Von Willebrand disease (VWD) is an inherited bleeding disorder caused by low levels of clotting proteins. Among the 3 types of VWD, type 3 is the least common but most severe.1 Type 3 VWD is inherited in an autosomal recessive fashion.2 Patients with type 3 disease have an undetectable level of the clotting protein von Willebrand factor (VWF) and a low level of factor VIII (FVIII) (1 to 5 IU/dL).3 The exact prevalence of VWD is unknown. According to the Centers for Disease Control and Prevention, only 3% of people in the US with VWD have type 3; the majority (85%) have type 1, the mildest form of the disease.1
The clinical presentation of type 3 VWD includes severe and recurrent bleeding episodes like epistaxis, menorrhagia, and gastrointestinal and joint bleeding; available data report that between 37% and 45% of these patients experience joint bleeding. In contrast, the estimated prevalence of joint bleeding in patients with type 1 VWD is 2% to 3%.2
The on-demand treatment protocol for VWD is an established management strategy, which focuses on the episodic correction of the hemostatic defects during bleeding episodes. People with VWD have a lower frequency of bleeding episodes than those with hemophilia. Therefore, treatment is typically administered during bleeding episodes or prophylactically in anticipation of invasive procedures. However, it has been speculated that people with type 3 VWD can benefit from long-term prophylaxis, which is expected to lower annual bleeding events.4 Desmopressin, used in treating some patients with type 1 VWD, is ineffective in type 3. Plasma-derived VWF (pdVWF) and/or FVIII concentrates and recombinant VWF (rVWF) are the approved treatments for patients with type 3 VWD and are used for short- and long-term prophylaxis.5 The prevalence of common bleeding symptoms for patients with type 3 VWD is available in Figure 1.2
Short-Term Prophylaxis
Surgery and invasive procedures risk severe bleeding in patients with VWD. This risk can be reduced with short-term prophylaxis using VWF with FVIII or VWF only. The evidence suggests this is an effective approach, and a hemostatic efficacy of between 93% and 100% has been achieved.3 The dosing recommendation for VWF varies; however, as a guide, minor surgeries require the patient maintain hemostasis for 1 to 5 days, while major surgeries require approximately 7 to 14 days of maintaining hemostasis.2 The target VWF plasma levels that are aimed to be achieved during prophylaxis for major surgery is 50 to 100 IU/dL. VWF and FVIII should be measured daily during the postoperative period; levels less than 50 IU/dL may lead to inadequate hemostasis, and levels greater than 150 IU/dL may increase the risk of thromboembolism.3 Caution should also be employed in individuals with risk factors for thromboembolism, such as those with immobility or obesity and those with a history of previous thrombosis, surgery, or the use of hormone replacement therapy.2
Short-term prophylaxis is also indicated in pregnancy for patients with type 3 VWD. In healthy women, VWF and FVIII increase during pregnancy, but in those with type 3 VWD, VWF and FVIII levels remain low.6 Therefore, prenatal care and delivery should be performed in centers that, in addition to specialists in high-risk obstetrics, have a hemophilia treatment center and/or a hematologist with expertise in hemostasis, and prophylaxis should be offered to these patients before invasive procedures such as chorionic villus sampling, cervical cerclage, or amniocentesis.2 The prevalence of postpartum hemorrhage in patients with VWD is between 5% and 40%, compared with a prevalence rate in the general population of 2% to 10%.6 The general recommendation is that VWF ristocetin cofactor (VWF:RCo) and FVIII levels should reach 50 IU/dL before delivery. Furthermore, there is a risk of delayed postpartum hemorrhage, so patients should be monitored for 2 weeks or more after delivery.2
Long-Term Prophylaxis
On-demand treatment alone may be inadequate for the subset of people with VWD who experience severe bleeding episodes. Recurrent severe bleeding events impact a patient’s quality of life and can be potentially life-threatening. For example, over 10% of patients with type 3 VWD may develop blood-induced arthropathy.7
The 2021 joint guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Hemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) recommend long-term prophylaxis for patients with VWD and a history of severe and frequent bleeds.8 In these patients, bleeding symptoms and the need for prophylaxis should be periodically assessed.
