Translating the success of prophylaxis in haemophilia to von Willebrand disease.

INTRODUCTION: There is limited awareness of von Willebrand disease (VWD), leading to challenges in both diagnosis and defining the optimal treatment approach for these patients. Patients with VWD are typically treated on-demand, with short-term prophylaxis used during surgery. In contrast, early initiation, and long-term use of prophylaxis is the standard of care in patients with severe haemophilia and can be successfully used to prevent joint bleeding and reduce chronic arthropathy. AIM: To provide an understanding of the current evidence for the prophylactic treatment of patients with VWD and compare this to the management of patients with haemophilia. METHODS: Review of published literature using a non-systematic search of PubMed and reference lists of sourced articles. RESULTS: The successes seen with prophylaxis in haemophilia provide the rationale for long-term prophylaxis in patients with severe forms of VWD; preventing spontaneous, excessive and sometimes life-threatening bleeding, and reducing chronic joint disease. Currently, there are a few clinical trials assessing the long-term benefits of prophylaxis in VWD, and guidelines for the optimal prophylaxis treatment approach are lacking. Greater attempts to provide comprehensive, long-term care for patients with VWD are needed but still lacking within the community. This review highlights the success of prophylaxis in haemophilia and how this knowledge might be applied and translated to patients with VWD. CONCLUSIONS: Lessons can be learned from the use of prophylaxis in haemophilia and prophylaxis should be considered the standard of care for a subgroup of patients with severe VWD.

The World Federation of Hemophilia Annual Global Survey 1999-2018.

INTRODUCTION: The World Federation of Hemophilia (WFH) strives to achieve care for all patients with inherited bleeding disorders through research, advocacy, capacity building and education. The WFH developed and implemented the Annual Global Survey (AGS), through which comprehensive demographic and treatment data on bleeding disorders are collected each year from its constituent non-governmental national organizations. AIM: To describe the development, methodology and achievements of the WFH AGS over the past 20 years. METHODS: The AGS is a yearly cross-sectional survey. Data are collected using a standardized form (available online and on paper), quality checked and reviewed, and published in English, French and Spanish. Over time, the AGS has been modified in response to changes in treatment landscape or emerging new issues. RESULTS: Over the past 20 years, the AGS has reported an increase in the number of countries participating in the survey, a tripling in the number of people identified with rare bleeding disorders and an increase in the amount of factor used to treat people with haemophilia. Yet, a large treatment inequity gap still exists across the globe. In response to this gap, the WFH has analysed the AGS reports which has stimulated further development in quality of care indicators, estimates of the global prevalence of haemophilia, patient-level data collection efforts like the World Bleeding Disorders Registry and the Gene Therapy Registry. CONCLUSION: The AGS has provided evidence to support research, programme planning and development activities of the WFH.

A phase III study comparing secondary long-term prophylaxis versus on-demand treatment with vWF/FVIII concentrates in severe inherited von Willebrand disease.

BACKGROUND: There is a lack of prospective clinical trials specifically designed to evaluate the benefits of prophylaxis with vWF/FVIII concentrates in patients with inherited von Willebrand disease (vWD). The aim of the study was to compare efficacy of secondary long-term prophylaxis (PRO) with vWF/FVIII in the prevention of bleeding episodes in severe vWD patients to standard of care (on-demand treatment; ODT). MATERIALS AND METHODS: In this 12-month, phase III, open-label study (PRO.WILL), vWD patients (aged ≥6 years) were randomised to PRO (n=9; 5 completed) or ODT (n=10; 7 completed) treatment with Fanhdi®/Alphanate® (Grifols) according to current licensing status for use in vWD. We assessed the proportion of patients who did not present any spontaneous bleeding episode, adverse events (AEs) or thrombotic events. RESULTS: All patients on ODT had vWD type 2 or 3 vs 70% of patients on PRO. All ODT patients experienced bleeds vs 60% on PRO. PRO patients showed fewer bleeds (n=32 vs n=172 [112 in the same patient, mostly mucosal]; p<0.0001) and lower risk of bleeding (relative attributable risk estimate: -0.667; 95% CI: -2.374, -0.107; p<0.001). Most frequent bleeds in ODT and PRO groups were, respectively, epistaxis (n=52 vs n=15) and gastrointestinal (n=13 [9 in the same patient] vs n=1). While most bleeds lasted one day under ODT (31/32), only epistaxis did so in PRO group (14/15). No AEs due to study medication were observed. DISCUSSION: Despite the small sample size and the heterogeneity of the study population, patients on vWF/FVIII prophylaxis showed a reduction in bleeding risk and rate compared to on-demand treatment.

Adult and pediatric mechanical circulation: a guide for the hematologist.

