New treatment approaches to von Willebrand disease

Transcription

1 VON WILLEBRAND DISEASE: REDISCOVERING AN OLD DISEASE New treatment approaches to von Willebrand disease Michelle Lavin 1 and James S. O Donnell 1,2,3 1 Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James s Hospital, Trinity College Dublin, Ireland; 2 National Centre for Hereditary Coagulation Disorders, St. James s Hospital, Dublin, Ireland; and 3 Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland von Willebrand disease (VWD) is the commonest inherited bleeding disorder and results from either a quantitative or qualitative deficiency in the plasma glycoprotein von Willebrand factor (VWF). Recent large cohort studies have significantly enhanced our understanding of the molecular mechanisms involved in the pathogenesis of VWD. In contrast, however, there have been relatively few advances in the therapeutic options available for the treatment of bleeding in patients with VWD. Established treatment options include tranexamic acid, 1-deamino-8-D-arginine vasopressin (DDAVP), and plasma-derived VWF concentrates. In addition, a recombinant VWF has also recently been developed. In this review, we focus on how recent insights into the clinical and molecular aspects underpinning VWD are already beginning to influence treatment in the clinic. For example, a number of different bleeding assessment tools (BATs) have been developed to objectively assess bleeding symptoms in patients with VWD. Interestingly, however, these BAT scores may also have an important role to play in predicting bleeding risk in VWD. Furthermore, recent studies have demonstrated that enhanced VWF clearance plays a critical role in the etiology of both type 1 and type 2 VWD. These findings have direct translational relevance with respect to the use of DDAVP in patients with VWD. As understanding of the mechanisms involved in VWD pathogenesis continues to advance, novel treatment options are likely to emerge. Critically, however, large adequately powered and stratified clinical trials will be required to address the outstanding questions that remain regarding VWD treatment optimization. Learning Objectives The reader will recognize the various therapeutic options available for the treatment of von Willebrand disease (VWD), including the recently developed recombinant VWF concentrate The reader will understand how emerging data regarding the molecular pathogenesis underlying VWD are influencing the design of personalized treatment regimens for individual patients with VWD Introduction von Willebrand disease (VWD) represents the commonest autosomally inherited human bleeding disorder, affecting as much as 0.1% of the general population. 1 On the basis of International Society of Thrombosis and Haemostasis (ISTH) classification criteria published in 2006, VWD is classified into 3 major categories. 2 Type 1 VWD is characterized by a mild-to-moderate reductioninfunctionallynormalplasma VWF. In type 2 VWD, patients demonstrate a bleeding tendency caused by a functionally abnormal VWF molecule. Finally, patients with type 3 VWD have a significant bleeding disorder caused by almost complete absence of plasma VWF. Importantly, a recent series of large cohort studies have collectively enhanced our understanding of the biological mechanisms underlying VWD pathogenesis. 3-6 Despite this, many important questions remain to be addressed in relation to defining optimal clinical management strategies for patients with VWD. Several excellent recent reviews have examined the VWD treatment options currently available, and how these agents can be used in clinical practice. In this article, we focus on how recent advances in this evolving field may influence the design of optimal treatment regimens for individual patients with inherited VWD. Treatment options in patients with VWD Antifibrinolytic therapies tranexamic acid or aminocaproic acid Tranexamic acid in particular has been widely used in the treatment of VWD and functions as an antifibrinolytic agent by binding to the lysine-binding sites of plasminogen. It can be useful in the treatment of mucosal bleeding in patients with all types of VWD, and may be used in combination with either 1-deamino-8-D-arginine vasopressin (DDAVP) or VWF-containing concentrates. 