Diagnosis and Management of Congenital von Willebrand Disease

This issue of Seminars in Thrombosis and Hemostasis comprehensively reviews von Willebrand factor (vWF), its function, von Willebrand disease (vWD), and the difficulties encountered in establishing a proper diagnosis. vWD is the most common congenital bleeding disorder. Most patients with this disorder have relatively mild bleeding manifestations, so vWD may be unrecognized until trauma or surgeries are encountered. Under these circumstances, the clinical manifestations may become serious, requiring an accurate diagnosis so that proper treatment can be initiated.

In the first contribution, Michiels and coworkers describe the response of various vWF assays to the administration of desmopressin (DDAVP) in order to improve the diagnosis of vWD and thus select better treatment options. There are basically three types of vWD: type 1 is a decreased production of vWF, type 2 is a dysfunctional molecule, and type 3 is the virtual absence of vWF, in other words, the severe form of type 1. Classically, besides bleeding times, vWD is diagnosed by measuring vWF by a ristocetin-based platelet agglutination test (vWF:Rcof), by the immunologic assay of vWF (vWF:Ag), and by factor VIIIc (FVIIIc) assays. By determining ratios of vWF:RCof and vWF:Ag, types 1 and 2 vWD may be differentiated, but frequently no clear diagnosis can be established. This is why other assays, such as vWF collagen binding activity (vWF:CBA) and multimeric analysis of vWF, are required. The authors could demonstrate on 24 patients with various forms of vWD that these assays can be greatly improved when a test dose of DDAVP is administered. Especially subtypes of vWD type 2 can be better identified.

The next article by de Groot examines the role of vWF in platelet function. vWF is an integral part of platelet adhesion at sites of injured endothelium and also participates in platelet aggregation. vWF is thus an important protein in primary hemostasis. On injury to endothelium, vWF will adhere to the exposed collagen structures, and individual platelets will attach to the bound vWF, whereby glycoprotein (GP) receptors, especially GPIb/V, IX complexes play a prominent role. Adhering platelets will spread and provide the surface for other platelets to attach. Although the principle of this process is well-established, details at the molecular level have yet to be worked out. The author also coordinates this knowledge with the various forms of vWD.

Neugebauer and associates describe their experience with two vWF:CBA assays used to determine activity of vWF in concentrates. These relatively new tests have been added to the battery of procedures used for diagnosing vWD. The two methods differ with respect to the form of collagen used to bind to the microtiter plates. One uses pepsin-digested collagen from human source, the other is collagen fibrils from equine origin. Although the two tests worked equally well in plasma from normal persons and patients with vWD, major differences were noted when therapeutic vWF concentrates were tested for their activity. It was then found that the differences resided in the affinity of the collagens to the various multimeric forms of vWF. There was a greater affinity to the large molecular weight and thus the active species when the test using collagen fibrils of equine origin was used. The data seem to suggest that preference should be given to that assay.

In the next article, Turecek and coworkers performed comparative studies on vWF activity using two ristocetin-based assays and an immunologic CBA assay. The vWF:RCof assays were performed using platelet aggregometry and by macroscopic observation. Plasma from healthy subjects and from patients with various forms of vWD as well as vWF concentrates were tested. Although the vWF:RCof assays are most widely used at this time in laboratories, these assays lack reproducibility and are cumbersome to perform. The authors found that the CBA assay for vWF activity measurement gave more reliable data and was more sensitive, with a better interassay variability. The assay is also easier to perform and allows better standardization.

Next, Vanhoorelbeke et al describe a modification of the traditional vWF:RCof assay in which they replaced platelet agglutination with an enzyme-linked immunosorbent assay (ELISA) method; in other words, they measure vWF:RCof activity immunologically. This modification improves accuracy of the assay and is easier to perform. They then compared this new assay with a CBA assay in its ability to discriminate types 1 and 2 vWD patients. Both assay systems were found to reliably differentiate types 1 and 2 vWD patients.

