scholarly journals Non‐additive effect on thrombin generation when a plasma‐derived factor VIII/von Willebrand factor (FVIII/VWF) is combined with emicizumab in vitro

2020 ◽  
Vol 18 (8) ◽  
pp. 1934-1939
Author(s):  
María Isabel Bravo ◽  
Aida Raventós ◽  
Alba Pérez ◽  
Montserrat Costa ◽  
Todd Willis
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Additive Effect ◽  
Von Willebrand ◽  
Willebrand Factor

Clinical cases of using coagulation factor VIII with von Willebrand factor in parturient women with type III von Willebrand disease

2020 ◽  
Author(s):  
И.В. Куртов ◽  
Е.С. Фатенкова ◽  
Н.А. Юдина ◽  
А.М. Осадчук ◽  
И.Л. Давыдкин
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Coagulation Factor Viii ◽  
Vitro Fertilization ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Болезнь Виллебранда (БВ) может представлять определенные трудности у рожениц с данной патологией. Приведены 2 клинических примера использования у женщин с БВ фактора VIII свертывания крови с фактором Виллебранда, показана эффективность и безопасность их применения. У одной пациентки было также показано использование фактора свертывания крови VIII с фактором Виллебранда во время экстракорпорального оплодотворения. Von Willebrand disease presents a certain hemostatic problem among parturients. This article shows the effectiveness and safety of using coagulation factor VIII with von Willebrand factor for the prevention of bleeding in childbirth in 2 patients with type 3 von Willebrand disease. In one patient, the use of coagulation factor VIII with von Willebrand factor during in vitro fertilization was also shown.

scholarly journals Ex Vivo Evaluation of the Effect of Plasma-Derived Factor VIII/Von Willebrand Factor in Patients with Severe Hemophilia_A on Prophylaxis with Emicizumab By Thrombin Generation Assay

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4233-4233
Author(s):  
Maria-Isabel Bravo ◽  
Aida Raventós ◽  
Alba Pérez ◽  
Elena G Arias-Salgado ◽  
María Teresa Alvarez Román ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Research Funding ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Concomitant Treatment ◽  
Healthy Controls ◽  
Normal Range ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Introduction: Hemophilia A (HA) patients under emicizumab prophylaxis treatment may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction. Thromboembolic events have been described with the concomitant use of emicizumab and activated prothrombin complex concentrate (aPCC), but not with recombinant activated factor VII (rFVIIa). Previous studies showed that the in vitro combination of emicizumab and plasma-derived Factor VIII/Von Willebrand Factor (pdFVIII/VWF) had a non-additive effect on thrombin generation (TG)(Bravo M-I, et al J Thromb Haemost. 2020;18:1934-39). The aim of this study was to evaluate the TG resulting from ex vivo combination of plasma samples from HA patients treated with emicizumab, with a pdFVIII/VWF concentrate (Fanhdi ®, Grifols). Methods: Twelve adult patients with severe HA without inhibitors on prophylaxis with emicizumab and nine healthy controls were included in the study. Blood samples were drawn in citrate plus corn trypsin inhibitor tubes. Then, platelet poor plasma (PPP) was collected for the TG assay, which measures the whole kinetics of TG. Thrombin peak (TP) and endogenous thrombin potential (ETP) were calculated using calibrated automated thrombogram (Thrombinoscope ™ software, Stago) after in vitro activation of coagulation by trigger solution, PPP Reagent LOW TM (4 μM phospholipids/1 pM tissue factor), fluorogenic substrate and CaCl 2 (FLUKAkit TM) reagents (Diagnostica Stago). Fluorescence was read in a Fluoroskan Ascent reader (Thermo) equipped with a 390/460 filter set. Samples were spiked with increasing concentrations of pdFVIII/VWF (10 to 400 IU/dL), rFVIIa (0.9 µg/mL) or aPCC (0.5 U/mL). Results: TG from healthy control samples was measured to establish TP and ETP normal ranges. TP and ETP results obtained from HA plasma with emicizumab were lower than in healthy controls. The addition of pdFVIII/VWF as of 25 IU/kg (prophylaxis dose in HA w/o inhibitors) to samples from HA patients concomitantly treated with emicizumab restored TP and ETP levels within healthy controls normal range (Table 1). Increasing ex vivo concentrations of pdFVIII/VWF maintained TP and ETP similar to healthy controls. The highest concentration of concomitant treatment with pdFVIII/VWF (200 IU/kg) and emicizumab did not result in excessive TP and, importantly, ETP levels were always within the normal range. The combination with the bypassing agent rFVIIa moderately increased TP and ETP values up to normal range. However, when HA plasma was spiked with aPCC in the presence of emicizumab, TP and ETP dramatically increased above normal range resulting in a synergistic procoagulant profile. Conclusions: The concomitant use of pdFVIII/VWF in patients with prophylaxis with emicizumab did not trigger a multiplying effect on TG. These results were aligned with previous in vitro data and suggested the low risk of overdose and thrombotic events of concomitant treatment emicizumab with the pdFVIII/VWF concentrate in HA patients. Figure 1 Figure 1. Disclosures Bravo: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Raventós: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Pérez: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Alvarez Román: Grifols: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo-Nordisk: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; CSL-Behring: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Butta: CSL-Behring: Research Funding; Roche: Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Novo-Nordisk: Speakers Bureau. Jiménez-Yuste: Bayer: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding. Costa: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®. Willis: Grifols: Current Employment, Other: Grifols is a manufacturer of the pdFVIII/VWF concentrate, Fanhdi®.