7,8 Tranexamic acid can be administered orally (typical dose mg/kg thrice daily), as a mouthwash (typical dose 10 ml of 5% wt/vol solution 4 times a day) or IV (typical dose 15 mg/kg thrice daily). Adverse effects associated with use of tranexamic acid include nausea, vomiting, and abdominal pain. In addition, tranexamic acid is generally avoided in patients with significant hematuria from the upper urinary tract (to prevent ureteric Conflict-of-interest disclosure: J.S.O. is on the Board of Directors or an advisory committee for Baxter, Bayer, Octapharma CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, and Pfizer; has received research funding from Baxter, Bayer, Pfizer, and Novo Nordisk; and has been affiliated with the Speakers Bureau for Baxter, Bayer, Novo Nordisk, Boehringer Ingelheim, Leo Pharma, and Octapharma. M.L. declares no competing financial interests. Off-label drug use: None disclosed. Hematology

2 clot colic and obstruction) and in individuals with a history of thromboembolic disease. DDAVP DDAVP is a synthetic analog of vasopressin that causes release of VWF and FVIII from endothelial cell (EC) stores. Consequently, DDAVP can be used to transiently increase plasma VWF and FVIII levels in some patients with VWD, thereby reducing the need for plasma-derived (pd-)vwf concentrate exposure. DDAVP can be administered subcutaneously (typical dose 0.3 mg/kg) (off-label in the United States), IV (typical dose 0.3 mg/kg in 100 ml of normal saline infused over 20 minutes), or as a nasal spray (typical adult dose 300 mg; typical pediatric dose 150 mg). 7,8 Adverse effects associated with use of DDAVP include hypotension and facial flushing. In addition, DDAVP can also cause fluid retention, secondary hyponatremia, and seizures. Consequently, DDAVP is generally avoided in children younger than 2 years, as well as in adult patients with cardiovascular disease. 9 DDAVP has a 1000-fold higher affinity for vasopressin type 2 receptors compared with type 1 receptors, and thus has very little oxytocic effect. In addition, no teratogenic effects have been associated with DDAVP use. Consequently, in responsive female patients with VWD, previous experience suggests that DDAVP can be used safely during pregnancy. 7,10,11 Recent studies have clearly demonstrated that reduced VWF synthesis and/or enhanced VWF clearance play key roles in the pathogenesis of type 1 VWD. 12,13 These insights have direct relevance with respect to DDAVP therapy. 14 In many patients with type 1 VWD, DDAVP therapy can effectively increase plasma VWF levels two- to fourfold. However, not all patients with type 1 VWD respond to DDAVP administration. In particular, patients with VWF mutations that interfere with normal VWF synthesis are unlikely to have significant EC stores of VWF. In addition, attenuated VWF responses to DDAVP may also result from abnormalities in VWF secretion, or variations in EC vasopressin receptor expression. Thus, to assess individual responses to DDAVP therapy, a DDAVP trial is recommended. In addition to measuring peak response (VWF:Ag, VWF:RCo, and FVIII:C) at 30 to 60 minutes after DDAVP, assays should be repeated at later time points (4-6 hours) to confirm the duration of the VWF and FVIII responses. 8 This is important because.30 individual VWF mutations in patients with type 1 VWD have already been associated with enhanced VWF clearance. 15 Although DDAVP is not generally useful in type 3 VWD, it is interesting that recent studies have suggested that in at least some patients with type 3 VWD, enhanced VWF clearance may contribute to the phenotype. 12 DDAVP can be of significant therapeutic use in patients with type 2A and 2M VWD who do not have a contraindication to its use. A DDAVP trial is also of value in these patients because recent studies have demonstrated that enhanced VWF clearance is also a feature in some patients with type 2 VWD. 16 Although some controversy exists, DDAVP is not widely used in type 2B VWD, where increased EC secretion of the abnormal VWF molecule can trigger enhanced platelet aggregation and thrombocytopenia. Finally, although DDAVP administration can produce a significant increase in plasma FVIII:C levels in patients with type 2N VWD, this released FVIII typically has a markedly reduced plasma half-life. Plasma-derived VWF-containing concentrates A number of different human pd-vwf containing concentrates have been developed for use