Hematology Advisor: What are some of the challenges pertaining to VWD diagnosis and treatment, and how should these be addressed in clinical practice?

Dr Lawrence: We continue to lack an assay that adequately captures the physiologic activity of VWF activity under shear flow stress, which has led to the controversy over both appropriate selection of activity assay and diagnostic criteria for VWD when using these assay results. Furthermore, the storage and transport of blood samples is known to impact the consistency of values reported for coagulation testing and has been seen with VW antigen, ristocetin cofactor activity, and factor 8 activity levels, further emphasizing the importance of repeat testing in patients and suggesting utility of onsite diagnostic testing when available.

The limited commercial availability of the VWF:GP1bM assay and the lack of standardization in VWF:collagen binding assays continue to leave room for debate about the integration of these assays in diagnostic testing. Experts in VWD management generally recommend that the benefits and limitations of these assays be weighed in the context of initial screening tests to help guide the utility of their use. Providers should — at minimum — consider sending these tests in patients with a suspected type 2 VWD subtype. Little guidance has been provided in choosing VWF collagen binding assays over the traditional VWF multimeric analysis, and hematology providers may need to consider intralaboratory variability in these specific tests when making their selection. Some patients with type 2M VWD may show discordance between the multimeric analysis and collagen binding assays if the defect in VWF is present in the collagen binding site, and thus utilizing both tests may remain prudent in some cases.

Continue Reading

There remain particular challenges in determining the clinical significance of patients with borderline VW antigen and/or activity levels (in the 30-50 IU/dL range). We know that VWF gene sequence variants are detected much less commonly in these patients. We also know that in some of these patients, there can be age-related increase in the VWF levels into the normal range. However, the presence of a bleeding phenotype is highly variable in these patients, and we do not know if age-related changes decreases the risk of bleeding.

The implementation of standardized bleeding assessment tools into clinical practice remains variable between institutions, and their utility in the pediatric population is still hotly contested. While a positive bleeding score may prompt more expeditious hematologic evaluation, a negative score likely does not exclude a bleeding predisposition in pediatric patients who have had few hemostatic challenges — for example, surgeries, procedures, or premenarche.

Although Vonvendi® is FDA-approved in adult populations, it has not yet been approved in pediatric patients — a challenge not unique to the treatment of children with rare bleeding disorders. Furthermore, real-world experience of using Vonvendi® is still early yet, thus it remains to be shown if Vonvendi® will demonstrate superior efficacy or safety profile compared to the less expensive plasma-derived concentrates. 

In general, symptom control in patients with VWD is generally quite good with the therapies used to date, including DDAVP, plasma-derived and recombinant factor concentrates, and antifibrinolytic therapies. However, there remains a paucity of data to guide the treatment of certain more refractory subsets of patients, including Type 3 VWD patients who have developed antibodies to VWF and type 2 variants who show suboptimal clinical response to plasma-derived concentrates. Vonvendi® or other prohemostatic agents like NovoSeven® (activated factor 7 concentrate) may have a role in the treatment of these patients, but published experience is limited to case reports. Patients with gut angiodysplasia similarly can experience refractory bleeding, calling into question the potential role of antiangiogenic agents in its management.

The proportion of patients with severe bleeding phenotype in VWD is generally lower, and only a small portion of patients require expensive prophylactic therapies. As such, the incentive towards curative options like gene therapy is lesser and the progress in this arena is far behind the advancements of gene therapy in hemophilia treatment. It is unclear how some of the unique biology of VWF activity in vivo — including its multimer assembly and degradation by the ADAMTS13 enzyme — will translate to challenges in moving gene therapy into clinical trials in humans.