced. vWF also plays a key role in the etiology of microvascular thromboses that are encountered in these patients.

Kadir and Chi review comprehensively the issues related to women with vWD. Menorrhagia and dysmenorrhea in these women are the leading clinical presentations. Establishing the correct diagnosis can be challenging under these circumstances and many treatment modalities (some of which are controversial) are available for these patients. The authors emphasize the need for a multidisciplinary team to manage these patients and call for multicenter trials to address the remaining controversial issues.

Frederici next describes the current status of managing patients with vWD. DDAVP and factor concentrates are the mainstay of treatment, but major differences exist in responses, and these relate to the underlying type of vWD. Type 3 patients should be treated mainly with concentrates, of which several are commercially available. Many contain both vWF activity and factor (F) VIII activity (FVIII:coagulant activity [C]); newer ones consist primarily of vWF. Major differences exist, however, among these concentrates with respect to their qualitative characteristics (i.e., their high molecular weight multimer composition). Patients may thus respond differently when given different concentrates.

Berntorp emphasizes the management of type 3 vWD patients with concentrates. This treatment may also be helpful in type 1 and 2 patients who do not respond adequately to DDAVP. The author describes the experience of using concentrates for prophylaxis of bleeding episodes in vWD patients in Sweden. This approach has been used successfully since the 1960s. Most of these patients have type 3 vWD, and the prophylactic use of concentrates has greatly reduced the number of annual bleeding episodes. An international effort is under way to expand this therapeutic approach to a larger group of vWD patients.

Budde and associates examine the quality issues of some of the commercially available vWF concentrates. They report on major differences among products, especially related to the presence of the high molecular weight multimers of vWF. These are important for primary hemostasis. Twelve concentrates were studied. The labeling of the concentrates varies and gives no real guideline as to what to expect in a bleeding vWD patient. The authors suggest an improved labeling system and propose a classification for the vWF/FVIII products.

In the last contribution, Michiels and coworkers propose guidelines for the labeling of factor concentrates used to treat vWD patients. Many manufacturers express the activity in their concentrates in terms of FVIII:C. This can be misleading because it does not accurately reflect the vWF activity. This is especially important for the newer concentrates that contain less FVIII:C activity than the older ones. The authors present evidence for using ristocetin cofactor activity (vWF:RCo) to express the activity in the vWF/FVIII concentrates instead of FVIII:C. This is especially meaningful when patients with types 2 and 3 vWD are treated. Large clinical trials will be needed to assess the validity of these proposed guidelines.

Appreciation is expressed to all authors for their excellent contributions to this issue, and special thanks are extended to Jan J. Michiels, M.D., Ph.D., and Emmanuel Favaloro, Ph.D., M.A.I.M.S., for assembling this issue. Readers will find important information on vWD, and the contributions should aid clinicians who care for these patients.