in the treatment of VWD. These concentrates constitute the treatment of choice for patients with VWD who have a contraindication to DDAVP, or for patients in whom VWF response after DDAVP is not considered adequate for a given bleeding episode or surgical challenge. Commercial pd-vwf concentrates differ in several aspects, including source of plasma, purification methodology, and viral inactivation steps (Table 1). In addition, these pd-vwf concentrates also differ with respect to their FVIII content and VWF multimer distribution. Although the levels of highmolecular-weight multimers present in pd-vwf concentrates are reduced compared with normal plasma, clinical studies have demonstrated that these products are efficacious in securing hemostasis and are generally well tolerated. Development of alloantibodies to VWF has been reported in 5% to 10% of patients with type 3 VWD. 17 The diagnosis and management of this rare but significant complication has recently been reviewed. 17 As demonstrated in Table 1, most of the available pd-vwf concentrates also contain significant amounts of FVIII. Consequently, repeated doses of pd-vwf concentrate used perioperatively, or in the treatment of major bleeding episodes in patients with VWD, can result in markedly elevated plasma FVIII:C levels. 18 In addition to the exogenously infused FVIII, these patients have normal levels of endogenous FVIII that is stabilized by the infused pd-vwf. Previous studies have shown that elevated FVIII:C levels constitute a dose-dependent risk factor for venous thromboembolism in the normal population. 19 In addition, thrombotic complications have also been reported in patients with VWD after repeated doses of pd-vwf concentrate. 18 This concern regarding the possible thrombotic risk associated with FVIII accumulation in the treatment of VWD can be addressed by using a pd-vwf concentrate that contains minimal FVIII (eg, Wilfactin in Europe; Table 1), or by using recombinant VWF as discussed next. Recombinant VWF In addition to the pd-vwf containing concentrates already available for clinical use, a first recombinant VWF (rvwf) concentrate has recently been developed (VONVENDI; Baxalta). This rvwf is expressed in Chinese hamster ovary cells, and because it is not exposed to ADAMTS13 during the manufacturing process, contains a full array of large and ultra-large (UL)-VWF multimers. 20 Gill et al recently reported phase 3 trial data evaluating the efficacy and safety of rvwf. 21 In this study, rvwf was used to treat 192 bleeding episodes in 22 patients with VWD (including 17 individuals with type 3 VWD). The overall hemostatic efficacy rating was either excellent (96.9%) or good (3.1%) in all cases, which is in keeping with previous studies performed using pd-vwf concentrates. Moreover, a single rvwf infusion was deemed adequate treatment of 157 (81.8%) of bleeding complications. In addition, rvwf was well tolerated with no thrombotic complications or anti-vwf neutralizing antibodies. Importantly, although the rvwf product is enriched in UL-VWF multimers compared with pd-vwf concentrates, there were no clinical signs of thrombosis or microangiopathy. This finding is consistent with postinfusion studies demonstrating that in vivo ADAMTS13-mediated proteolysis occurs promptly after rvwf infusion. 20,21 In terms of clinical use, the rvwf product differs from commercial pd-vwf concentrates in 2 aspects. First, data from both the phase 1 and phase 3 studies suggest that in a nonbleeding state, the mean plasma VWF:RCo t 1/2 for rvwf (19.6 hours) is considerably longer than that of pd-vwf (range, hours). 20,21 The biological mechanisms underlying this difference in half-life remain unclear, but likely relate in part to differences in glycosylation profile. Second, unlike most pd-vwf products, rvwf does not contain significant amounts of FVIII. Consequently, to ensure immediate hemostatic FVIII levels in patients with bleeding complications, the initial dose of rvwf in the phase 3 trial was administered in 684 American Society of Hematology