Mechanical circulatory support (MCS) is the overarching term that encompasses the temporary and durable devices used in patients with severe heart failure. MCS disturbs the hematologic and coagulation system, leading to platelet activation, activation of the contact pathway of coagulation, and acquired von Willebrand syndrome. Ischemic stroke and major hemorrhage occur in up to 30% of patients. Hematologists are an essential part of the MCS team because they understand the delicate balance between bleeding and clotting and alteration of hemostasis with antithrombotic therapy. However, prior to this important collaborative role, learning the terminology used in the field and types of MCS devices allows improved communication with the MCS team and best patient care. Understanding which antithromobotic therapies are used at baseline is also required to provide recommendations if hemorrhage or thrombosis occurs. Additional challenging consultations in MCS patients include the influence of thrombophilia on the risk for thrombosis and management of heparin-induced thrombocytopenia. This narrative review will provide a foundation to understand MCS devices how to prevent, diagnose, and manage MCS thrombosis for the practicing hematologist.

Current challenges in the diagnosis and management of patients with inherited von Willebrand's disease in Italy: an Expert Meeting Report on the diagnosis and surgical and secondary long-term prophylaxis.

Recent advances in the care of von Willebrand's disease (vWD) have allowed the majority of patients to be managed adequately. Even in the more severe forms, it is now possible to control recurrent bleeding through secondary long-term prophylaxis with von Willebrand factor-containing concentrates. Moreover, in the setting of surgical prophylaxis, the combination of interdisciplinary management and close patient monitoring yields a positive outcome in nearly all cases, although safety concerns remain. In clinical practice, the effectiveness of therapy is hindered by the difficulties in making a rapid, yet accurate diagnosis, in identifying the subgroup of bleeders who may benefit most from a specific strategy, and in selecting the optimal product and regimen.Since specific guidelines for heavy bleeders requiring short- and long-term prophylaxis are still lacking, sharing the experience of experts dealing with vWD patients on a daily basis is crucial to fill gaps in information relating to patient management. To address this important issue, 13 Italian haematologists met in Milan on April, 2, 2016 and in Florence on July, 9, 2016. A 30-question survey constituted the input to discuss (i) optimisation of the diagnostic workflow for vWD, (ii) the characteristics of patients who may benefit from secondary long-term prophylaxis (in particular with the purified von Willebrand factor concentrate with a low content of factor VIII), (iii) the key elements to consider when selecting a concentrate and (iv) the pre-operative and post-operative management of vWD patients. A summary of the main points covered is provided in this report.

Management of VWD.

VWD is the most common inherited bleeding disorder known. It is caused by a deficiency or dysfunction of the VWF molecule. Bleeding risk varies between modest increases in bleeding seen only with procedures to major risk of spontaneous hemorrhage depending upon the type of VWD. The treatment approach to VWD has changed little in the past 2 decades, but there are numerous subtleties in optimal management. Management includes the prevention or treatment of bleeding by raising endogenous VWF levels with medications such as desmopressin or providing exogenous VWF concentrates. Fibrinolytic inhibitors and topical hemostatic agents are also effective adjunctive measures. Bleeding specific to women presents a special challenge because of heavy menstrual bleeding and pregnancy. Successful management of pregnancy in patients with VWD involves coordination with obstetrics, anesthesia, and the coagulation laboratory monitoring VWF:RCo and FVIII:C levels. Prophylactic treatment with VWF concentrates is emerging as an effective preventive therapy in patients with severe disease. Antibodies to VWF present a special challenge in the management of rare patients with type 3 disease. New therapies on the horizon include recombinant VWF, anti-VWF aptamers, and medications such as IL-11 to raise VWF levels. The key to effective treatment of VWD is an accurate diagnosis of the specific type and selection of hemostatic products appropriate for the clinical situation.

Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease. Results of a cohort study.

In patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P® or Wilate® (n=24). Median [min-max] dose [vWF:RCo] was 40 [20-47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12-month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the pre-prophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy.

Prophylaxis in bleeding disorders.

Primary prophylaxis with coagulation factor concentrates has become the standard of care for children with hemophilia to reduce the risk of bleeding and related morbidity. However, several important questions remain unanswered regarding the optimal use of prophylaxis in patients with bleeding disorders. Limited data are available on the use of primary prophylaxis in adults with hemophilia, although tailoring the dose and schedule of prophylaxis in adults based on the clinical course of the disease may improve convenience and reduce costs without compromising efficacy. Patients with severe forms of von Willebrand disease (VWD) are at risk of serious bleeding episodes and may therefore benefit from prophylaxis; results from ongoing trials, such as the VWD International Prophylaxis (VIP) trial, are expected to provide more insight into the efficacy and safety of prophylaxis in these patients. For patients with other rare bleeding disorders, prophylaxis may be considered, depending on the clinical course of the disease and the availability of factor replacement therapy products; definitive recommendations, however, are not possible given the lack of comprehensive studies evaluating prophylaxis in this setting. Ongoing studies will help further define the role of coagulation factor concentrate prophylaxis in patients with bleeding disorders.

