Models for Prediction of Factor VIII Half-Life in Severe Haemophiliacs: Distinct Approaches for Blood Group O and Non-O Patients

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• rVWF is safe, well tolerated, and has a PK profile generally comparable to pdVWF, but promotes enhanced stabilization of endogenous FVIII.Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasmaderived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC 0-' ) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved. This trial was registered at www.clinicaltrials.gov as #NCT00816660. (Blood. 2013;122(5):648-657)

Section: Discussionmentioning

confidence: 93%

Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial

Mannucci

Kempton

Millar

et al. 2013

116

113

“…[11][12][13] To assess the effect of LRP1 on the correlation between plasma levels of both proteins, FVIII levels were plotted versus VWF levels ( Figure 2D). For both mouse strains, a clear correlation between FVIII and VWF levels was observed, in that low FVIII levels were associated with low VWF levels and high FVIII levels with high VWF levels.…”

Section: Increased Fviii and Vwf Plasma Levels In Maclrp1 ؊ Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…11,12 To this end, we have recently demonstrated that the half-life of FVIII can be fairly well predicted using blood group and the ratio of VWF propeptide over VWF antigen (a surrogate marker for VWF clearance) as parameters. 13 Thus, understanding VWF clearance is necessary to understand clearance of FVIII.At present, there is limited information about the molecular mechanisms responsible for the clearance of VWF. As for the identity of tissues that contribute to VWF clearance, we have demonstrated previously that the liver takes up the bulk of VWF, although other organs such as the spleen also are able to remove VWF from the circulation.…”

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confidence: 99%

See 1 more Smart Citation

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Rastegarlari

Pegon

Casari

et al. 2012

Self Cite

102

130

The relationship between low-density lipoprotein receptor-related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophagespecific deficiency of LRP1 (macLRP1 ؊ ) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1 ؊ mice compared with control mice (1.6 ؎ 0.4 vs 1.0 ؎ 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1 ؊ mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1 ؊ mice did not result in further rise of VWF levels (0.1 ؎ 0.2 U/mL), in contrast to macLRP1 ؉ mice (rise in VWF, 0.8 ؎ 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWFcoated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm 2 , implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving ␤2-integrins that binds both VWF and LRP1 also is implicated because inhibition of ␤2-integrins led to increased VWF levels in control (rise, 0.19 ؎ 0.16 U/mL) but not in macLRP1 ؊ mice (0.08 ؎ 0.15 U/mL). (Blood. 2012; 119(9):2126-2134) Introductionvon Willebrand factor (VWF) is a hemostatic protein, the physiologic relevance of which is illustrated by the severe bleeding tendency associated with its functional deficiency. The contribution of VWF to hemostasis is 2-fold: (1) VWF is essential for the recruitment of platelets to the damaged vessel wall, particularly under conditions of arterial shear; and (2) VWF functions as a carrier protein for factor VIII (FVIII), a protein cofactor critical to the coagulation system.Whereas biosynthesis and secretion of VWF have been subject of study for more than 35 years, it is only in the last decade that clearance mechanisms of VWF have gained attention. 1,2 This has led to the discovery that increased clearance of VWF may explain part of the reduced VWF levels in von Willebrand disease (VWD). [3][4][5][6] This seems to be most prominent in case of VWDtype 1, although VWD-type 2 variants also are associated with reduced survival of the mutated VWF molecules. 2,7,8 The increased attention is further related to the development of novel therapeutic FVIII concentrates that are used in the treatment of hemophilia A. Given that FVIII circulates in a tight complex with VWF, it is already known that VWF is a major determinant of FVIII clearance. Indeed, the half-life of FVIII is considerably reduced in patients lacking VWF antigen or in those in which VWF is unable to bind FVIII correctly (VWD-type 2N). 9,10 Moreover, preinfusion VWF levels are positively correlated with FVIII half-life. 11,12 To this end, we have recently demonstrate...

“…[83][84][85] Moreover, FVIII half-life can be accurately predicted for each patient using an algorithm based on blood group and preinfusion levels of VWF and of VWF propeptide. 85 …”

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confidence: 99%

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Self Cite

327

336

To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra-and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. (Blood. 2015;125(13): 2019-2028 Introduction von Willebrand (VW) factor (VWF) is a multimeric glycoprotein present in blood plasma, the subendothelial matrix, as well as storage granules in endothelial cells (Weibel-Palade [WP] bodies [WPBs]) and platelets (a-granules).1 Although a series of novel functional properties of VWF has recently been proposed, 2 the protein is mostly known for its contribution to the hemostatic process: it mediates platelet adhesion and aggregation at sites of vascular injury and carries coagulation factor VIII (FVIII) in the circulation. 1 Patients lacking VWF manifest a severe hemorrhagic phenotype, originating from defective formation of platelet-rich thrombi and a secondary deficiency of FVIII impairing the generation of a fibrin network. Functional and/or quantitative deficiencies of VWF are known as von Willebrand disease (VWD), a disorder affecting 0.01% to 1% of the population. 3 Quantitative deficiencies of VWF result from changes in biosynthesis, secretion, and/or clearance of the protein. In this review, we will provide an overview of the current knowledge on each of these processes and we will discuss how they can be affected by the presence of protein defects. Part I: Basics of VWF biosynthesisPrimary structure VWF is produced in endothelial cells and megakaryocytes as a single prepropolypeptide of 2813 aa. The primary sequence of VWF was reported in 1986, and rapidly the presence of repeating domain structures within the protein was recognized. 4 The different domains are arranged in the order: D1-D2-D9-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK, with the D1-D2 domains representing the propeptide and the remainder corresponding to the mature VWF subunit (Figure 1). [4][5][6] Progress in structural and bioinformatical analysis of protein structures...