3 Table 1. VWF concentrates in use for the treatment of VWD Product Manufacturer Source of plasma Viral inactivation VWF:RCo/FVIII ratio Licensed in both US and Europe Alphanate (USA) Grifols, USA USA SD and dry heat (80 C for 72 h) Fandhi (Europe) Grifols, Spain USA, Slovakia, Spain, Czech Republic Humate P (USA) CSL Behring, Germany USA Pasteurization (60 C for 10 h) Haemate P (Europe) USA Wilate Octapharma, Austria USA, Sweden, Austria, Germany SD and dry heat (100 C for 2 h) 0.9 Licensed elsewhere Wilfactin LFB, France Germany, France, Switzerland SD and dry heat (80 C for 72 h) 50 Nanofiltration (35 nm) Immunate Baxalta, Austria USA, Austria, Germany, SD and vapor heat (60 C for 1.1 Sweden, Czech Republic 10 h) at 190 mbar Factor 8Y BioProducts Laboratory, England USA Dry heat (80 C for 72 h) 0.81 Biostate (Australia/Asia) CSL Bioplasma, Australia USA, Australia, New Zealand, SD and dry heat (80 C for 72 h) 2 Voncento (Europe) Malaysia, Singapore, 2.4 Hong Kong USA VONVENDI Baxalta, USA N/A - Recombinant N/A N/A SD, solvent detergent. combination with rfviii (ratio of 1.3:1 VWF:RCo/FVIII:C). In the absence of rfviii coadministration, infusion of rvwf in patients with type 3 VWD still lead to normalization in plasma FVIII:C levels as a result of the stabilization of endogenously secreted FVIII. For example, within 6 hours after administration of rvwf alone in nonbleeding patients with VWD, median FVIII:C levels were increased.40 IU/dL. 21 Furthermore, median plasma FVIII:C levels were sustained.70 IU/dL for 48 hours after a single rvwf infusion. Interestingly, rvwf appears to be more effective in stabilizing endogenous FVIII compared with pd-vwf. Further studies will be required to determine whether this enhanced FVIII-stabilizing effect of rvwf relates to its longer plasma half-life or its increased highmolecular-weight multimeric content. Clinical management of bleeding episodes and adjunctive therapies Multidisciplinary teams involved in providing care for patients with VWD face a number of common clinical challenges. These typically include the treatment of acute bleeding episodes, such as menorrhagia, gastrointestinal bleeding, and even hemarthroses in more severe cases. In addition, adequate hemostasis must be maintained during dental or surgical interventions, and around the time of delivery. Suggested management strategies for these common scenarios have been described in a number of recent reviews 8,10,22-24 and are summarized in Table 2. In addition to tranexamic acid, DDAVP, and VWF-containing concentrates, several other adjunctive therapies can also be useful for specific indications. For example, both the combined oral contraceptive pill and the intrauterine levonorgestrel-releasing device (Mirena) are useful in the treatment of VWD-related menorrhagia. Although the bleeding phenotype in many patients with VWD is mild, in some patients with severe VWD (particularly patients with type 3), bleeding complications can significantly affect quality of life and may be life threatening. 25,26 In such cases, long-term prophylactic treatment with pd-vwf concentrate has been explored. The VWD Prophylaxis Network (VWD PN) recently reported data regarding the clinical efficacy of prophylaxis in patients with severe VWD. 25 It is clear that the use of prophylaxis therapy may increase with the availability of a rvwf product. Acquired von Willebrand syndrome (AVWS) is a relatively uncommon bleeding disorder that results from reduced plasma VWF activity in individuals with no personal or family history of VWD. 27 Previous studies have reported 30% to 50% of AVWS cases to be associated with underlying lymphoproliferative disorders. 27 In addition, more recent data have demonstrated that AVWS is also common in patients with cardiovascular disorders including aortic valve stenosis and those treated with left ventricular assist devices. 28 Management of bleeding complications in AVWS frequently poses a major clinical challenge. Although DDAVP and VWF-containing concentrates can be useful in transiently increasing plasma VWF levels, markedly enhanced clearance of VWF and FVIII in AVWS limits the efficacy of these agents. 29 Consequently, a number of other adjunctive therapies have also been used in the treatment of AVWS (Table 3). 