Interleukin 11 significantly increases plasma von Willebrand factor and factor VIII in wild type and von Willebrand disease mouse models

Blood ◽  
2001 ◽  
Vol 97 (2) ◽  
pp. 465-472 ◽  
Author(s):  
Cécile V. Denis ◽  
Kyubum Kwack ◽  
Simin Saffaripour ◽  
Srinivas Maganti ◽  
Patrick André ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Messenger Rna ◽  
Von Willebrand Disease ◽  
Continuous Exposure ◽  
Wild Type ◽  
Platelet Counts ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Interleukin (IL)-11 is a cytokine with thrombopoietic activity that has been shown to increase plasma von Willebrand factor (vWf) in preliminary clinical studies. This led to further evaluation of the effect of recombinant human (rh)IL-11 on vWf and factor VIII (FVIII) secretion. In vitro, rhIL-11 did not increase vWf production by cultured endothelial cells, which suggests an indirect mechanism. Also, in vivo, plasma vWf was not elevated in mice shortly after a single intravenous (IV) bolus injection of 250 or 1000 μg/kg rhIL-11. The effect of continuous exposure to rhIL-11 was accessed by treating wild type mice for 7 consecutive days with subcutaneous 250 μg/kg/d rhIL-11. Platelet counts increased by 25% and 40% after 4 and 7 days, respectively. Plasma vWf and FVIII levels increased 2-fold after 4 and 7 days. Surprisingly, no effect of rhIL-11 on vWf or FVIII messenger RNA was observed, which suggests that the regulation by rhIL-11 occurs after transcription. No increase in soluble P-selectin was observed after rhIL-11 treatment, indicating that platelet activation is not the source of elevated vWf. Similarly to wild type mice, vWf heterozygous mice responded to rhIL-11 treatment by a significant increase in platelet counts and vWf and FVIII levels. Importantly, in vWf-deficient mice, rhIL-11 also induced a significant increase in FVIII independent of vWf and was able to reduce skin bleeding time. These results suggest that a clinical evaluation of the effects of rhIL-11–induced vWf/FVIII elevation in maintaining hemostasis in mild hemophilia A or von Willebrand disease would be worthwhile.

