Current and Emerging Options for the Management of Inherited von Willebrand Disease

Drugs, Aug 2017

Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of ~1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common symptoms are mucocutaneous bleeding, hematomas, and bleeding after trauma or surgery. For decades, treatment to prevent or treat bleeding has consisted of desmopressin in milder cases and of replacement therapy with plasma-derived concentrates containing VWF and Factor VIII (FVIII) in more severe cases. Both are usually combined with supportive therapy, e.g. antifibrinolytic agents, and maximal hemostatic measures. Several developments such as the first recombinant VWF concentrate, which has been recently licensed for VWD, will make a more “personalized” approach to VWD management possible. As research on new treatment strategies for established therapies, such as population pharmacokinetic-guided dosing of clotting factor concentrates, and novel treatment modalities such as aptamers and gene therapy are ongoing, it is likely that the horizon to tailor therapy to the individual patients’ needs will be extended, thus, further improving the already high standard of care in VWD in most high-resource countries.

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Current and Emerging Options for the Management of Inherited von Willebrand Disease

Current and Emerging Options for the Management of Inherited von Willebrand Disease Jessica M. Heijdra 0 1 2 Marjon H. Cnossen 0 1 2 Frank W. G. Leebeek 0 1 2 Key Points 0 1 2 0 Department of Hematology, Erasmus University Medical Center , Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam , The Netherlands 1 Department of Pediatric Hematology, Erasmus University Medical Center - Sophia Children's Hospital , Wytemaweg 80, 3015 CN Rotterdam , The Netherlands 2 & Frank W. G. Leebeek Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of *1% and clinically relevant bleeding symptoms in approximately 1:10,000 individuals. VWD is caused by a deficiency and/or defect of von Willebrand factor (VWF). The most common symptoms are mucocutaneous bleeding, hematomas, and bleeding after trauma or surgery. For decades, treatment to prevent or treat bleeding has consisted of desmopressin in milder cases and of replacement therapy with plasma-derived concentrates containing VWF and Factor VIII (FVIII) in more severe cases. Both are usually combined with supportive therapy, e.g. antifibrinolytic agents, and maximal hemostatic measures. Several developments such as the first recombinant VWF concentrate, which has been recently licensed for VWD, will make a more ''personalized'' approach to VWD management possible. As research on new treatment strategies for established therapies, such as population pharmacokinetic-guided dosing of clotting factor concentrates, and novel treatment modalities such as aptamers and gene therapy are ongoing, it is likely that the horizon to tailor therapy to the individual patients' needs will be extended, thus, further improving the already high standard of care in VWD in most high-resource countries. 1 Introduction Von Willebrand disease (VWD) is the most common inherited bleeding disorder with an estimated prevalence of *1% [ 1 ]. Clinically relevant bleeding symptoms are present in approximately 1:10,000 individuals [ 2 ]. VWD is caused by a quantitative and/or qualitative defect in von Willebrand factor (VWF). 1.1 Function of von Willebrand Factor (VWF) VWF plays an important role in primary hemostasis. It circulates in the plasma in a globular, inactive form. When vascular damage occurs, VWF binds to the exposed vascular subendothelial collagen and uncoils. Once VWF is uncoiled, the binding site for platelet glycoprotein Iba on the VWF A1 domain becomes exposed, allowing platelets to bind [ 3 ]. Concomitantly, platelets also bind to vascular collagen. After activation by thrombin and other agonists, platelets undergo shape changes and platelet integrin aIIbb3 (the GPIIb-IIIa complex) becomes able to bind VWF with high affinity, but also fibrinogen and fibronectin, leading to subsequent platelet aggregation [ 4 ]. 1.2 Pathophysiological Mechanisms in von Willebrand Disease (VWD) The function of VWF and pathophysiology of VWD is better understood if the different phases of VWF-synthesis, -secretion, and -clearance are taken into account. 1.2.1 Synthesis of VWF VWF is synthesized in endothelial cells and megakaryocytes. The protein pre-pro-VWF is produced after primary translation and glycosylation of mRNA by ribosomes in the endoplasmic reticulum of endothelial cells and megakaryocytes. This protein includes a signal peptide, a large propeptide and the mature VWF subunit, which is composed of several structural domains, named A to D. After cleavage of the signal peptide, the VWF subunits dimerize and are transported into the Golgi apparatus, where disulfide bridges are formed between the D3 domains. This leads to formation of VWF multimers. The propeptide is subsequently cleaved but remains noncovalently bound to the forming VWF multimer, facilitating the disulfide bond formation. These ultra large VWF multimers are the most hemostatically potent multimers [ 5 ]. 1.2.2 Secretion of VWF After synthesis, up to 95% of VWF is secreted constitutively into the circulation, whereas the remainder is stored in Weibel-Palade bodies in the endothelium, and in platelet a-granules [ 6 ]. Adrenergic stress, thrombin generation, or treatment with desmopressin (DDAVP) stimulates the release of stored VWF [ 7 ]. After secretion, the ultra large multimers are proteolyzed by ADAMTS13—a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13—into smaller multimers that circulate in plasma [ 8 ]. 1.2.3 Clearance of VWF After secretion of VWF into the circulation, the survival of the VWF multimers depends on their size, interaction with platelets and other cells, susceptibility to proteolysis, and the rate of clearance from the circulation [ 9 ]. These mechanisms of VWF clearance are not yet fully understood. Abnormal clearance of VWF may also contribute to the pathogenesis of VWD, as several gene mutations have been identified that are specifically associated with increased clearance of endogenous VWF [ (...truncated)


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Jessica M. Heijdra, Marjon H. Cnossen, Frank W. G. Leebeek. Current and Emerging Options for the Management of Inherited von Willebrand Disease, Drugs, 2017, pp. 1-17, DOI: 10.1007/s40265-017-0793-2