29 Toward personalized care in VWD integrating the old and the new In terms of planning a personalized treatment regimen for an individual patient with VWD, several important factors must be considered. These include VWD subtype and basal plasma VWF:Ag, VWF:RCo, and FVIII:C levels. In addition, the patient s personal bleeding history and the nature of the current bleeding challenge are important. Finally, the patient s previous response to DDAVP and/or other therapies, as well as any contraindications to specific therapeutic options, are reviewed. In addition to these established factors, recent developments in our understanding of the clinical and molecular aspects underpinning VWD suggest a number of additional factors that may be important in designing optimal personalized treatment plans. Can bleeding phenotype be predicted in patients with VWD? On the basis of the published literature, it is clear that the bleeding phenotype in patients with VWD varies significantly. 6 This phenotypic variability poses a significant clinical challenge in terms of Hematology

4 Table 2. Suggested VWD management strategies Type of bleeding Target VWF:RCo / FVIII level (IU/dL) DDAVP responsive DDAVP nonresponsive Adjunctive therapies Acute bleeding Minor.30 IU/dL TA 6 DDAVP TA 6 VWF concentrate Major (life threatening) '100 IU/dL TA 1 VWF concentrate TA 1 VWF concentrate Consider platelets if bleeding persists Surgery Minor.30 IU/dL until healing complete Pre-op: TA; IV DDAVP Pre op: TA 1 VWF concentrate Post-op: TA for 3-5 d Post-op: TA for 3-5 d Major '100 IU/dL until 36 h post-op Pre-op: TA; IV DDAVP Pre-op: TA 1 VWF Maintain.50 IU/dL for 5-10 d May require VWF concentrate concentrate if tachyphylaxis Dental extraction.50 IU/dL for 12 h Pre: DDAVP Pre: VWF concentrate Post: TA for 3 d Post: TA for 3 d Menorrhagia TA to cover days of heaviest flow Monthly intranasal DDAVP TA to cover days of heaviest flow OCP Levonorgestrel intrauterine device (Mirena) Iron supplementation Endometrial ablation Hysterectomy OCP, oral contraceptive pill; TA, tranexamic acid. defining optimal treatment of a given individual patient with VWD undergoing surgery. Although accurate assessment of hemorrhagic symptoms is a well-recognized challenge in patients with VWD, particularly in young children who have not been subjected to significant hemostatic challenges, objective quantitation of bleeding symptoms has been significantly advanced in recent years after the introduction of a number of bleeding assessment tools (BATs). 30 Tosetto et al evaluated bleeding severity in a large panel of type 1 VWD families enrolled in the European MCMDM-1 VWD study using an objective BAT. 31 Interestingly, in this retrospective analysis, mucocutaneous bleeding score (BS) was shown to be superior to circulating levels of VWF:Ag and FVIII:C in predicting bleeding Table 3. Suggested AVWS management strategies Management of acute bleeding Treatment of underlying disorder Cardiovascular disorders Myeloproliferative disorders Lymphoproliferative/myeloma/malignancy Monoclonal gammopathy of undetermined significance Autoimmune disorders Hypothyroidism DDAVP Treatment VWF-containing concentrate Intravenous immunoglobulin (IVIG) Plasmapheresis Antifibrinolytic therapy Recombinant factor VIIa Surgical repair Cytoreductive therapy Chemotherapy Usually untreated Immunosuppression Thyroxine replacement Notes Rapid fall-off in plasma VWF response may be seen Frequent monitoring of VWF, including a functional assay (eg, VWF:RCo) May not be suitable in elderly patients and those with history of cardiovascular disease Rapid fall-off in plasma VWF response may be seen Frequent monitoring of VWF, including a functional assay (eg, VWF:RCo) Patients with IgG paraprotein often respond well Increase in plasma VWF typically observed after h Duration of effect may vary from few days up to 3 wk Patients with IgM paraprotein unlikely to respond Short duration of response; bridge to definitive treatment May be useful to treat minor bleeds, or as an adjunctive therapy for more serious hemorrhage Few reports of use in AVWS Caution regarding risk of thromboembolism, especially in elderly patients 686 American Society of Hematology

