Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo

Shi, Qizhen; Kuether, Erin L.; Schroeder, Jocelyn A.; Perry, C.L.; Fahs, Scot A.; Gill, Joan Cox; Montgomery, Robert R.

doi:10.1111/j.1538-7836.2012.04902.x

Cited by 22 publications

(34 citation statements)

References 29 publications

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“…Support for this concept comes from studies in hemophilic mice demonstrating that the administration of human rFVIII induced significantly higher levels of inhibitory anti-FVIII IgG than the co-administration of rFVIII and VWF. [60][61][62][63][64] Moreover, hemophilic mice showed considerably higher titers of inhibitors specifically directed at light chain epitopes when treated with rFVIII than when treated with FVIII/VWF. 60 Franchini raised the objection that upon infusion exogenous free rFVIII rapidly (within seconds) binds to VWF already present in the patient's plasma in a 50-fold molar excess.…”

Section: Von Willebrand Factor Shields Fviii Epitopes From Recognitiomentioning

confidence: 99%

“…The animal experiments by Shi et al are summarized in Table 2. 64 The authors meticulously ruled out the possibility that dilution artefacts had impacted their findings. 23 Thus, the study convincingly demonstrated that VWF, the natural chaperone protein of FVIII, not only protects FVIII against degrading enzymes, 56,57 but also from inactivation by preexisting inhibitory antibodies.…”

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confidence: 99%

“…82,83 Accordingly, the participants of the International Workshop on Immune Tolerance Induction declared by consensus that FVIII products with and without VWF may be used for ITI, but that after failure with rFVIII, switching to a VWFcontaining pdFVIII product should be considered (evidence level IIB). 91 At the functional level, in vitro experiments have shown that VWF dose-dependently interferes with the neutralizing effect of light chain-specific inhibitors on rFVIII:C. 64,[92][93][94] Shi and colleagues provided both in vitro and in vivo evidence that rFVIII in a preformed complex with VWF (rFVIII-VWF) is better protected from the inactivation by inhibitors than rFVIII that encounters inhibitors and VWF at the same time. In particular, when 'naked' rFVIII was mixed with murine plasma containing VWF and inhibitors, the normalized apparent Bethesda titers (as a measure of FVIII inactivation) were 5.8-fold lower compared to VWF-free control mixtures.…”

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confidence: 99%

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Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Oldenburg¹,

Lacroix‐Desmazes

Lillicrap

2015

Haematologica

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The rising incidence of neutralizing antibodies (inhibitors) against therapeutic factor VIII prompted the conduct of studies to answer the question as to whether this rise is related to the introduction of recombinant factor VIII products. The present article summarizes current opinions and results of non-clinical and clinical studies on the immunogenic potential of recombinant compared to plasma-derived factor VIII concentrates. Numerous studies provided circumstantial evidence that von Willebrand factor, the natural chaperone protein present in plasma-derived factor VIII products, plays an important role in protecting exogenous factor VIII from uptake by antigen presenting cells and from recognition by immune effectors. However, the definite contribution of von Willebrand factor in reducing the inhibitor risk and in the achievement of immune tolerance is still under debate. ABSTRACTinhibitors in stable PTPs after switching treatment is consistently lower than in previously untreated patients (PUPs), 31,32 probably because many of them have developed some kind of cross-tolerance. Thus, the immunogenicity of a given FVIII concentrate in PTPs is relevant for PTPs only. However, in daily clinical practice, more situations that demand a decision between treatment options are related to PUPs, i.e. patients in their early years of life who are newly diagnosed with hemophilia A or who sustain their first bleeding episode. 27,33 Are inhibitor testing methods a critical confounder?One of the most cited arguments used to confute a higher incidence of inhibitors associated with rFVIII treatment is that the testing frequencies and methods used for the detection of inhibitors have increased and improved over time. These improvements coincide with the introduction of rFVIII, which might have favored the detection of borderline and transient inhibitors in rFVIII-treated patient groups. 23,31,34 In fact, in 1995, the so-called "Nijmegen" method, a modification of the till then most widely used "Bethesda assay", was launched. 35 However, despite the improvements made over recent years, the methods used to detect inhibitors have not yet been standardized, 28,36 and the classical Bethesda assay originally published in 1975 is still the most frequently used assay. 34,36 Furthermore, the major advantage of the Nijmegen modification of the Bethesda assay lies in the improvement in the test's specificity near the cut-off value. 28,35,37 Hence, the advent and use of the Nijmegen assay should have caused a decrease in the rate of false positive test results and, consequently, a decrease rather than an increase in the inhibitor incidence in studies dating back to the 1990s. On the other hand, it is very possible that the increased testing frequency in the last two decades had an impact on the reported incidence of inhibitors. Studies reporting on the incidence of high-responding inhibitors [> 5 Bethesda units (BU) per milliliter] (Figure 1) avoided potential bias from assay performance and testing frequencies, because high-res...

