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The Emergence of Prophylaxis as the Standard of Care to Treat Joint Bleeding Associated with Von Willebrand Disease

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Published Online: Aug 20th 2011 US Hematology, 2007;1(1):6-10 DOI:
Authors: Peter A Kouides
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Von Willebrand disease (VWD)—a disorder due to dysfunctional or deficient von Willebrand factor (VWF)—is the most common inherited disorder of hemostasis and is prevalent in approximately 1% of the total worldwide population,1,2 although the prevalence of symptomatic VWD is about 10 times lower.3

Von Willebrand disease (VWD)—a disorder due to dysfunctional or deficient von Willebrand factor (VWF)—is the most common inherited disorder of hemostasis and is prevalent in approximately 1% of the total worldwide population,1,2 although the prevalence of symptomatic VWD is about 10 times lower.3
The International Society on Thrombosis and Haemostasis (ISTH)4 classified VWD into three primary categories: type 1, type 2, and type 3. Type 2 is further divided into four sub-categories: type 2A, type 2B, type 2M, and type 2N. Type 1 is the mildest form of VWD and accounts for approximately 75% of VWD.5 It is defined by a partial quantitative deficiency in VWF and it is estimated that 56.3 and 30.7% of type 1 patients suffer from epistaxis and menorrhagia, respectively (see Table 1). Combined, type 2 accounts for an estimated 25% of VWD patients, and is caused by qualitative abnormalities in VWF. The most common bleeding symptoms in type 2 VWD are epistaxis (63%) and bleeding after dental extraction (39%) (see Table 1). Type 3 is the most severe form of the disease and the least common, with an incidence of 0.55–3.2 per million in Western countries.6 Type 3 is characterized by low or no detectable VWF in plasma and is associated with the most severe bleeding symptoms. Epistaxis occurs in 74% of type 3 patients, 52% suffer bleeding after dental extraction, and joint bleeding occurs in 42% of type 3 cases (see Table 1).2

Joint Bleeding Associated with Von Willebrand Disease

Joint disease is one of the most severe complications of inherited bleeding disorders in general; however, the exact prevalence of this complication in VWD is still unclear. Lak et al. reported that 37% of 385 Iranian children with type 3 VWD had at least one episode of joint bleeding.7 In the US, a Universal Data Collection Program (UDCP) has been established to collect clinical data from Hemophilia Treatment Centers (HTCs). To date, the UDCP has reported that 14% of type 3 VWD patients suffered from target joint complications and 28.4% had limitations to movement because of joint complications.8 Target joint bleeds are less common in VWD patients with type 1 and 2 disease, at rates of 1.4 and 1.1%, respectively.
The current standard of care for joint bleeding in severe VWD is through VWF replacement with virally inactivated factor VIII/von Willebrand factor (FVIII/VWF) concentrates. Desmopressin (DDAVP), which is used primarily to treat bleeds in type 1 VWD, is not effective for the treatment of joint bleeding and is suitable for use only in mild to moderate bleeds. Untreated joint bleeds can lead to acute and chronic pain, joint swelling, and loss of range of motion. In severe cases, patients can be wheelchair-bound. Recently, it has been suggested that prophylaxis treatment with FVIII/VWF concentrates could be implemented at an early age to prevent the worsening symptoms and the development of athropathy.8

Early Experience of Prophylaxis in Joint Bleeding

A large proportion of research into the use of prophylaxis in VWD patients has been performed in Sweden. In the 1950s, the first hemophilia patients with joint bleeding and arthropathy were admitted onto a long-term prophylaxis treatment regimen.9 In these patients, long-term prophylaxis was seen to be beneficial in improving the quality of life of patients with recurring bleeds. In the 1990s, an individualized care program was designed for hemophilia and VWD patients registered at Malmo University Hospital, Sahlgrenska University Hospital, and Karolinska Hospital. This care program provided further early data on potential benefits of prophylaxis therapy in patients with recurring bleeds.11