5 after surgery. Subsequently, in a prospective observational cohort study, Federici et al investigated the use of a BAT to predict clinical outcomes in a cohort of 796 Italian patients with inherited VWD (types 1, 2 and 3). 32 Of this cohort, 9.4% developed at least 1 spontaneous bleeding event during the 1-year follow-up period. Although the clinical BS, VWF:RCo, and FVIII:C were all associated with risk of bleeding, only a BS.10 remained significantly associated with bleeding risk after multivariate analysis. Further prospective trials will be necessary to fully define the clinical utility of BAT scores (and/or specific BAT subdomains) in accurately predicting bleeding risk in patients with VWD. Nevertheless, particularly in adult patients who have undergone multiple previous hemostatic challenges, BAT scores are useful in facilitating efficient communication between health care providers. Is DDAVP efficacious in VWD patients with enhanced clearance? Although the biological mechanisms responsible for modulating VWF clearance from the plasma remain poorly understood, recent data have clearly shown that enhanced VWF clearance plays a critical role in the etiology of both type 1 and type 2 VWD. 15,16,33 This observation has led some authors to hypothesize that the clinical efficacy of DDAVP may be attenuated in VWD patients with enhanced VWF clearance. Although these patients may have an initial good response at 1 hour post-ddavp, the in vivo half-life of the secreted mutant VWF (and consequently also endogenous FVIII) is markedly reduced. Consequently, VWF-containing concentrate may constitute a longer-lasting and efficacious therapeutic option in these individuals. Castaman et al studied the hemostatic efficacy of DDAVP in 2 groups of patients with type 1 VWD as a result of enhanced clearance. 34 A total of 20 patients (16 with R1205H and 4 with C1130F) underwent dental extractions. These patients were all treated using a single dose of DDAVP together with oral tranexamic acid for 5 days. Interestingly, despite the reduced duration of VWF response after DDAVP therapy, none of these 20 patients developed bleeding complications. During the follow-up period, 17 of these patients also underwent a number of additional surgical or invasive procedures after DDAVP infusion. Of these 20 procedures, only 3 were complicated by bleeding, and only a single patient required additional pd-vwf concentrate because of ongoing bleeding. Similarly, DDAVP has also been used successfully to manage delivery in pregnant women with VWD and enhanced VWF clearance. 11,34 Collectively, these data suggest that, notwithstanding the markedly reduced VWF half-life observed in patients with type 1 VWD as a result of enhanced clearance, DDAVP therapy can still be efficacious in this cohort. However, further adequately powered studies will be required to define which procedures can be safely covered with DDAVP, and whether clinical efficacy may vary according to specific underlying VWF mutations and VWF half-life. Nevertheless, identification of type 1 and 2 VWD patients with enhanced clearance phenotypes and short VWF-FVIII half-lives after DDAVP is useful in informing the design of personalized treatment plans. This is particularly the case for patients undergoing major surgery, where repeated DDAVP infusions would be required at closely spaced intervals to maintain hemostatic VWF and FVIII levels. What is optimal management for patients with low VWF levels? The genetic mutations and biological mechanisms that lead to type 2 and type 3 VWD have been extensively characterized. 1 In contrast, however, the molecular mechanisms involved in the pathogenesis of type 1 VWD remain poorly understood. However, this area has developed in recent years after a series of type 1 VWD cohort studies. 1 Interestingly, these studies consistently demonstrated that VWF coding mutations are significantly more common in patients with plasma VWF levels,30 IU/dL. In contrast, VWF mutations are less common in patients with intermediate plasma VWF levels (30-50 IU/dL). On the basis of these cumulative data, the US National Heart, Lung and Blood Institute (NHLBI) 35 and the UK Hemophilia Centre Doctors Organization (UKHCDO) 8 have recommended modification of the previous ISTH VWD classification criteria. In particular, the NHLBI proposed that patients with reduced plasma VWF:Ag levels and bleeding phenotypes should be considered in 2 distinct subsets. 