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)