Opportunities and Needs in VWD Research, Training, and Practice

Many recommendations in this guideline are based on relatively limited evidence, thus underscoring the need for further research. Some of these opportunities are discussed below.

Pathophysiology and Classification of VWD

Determinants of VWF level and bleeding risk. The risk of bleeding in persons who have VWD depends on the level of functional VWF and on many other factors that are poorly understood. The plasma level of VWF can be influenced by mutations within or near the VWF gene. In addition, VWF levels depend on ABO blood type,⁴³ possibly on the Secretor locus,¹⁰⁹ and on hormonal status and stress, as discussed in "The VWF Protein and Its Functions In Vivo" section. Relatively few of the genetic and nongenetic determinants of VWF level have been characterized, and how they interact is not known. In addition, little quantitative information is available on the risk of specific bleeding symptoms as a function of the level of VWF in plasma. This information would be particularly useful for the management of patients who have VWF levels in the range of 30—50 IU/dL, for whom the risk of medically significant bleeding is not well defined.

VWF level in plasma alone does not account for the observed variation in bleeding symptoms, and recent studies are starting to uncover some of the underlying reasons. For example, persons who have both low VWF and defects in platelet aggregation have more severe bleeding.³⁸⁷ Increased bleeding also has been associated with specific DNA markers for platelet membrane proteins.³⁸⁸ It is likely that multiple hemostatic risk factors interact with VWF level in plasma to determine the likelihood of bleeding or thrombosis. Understanding these interactions and incorporating them into clinical practice will require additional basic, clinical, and epidemiological research.

Heterogeneity of type 1 VWD. Partial quantitative deficiency of VWF can be caused by several mechanisms, as discussed in the section on "Classification of VWD Subtypes." Some persons have dominant VWF mutations that either decrease the secretion of VWF multimers or accelerate their clearance from the circulation. The prevalence of increased clearance as a cause of type 1 VWD is not known. Whether these different disease mechanisms correlate with distinct clinical features, including response to specific treatments, also is not known. Because type 1 VWD is the most common form of VWD, answers to these questions may have important consequences for medical practice.

Heterogeneity of type 2 VWD. The concentration of hemostatically effective large VWF multimers can be selectively decreased by accelerated proteolysis or by a variety of defects in multimer assembly.⁴⁹ These variants now are grouped together as type 2A VWD, but further subdivision of this category would be justifiable if specific mechanisms of disease were associated with different clinical symptoms or responses to therapy.

Most persons who have type 2M VWD have been identified by finding a profound defect in ristocetin-induced binding to platelets associated with a normal VWF multimer pattern.^55,67,72 Defects in binding to collagen or other connective tissue elements could cause a similar bleeding phenotype, but the VWF:RCo assay is insensitive to such defects.⁷³ Collagen-binding abnormalities can be detected by the VWF:CB assays, but those assays are not used widely in the United States. The prevalence and medical significance of collagen-binding defects in type 2M VWD deserve further study.

Diagnosis and Evaluation

Assessment of bleeding signs and symptoms. The initial evaluation of patients for a medically significant bleeding disorder can be difficult because mild bleeding is very common in the healthy population. Specific symptoms have been assessed for clinical relevance in retrospective studies, and some appear to discriminate among healthy controls and persons who have diagnosed bleeding disorders (Box 1). However, the utility of these questions must be established prospectively for less highly selected persons.

Quality and availability of laboratory testing. Reliable testing for VWF:Ag and FVIII is widely available, but VWF:RCo, RIPA, and VWF multimer analysis are much more variable in their performance characteristics and can be difficult to obtain. Also, tests of VWF—FVIII binding (VWF:FVIIIB) are offered by very few laboratories. More robust methods for assessing VWF function and multimer structure must be developed for routine use in the diagnosis of VWD. In addition, the sensitivity and specificity of test ratios such as VWF:RCo/VWF:Ag should be established for identifying the qualitative defects that characterize type 2A and type 2M VWD. Criteria should be established for VWF multimer analysis to distinguish a significant decrease in large multimers (in types 2A and 2B VWD) from a substantially normal multimer distribution (in types 1, 2M, and 2N VWD).

VWF gene sequencing. Mutations that cause many types of VWD can be identified by sequencing the VWF gene in DNA samples from patients.²³ The locations of mutations appear to correlate well with some disease phenotypes, suggesting that DNA sequencing could be a useful diagnostic method in VWD. With appropriate study and experience, DNA sequencing may become economical and feasible for routine use. In addition, the widespread application of VWF gene sequencing would provide invaluable information about the prevalence of VWF mutations as a function of VWF level, the strength of the relationship between VWF genotype and VWD phenotype, the penetrance of specific mutations, and the biochemical mechanisms that cause VWD. This knowledge also would be an outstanding resource for the identification and characterization of other factors that modify bleeding symptoms in VWD.

Management of VWD

Many of the standard treatments for VWD have limited experimental support. For example, the intensity and duration of therapy necessary to control bleeding have not been established for many clinical situations and often have been extrapolated from anecdotal experience in hemophilia. The indications for prophylaxis of bleeding also are not well defined. These issues should be addressed by appropriate clinical studies.