The role of prophylaxis in the management of von Willebrand disease: today and tomorrow.

Some patients with von Willebrand disease (VWD) will experience severe bleeding complications requiring intensive treatment. Up to 40% of patients with type 3 VWD experience joint bleeding, which can lead to haemophilic arthropathy. Patients with type 2A or 2B VWD are at risk of developing recurrent gastrointestinal bleeding, which is associated with angiodysplasia. Some children with VWD will experience epistaxis of sufficient frequency, duration, or severity to cause anaemia and have negative effects on overall health, development, and quality of life. For these patients, prophylactic use of concentrates containing von Willebrand factor may help to avoid bleeding events and their associated complications. The available clinical data suggest that secondary prophylaxis is beneficial in patients with type 3 VWD and certain patients with type 1 or 2 VWD. The VWD International Prophylaxis (VIP) trial is an ongoing study that will help to identify which patients are most likely to benefit from long-term prophylaxis, and determine the optimal approach to prophylaxis in various settings.

Use of recombinant factor VIIa in inherited and acquired von Willebrand disease.

Recombinant factor VIIa (rFVIIa) is increasingly used outside the labeled indications for the treatment of life-threatening bleeding episodes after failure of respective standard therapy. In this article, the authors focus on the use of the agent in patients with inherited or acquired von Willebrand disease (vWD). Although the current experience is sparse, published cases indicate the high efficacy of rFVIIa for the treatment of patients refractory to conventional treatment. The agent may be used in patients with congenital vWD complicated by alloantibodies directed against substituted von Willebrand factor or in the presence of concomitant hemostatic defects as well as acquired vWD with hitherto limited therapeutic options. Controlled clinical studies are necessary to define the use of rFVIIa in this clinical setting.

Anesthetic management in a pediatric patient with Noonan syndrome, mastocytosis, and von Willebrand disease: a case report.

This case report describes anesthetic considerations for a 6-year-old boy, admitted for adenoidectomy under general anesthesia, who had a complicated medical history, including mastocytosis, Noonan syndrome, and von Willebrand disease. Each affected the anesthetic plan and was addressed preoperatively among all surgical and anesthesia providers. Mastocytosis created a major concern, with its increased numbers of histamine-filled mast cells. Each drug that was added or eliminated from the anesthetic plan, to prevent histamine release by the activation of triggers, was considered. Patient handling and temperature control were also concerns. One of Noonan syndrome's characteristics is heart anomalies. This patient had a history of a patent foramen ovale and pulmonary stenosis; therefore, air was carefully removed from all intravenous lines and syringes. The main concern for bleeding difficulties was attributed to the history of von Willebrand disease, which results in prolonged bleeding time and can lead to delayed bleeding or serious postsurgical hemorrhage. Desmopressin was administered preoperatively to increase platelet aggregation and the von Willebrand factor level. The use of aspirin and other nonsteroidal anti-inflammatory drugs was avoided. We discuss the clinical and anesthetic management of this case with a review of pertinent literature.

Prophylaxis in von Willebrand disease.

Von Willebrand disease (VWD), the most common hereditary bleeding disorder, is divided into three types depending on the quantitative (type 1 and 3) or qualitative (type 2) abnormality of von Willebrand factor (VWF). About 70-80% of VWD patients can be treated with the synthetic product desmopressin, while the others necessitate factor VIII/VWF concentrates. In addition to the treatment of bleeding episodes, therapeutic regimens include short- or long-term prophylaxis. While the literature data on short-term prophylaxis in VWD are consistent and clearly show the safety and efficacy of such a therapeutic approach, little evidence is available regarding long-term prophylaxis, and although the preliminary results are encouraging, they need to be validated by large prospective studies.

Highly purified VWF/FVIII concentrates in the treatment and prophylaxis of von Willebrand disease: the PRO. WILL Study.