35 Patients with more marked reductions in plasma VWF levels (,30 IU/dL) are likely to have VWF gene mutations, exhibit autosomal dominant inheritance patterns, and should be labeled Type 1 VWD. In contrast, patients with intermediate plasma VWF:Ag levels (30-50 IU/dL) should be considered in a distinct category labeled Low VWF levels. Because the pathophysiology responsible for mediating low VWF levels remains largely undefined, treatment of these patients continues to pose significant clinical challenges. On the basis of current data, it seems likely that most patients with low VWF levels will respond to DDAVP. However, further studies will be required to determine whether increased clearance may also contribute to the pathogenesis of Low VWF levels. In addition, given that plasma VWF levels increase progressively with aging, 36 it is not clear whether the bleeding phenotype in this group will be corrected with increasing age. Nonetheless, this low VWF levels group has major public health ramifications, because an estimated ~0.3% of the general population will be affected. 35 For example, this diagnosis will apply to an estimated 7.5 million people in the US alone. Is platelet-vwf important in the clinical management of VWD? An estimated 10% to 20% of the total VWF:Ag present in normal platelet-rich plasma is present within the a-granules of platelets. 37 This platelet-vwf is enriched in hemostatically active highmolecular-weight multimers, and is released in high local concentrations at sites of vascular injury after platelet activation. Recent studies have demonstrated that this platelet-vwf is also more resistant to ADAMTS13 proteolysis. 38 In addition, a series of in vitro and in vivo experiments have shown that platelet-vwf also plays an important role in regulating normal hemostasis. 37,39 Previous studies have also suggested that platelet-vwf may also contribute to the variable bleeding phenotype associated with VWD. 39 Collectively, these observations are of significance with respect to the treatment of VWD. In particular, it is well recognized that some persons with VWD may have persistent bleeding, despite having apparently normal plasma VWF activity levels after VWF concentrate infusion. In such patients, platelet transfusion is often useful in securing hemostasis. Conversely, in patients with type 1C or type 3 VWD and enhanced VWF clearance, normal platelet VWF stores may be important in attenuating the bleeding phenotype. Future of VWD clinical management Tonight, I m launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes and to give all of us access to the personalized information we need to keep ourselves and our families healthier. President Barack Obama, State of the Union Address, January 20, 2015 Hematology

6 Personalized or (precision) medicine takes into account the genetic constitution of an individual patient in making diagnoses and tailoring treatment plans. The recent development of personalized medicine is based primarily on rapid advances in genome sequencing, as well as the development of computational tools that can systematically analyze big data sets. Collectively, these tools have the potential to revolutionize medicine. In this context, it is perhaps unsurprising that recent studies have already significantly advanced our understanding of the molecular pathogenesis underlying VWD, and in particular type 1 VWD. As discussed in this review, these molecular insights are already beginning to influence VWD treatment in the clinic. In addition, it seems likely that the introduction of the first recombinant VWF concentrate will also significantly affect current clinical practice. Nevertheless, major therapeutic advances in the management of patients with VWD remain limited. Further novel therapies are likely to emerge in the medium term. For example, recent studies have already provided significant insights into the biological mechanisms underlying VWF clearance in vivo. 15,40 As our understanding of this field continues to advance, novel opportunities to develop longer-lasting treatment options for both VWD and hemophilia A are likely to emerge. Critically, however, large adequately powered stratified clinical trials will be required to address the outstanding questions that remain regarding the optimization of VWD treatment. Furthermore, with the emergence of safe and efficient genome editing technologies, the prospects for future targeted genetic therapies for hemostatic disorders also offer significant promise. Although the clinical rationale for gene therapy for VWD is not clear, preclinical success has already been described. 41 Acknowledgments J.S.O D. is supported by a Science Foundation Ireland Principal Investigator Award (11/PI/1066). 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