Furlan and Lämmle describe their experience with a vWF-cleaving protease. Physiologically, the large multimers of vWF are cleaved by a specific metalloprotease. It was found that there is a deficiency of this protease or an antibody against this enzyme in patients with thrombotic thrombocytopenic purpura (TTP). Patients with TTP who have a deficiency of this protease benefit from infusions of fresh frozen plasma; those with antibodies require immunosuppressive therapy. Patients with a disease similar to TTP, hemolytic-uremic syndrome (HUS), have normal levels of the vWF-cleaving protease. Determination of this enzyme by appropriate methods will thus not only allow a differentiation between TTP and HUS but also guide treatment of TTP patients.

In the next article, Budde and associates review extensively the laboratory diagnosis of vWD. vWD is encountered in three basic forms: type 1 is characterized by a quantitative defect in vWF; type 2 is a qualitative defect in vWF; and type 3 is the severe form of type 1, in which vWF is virtually absent. Type 2 vWD can be subdivided in types 2A, 2B, 2M, and 2N. The authors describe their experience with 303 patients with vWD. All had a careful and extensive history taken, all were subjected to a battery of screening tests (bleeding times, platelet counts, activated partial thromboplastin time and filter tests), and all were tested with confirmatory assays: vWF:RCof, vWF:CBA, vWF:Ag, ristocetin-induced platelet agglutination (RIPA), and FVIIIc assays. Final classification was performed by multimeric analysis and measurement of platelet vWF. The difficulties in properly classifying patients with vWD are expertly described.

Favaloro reports on his experience with a vWF:CBA over the last 15 years. Although this assay is relatively new to the routine analysis of vWF, the author has used it for a long period of time. Most assays presently employed in the diagnostic work-up of patients with vWD are described, and their value in making the proper classification is examined. Comparisons allow the reader to determine which assays to use for maximum benefit. The author clearly elaborates a practical panel of assays that allows, in most instances, a correct classification of vWD.

Next, Auerswald and coworkers report on the treatment of 14 patients with vWD with a new high purity, double virus-inactivated FVIII/vWF concentrate, Immunate^℗. The concentrate is derived from human plasma. Patients with acute bleeding or those who had to be subjected to major surgery were treated. All aspects of vWF were monitored multiple times before and during treatment. The clinical efficacy of the concentrates was rated as good to excellent, and no serious side effects were noted. Three patients had rebleeding episodes; one of these had FXIII deficiency in addition to vWD. Pharmacokinetic data suggested that a modification of the treatment schedule used might be possible.

The next article by Schwartz and coworkers reviews the structure-function relationship of vWF and describes the results of infusion studies of recombinant vWF into animals with vWD. Two different recombinant vWF concentrates were investigated, one being a fully processed vWF, the other a preparation in which the propeptide is still covalently linked to the mature vWF. When the pro-vWF was administered to dogs with vWD, the propeptide was removed in the circulation, indicating that this cleavage can occur extracellularly. In a murine model of vWD the mechanisms involved in the clearance of FVIII:C from the circulation was studied. Apparently, the low levels of FVIII in the absence of vWF are due to binding of FVIII to the low-density LRP and its rapid removal from the circulation by endocytosis. It could be shown that the infusion of LRP into vWF knockout mice significantly improved the recovery of FVIII and its survival time.

The last article by Budde and associates reviews acquired von Willebrand syndrome (avWS). The authors compare their own experience with data from the literature and from an international registry. avWS is associated with a large number of diseases, especially lymphoproliferative and cardiovascular disorders. The mechanisms by which the disease is acquired are variable, as is the clinical presentation. The largest group reported in the literature and the registry is patients with lymphoproliferative disorders, followed by patients with myeloproliferative disorders. This article reviews all groups of patients, their clinical presentation, and their laboratory findings. The authors conclude that avWS is probably underdiagnosed at this time, and they encourage health practitioners to be more vigilant in identifying this potentially dangerous complication.

It is hoped that this comprehensive review of vWF and vWD helps the reader to unravel some of the complexities of this entity. It is after all the most common congenital bleeding disorder. My thanks and sincere appreciation go to all authors for their excellent contributions and special thanks to Dr. Jan J. Michiels for assembling this important issue.

NOTE ADDED IN PROOF: Since the writing of these articles, the International Society on Thrombosis and Hemostasis has published a report with new nomenclature for vWF assays (Thrombosis and Hemostasis 2001;86:712). In page proofs, some of the authors chose to change to the new acronyms, while others did not.