DDAVP. Many persons who have VWD respond to DDAVP with a clinically useful rise in VWF and FVIII, but the likelihood of a good outcome depends on the type of VWD and the underlying biochemical mechanism of disease. In type 1 VWD, persons who have accelerated clearance of plasma VWF may have a transient response to DDAVP.^41,232 Whether DDAVP should be used at all in persons who have type 2B VWD is controversial.^{229,237,257—259,389—391} In type 2N VWD, the baseline FVIII level may be a good predictor of the magnitude and duration of the FVIII response to DDAVP.^{77,224,228,392} The drug is thought to be safe for use in pregnancy, but the published experience in this setting is limited.^273,274 Hyponatremia and thrombotic events have occurred after DDAVP, but risk factors for these events and their incidence have not been established. These important clinical issues should be addressed by studies of DDAVP in specific types of VWD. In addition, the availability of DDAVP for subcutaneous administration may improve management of VWD.

Factor Concentrates. The available plasma—derived products that contain VWF also contain FVIII as part of the FVIII—VWF complex, and only two such products (Humate–P^® and Alphanate SD/HT^®) are currently licensed in the United States for treatment of VWD. When administered to patients who have VWD, the infused FVIII may add to the endogenous FVIII production and cause markedly elevated FVIII levels that are much greater than the VWF levels achieved with treatment; these have been associated with thrombosis.²¹⁵ High FVIII levels can be avoided by adjusting the dose of product administered, but VWF levels then may be relatively low. Whether FVIII or VWF levels, or both, should be used to monitor treatment with FVIII—VWF concentrates is unknown. Use of a pure VWF product in place of FVIII—VWF concentrates would avoid the disproportionate increase in FVIII. A pure VWF concentrate has been used in Europe³⁹³ but is not currently available in the United States. Studies are needed to establish appropriate treatment and monitoring regimens for these products. In addition, prelicensure studies of recombinant VWF are needed to establish its safety, efficacy, and role in the treatment of VWD. The licensing of other products, containing both VWF and FVIII, also would enhance therapeutic options.

Platelets. Approximately 15 percent of the total VWF in blood is found within platelets, and platelet VWF appears to contribute to hemostasis. Although VWD patients who have abnormal or low platelet VWF have been described, there has been only limited exploration of the feasibility and utility of such testing, in part because of limitations of practical methodologies. Clinically, platelet transfusions have been reported to stop bleeding in some patients who have VWD and were not helped by transfusion of FVIII—VWF concentrates.^293,294 The efficacy and appropriate use of platelet transfusions in persons who have VWD or AVWS need to be established.

Antifibrinolytics. Tranexamic acid and aminocaproic acid have been used alone or as adjunctive therapy to treat bleeding in VWD. The safety, efficacy, and optimal dosing of these agents in VWD should be established by suitable clinical studies. In addition, the availability of orally administered tranexamic acid would broaden the therapeutic options for antifibrinolytic therapy.

Gene Therapy of VWD

Severe type 3 VWD potentially can be treated with gene therapy. The gene for VWF is larger than could easily be introduced into many vectors, but "gutless" adenoviral vectors could easily accommodate a gene the size of VWF (8.5 kilobases). The prevalence of type 3 VWD and its clinical symptoms, however, does not place it in a high priority category for gene therapy trials. Point mutation repair initially was an exciting approach for VWD,^394,395 but followup studies have not achieved the same rate of success in vitro.^396,397

Issues Specific to Women

VWF is particularly important for hemostasis during menses and at childbirth. Consequently, women are affected disproportionately by having VWD, especially during their childbearing years.

Menorrhagia. The incidence of menorrhagia appears to vary inversely with VWF level, independent of whether women meet criteria for having VWD.⁴⁵ Because menorrhagia is so common, even a small reduction in its severity could have significant implications for women’s health. As discussed in the section on menorrhagia, several treatments have been used for menorrhagia associated with VWD, but their efficacy has not been demonstrated convincingly. Therefore, clinical studies would be useful to establish the effect of VWF level on menorrhagia and to evaluate specific treatments for women who have VWD or low plasma levels of VWF.

Labor and delivery. Several small case series indicate that women who have VWD and VWF levels <50 IU/dL at delivery have an increased incidence of immediate and delayed postpartum hemorrhage. These complications appear to be prevented by replacement therapy with FVIII—VWF concentrate before delivery and by either concentrate or DDAVP in the postpartum period.^85,354,377 How the risk of bleeding correlates with VWF level or FVIII level is not known, and the required intensity and duration of therapy have not been established.

Training of Specialists in Hemostasis

In the United States, despite scientific progress in basic and clinical research in bleeding and thrombotic disorders, including VWD, there is a shortage of skilled clinicians and laboratorians with expertise in hemostasis.³⁹⁸ Training opportunities need to be developed and/or expanded for hemostasis specialists. Recent clinical training opportunities include a new NHLBI initiative for training in nonmalignant hematology (RFA HL06–006; information available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-06-006.html) and a recent initiative from the U.S. National Hemophilia Foundation (NHF Clinical Fellowship Program). Recognition of hemostasis as a bona fide clinical and laboratory subspecialty in the United States could enhance entry into the field.

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