Long-term prophylaxis for people with VWD refers to routine replacement therapy occurring at least weekly for a period of 6 months or more.3 Joint and gastrointestinal bleeding are the main indications for long-term prophylaxis in patients with type 3 VWD.9 Recommended therapies for long-term prophylaxis in type 3 VWD are pdVWF and rVWF. A Swedish study previously reported that among children with VWD (inclusive of types 1 to 3), starting routine prophylaxis before the age of 5 years provided relief, and these children experienced no joint bleeds and developed no clinical signs of arthropathy.10 A study involving patients with severe and symptomatic VWD across a wide age range (aged 1 to 85 years) also reported good/excellent effectiveness in 100% of patients who received long-term prophylaxis. Routine prophylaxis with plasma‐derived FVIII/VWF concentrate was effective and well tolerated to prevent recurrent joint bleeding, hematoma, and ear, nose, and throat bleeding.9 In a retrospective study of 59 individuals with severe VWD disease, routine prophylaxis reduced the annualized number of joint bleeding episodes from 15.6 to 1.3.11 Similarly, another prospective study found that routine prophylaxis reduced the median annual bleeding rate from 25 to 6.1.12
Plasma-derived VWF is an effective prophylactic agent; a study of children and adolescents with VWD and clinically relevant bleeding found that prophylactic treatment stopped recurrent bleeding episodes in 31 of 32 patients.13
Recombinant VWF to Address Challenges of Long-Term Prophylaxis for Severe Type 3 VWD
Although long-term prophylaxis with pdVWF concentrate can effectively reduce the risk of bleeding episodes in patients with type 3 VWD, these agents have limitations that can compromise their optimal use. For example, the VWF and FVIII ratio can vary between different pdVWF concentrates and batch-to-batch variations in VWF:RCo activity. Furthermore, hemostatically effective ultra-large multimers (ULMs), thought to play a critical role in platelet aggregation and clot formation, are variably deficient in current preparations of pdVWF concentrates.14 A challenge to note is the accumulation of FVIII, which can occur with repeated administration and increase the risk of thromboembolic events, particularly during surgical procedures.5
Recombinant VWF addresses some of the limitations associated with pdVWF, including the presence of ULMs, improving treatment outcomes.15 The safety and efficacy of rVWF for patients with severe VWD undergoing elective surgery has been demonstrated.5 A prospective, open-label, nonrandomized, phase 3 study investigated the efficacy and safety of rVWF prophylaxis in 2 cohorts of patients aged 18 years and older with severe VWD (N=23): a cohort where patients previously received on-demand treatment for spontaneous bleeding (n=13) and a cohort where patients were switched to rVWF prophylaxis from pdVWF prophylaxis (n=10). Patients received intravenous infusion of rVWF up to 18 months, with a primary endpoint investigating the annualized bleeding rate in patients treated for spontaneous bleeding during rVWF prophylaxis over a 12-month study period. The results found that in patients previously receiving on-demand treatment, prophylaxis with rVWF reduced spontaneous annual bleeding rate by 91.5%, and the mean spontaneous annualized bleeding rate for treated bleeds decreased from 6.54 to 0.56 in these patients. In the cohort of patients previously receiving pdVWF prophylactically who were switched to rVWF, the spontaneous annual bleeding rate was reduced by 45%.16
Routine Prophylaxis, Monitoring, and Side Effect Mitigation
There are challenges regarding the optimal dose and duration of treatment for routine prophylaxis due to variations in the protocols used in different studies. International guidelines recommend that for routine prophylaxis, rVWF may be administered at a recommended dose of 40 to 80 VWF:RCo activity unit/kg.8 A suggested protocol for routine prophylaxis in patients with severe type 3 VWD is 40 to 60 IU/kg, administered twice weekly.17 Following the administration of rVWF, FVIII levels rise to hemostatic levels (>40 IU/dL) and remain at hemostatic levels for at least 72 hours post-administration. The observed half-life of rVWF is 22.6 hours in contrast with pdVWF, which has a mean half-life of 12.8 to 15.8 hours.15
Anaphylactic reactions are generally rare. However, infusion should be stopped if anaphylactic symptoms occur during the infusion treatment, such as urticaria, chest tightness, or pruritus.