Current Evidence for Prophylaxis

A survey carried out by the Malmo University Hospital in 2005 included 48 patients with VWD. The patients had VWF ristocetin co-factor activity (VWF:RCo) <8% and FVIII coagulation activity (FVIII:C) <10%. Thirteen patients were treated with on-demand replacement therapy and the other 35 patients were treated with prophylaxis for at least one year.9 The authors reported that the number of joint bleeds per patient decreased from frequent events per year to less than one bleed per year in the cohort on prophylaxis. The authors concluded that prophylaxis is warranted in type 3 VWD and in certain severe bleeding cases in type 2 and 1 VWD. Interestingly, patients within the study who began prophylaxis at an early age due to mucosal bleeds did not develop joint complications later in life.
A cohort study in Italy involving 452 VWD patients, 11 of whom were on prophylaxis due to recurring bleeds, found that in comparison with the VWD patients receiving on-demand replacement therapy, the prophylaxis patients had significantly fewer hospitalizations, fewer red blood cell transfusions, and a reduction in bleeding episodes.12
Another study in Sweden examined long-term secondary prophylaxis in 37 severe VWD patients.13 The most common reasons for commencing prophylaxis were recurrent joint bleeds, gastrointestinal (GI) bleeds, and nose and mouth bleeds. Prophylaxis was defined as at least one infusion of replacement therapy per week for a period of at least 45 weeks per year. The number of injections per week ranged from one to three, which was dependent on the patient’s response to treatment and severity of bleeding episodes. The authors concluded that the number of bleeding episodes reduced significantly during prophylaxis. The median number of bleeds per year was 11 prior to prophylactic treatment, and this was significantly reduced to a median of one per year following prophylaxis with plasma concentrate. One patient developed neutralizing antibodies (inhibitors) to VWF during therapy.
Prophylaxis was also seen to be important in the prevention of joint bleeding and the development of arthropathy in pediatric type 3 VWD patients with severe musculoskeletal bleeds.14 Four patients were transferred from an on-demand regimen of FVIII/VWF concentrates (Humate P) to long-term prophylaxis of 55U/kg Humate P once or twice a week. A significant reduction in the recurrence of musculoskeletal bleeds was noted in the patients after the change in therapy. Furthermore, none of the patients suffered from joint bleeds or complications while on prophylaxis.
A recent retrospective survey collected data from 10 Italian hemophilia centers on VWD patients treated with secondary long-term prophylaxis with Humate P.15 In total, 17 patients were reported to be on prophylaxis with Humate P, of whom 35% suffered from recurring joint bleeds prior to therapy. Humate P was administered either twice or three times per week. The clinical response to secondary prophylaxis in all cases was ‘excellent or good,’ with no serious adverse events reported.

Complications of Prophylaxis Treatment

To date, there is no recombinant VWF-containing FVIII concentrate. Concerns have been expressed that the prophylactic use of plasma-derived VWF/FVIII concentrate could lead to the transmission of blood-borne viruses or other pathogens such as causative agents of HIV, West Nile disease, severe acute respiratory syndrome (SARS), and the Chinkyunga virus. The theoretical risk of these potential infectious agents may make parents concerned about allowing their children to be treated with plasma-derived products on a regular basis to prevent joint complications later in life. However, there have been no documented cases of viral transmission to patients who have received plasma-derived FVIII concentrate containing VWF.9
Long-term prophylaxis treatment has occasionally been associated with inhibitor development. In a Swedish study, three out of the 37 patients using long-term prophylaxis developed inhibitors to VWF.13 All three patients who developed inhibitors had type 3 VWD. After treatment with immune tolerance induction, two of the three patients eliminated their inhibitors and continued on their previous prophylaxis regimen. The third patient transferred to on-demand treatment with VWF/ FVIII concentrates.
To date, the cost-effectiveness of primary prophylaxis to prevent arthropathy in patients with severe VWD has not been examined. However, there is concern in the US that the insurance policies of some patients will not reimburse regular prophylaxis treatment, with the introduction of caps being placed on the total reimbursement a person is permitted to claim in their lifetime for long-term episodic treatment. This matter will need to be addressed before long-term prophylaxis is advised. Indeed, similar barriers to widespread acceptance of prophylaxis in patients with severe hemophilia have been reported, and the recent Proceedings of the Second International Prophylaxis Study Group (IPSG) symposium stated that: “It is imperative to prove the cost-effectiveness of different forms of prophylaxis to bring about more widespread support.”17

