Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo

Pan, Junliang; Dinh, Thanh; Rajaraman, Anusha; Lee, Mike; Scholz, Alexander; Czupalla, Cathrin J.; Kiefel, Helena; Zhu, Li; Xia, Lijun; Morser, John; Jiang, Haiyan; Santambrogio, Laura; Butcher, Eugene C.

doi:10.1182/blood-2015-12-684688

Cited by 83 publications

(78 citation statements)

References 51 publications

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“…34 Recent studies have also documented the presence of FVIII on the VWF strings that are released from the endothelium. 35 However, the documentation of FVIII expression in lymphatic endothelium and certain types of fenestrated endothelium (in the liver sinusoids and renal glomerulus), with little or no coexpression of VWF, 36 suggests that there is still more to learn about the precise endothelial sources of production of these 2 proteins. Nevertheless, it seems clear that different endothelial beds show differential expression of VWF and FVIII.…”

Section: Biology Of Vwf and Fviiimentioning

confidence: 99%

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Pipe

Montgomery

Pratt

et al. 2016

Blood

185

186

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A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) and reduce dosing frequency by utilizing bioengineering techniques including PEGylation, Fc fusion, and single-chain design. However, these approaches have achieved only moderate increases in halflife of 1.5-to 2-fold compared with marketed FVIII products. Clearance of PEGylated rFVIII, rFVIIIFc, and rVIII-SingleChain is still regulated to a large extent by interaction with VWF. Therefore, the half-life of VWF (∼15 hours) appears to be the limiting factor that has confounded attempts to extend the half-life of rFVIII. A greater understanding of the interaction between FVIII and VWF is required to drive novel bioengineering strategies for products that either prolong the survival of VWF or limit VWF-mediated clearance of FVIII. (Blood.

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Section: Biology Of Vwf and Fviiimentioning

confidence: 99%

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Pipe

Montgomery

Pratt

et al. 2016

Blood

185

186

View full text Add to dashboard Cite

show abstract

“…VWF is synthesized by the vascular endothelium and megakaryocytes, and is released either constitutively or on demand from endothelial cell Weibel-Palade bodies or platelet α-granules. The majority of FVIII is synthesized and secreted by sinusoidal and lymphatic endothelial cell beds (6)(7)(8)(9). In contrast, pathways that contribute to VWF-FVIII clearance have been only partially characterized.…”

Section: Introductionmentioning

confidence: 99%

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Swystun¹,

Lai²,

Notley³

et al. 2018

Journal of Clinical Investigation

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variants demonstrated that the STAB2 p.E2377K variant associates with a 33.6% and 26.8% increase in VWF and FVIII levels, respectively (25), suggesting that stabilin-2 is a significant regulator of plasma VWF-FVIII levels. Based on its known function and association with plasma VWF levels, stabilin-2 may act as a clearance receptor for VWF and/or FVIII; however, the mechanistic basis for this relationship has not been assessed.In addition to facilitating protein clearance, binding of VWF-FVIII to endocytic receptors can regulate interactions with cells in the immune system. The development of FVIII neutralizing antibodies (termed inhibitors) in response to infused FVIII replace-STAB2 encodes stabilin-2, a class H scavenger receptor expressed on the sinusoidal endothelial cells of the liver, spleen, and lymphatics that functions as a clearance receptor for hyaluronic acid and other glycosaminoglycans (21-23). Stabilin-2 is composed of repetitive extracellular fasciclin and EGF-like domains with a single X-link domain that is C-type lectin-like, located near its transmembrane region. Subsequent to the CHARGE study, additional GWAS-based publications have independently confirmed that common STAB2 variants associate with plasma

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“…Hepatic expression of VWF reconstitutes the plasma VWF compartment (‘plasma phase’) only. As very recent evidence suggests that the majority of VWF and FVIII is not produced in the same endothelial beds , VWF and FVIII probably first associate in the plasma; therefore, the lack of endothelial or platelet‐derived VWF is not likely to significantly impact the characterization of the type 2N VWD phenotype in our model. The variable supraphysiological expression of VWF induced by the hydrodynamic procedure, however, may alter evaluation of the true FVIII‐binding capacity of type 2N variant VWF.…”

Section: Discussionmentioning

confidence: 77%

Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice

Swystun

Georgescu

Mewburn

et al. 2017

Journal of Thrombosis and Haemostasis

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Background von Willebrand factor (VWF) and factor VIII (FVIII) circulate as a non-covalent complex, with VWF serving as the carrier for FVIII. VWF indirectly influences secondary hemostasis by stabilizing FVIII and transporting it to the site of primary hemostasis. Type 2N von Willebrand disease involves impaired binding of VWF to FVIII, resulting in decreased plasma levels of FVIII. Objectives In these studies, we characterize the impact of three type 2N VWD variants (R763A, R854Q, R816W) on VWF secretion, FVIII stabilization and thrombus formation in a murine model. Methods Type 2N VWD mice were generated by hydrodynamic injections of mutant murine VWF cDNAs and the influence of these variants on VWF secretion and FVIII binding was evaluated. In vivo hemostasis and the dynamics of thrombus formation and embolization were assessed using a murine tail vein transection hemostasis model and an intravital thrombosis model in the cremaster arterioles. Results Type 2N VWD variants were associated with decreased VWF secretion using cell and animal-based models. FVIII-binding to type 2N variants was impaired in vitro and was variably stabilized in vivo by expressed or infused 2N variant VWF protein. Both transgenic type 2N VWD and FVIII knockout (KO) mice demonstrated impaired thrombus formation associated with decreased thrombus stability. Conclusions The type 2N VWD phenotype can be recapitulated in a murine model and is associated with both quantitative and qualitative VWF deficiencies and impaired thrombus formation. Patients with type 2N VWD may have normal primary hemostasis formation but decreased thrombus stability related to ineffective secondary hemostasis.

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Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo

Abstract: Key Points

Cited by 83 publications

References 51 publications

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity

Abnormal von Willebrand factor secretion, factor VIII stabilization and thrombus dynamics in type 2N von Willebrand disease mice

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