The hope and reality of long‐acting hemophilia products

Pipe, Steven W.

doi:10.1002/ajh.23146

Cited by 47 publications

(59 citation statements)

References 71 publications

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“…4 Because of the short t 1/2 , 4 currently available products are typically infused intravenously ;3 times per week for effective prophylaxis. Thus, there has been considerable interest in developing longer-lived FVIII products that could be administered less frequently.…”

Section: Discussionmentioning

confidence: 99%

“…3 Similarly, treatment of HA patients with recombinant FVIII free of VWF is successful because of the stabilization of exogenous FVIII by endogenous VWF. 4 In contrast, correction of low FVIII levels in patients with type 2N or type 3 VWD requires infusion of VWF-containing plasma concentrates. 5 Secreted from endothelial cells as a multimeric glycoprotein, VWF is composed of a series of repeated domains (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

Yee

Gildersleeve

et al. 2014

Blood

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• The D9D3 domains of VWF are sufficient to stabilize FVIII in vivo.• The prolongation of VWF D9D3 survival in vivo by Fc fusion elevates FVIII levels in the setting of VWF but not FVIII deficiency.Plasma factor VIII (FVIII) and von Willebrand factor (VWF) circulate together as a complex. We identify VWF fragments sufficient for FVIII stabilization in vivo and show that hepatic expression of the VWF D9D3 domains (S764-P1247), either as a monomer or a dimer, is sufficient to raise FVIII levels in Vwf 2/2 mice from a baseline of ∼5% to 10%, to ∼50% to 100%. These results demonstrate that a fragment containing only ∼20% of the VWF sequence is sufficient to support FVIII stability in vivo. Expression of the VWF D9D3 fragment fused at its C terminus to the Fc segment of immunoglobulin G1 results in markedly enhanced survival in the circulation (t 1/2 > 7 days), concomitant with elevated plasma FVIII levels (>25% at 7 days) in Vwf 2/2 mice. Although the VWF D9D3-Fc chimera also exhibits markedly prolonged survival when transfused into FVIII-deficient mice, the cotransfused FVIII is rapidly cleared. Kinetic binding studies show that VWF propeptide processing of VWF D9D3 fragments is required for optimal FVIII affinity. The reduced affinity of VWF D9D3 and VWF D9D3-Fc for FVIII suggests that the shortened FVIII survival in FVIII-deficient mice transfused with FVIII and VWF D9D3/D9D3-Fc is due to ineffective competition of these fragments with endogenous VWF for FVIII binding. (Blood. 2014; 124(3):445-452)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

Yee

Gildersleeve

et al. 2014

Blood

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“…Primary prophylaxis with infusions of coagulation factor VIII (FVIII; haemophilia A) or factor IX (FIX; haemophilia B) is the gold standard of care for haemophilia patients today, with the aim of preventing bleeds, slowing the progression of joint destruction and preserving musculoskeletal function [1,2,4,5].…”

Section: Introductionmentioning

confidence: 99%

Concizumab, an anti‐tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay

et al. 2017

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Aims: Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentrationdependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. Methods: For the ex vivo spiking study, platelet-poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001-500 nM concizumab. For the multiple-dosing study, four healthy males received concizumab 250 lg kg À1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram â system with 1 pM tissue factor. Results: In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near-normal levels at concizumab concentrations >10 nM. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. Conclusions: Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy.

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“…3 A study was carried out to evaluate the progress of musculoskeletal ability and pain in haemophilia A and B patients during a given period of time and to find out the role of rehabilitation and physiotherapy in this process. In the physiotherapy/ rehabilitation group, pain index by visual analogue scale (VAS) improved through time by 26%/4.6%.…”

Section: Discussionmentioning

confidence: 99%

Role of Physiotherapy in Hemophilia Patient: A Case Study on New Dimension of Physiotherapy Application

Doly¹

2017

MOJYPT

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Abbreviations: FFP, fresh frozen plasma; BSMMU, bangabandhu sheikh mujib medical university DMC, Dhaka medical college; PWH, person of world hemophilia; VAS, visual analogue scale IntroductionHemophilia is not a common disease. It is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. It is a hereditary bleeding disorder caused by a lack or absent of blood clotting factor -VIII or IX. There are two main types of haemophilia: haemophilia A, which occurs due to not enough clotting factor VIII, and haemophilia B, which occurs due to not enough clotting factor IX). Joint bleeding is common in hemophilia followed by muscle bleeding, other bleeding and brain hemorrhage. The prevalence of hemophilia is estimated to be about 1:10000 birth and that of the severe form of the disease to be about 6% per 100000 population.1 Even medical personnel are sometimes not familiar with its diagnosis and management which is pathetic. As such many health care professionals are not aware of the integral role physiotherapists play in the management of people with bleeding disorders or sometimes they refer patient to other medical professional for physiotherapy. Lack of referral system makes this problem more severe though scenario is changing day by day. Seminar, symposium, conference and workshop regarding Haemophilia can build up awareness. Physiotherapy is recognized as a mean to improve quality of life, improve healing times and decrease frequency of bleeds, and to aid in the prevention of joint destruction due to multiple bleeds. Case historyMaster Abdullah-14years old boy is the subject under study. At his first years of birth, he used to have bruises often all over his body. They would disappear often a few days. When he was 3years old, he fell from a chair and his mouth struck at the brain of a vessel on the floor. He was taken to Bangabandhu Sheikh Mujib Medical University (BSMMU) where his condition was diagnosed as Hemophilia-A at a severe level, less than 1%. He had frequent bleeding in the right knee joint and sometime gum bleeding. At the age of 5years he had a major bleed in the urinary track and developed Hematuria. His left knee had become stiff due to prolonged bleeds and also because of a fall few years ago. The knee joint had been dislocated. He used to treat with pain killer, ice, Fresh Frozen Plasma (FFP). He started receiving factor replacement since a few years. He was admitted to school at the age of 6yrs. He had to change school since the management refused to take any care about him. At present he has no problem with teachers or schoolmates on account of hemophilia, but now he faces some problem or non-co-operation from his family members specially his father. His father thinks or believes that "It is a non-curative disease and his wife is responsible for the disease" so he is not interested to do any treatment or other co-operation even not continue education. Sometimes he also avoids his wife. From January 2017, he has been suffering rec...

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The hope and reality of long‐acting hemophilia products

Cited by 47 publications

References 71 publications

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

A von Willebrand factor fragment containing the D′D3 domains is sufficient to stabilize coagulation factor VIII in mice

Concizumab, an anti‐tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay

Role of Physiotherapy in Hemophilia Patient: A Case Study on New Dimension of Physiotherapy Application

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