scholarly journals Novel therapeutics for hemophilia and other bleeding disorders

Blood ◽  
2018 ◽  
Vol 132 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Michael U. Callaghan ◽  
Robert Sidonio ◽  
Steven W. Pipe
Keyword(s):  
Factor Viii ◽  
New Technologies ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Routes Of Administration ◽  
New Approaches ◽  
Dosing Regimens ◽  
Von Willebrand

Abstract Hemophilia and von Willebrand disease are the most common congenital bleeding disorders. Treatment of these disorders has focused on replacement of the missing coagulation factor to prevent or treat bleeding. New technologies and insights into hemostasis have driven the development of many promising new therapies for hemophilia and von Willebrand disease. Emerging bypass agents including zymogen-like factor IXa and Xa molecules are in development and a bispecific antibody, emicizumab, demonstrated efficacy in a phase 3 trial in people with hemophilia A and inhibitors. Tissue factor pathway inhibitor, the protein C/S system, and antithrombin are targets of novel compounds in development to alter the hemostatic balance and new approaches using modified factor VIII molecules are being tested for prevention and eradication of inhibitor antibodies in hemophilia A. The first recombinant von Willebrand factor (VWF) product has been approved and has unique VWF multimer content and does not contain factor VIII. These new approaches may offer better routes of administration, improved dosing regimens, and better efficacy for prevention and treatment of bleeding in congenital bleeding disorders.

Risk and Management of Intracerebral Hemorrhage in Patients with Bleeding Disorders

2022 ◽  
Author(s):  
Akbar Dorgalaleh ◽  
Yadolah Farshi ◽  
Kamand Haeri ◽  
Omid Baradarian Ghanbari ◽  
Abbas Ahmadi
Keyword(s):  
Risk Factors ◽  
Intracerebral Hemorrhage ◽  
Platelet Function ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Vacuum Extraction ◽  
Bleeding Disorders ◽  
Platelet Function Disorders ◽  
Von Willebrand

AbstractIntracerebral hemorrhage (ICH) is the most dreaded complication, and the main cause of death, in patients with congenital bleeding disorders. ICH can occur in all congenital bleeding disorders, ranging from mild, like some platelet function disorders, to severe disorders such as hemophilia A, which can cause catastrophic hemorrhage. While extremely rare in mild bleeding disorders, ICH is common in severe coagulation factor (F) XIII deficiency. ICH can be spontaneous or trauma-related. Spontaneous ICH occurs more often in adults, while trauma-related ICH is more prevalent in children. Risk factors that can affect the occurrence of ICH include the type of bleeding disorder and its severity, genotype and genetic polymorphisms, type of delivery, and sports and other activities. Patients with hemophilia A; afibrinogenemia; FXIII, FX, and FVII deficiencies; and type 3 von Willebrand disease are more susceptible than those with mild platelet function disorders, FV, FXI, combined FV–FVIII deficiencies, and type 1 von Willebrand disease. Generally, the more severe the disorder, the more likely the occurrence of ICH. Contact sports and activities can provoke ICH, while safe and noncontact sports present more benefit than danger. An important risk factor is stressful delivery, whether it is prolonged or by vacuum extraction. These should be avoided in patients with congenital bleeding disorders. Familiarity with all risk factors of ICH can help prevent occurrence of this diathesis and reduce related morbidity and mortality.

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

Blood ◽  
2015 ◽  
Vol 125 (13) ◽  
pp. 2019-2028 ◽  
Author(s):  
Peter J. Lenting ◽  
Olivier D. Christophe ◽  
Cécile V. Denis
Keyword(s):  
Life Cycle ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Current Knowledge ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Proinflammatory Response ◽  
Wide Range ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract 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.

scholarly journals The roles of von Willebrand factor and factor VIII in arterial thrombosis: studies in canine von Willebrand disease and hemophilia A

Blood ◽  
1993 ◽  
Vol 81 (10) ◽  
pp. 2644-2651 ◽  
Author(s):  
TC Nichols ◽  
DA Bellinger ◽  
RL Reddick ◽  
SV Smith ◽  
GG Koch ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Arterial Thrombosis ◽  
Hemophilia A ◽  
Full Range ◽  
Von Willebrand Disease ◽  
Arterial Stenosis ◽  
Canine Plasma ◽  
Von Willebrand ◽  
Willebrand Factor