Intracellular Co-Localization of Factor VIII and Von Willebrand Factor Is Necessary for In Vivo FVIII Secretion.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 41-41 ◽  
Author(s):  
Patricia A. Lamont ◽  
Margaret V. Ragni
Keyword(s):  
Liver Transplantation ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Hemophilia A ◽  
Liver Function Tests ◽  
Von Willebrand Disease ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Although the extracellular association of Factor VIII (FVIII) and Von Willebrand Factor (VWF) is well established, the intracellular interaction of FVIII and VWF is not well understood. Recently, the importance of intracellular co-localization of FVIII and VWF for in vitro FVIII secretion was demonstrated in endothelial cell lines. Whether intracellular co-localization of FVIII and VWF is required for in vivo FVIII secretion, however, is not known. We previously showed that liver transplantation leads to phenotypic cure of hemophilia A, by virtue of FVIII production in the allograft liver. Because FVIII is synthesized only in the allograft liver but not in endothelial cells of transplant recipients, and VWF is synthesized in extrahepatic tissue, this is an ideal model to study whether co-localization of FVIII and VWF is required for in vivo FVIII secretion. We, therefore, studied FVIII and VWF response after desmopression (DDAVP) infusion, administered at 0.3 mcg/kg by intravenous infusion over 30 minutes, in each of two men with severe hemophilia A (FVIII:C <0.01 U/ml) who had undergone orthotopic liver transplantation for endstage liver disease six months earlier. Both men had HIV and hepatitis C co-infection and were clinically well, with mildly elevated liver function tests, and FVIII:C levels >30% following transplantation. Coagulation studies, drawn before and after DDAVP, revealed that VWF:RCoF and VWF:Ag, but not FVIII:C, increased after DDAVP administration (see Table). The prolonged aPTT and correction in a 1:1 aPTT mix confirmed the absence of an inhibitor in these subjects. The lack of FVIII response to DDAVP supports previous in vitro work, and demonstrates for the first time that intracellular co-localization of FVIII and VWF is essential for in vivo FVIII secretion. These data also suggest that extrahepatic FVIII synthesis is necessary for in vivo response of the DDAVP releasable pool of FVIII. By contrast, co-localization does not appear to be necessary for VWF secretion. Although it is not possible to exclude that a chronic, exhaustive post-transplant increase in VWF may have limited VWF response to DDAVP, it is clear that FVIII did not increase following DDAVP. These findings have important implications for the design of gene therapies for hemophilia A and Von Willebrand Disease. Subject Demographic Sample aPTT aPTT mix FVIII:C VWF:RCoF VWF:Ag 01-BW 32yoM Hem A Pre-DDAVP 44.4 sec 37.7 sec 0.50 U/ml 2.17 U/ml 2.42 U/ml HIV+/HCV+ Post-DDAVP 44.8 sec 37.4 sec 0.48 U/ml 2.91 U/ml 2.91 U/ml 02-PB 36yoM Hem A Pre-DDAVP 49.5 sec 38.0 sec 0.32 U/ml 1.61 U/ml 2.16 U/ml HIV+/HCV+ Post-DDAVP 50.8 sec 38.5 sec 0.30 U/ml 2.20 U/ml 2.50 U/ml

Altered Serum Factor Vlll-Related Antigen (VIII: AGN)/von Willebrand Factor (VIII: vWf) in Haemophiliacs with Inhibitors to Factor VIII Procoagulant Activity (VIII: C)

1981 ◽  
Vol 45 (01) ◽  
pp. 068-072 ◽  
Author(s):  
J O Ballard ◽  
J C Sanders ◽  
M E Eyster
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
High Titer ◽  
Normal Subjects ◽  
Procoagulant Activity ◽  
Crossed Immunoelectrophoresis ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Altered Serum