Two therapeutic approaches are available to manage patients with von Willebrand disease (VWD): (i) the release of endogenous von Willebrand factor (VWF) from endothelial compartments induced by desmopressin (DDAVP); (ii) the transfusion of exogenous VWF contained in VWF/FVIII plasma-derived concentrates. Only a few high-purity VWF/FVIII concentrates have been extensively evaluated in pharmacokinetic (PK) trials as well as in retrospective or prospective efficacy studies in VWD. The Alphanate Study Group published results of PK and clinical efficacy studies in 2002. Efficacy results showed that 75% of bleeding episodes were controlled with one or two infusions, and 71% of patients who received prophylactic treatment for surgeries or invasive procedures had good clinical responses. In another retrospective study, 22 VWD patients in Italy received Fanhdi, a VWF concentrate similar to Alphanate. Excellent-good clinical responses were seen in 92% of bleeding episodes and in 93% of surgical procedures. More recently, the efficacy and safety of Fanhdi have been evaluated retrospectively in a larger cohort of Italian patients (n = 103) with 97% (bleedings) and 99% (surgeries) of excellent/good clinical responses. The largest experience on secondary prophylaxis in VWD has been collected in Sweden in 35 patients with severe forms of VWD. Secondary prophylaxis was also implemented in a cohort of Italian patients with VWD. Prophylaxis was started because of GI bleeds in seven patients with types 3 (n = 1), 2A (n = 4), 2M (n = 1) and type 1 (n = 1) and for joint bleeds in four patients with type 3 VWD (n = 4). Prophylaxis prevented bleeding completely in eight patients and largely reduced hospitalization for blood transfusions in the remaining three. The cost-effectiveness of these prophylaxis regimens versus on demand therapy will be now investigated in one large prospective study (PRO.WILL) organized in Italy.

Fanhdi, efficacy and safety in von Willebrand's disease: prospective international study results.

UNLABELLED: Recently, three multicentre prospective international studies have been carried out to evaluate the clinical efficacy and safety of Fanhdi [high-purity, double-inactivated plasma-derived factor VIII/von Willebrand factor (VWF) concentrate] in patients with von Willebrand's disease (VWD). Pharmacokinetic parameters, clinical efficacy and safety of Fanhdi in acute bleedings episodes or invasive procedures were determined in this population. RESULTS: Pharmacokinetic parameters observed were similar to previous reported for other highly purified plasma-derived FVIII/VWF concentrate. The mean in vivo recovery (IU dL(-1) per IU kg(-1)) was 1.9 +/- 0.6 for VWF:RCof; 2.1 +/- 0.6 for VWF:Ag and 2.6 +/- 0.6 for FVIII:C. The mean half-life (h) was 14.4 +/- 10.5 for VWF:RCof; 27.5 +/- 11.0 for VWF:Ag and 33.4 +/- 16.4 for FVIII:C. Therapeutic benefit of Fanhdi in VWD patients treated during bleeding episodes was clearly demonstrated. The achievement of haemostasis was excellent or good in 100% of the cases (major or minor bleeding episodes). Also, the clinical efficacy of Fanhdi in preventing excessive bleeding during surgery showed a very good profile. Efficacy was rated as excellent in six cases (three major/three minor surgical procedures) and good in three cases (two major/one minor surgical procedures). In addition, the product was well tolerated and no adverse events potentially related to the study drug were reported. CONCLUSIONS: Fanhdi is an effective and safe plasma-derived FVIII/VWF concentrate that can be used as an alternative to the current replacement therapy in patients with VWD to provide an adequate haemostasis during surgical procedures and treatment of bleeding episodes.

Testing for von Willebrand disease in women with menorrhagia: a systematic review.

OBJECTIVE: To review the evidence supporting screening of adult women with menorrhagia for von Willebrand disease. DATA SOURCES: MEDLINE search from January 1,1990, to December 31, 2003, for articles in English, using keywords "menorrhagia," "von Willebrand disease," "diagnosis," and "screening," with a hand-search of bibliographies of identified articles, review of published abstracts, and discussion with experts. METHODS OF STUDY SELECTION: One hundred seven articles meeting search criteria were reviewed. Articles included in the study were those that provided primary data on the prevalence of von Willebrand disease in adult women with menorrhagia, quality of life, surgical complications, and the effectiveness of medical therapy in women with menorrhagia and von Willebrand disease and test characteristics of screening tests for von Willebrand disease. TABULATION, INTEGRATION, AND RESULTS: The reported prevalence of von Willebrand disease in women with menorrhagia ranged from 5-20% in 5 published studies. Comparison of results was limited by small sample sizes and large confidence intervals, as well as differences in the definitions of menorrhagia and von Willebrand disease used in the studies. Although menorrhagia in women with known von Willebrand disease has a substantial impact on quality of life, there are no data suggesting that this impact is substantially greater than that of menorrhagia in women without von Willebrand disease. Data on the risk of surgical bleeding in women with von Willebrand disease are limited, with only 3 studies with a total of 29 patients identified. Data on the effectiveness of specific therapies are also limited; only one controlled trial was identified. Of single tests for screening, one study of the ristocetin cofactor assay had a sensitivity of 79% and specificity of 90%. Studies of a test of platelet adhesion and aggregation resulted in pooled sensitivities of 83-94% and specificities of 80-88%; however, significant heterogeneity was present. CONCLUSION: There are inadequate data to justify routine testing for von Willebrand disease in adult women with menorrhagia outside of the research setting.