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Section: Von Willebrand Factor Shields Fviii Epitopes From Recognitiomentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Oldenburg¹,

Lacroix‐Desmazes

Lillicrap

2015

Haematologica

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“…24,25 VWF has a dose-dependent protective effect on FVIII from inhibitor inactivation. 26 The interaction between VWF and FVIII is critical in maintaining the clinical efficacy of platelet-derived FVIII gene therapy in HA mice in the presence of inhibitors. 27 How VWF affects FVIII immune responses in HA with a setting of preexisting anti-FVIII immunity is still uncertain and is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

The impact of von Willebrand factor on factor VIII memory immune responses

et al. 2017

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Immune tolerance induction (ITI) with aggressive infusion of factor VIII (FVIII) is the current strategy used to eradicate FVIII inhibitors and restore normal FVIII pharmacokinetics in inhibitor patients. Whether the use of FVIII products containing von Willebrand factor (VWF) will affect the efficacy of ITI is still controversial. In this study, we explored the impact of VWF on FVIII memory immune responses in hemophilia A (HA) mice. A T-cell proliferation assay and cytokine profile analysis were used to study FVIII-primed CD4+ T cells. When CD4+ T cells from primed FVIIInull mice were restimulated with recombinant human FVIII (rhF8) plus recombinant human VWF (rhVWF) in vitro, the percentages of daughter CD4+ T cells were significantly decreased compared with the groups cultured with rhF8 only. Levels of interferon-γ and interleukin 10 were significantly lower in the rhF8 plus rhVWF groups than in the rhF8 groups. When memory B-cell pools from primed FVIIInull mice were cultured with rhF8 with or without rhVWF to induce differentiation of memory B cells into antibody-secreting cells (ASCs), the number of ASCs was significantly lower in the rhF8 plus VWF group than in the rhF8 group. When memory B-cell pools were transferred into NSGF8KO mice followed by rhF8 immunization with or without rhVWF, the titers of anti-F8 inhibitors and total immunoglobulin G were significantly higher in the rhF8 group than in the rhF8 plus rhVWF group, with an average difference of 2.23- and 2.04-fold. Together, our data demonstrate that VWF attenuates FVIII memory immune responses in HA mice.

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“…Additional mouse models related to this line have been produced, one particular model is the von Willebrand factor (vWF)-fVIII double knockout strain (vWF null FVIII null ) [51,52]. vWF is a multimeric glycoprotein that serves as a carrier protein for factor VIII.…”

Section: Hemophilia a Rodent Modelsmentioning

confidence: 99%

In vitro and In vivo Model Systems for Hemophilia A Gene Therapy

Mao¹,

Kapranov

et al. 2013

J Genet Syndr Gene Ther

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Hemophilia A is a hereditary disorder caused by various mutations in factor VIII gene resulting in either a severe deficit or total lack of the corresponding activity. Recent success in gene therapy of a related disease, hemophilia B, gives new hope that similar success can be achieved for hemophilia A as well. To develop a gene therapy strategy for the latter, a variety of model systems are needed to evaluate molecular engineering of the factor VIII gene, vector delivery efficacy and safety-related issues. Typically, a tissue culture cell line is the most convenient way to get a preliminary glimpse of the potential of a vector delivery strategy. It is then followed by extensive testing in hemophilia A mouse and dog models. Newly developed hemophilia A sheep may provide yet another tool for evaluation of factor VIII gene delivery vectors. Hemophilia models based on other species may also be developed since hemophiliac animals have been identified or generated in rat, pig, cattle and horse. Although a genetic nonhuman primate hemophilia A model has yet to be developed, the non-genetic hemophilia A model can also be used for special purposes when specific questions need to be addressed that cannot not be answered in other model systems. Hemophilia A is caused by a functional deficiency in the factor VIII gene. This X-linked, recessive bleeding disorder affects approximately 1 in 5000 males [1–3]. Clinically, it is characterized by frequent and spontaneous joint hemorrhages, easy bruising and prolonged bleeding time. The coagulation activity of FVIII dictates severity of the clinical symptoms. Approximately 50% of all cases are classified as severe with less than 1% of normal levels of factor VIII detected [4]. This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding. In contrast, patients with 5–30% of normal factor VIII activity exhibit mild clinical manifestations.

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Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo

Cited by 22 publications

References 29 publications

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity

The impact of von Willebrand factor on factor VIII memory immune responses

In vitro and In vivo Model Systems for Hemophilia A Gene Therapy

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