SummaryInhibitors to factor VIII (anti-F VIII) developing in patients with classic haemophilia have apparent specificity for the factor VIII procoagulant activity (VIII: C), rather than the factor VIII-related antigen (VIII :AGN) and von Willebrand factor (VIII :vWf) regions of the factor VIII complex.Since procoagulant function is absent following in vitro clotting, but serum retains VIII: AGN/vWf properties, we searched for differences in VIII :AGN and VIII :vWf of inhibitor serum that might relate to the presence of anti-F VIII.Rocket immunoelectrophoresis and the washed platelet ristocetin assay were performed on the plasma and serum of nine haemophiliacs with inhibitors, 23 non-inhibitor haemophiliacs and six normal subjects. Unlike normal and non-inhibitor haemophilic sera, that from five of nine inhibitor patients demonstrated absent VIII : vWf and significantly lower VIII: AGN (p <0.05). Furthermore, VIII: AGN of faster mobility was detected on crossed immunoelectrophoresis of the sera of three inhibitor patients. Thrombin clotting of plasma from haemophiliacs with high titer anti-F VIII was associated with a greater loss of VIII: vWf than seen with non-inhibitor haemophilic plasma. This effect was independent of the presence of platelets.These data indicate that in vitro clotting is associated with alteration in the serum VIII: AGN/vWf of some haemophiliacs with anti-F VIII.

Effect of Dextran on Factor Vlll/von Willebrand Factor Structure and Function

1985 ◽  
Vol 54 (03) ◽  
pp. 697-699 ◽  
Author(s):  
J Batlle ◽  
F del Río ◽  
M F López Fernández ◽  
R Martín ◽  
A López Borrasca
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Platelet Rich Plasma ◽  
Activity Factor ◽  
Before And After ◽  
Triplet Structure ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryFactor VIII/von Willebrand factor was analyzed before and after the infusion of 500 ml of Dextran 70 to normal volunteers. Factor VIII procoagulant activity, factor VIII related antigen and ristocetin cofactor activity showed a significant decrease, reaching after six hours the minimum level, which did not correlate with the hemodilution effect caused by dextran. Ristocetin-induced platelet agglutination (RIPA) in volunteers’ platelet-rich plasma (PRP) did not show any significant change between preinfusion time and six hours after the infusion. Multimeric analysis of von Willebrand factor (vWF) showed a progressive decrease of all the multimers which was more pronounced in the largest multimers. No change was seen in the “triplet” structure of vWF. No effect was noticed when dextran was incubated “in vitro” either with PRP or platelet-poor plasma. The modification induced by dextran is close to the pattern seen in subtype Ib von Willebrand’s disease.

Coagulation Disorders Caused by Hydroxyethyl Starch

1997 ◽  
Vol 78 (03) ◽  
pp. 0974-0983 ◽  
Author(s):  
Johannes Treib ◽  
Anton Haass ◽  
Gerhard Pindur
Keyword(s):  
United States ◽  
Factor Viii ◽  
Hydroxyethyl Starch ◽  
Von Willebrand Factor ◽  
The United States ◽  
Degree Of Substitution ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryInitially, hydroxyethyl starch (HES) was only characterized by its in vitro molecular weight (MW). This is not sufficient because HES is degraded in vivo. One relevant parameter that predicts the rate of enzymatic breakdown is the degree of substitution, a measure of the average number of hydroxyethyl groups per glucose unit. The higher this degree of substitution, the slower the break-down. In addition, because the glucose units can be substituted at carbon 2,3 and 6, different substitution patterns are possible. They are classified by their C2/C6 hydroxyethylation ratio. A higher C2/C6 ratio results in less metabolism of the starch in vivo and results in a larger in vivo MW. This in turn affects therapy, because the larger the in vivo MW, the longer is the duration of the volume effect of HES.Of particular importance is the fact that HES with a high in vivo MW affects factor VIII/von Willebrand factor which can lead to an acquired von Willebrand syndrome. During a 10-day volume therapy with a medium-MW HES 200, a form that is difficult to metabolize, we observed an 80% drop in factor VIII/von Willebrand factor. Therapy with a medium-MW HES 200, a form that is easily degraded, and therapy with a low-MW HES 70 did not result in a relevant decline of factor VIII/von Willebrand factor.This explains why hemorrhagic complications have been observed repeatedly in the United States after therapy with HES infusions, some of them lethal. In the United States high-MW HES 480 which is difficult to degrade is most frequently used and results in a larger in vivo MW and subsequent decrease in factor VIII/von Willebrand factor levels. In Europe, medium-MW HES 200 that is easily degraded and low-MW HES 70 are preferred. In the future, HES should be characterized by the in vivo, not the in vitro MW.