Failure to achieve therapeutic levels of VWF despite adequate dosing may indicate the presence of alloantibodies. Approximately 5% to 10% of patients with type 3 VWD develop alloantibodies, which can increase the risk of anaphylactic reactions.18 If a patient receiving pdVWF develops alloantibodies, treatment should be switched to a high-dose recombinant FVIII to avoid anaphylactic reactions.4 Without the stabilizing effect of VWF, the short half-life of FVIII poses a challenge in managing VWD with alloantibodies. There has been a case report that describes the successful use of emicizumab, a FVIII mimetic, to manage a patient with hemarthrosis and alloantibodies.19
Recombinant VWF Treatment Side Effects and Considerations
Documented side effects of rVWF include dizziness, nausea, vomiting, dysgeusia, infusion site paresthesia, chest pain, tachycardia, generalized pruritus, and T-wave inversion.15,17 However, symptoms of chest pain and increased heart rate have been reported to improve with 10 minutes of oxygen administration and were observed to fully resolve within 3 hours.15
Despite sterilization, there is a hypothetical risk of infections with plasma-derived products; as such, patients receiving plasma-derived products should be immunized against hepatitis A and B.2 It is also best for patients to avoid aspirins, nonsteroidal anti-inflammatory drugs, and other antiplatelets. However, international guidelines conditionally recommend that patients with cardiovascular disease who require antiplatelets should be given the necessary antiplatelets.8
References
1. What is von Willebrand disease (VWD)? Centers for Disease Control and Prevention. Updated December 30, 2022. Accessed January 25, 2023. https://www.cdc.gov/ncbddd/vwd/facts.html
2. NHLBI von Willebrand Disease Expert Panel. The diagnosis, evaluation and management of von Willebrand disease. US Department of Health and Human Services. Published December 2007. Accessed January 25, 2023. https://www.nhlbi.nih.gov/sites/default/files/media/docs/vwd.pdf
3. Franchini M, Seidizadeh O, Mannucci PM. Prophylactic management of patients with von Willebrand disease. Ther Adv Hematol. 2021;12:20406207211064064. doi:10.1177/20406207211064064
4. Miesbach W, Berntorp E. Translating the success of prophylaxis in haemophilia to von Willebrand disease. Thromb Res. 2021;199:67-74. doi:10.1016/j.thromres.2020.12.030
5. Peyvandi F, Mamaev A, Wang JD, et al. Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. J Thromb Haemost. 2019;17(1):52-62. doi:10.1111/jth.14313
6. Janbain M, Kouides P. Managing pregnant women with hemophilia and von Willebrand disease: how do we provide optimum care and prevent complications? Int J Womens Health. 2022;14:1307-1313. doi:10.2147/IJWH.S273043
7. van Galen KPM, Sanders YV, Vojinovic U, et al. Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study. Haemophilia. 2015;21(3):e185-e192. doi:10.1111/hae.12670
8. Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5(1):301-325. doi:10.1182/bloodadvances.2020003264
9. Rugeri L, Harroche A, Repessé Y, et al. Effectiveness of long-term prophylaxis using pdFVIII/VWF concentrate in patients with inherited von Willebrand disease. Eur J Haematol. 2022;109(1):109-117. doi:10.1111/ejh.13778
10. Berntorp E, Petrini P. Long-term prophylaxis in von Willebrand disease. Blood Coagul Fibrinolysis. 2005;16(suppl 1):S23-S26. doi:10.1097/01.mbc.0000167659.23262.18
11. Abshire TC, Federici AB, Alvárez MT, et al. Prophylaxis in severe forms of von Willebrand’s disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN). Haemophilia. 2013;19(1):76-81. doi:10.1111/j.1365-2516.2012.02916.x
12. Abshire T, Cox-Gill J, Kempton CL, et al. Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network. J Thromb Haemost. 2015;13(9):1585-1589. doi:10.1111/jth.12995
13. Halimeh S, Krümpel A, Rott H, et al. Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease. Results of a cohort study. Thromb Haemost. 2011;105(4):597-604. doi:10.1160/TH10-09-0616
14. Peyvandi F, Garagiola I, Baronciani L. Role of von Willebrand factor in the haemostasis. Blood Transfus. 2011;9(suppl 2):s3-8. doi:10.2450/2011.002S.
15. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015;126(17):2038-2046. doi:10.1182/blood-2015-02-629873
16. Leebeek FWG, Peyvandi F, Escobar M, et al. Recombinant von Willebrand factor prophylaxis in patients with severe von Willebrand disease: phase 3 study results. Blood. 2022;140(2):89-98. doi:10.1182/blood.2021014810
17. VONVENDI®. Prescribing information. Baxalta US Inc; 2022. Accessed January 25, 2023. https://www.fda.gov/media/94863/download
18. James PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood. 2013;122(5):636-640. doi:10.1182/blood-2012-10-462085
19. Weyand AC, Flood VH, Shavit JA, Pipe SW. Efficacy of emicizumab in a pediatric patient with type 3 von Willebrand disease and alloantibodies. Blood Adv. 2019;3(18):2748-2750. doi:10.1182/bloodadvances.2019000656
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Hematology Advisor had no role in this content’s preparation.
Reviewed February 2023
