Page 12 - Haematologica Vol. 107 - September 2022

EDITORIAL C.V. Denis and P.J. Lenting How to keep the factor VIII/von Willebrand factor
complex in the circulation
Cécile V. Denis and Peter J. Lenting
Laboratory for Hemostasis, Inflammation & Thrombosis (HITh), Unité Mixte de Recherche (UMR)-1176, Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paris-Saclay, Le Kremlin-Bicêtre, France
E-mail: cecile.denis@inserm.fr
https://doi.org/10.3324/haematol.2021.280222
von Willebrand disease and hemophilia A: current treatments
von Willebrand factor (VWF) and factor VIII (FVIII) make an enigmatic duo that is present in the circulation as a tightly bound complex.1 Their individual roles in hemosta- sis have been well-established, and functional deficiency of either the former or the latter protein is associated with severe bleeding complications, known as von Willebrand disease (VWD) and hemophilia A, respectively. Over the last several decades, the clinical management of the se- vere forms of these disorders predominantly relied on re- placement therapy using concentrates enriched in VWF, FVIII or both. In contrast, the moderate and mild variants of VWD and hemophilia A benefited from using desmo- pressin, a vasopressin 2-receptor agonist that stimulates the rapid release of endothelial VWF and FVIII.2,3 Despite its numerous advantages (such as ease of administration, low costs, no risk of inhibitor development or of transmit- table disease), desmopressin also has a number of limi- tations. Post-treatment increases of VWF and FVIII are transient and limited by the natural short half-life (about 12 h) of the FVIII/VWF complex, and repetitive use of des- mopressin results in a diminished responsiveness (tachy- phylaxis) due to exhaustion of the VWF storage organelles.2,4 Furthermore, desmopressin has variable ef- fectiveness in VWD-type 2A and 2M as well as in hemo- philia A, and it is contraindicated for VWD-type 2B as it may worsen the thrombocytopenia in these patients.2,5 It is worth noting that desmopressin is foremost an anti-di- uretic, and the desmopressin-induced secretion of VWF from storage organelles is actually an off-target effect. Fi- nally, desmopressin use is associated with some side ef- fects (transient headaches, facial flushing, hypotension, hyponatremia and mild tachycardia), although these are generally mild and well-tolerated.6,7
Increasing endogenous von Willebrand factor and
factor VIII levels
While the abovementioned treatment options are satis- factory to some extent, treatment still needs to be opti- mized. With regard to severe hemophilia A, new approaches have been approved for the clinic (e.g., ex- tended half-life variants of FVIII, emicizumab) or are in ad- vanced clinical development (e.g., fitusiran, concizumab,
marstacimab, efanesoctocog alfa, valoctocogene roxapar- vovec). In contrast, few novel strategies are emerging or even appearing on the visible horizon with regard to VWD or mild hemophilia A. Interestingly, the majority of patients with VWD or mild/moderate hemophilia A could already benefit from an increase in endogenous levels of the VWF/FVIII complex, as is evident from the successful use of desmopressin. It could thus be worthwhile designing approaches that aim to increase endogenous FVIII and VWF levels in a more sustainable manner compared to desmopressin. A first approach was described already 20 years ago: treatment with interleukin-11 was associated with an increase in VWF in both mouse and canine models.8,9 The underlying mechanism seemed to be re- lated to an upregulation of VWF mRNA in response to in- terleukin-11.9 However, follow-up phase II clinical studies were somewhat disappointing, as treatment with inter- leukin-11 was associated with only a modest rise in VWF plasma levels (1.1-1.5 fold).10,11
The anti-von Willebrand factor aptamer BT200
In this issue of Haematologica, Kovacevic and colleagues present a new strategy that is associated with increased VWF/FVIII levels, centered around the aptamer BT200.12 Originally, the authors developed BT200 as an antithrom- botic agent to interfere with the platelet-binding activity of VWF.13 BT200 is a short hairpin-structured oligonu- cleotide consisting of the methylated nucleobases ade- nine, cytosine, guanine and uracil, and is an optimized derivative from the previously described aptamer ARC1779.14 Both BT200 and ARC1779 have in common that they specifically bind to the A1 domain of VWF, thereby interfering with the binding of VWF to its pla- telet-receptor glycoprotein Iba (GpIba).13 Preclinical studies in primates demonstrated that the improved BT200 aptamer is not only highly efficient (inhibition of VWF A1 domain activity: IC50 = 70-180 nM), but also has an excellent bioavailability following subcutaneous in- jection (>77%) and a long half-life (>100 h) due to its pegylated character.13 Studies using blood samples of stroke patients further confirmed that BT200 has a po- tent antithrombotic activity.15
Initial studies using ARC1779 revealed that this molecule led to an increase of VWF levels in patients with VWD-
Haematologica | 107 September 2022
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