Rational design of small molecules targeting the C2 domain of coagulation factor VIII

Blood ◽  
2014 ◽  
Vol 123 (1) ◽  
pp. 113-120 ◽  
Author(s):  
Gerry A. F. Nicolaes ◽  
Mahesh Kulharia ◽  
Jan Voorberg ◽  
Paul H. Kaijen ◽  
Aleksandra Wroblewska ◽  
...  
Keyword(s):  
Factor Viii ◽  
Small Molecules ◽  
Rational Design ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
C2 Domain ◽  
Key Points ◽  
Thrombin Formation

Key Points Novel small molecules have been identified that specifically target FVIII. These small molecules are able to reduce in vitro thrombin formation in full blood.

scholarly journals Inhibition of human coagulation factor VIII by monoclonal antibodies. Mapping of functional epitopes with the use of recombinant factor VIII fragments

1989 ◽  
Vol 263 (1) ◽  
pp. 187-194 ◽  
Author(s):  
A Leyte ◽  
K Mertens ◽  
B Distel ◽  
R F Evers ◽  
M J M De Keyzer-Nellen ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Factor Viii ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Procoagulant Activity ◽  
Coagulation Factor Viii ◽  
Coagulation Cascade ◽  
Restriction Enzyme Digestion ◽  
Proteolytic Activation

The epitopes of four monoclonal antibodies against coagulation Factor VIII were mapped with the use of recombinant DNA techniques. Full-length Factor VIII cDNA and parts thereof were inserted into the vector pSP64, permitting transcription in vitro with the use of a promoter specific for SP6 RNA polymerase. Factor VIII DNA inserts were truncated from their 3′-ends by selective restriction-enzyme digestion and used as templates for ‘run-off’ mRNA synthesis. Translation in vitro with rabbit reticulocyte lysate provided defined radiolabelled Factor VIII fragments for immunoprecipitation studies. Two antibodies are shown to be directed against epitopes on the 90 kDa chain of Factor VIII, between residues 712 and 741. The 80 kDa chain appeared to contain the epitopes of the other two antibodies, within the sequences 1649-1778 and 1779-1840 respectively. The effect of antibody binding to these sequences was evaluated at two distinct levels within the coagulation cascade. Both Factor VIII procoagulant activity and Factor VIII cofactor function in Factor Xa generation were neutralized upon binding to the region 1779-1840. The antibodies recognizing the region 713-740 or 1649-1778, though interfering with Factor VIII procoagulant activity, did not inhibit in Factor Xa generation. These findings demonstrate that antibodies that virtually inhibit Factor VIII in coagulation in vitro are not necessarily directed against epitopes involved in Factor VIII cofactor function. Inhibition of procoagulant activity rather than of cofactor function itself may be explained by interference in proteolytic activation of Factor VIII. This hypothesis is in agreement with the localization of the epitopes in the proximity of thrombin-cleavage or Factor Xa-cleavage sites.

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 The 3.2 Å structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain

2019 ◽  
Vol 18 (1) ◽  
pp. 57-69 ◽  
Author(s):  
Ian W. Smith ◽  
Anne E. d'Aquino ◽  
Christopher W. Coyle ◽  
Andrew Fedanov ◽  
Ernest T. Parker ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Coagulation ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
C2 Domain ◽  
Blood Coagulation Factor Viii

scholarly journals Protein residue network analysis reveals fundamental properties of the human coagulation factor VIII

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tiago J. S. Lopes ◽  
Ricardo Rios ◽  
Tatiane Nogueira ◽  
Rodrigo F. Mello
Keyword(s):  
Factor Viii ◽  
Treatment Options ◽  
Coagulation Factor ◽  
Interaction Network ◽  
Biological Properties ◽  
Coagulation Factor Viii ◽  
Coagulation Disorder ◽  
Residue Interaction ◽  
Derived Properties

AbstractHemophilia A is an X-linked inherited blood coagulation disorder caused by the production and circulation of defective coagulation factor VIII protein. People living with this condition receive either prophylaxis or on-demand treatment, and approximately 30% of patients develop inhibitor antibodies, a serious complication that limits treatment options. Although previous studies performed targeted mutations to identify important residues of FVIII, a detailed understanding of the role of each amino acid and their neighboring residues is still lacking. Here, we addressed this issue by creating a residue interaction network (RIN) where the nodes are the FVIII residues, and two nodes are connected if their corresponding residues are in close proximity in the FVIII protein structure. We studied the characteristics of all residues in this network and found important properties related to disease severity, interaction to other proteins and structural stability. Importantly, we found that the RIN-derived properties were in close agreement with in vitro and clinical reports, corroborating the observation that the patterns derived from this detailed map of the FVIII protein architecture accurately capture the biological properties of FVIII.

scholarly journals Backbone resonance assignments of the C2 domain of coagulation factor VIII

2012 ◽  
Vol 7 (1) ◽  
pp. 31-34
Author(s):  
Kristin M. Nuzzio ◽  
David B. Cullinan ◽  
Valerie A. Novakovic ◽  
John M. Boettcher ◽  
Chad M. Rienstra ◽  
...  
Keyword(s):  
Factor Viii ◽  
Resonance Assignments ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
C2 Domain ◽  
Backbone Resonance Assignments ◽  
Backbone Resonance

scholarly journals Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII

2003 ◽  
Vol 1 (8) ◽  
pp. 1777-1784 ◽  
Author(s):  
M. T. Reding ◽  
D. K. Okita ◽  
B. M. Diethelm-Okita ◽  
T. A. Anderson ◽  
B. M. Conti-Fine
Keyword(s):  
T Cell ◽  
Factor Viii ◽  
Cell Epitope ◽  
Coagulation Factor ◽  
Cd4 T Cell ◽  
Coagulation Factor Viii ◽  
C2 Domain ◽  
T Cell Epitope

scholarly journals A Macroglobulin with Inhibitory Activity Against Coagulation Factor VIII

Blood ◽  
1970 ◽  
Vol 35 (3) ◽  
pp. 370-376 ◽  
Author(s):  
P. A. CASTALDI ◽  
R. PENNY
Keyword(s):  
Factor Viii ◽  
Specific Activity ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
Clotting Factor ◽  
Factor Deficiency ◽  
Spontaneous Correction ◽  
Characteristic Features

Abstract Deficiency of coagulation factor VIII occurred in a patient with a monoclonal gamma-M protein and characteristic features of Waldenström’s macroglobulinemia. The protein, found to contain lambda light chains, had specific activity against normal factor VIII that was reversible by reduction with 2-mercaptoethanol. Spontaneous correction of the clotting factor deficiency occurred during treatment. It is suggested that the macroglobulin in this patient removed or masked factor VIII by adsorption and that alteration of the protein in vitro by mercaptoethanol and in vivo by treatment removed this capacity.

Discontinuous epitopes on the C2 domain of coagulation Factor VIII mapped by computer-designed synthetic peptides

2011 ◽  
Vol 155 (4) ◽  
pp. 487-497 ◽  
Author(s):  
Aurélien Lebreton ◽  
Violaine Moreau ◽  
Priscilla Lapalud ◽  
Christopher Cayzac ◽  
Sébastien André ◽  
...  
Keyword(s):  
Factor Viii ◽  
Synthetic Peptides ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
C2 Domain ◽  
Discontinuous Epitopes
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