scholarly journals In vitro reactivity of factor VIII inhibitors with von Willebrand factor in different commercial factor VIII concentrates

2007 ◽  
Vol 82 (6) ◽  
pp. 460-462 ◽  
Author(s):  
Giuseppe Tagariello ◽  
Daniela Zanotto ◽  
Paolo Radossi ◽  
Roberto Sartori ◽  
Donata Belvini ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Factor Viii Concentrates ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Von Willebrand Factor in Angiogenesis and Angiodysplasia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. SCI-43-SCI-43
Author(s):  
Anna M Randi
Keyword(s):  
Blood Vessel ◽  
Factor Viii ◽  
Mouse Models ◽  
Von Willebrand Factor ◽  
Clinical Implications ◽  
Blood Vessel Formation ◽  
Vessel Formation ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor (VWF) is best known for its key role in haemostasis, capturing platelets at sites of endothelial damage and acting as carrier for coagulation Factor VIII. The importance of VWF in haemostasis is illustrated by the fact that its deficiency and/or abnormality causes von Willebrand disease (VWD), the most frequent inherited bleeding disorder, whilst raised levels of VWF are associated with an increased risk of arterial thrombosis. VWF is synthesized in megakaryocytes and in endothelial cells from most, but not all, vascular districts. Besides the well characterized binding to Factor VIII and with platelet receptors, VWF can interact with a plethora of proteins, from extracellular matrix components to growth factors and even DNA, suggesting that VWF may influence multiple processes. Moreover, VWF is required for the formation of Weibel Palade Bodies (WPB), endothelial storage organelles which contain many vascular regulators. It is therefore likely that this large protein, critically located at sites of vascular injury, is able to influence several vascular functions. Indeed over the last two decades novel functions for VWF in the vasculature have been identified, including the ability to modulate blood vessel formation. Studies in a mouse models of severe VWF deficiency have shown constitutively enhanced vascular networks in selected tissues, and enhanced angiogenesis in Matrigel and in response to ischemia in the brain. Moreover, studies on circulating endothelial progenitors from patients with type 3 VWD and lack of VWF synthesis have shown enhanced in vitro angiogenesis. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal (GI) bleeding due to vascular malformations, called angiodysplasia. These lesions, found in patients with congenital VWD and acquired von Willebrand syndrome (AVWS), can cause severe gastrointestinal bleeding, often unresponsive to conventional replacement therapy. Therefore, understanding the mechanisms through which VWF modulates blood vessel formation is likely to have direct implications for the treatment of these patients. In vitro and in vivo studies indicate that VWF can regulate angiogenesis through multiple pathways. Strong candidates for this role are VWF binding partners, such as integrin αvβ3, and components of Weibel Palade bodies (WPB), such as Angiopoietin-2 and Galectin-3, whose storage is regulated by VWF. Several of these pathways converge on the master regulator of angiogenesis, also essential for maintaining endothelial homeostasis, namely the vascular endothelial growth factor (VEGF) pathway. Multiple regulators may act in concert, their relevance differing in congenital VWD vs acquired AVWS. Interestingly, recent studies in mouse models suggest that the roles of VWF may be tissue-specific. If confirmed, this will have important implications for the translational and clinical implications of these findings for patient with VWD. In summary, the finding that VWF is able to regulate blood vessel formation has opened a new area of research for this incredibly interesting and versatile protein, one which has profound implications for the treatment of patients with VWD and AVWS. Disclosures Randi: LFB: Other: Invited to one advisory board meeting 2018, Patents & Royalties, Research Funding, Speakers Bureau; Shire: Honoraria.

Sign in / Sign up

Export Citation Format

Share Document