With MUDr. Eva Drbohlavová on Innovations in the Treatment of von Willebrand Disease and Improving Patients' Quality of Life

With MUDr. Eva Drbohlavová on Innovations in the Treatment of von Willebrand Disease and Improving Patients' Quality of Life

Von Willebrand Disease (vWD), as the most common congenital bleeding disorder, remains underdiagnosed. However, thanks to new insights and advances in genetic testing, both diagnosis and long-term prophylaxis of the disease are gradually improving, leading to a significant reduction in bleeding and better quality of life for patients. We discuss this in more detail with MUDr. Eva Drbohlavová from the Department of Clinical Hematology at the Regional Hospital Liberec.

What do the latest findings in the field of long-term prophylaxis for von Willebrand Disease bring? And what are the current indications for its initiation?

The essence of vWD is either a quantitative or qualitative deficiency of von Willebrand factor (vWF). Diagnosis is based on family and personal history of bleeding, basic and specific tests, and more recently, genetic tests that can help distinguish between the different subtypes of the disease. Patients mainly suffer from epistaxis, women experience heavy menstrual bleeding (HMB), there is a risk of bleeding during surgical procedures, and type 3 also carries a risk of gastrointestinal tract (GIT) and joint bleeding—similar symptoms to those seen in hemophilia patients. The bleeding phenotype may not correlate with vWF levels, making genetic tests significant in these cases.

According to the guidelines of the International Society on Thrombosis and Haemostasis (ISTH), prophylaxis is generally recommended for patients with vWD with a history of severe and frequent bleeding. Clinically, these are patients with type 3 vWD, but also type 2 and those with severe bleeding manifestations. Additionally, these are patients who repeatedly bleed and experience a decrease in hemoglobin requiring transfusion.

What is the safety and efficacy of long-term prophylaxis for different types of vWD? What are the current discussions in this area?

Evidence that vWD patients benefit from prophylaxis includes the WILL-31 study with pdVWF/FVIII (1:1) at a dosage of 2-3 times weekly at 20-40 IU/kg. In type 3 vWD, there was an 86% reduction in the overall annual bleeding rate (ABR). Prophylaxis was very well tolerated, with no accumulation of vWF or FVIII, and no thrombotic events, which is a primary concern. Another potential risk is the formation of allogeneic antibodies—an inhibitor. We have various products available with different ratios of vWF and FVIII, and their use is determined by the type of disease. We have pdVWF/FVIII (2.4:1), pdVWF/FVIII (1:1), and now also rVWF. In clinical practice, we are concerned about high FVIII levels due to the risk of thrombotic complications. On the other hand, it is unclear what the target trough levels of vWF should be for vWD prophylaxis, unlike in hemophilia prophylaxis.

How can we personalize treatment in long-term prophylaxis and monitor its impact on patients' quality of life?

The most widely used tool for diagnosis is the BAT (Bleeding Assessment Tool Score). For assessing quality of life, we have other structured questionnaires. Personally, I believe that a detailed bleeding history, both personal and family, is a cornerstone of diagnosing congenital bleeding disorders. Regarding the quality of life on prophylaxis, communication with the patient is also crucial, as well as trust and the ability to discuss other aspects of their life, such as coping with the disease, adherence to treatment, and the benefits they gain from it. While these aspects can be standardized with questionnaires, often more is learned through direct communication than from a mere questionnaire.

During treatment (prophylactic and on-demand, for example, before surgery), it is useful to measure vWF and FVIII levels, record the highest and lowest achieved values, and check the efficacy and safety of the administered treatment. Pharmacokinetic curves, as used in hemophilia patients, can also assist. Recently, a PK model was developed to predict vWF and FVIII levels after perioperative administration of pdVWF/FVIII (2.4:1). At the ISTH 2024 congress, the PK VIN study was presented, where this model was used to predict levels during perioperative management of patients with type 1 and 2 vWD. The predicted vWF and FVIII levels were achieved, the PK model was evaluated as safe, leading to patient and physician satisfaction, and it was cost-effective.

Can you share your experiences and successes with modalities used in long-term prophylaxis?

In our center, we have a patient with type 2M vWD on long-term prophylaxis, who suffered from repeated severe epistaxis and failed previous treatments (tranexamic acid, rutin/ascorbic acid, iron infusions, and ultimately transfusions). On prophylaxis with pdVWF/FVIII (2.4:1) twice a week at 35 IU/kg, the episodes of epistaxis significantly reduced, the patient's blood count normalized without the need for iron supplementation or transfusion, and he quickly learned self-administration. This significantly improved his quality of life, reduced the number of healthcare visits, and related work absences.

How do you see prophylaxis in the future? What role might non-protein regimens or gene therapy play? What can bring more effective long-term protection against bleeding?

One of the recent treatment options for vWD patients is recombinant vWF (rVWF). Its pharmacokinetics, safety, and efficacy have been reported in two prospective studies—for on-demand treatment and prophylaxis, where vWD patients received 50 IU/kg IV twice weekly. There was a reduction in spontaneous bleeding, and no thrombotic events were reported. During rVWF prophylaxis, adding FVIII does not bring any benefit. The safety and efficacy of rVWF use in patients undergoing surgery were also confirmed in a phase III study. In 89% of cases, adding FVIII was unnecessary, and rVWF was administered alone with very good effect. One thrombotic event was described in this study.

Another option is emicizumab—a bispecific antibody that bridges factors IXa and X and is approved for patients with hemophilia A with or without an inhibitor. Its advantage is subcutaneous administration. Off-label use of emicizumab has already been successfully reported in patients with type 3 vWD. I believe it will also find application in this indication and will expand within on-label indication.

Pegylated aptamer BT200 binds to the A1 domain of vWF and reduces the clearance of vWF/FVIII. Its use was evaluated in a phase II study in patients with type 2B vWD associated with thrombocytopenia. There was a threefold increase in platelets.

Gene analysis is currently used to confirm the diagnosis of vWD and some of its subtypes, but gene therapy, which is already available for hemophilia A and B, lags behind in vWD. This is partly because available treatment modalities are effective and safe, and also because there are fewer suitable candidates for prophylaxis in vWD. The combination of adjunctive treatments (antifibrinolytics and hormonal therapy) with desmopressin and vWF concentrates leads to very effective bleeding control in most vWD patients. Additionally, there is a technical problem with the structurally large vWF gene, whose splicing (to fit into a vector) leads to loss of function. Finally, the target cell is the endothelial cell, and it is challenging to find an appropriate vector that targets it.

MUDr. Andrea Skálová Editorial Team, Medscope.pro