The Von Willebrand Disease Prophylaxis Network

The VWD Prophylaxis Network (VWDPN) is an international study group that has set out to investigate the role of prophylaxis in severe VWD.16 The first goal of the VWDPN was to establish the number of severe VWD patients in Europe and North America currently treated with prophylaxis. Seventy-four centers participated in the survey, wherein the total number of VWD patients was 6,208; only 102 (1.6%) were receiving prophylaxis treatment. In North America and Europe, 7.8 and 17.6% of type 1 and type 2 patients, respectively, were administered with prophylaxis. In Europe, 29% of type 3 patients were on prophylaxis treatment, compared with only 12% in North America. Joint bleeding was the most common reason for commencing prophylaxis, followed by epistaxis, and then GI tract bleeding. The greatest degree of loss of range of motion occurred in the ankle joint. In all affected joints, range of motion deteriorated with age.
The VWDPN has set goals to determine optimal treatment regimens for prophylaxis, measure alterations in quality of life, identify the risk of inhibitor development, and observe reasons for hospitalizations for patients on prophylaxis. In 2006, the VWDPN began the VWD International Prophylaxis (VIP) Study, which aims to establish the effect of prophylaxis treatment on bleeding episodes, by comparing the number of bleeds per year prior to prophylaxis to the number after prophylaxis has been initiated.

International Prophylaxis Study

The VIP study also aims to establish a set of treatment guidelines for the management of joint bleeds, GI bleeds, epistaxis, and menorrhagia. Other study objectives include identifying those patients who would benefit from prophylaxis treatment, establishing the frequency of development of inhibitor antibody to VWF, and examining the reasons and occurrence of hospitalizations. Enrolled participants will be monitored for changes in their quality of life and the incidence of any adverse side effects.
Each study group, into which patients will be enrolled depending on their entry criteria, will consist of 40–50 patients. Type 1 patients who have less than 20% of the normal level of VWF in their plasma and/or no response to DDAVP will be eligible for enrollment. All type 2B patients will be considered, as will type 2 patients with no response to DDAVP. All type 3 patients will be considered for inclusion. The specific inclusion criteria for the ‘joint bleeding’ group will be the documentation of at least two spontaneous bleeding events in the same joint, or three or more bleeding episodes in one or more joints occurring within the six months prior to enrollment into the study. For the ‘epistaxis,’ ‘GI bleeding,’ and ‘menorrhagia’ groups, patients will be eligible if they have had three or more bleeding episodes requiring replacement therapy with FVII/VWF concentrates or a packed red blood cell transfusion within the six months prior to enrollment into the study.
Patients will be treated with a three-stage dosing regimen, starting at 50IU VWF:RCo/kg VWF/FVIII concentrate once per week. This will be increased to twice per week administration, and finally to three times per week administration if a breakthrough bleeding episode occurs during the study. Subjects will be followed for at least one year and all will be treated with VWF/FVIII products licensed for use in VWD. An independent monitoring board will receive regular updates on the enrollment, data quality and completeness, and safety of the study.


Joint bleeding increases the severity of joint disease, one of the most severe complications of VWD. Several studies have demonstrated that the use of prophylaxis early in life, when started for other indications, can prevent the occurrence of joint bleeding and resultant arthropathy. More recently, studies have reported a significant decrease in the number of joint bleeds per year in patients receiving prophylaxis compared with those treated with on-demand therapy.
Based on the experience in Sweden, already published by Berntorp et al., it appears that secondary prophylaxis can reduce recurrent joint bleeding and resultant arthropathy. Although data demonstrating the value of prophylaxis in VWD are not extensive, observations and studies to date have shown the data to be consistent with the much greater experience in hemophilia. The VWDPN and VIP study will hopefully provide essential data for the evaluation of prophylaxis in VWD in the future. ■


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