We have studied the roles of von Willebrand factor (vWF) and factor VIII in arterial thrombosis in four canine phenotypes: normal (n = 6), hemophilia A (n = 11), von Willebrand disease (vWD) (n = 9), and hemophilia A/vWD (n = 1). vWF activity was determined by botrocetin- induced agglutination of fixed human platelets and vWF antigen (vWF:Ag) by Laurell electroimmunoassay and crossed immunoelectrophoresis. Plasma from normal dogs and those with hemophilia A had vWF activity, vWF:Ag, and a full range of vWF:Ag multimers on gel electrophoresis equivalent to normal canine plasma pool. Platelet cytosol contents were isolated by freezing and thawing, triton X-100 solubilization, or sonication of washed platelets with and without protease inhibitors and inhibitors of platelet activation. Washed platelets were also stimulated with calcium ionophore and MgCl2. There was no measurable vWF activity or vWF:Ag in platelet lysates or releasates in any dog regardless of phenotype. All dogs were studied using a standard arterial stenosis and injury procedure to induce arterial thrombosis. Thromboses were detected by cyclic reductions in Doppler blood flow velocity. Vessels were examined by light and scanning electron microscopy. Thrombosis developed in the arteries of normal (9 of 10) and hemophilia A dogs (16 of 16) but in none of the vWD dogs (0 of 10). Infusion of canine vWF cryoprecipitate into vWD dogs markedly shortened bleeding time but did not support thrombosis as seen in dogs with vWF in the plasma and subendothelium. Thrombosis, then, fails to occur when vWF is absent from the plasma and subendothelial compartments or present only in the plasma compartment. These data are consistent with the hypothesis that vWF in the plasma and subendothelium supports thrombosis. Neither plasma FVIII nor platelet vWF is essential for thrombosis in this model.

scholarly journals How I treat patients with inherited bleeding disorders who need anticoagulant therapy

Blood ◽  
2016 ◽  
Vol 128 (2) ◽  
pp. 178-184 ◽  
Author(s):  
Karlyn Martin ◽  
Nigel S. Key
Keyword(s):  
Atrial Fibrillation ◽  
Hemophilia A ◽  
Thrombotic Event ◽  
Management Strategies ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Atherothrombotic Disease ◽  
Risk Of Hemorrhage ◽  
Evidence Based Guidelines ◽  
Von Willebrand

Abstract Situations that ordinarily necessitate consideration of anticoagulation, such as arterial and venous thrombotic events and prevention of stroke in atrial fibrillation, become challenging in patients with inherited bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease. There are no evidence-based guidelines to direct therapy in these patients, and management strategies that incorporate anticoagulation must weigh a treatment that carries a risk of hemorrhage in a patient who is already at heightened risk against the potential consequences of not treating the thrombotic event. In this paper, we review atherothrombotic disease, venous thrombotic disease, and atrial fibrillation in patients with inherited bleeding disorders, and discuss strategies for using anticoagulants in this population using cases to illustrate these considerations.

Congenital Bleeding Disorders

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 559-574 ◽  
Author(s):  
Margaret E. Rick ◽  
Christopher E. Walsh ◽  
Nigel S. Key
Keyword(s):  
Gene Transfer ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
History Of ◽  
Von Willebrand

Abstract Both clinical and basic problems related to the congenital bleeding disorders continue to confront hematologists. On the forefront are efforts to bring genetic correction of the more common bleeding disorders such as hemophilia A to the clinic in a safe and accessible manner. A second issue, particularly for patients with hemophilia, is the development of inhibitors—questions of how they arise and how to prevent and treat these problems that confound otherwise very successful replacement therapy and allow patients to maintain normal lifestyles. A third issue is the continuing question of diagnosis and management of von Willebrand disease, the most common congenital bleeding disorder, especially in individuals who have borderline laboratory values, but have a history of clinical bleeding. In Section I, Dr. Christopher Walsh discusses general principles of effective gene transfer for the hemophilias, specific information about viral vectors and non-viral gene transfer, and alternative target tissues for factor VIII and factor IX production. He highlights information about the immune response to gene transfer and reviews data from the hemophilia gene transfer trials to date. The future prospects for newer methods of therapy such as RNA repair and the use of gene-modified circulating endothelial progenitors are presented as possible alternatives to the more traditional gene therapy approaches. In Section II, Dr. Nigel Key focuses on inhibitor development in patients with hemophilia A. He reviews the progress in our understanding of the risk factors and presents newer information about the immunobiology of inhibitor development. He discusses the natural history of these inhibitors and the screening, laboratory diagnosis, and treatment, including the use of different modalities for the treatment of acute bleeding episodes. Dr. Key also presents information about the eradication of inhibitors by immune tolerance induction and reviews recent information from the international registries regarding the status and success of immune tolerance induction. In Section III, Dr. Margaret Rick discusses the diagnosis, classification, and management of von Willebrand disease. Attention is given to the difficulty of diagnosis in patients with mild bleeding histories and borderline laboratory test results for von Willebrand factor. She presents the value of different laboratory assays for both diagnosis and classification, and she relates the classification of von Willebrand disease to the choice of treatment and to the known genetic mutations. Practical issues of diagnosis and treatment, including clinical cases, will be presented.

scholarly journals Targeted DNA Sequencing for Hemophilia A, B, and von Willebrand Disease: Analytical Precision in Clinical Laboratories and Improved Disease Characterization

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5042-5042
Author(s):  
Patricia Severino ◽  
Liliane Santana Oliveira ◽  
Natalia Torres ◽  
Joao Carlos Guerra ◽  
Nelson Hamerschlak ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Sanger Sequencing ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Coagulation Factor ◽  
Von Willebrand Disease ◽  
Targeted Sequencing ◽  
Probe Design ◽  
Clinical Laboratories ◽  
Von Willebrand

Abstract Hemophilia A, B, and von Willebrand disease correspond to more than 90% of all inherited bleeding disorders associated with coagulation factor deficiencies. Symptoms between these deficiencies may vary greatly and yet are often phenotypically similar. Bleeding episodes can range from mild to severe, at times with life threatening hemorrhages. Currently, biochemical assays are performed to assess the function of each coagulation factor, but diagnosis remains cumbersome and prone to multiple sources of variability between laboratories. Genetic evaluation allows for the examination of multiple coagulation factor genes simultaneously and may quickly identify possible causes to the disease. Additionally, genetic testing should be more reproducible and readily comparable between clinical laboratories. In this work we evaluate the potential use of targeted sequencing of three coagulation factors genes – F8, F9 and VWF – for the concurrent diagnosis and characterization of hemophilia A, B, and von Willebrand disease samples. For targeted DNA sequencing we selected specific DNA probes using genomic coordinates spanning the complete intronic and exonic regions of the three genes, as well as flanking gene sequences. Eleven hemophilia A samples and four hemophilia B samples, clinically characterized and submitted to Sanger sequencing for F8 and F9 genes coding regions, respectively, were included in this study. Our results indicate that even though DNA quality may be ideal for traditional DNA sequencing, enrichment techniques require more intact fragments, as reflected by variations in sequencing coverage between samples: quadruplicate results per sample showed 100X coverage varying from 80% of sequenced regions to less then 20%. Point substitutions found in F9 genes by Sanger sequencing were confirmed by targeted sequencing, but results for F8 gene were less satisfactory, in agreement with probe design limitations at this point. Of interest for hemophilia A patients, four samples possessed, in addition to the alterations in F8, point mutations in VWF. Probe design and sequencing parameters did not allow for the identification of F8 intron 1 and intron 22 inversions, frequent alterations in hemophilia A, but optimization procedures are currently underway. We conclude that targeted sequencing approach may be a viable and more complete solution for the diagnosis and management of hemophilia A, B and von Willebrand disease. Disclosures No relevant conflicts of interest to declare.

Structure of Blood Coagulation Factor VIII in Complex with an Anti-C1 Domain Pathogenic Antibody Inhibitor

Blood ◽  
2021 ◽  
Author(s):  
Joseph S Gish ◽  
Lexi Jarvis ◽  
Kenneth C Childers ◽  
Shaun C Peters ◽  
Connor S Garrels ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Domain Antibody ◽  
C1 Domain ◽  
Group A ◽  
Surface Loops ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Blood Coagulation Factor Viii

Antibody inhibitor development in hemophilia A represents the most significant complication resulting from factor VIII (fVIII) replacement therapy. Recent studies have demonstrated that epitopes present in the C1 domain contribute to a pathogenic inhibitor response. In this study, we report the structure of a Group A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted, bioengineered fVIII construct (ET3i). The 2A9 epitope forms direct contacts to the C1 domain at three different surface loops consisting of Lys2065-Trp2070, Arg2150-Tyr2156 and Lys2110-Trp2112. Additional contacts are observed between 2A9 and the A3 domain, including the Phe1743-Tyr1748 loop and the N-linked glycosylation at Asn1810. Most of the C1 domain loops in the 2A9 epitope also represent a putative interface between fVIII and von Willebrand factor (vWF). Lastly, the C2 domain in the ET3i:2A9 complex adopts a large, novel conformational change, translocating outward from the structure of fVIII by 20 Å. This study reports the first structure of an anti-C1 domain antibody inhibitor and the first fVIII:inhibitor complex with a therapeutically active fVIII construct. Further structural understanding of fVIII immunogenicity may result in the development of more effective and safe fVIII replacement therapies.

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