Compensated pathogenic variants in coagulation factors VIII and IX present complex mapping between molecular impact and hemophilia severity

SummaryRecombinant activated factor VII (rFVIIa, Novo Seven®) has been successfully used to treat bleeding episodes in patients with antibodies against coagulation factors VIII and IX. In recent years, rFVIIa has also been employed for the management of uncontrolled bleeding in a number of congenital and acquired haemos- tatic abnormalities. Based on a literature search, this review examines the current knowledge on therapy with rFVIIa, from the now well-standardized uses to the newer and less well-characterised clinical applications.

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Ham-Wasserman Lecture

Hematology ◽

10.1182/asheducation-2002.1.1 ◽

2002 ◽

Vol 2002 (1) ◽

pp. 1-9 ◽

Cited By ~ 40

Author(s):

Pier M. Mannucci

Keyword(s):

Large Scale ◽

Coagulation Factors ◽

Gene Replacement ◽

Infectious Complications ◽

Inherited Disorders ◽

Secondary Tumors ◽

Human Immunodeficiency Viruses ◽

First Millennium ◽

Viii And Ix ◽

Bloodborne Infections

Abstract Known since the beginning of the first millennium, the hemophilias are among the most frequent inherited disorders of blood coagulation and definitely the most severe. In the 1970s, with the availability of concentrated preparations of the deficient coagulation factors VIII and IX and with the large-scale adoption of home treatment, hemophilia care became one of the most gratifying examples of successful secondary prevention of a chronic disease. Unfortunately, in the early 1980s it was recognized that factor concentrates prepared from plasma pooled from thousands of donors transmitted the hepatitis and the human immunodeficiency viruses. The scientific community reacted promptly to the devastation brought about by hepatitis and AIDS. The last 15 years of the second millennium have witnessed the development of methods that, when applied during concentrate manufacturing, inactivate viruses escaping the screening procedures. The adoption of these measures has reduced dramatically the risk of transmission of bloodborne infections. The production of recombinant factors and their availability for patients’ treatment epitomize progress in hemophilia care through DNA technology. Methods based on the polymerase chain reaction (PCR) have unraveled an array of gene lesions associated with hemophilia, permitting improved secondary control of the disease through carrier detection in women from affected families and prenatal termination of their affected male infants. This article will review the aforementioned areas of progress and discuss unresolved problems (such as treatment of patients with antibodies, the risk of new infectious complications, and the issue of secondary tumors). Hopes and expectations for further improvement in the third millennium and particularly the prospects of hemophilia cure though gene replacement therapy will also be mentioned.

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THE EFFECT OF THE VENOM OF THE ORIENTAL HORNET ON COAGULATION FACTORS

10.1055/s-0038-1644338 ◽

1987 ◽

Author(s):

A Kornberg ◽

S Kaufman ◽

L Silber ◽

J Ishay

Keyword(s):

Human Plasma ◽

Degradation Products ◽

Anticoagulant Activity ◽

Coagulation Factors ◽

Plasma Fibrinogen ◽

Thrombin Time ◽

Clotting Factors ◽

Viii And Ix

The extract from the venom sac of Vespa orientalis (VSE) inactivates exogenous and endogenous thromboplastin (Joshua and Ishay, Toxicon, 13:11-20,1975). The prolongation of both prothrombin time (PT) and recalcification time suggests inactivation of other factors. The aim of the present study is to investigate the effect of VSE on clotting factors. A lyophilized VSE with protein concentration of 5 mg/ml was used. Studies were performed in vitro with human plasma and in vivo in cats. Routine methods were employed for the assay of PT, activated tissue thromboplastin (APTT), thrombin time (TT), fibrinogen degradation products (FDP), fibrinogen and factors V,VII,VIII,IX,X. Human plasma was incubated with various concentrations of VSE (0,1,5,10,50,100 μg/ml) for 60 min and for various incubation times (0,5,15,30,+ 60,90,120 min) with 50 μg/ml VSE (n=8). 1 μg/ml VSE prolonged PT from 13.5 to 16 sec (p<0.05) and APTT from 62 to 180 sec. PT was maximal (17.7 sec) with 10 μg/ml and APTT (442 sec) with 50 μg/ml VSE. Factors V,VII,X decreased gradually from 94-105% to 11%,11% and 29% with 100 μg/ml VSE and VIII and IX to 1% even with 1 μg/ml VSE. After 5 min with constant concentration of VSE (50 μg/ml) PT was 14.9 sec (normal 13 sec) and APTT 165 sec (normal 54 sec). Both were maximal (17.5 and 298 sec) after 60 min. Factors VII and X decreased to 13% and 32% and VIII and IX to >1% after 60 min of incubation. Injection of 5 mg/kg VSE to cats (n=6-8) resulted in prolongation of PT from 9.4 to 11.2 sec and of APTT from 19.5 to 63 sec after 5 min. Both were maximal after 90 min (12.3 and 127 sec). Factors V,VII and X decreased from 100% to 7.6%, 13% and 37% and VIII and IX to 1% after 10 min. In all experiments TT and plasma fibrinogen were not affected and FDP were normal. Heating of VSE for 5 min at 80°C abolished completely the anticoagulant activity but dialysis for 24 hr at 4°C had no effect on it. The activity was eluted on Sephadex-25 both in void and post void volumes. The results show that VSE has a potent anticoagulant activity against various factors. Factors VIII and IX are markedly decreased. The effect on V, VII and X is moderate. Plasma fibrinogen is not affected. The nature and clinical significance of the anticoagulant activity merit further investigation.

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In vitro differentiation of mouse ES cells into hepatocytes with coagulation factors VIII and IX expression profiles

Science in China Series C Life Sciences ◽

10.1007/s11427-006-0259-3 ◽

2006 ◽

Vol 49 (3) ◽

pp. 259-264 ◽

Cited By ~ 3

Author(s):

Ying Meng ◽

Shaoliang Huang ◽

Jun Min ◽

Zhongmin Guo

Keyword(s):

Expression Profiles ◽

Es Cells ◽

Coagulation Factors ◽

In Vitro Differentiation ◽

Mouse Es Cells ◽

Viii And Ix

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Therapeutic levels of human factor VIII and IX using HIV-1–based lentiviral vectors in mouse liver

Blood ◽

10.1182/blood.v96.3.1173.015k34_1173_1176 ◽

2000 ◽

Vol 96 (3) ◽

pp. 1173-1176 ◽

Cited By ~ 3

Author(s):

Frank Park ◽

Kazuo Ohashi ◽

Mark A. Kay

Keyword(s):

Fold Increase ◽

Lentiviral Vectors ◽

Coagulation Factors ◽

Human Factor Viii ◽

Immunodeficiency Virus ◽

Viii And Ix ◽

Immunocompetent Mice ◽

Dose Dependent ◽

Hiv 1

Lentiviral vectors have the potential to play an important role in hemophilia gene therapy. The present study used human immunodeficiency virus (HIV)-based lentiviral vectors containing an EF1 enhancer/promoter driving human factors VIII (hFVIII) or IX (hFIX) complementary DNA expression for portal vein injection into C57Bl/6 mice. Increasing doses of hFIX-expressing lentivirus resulted in a dose-dependent, sustained increase in serum hFIX levels up to approximately 50-60 ng/mL. Partial hepatectomy resulted in a 4- to 6-fold increase (P < 0.005) in serum hFIX of up to 350 ng/mL compared with the nonhepatectomized counterparts. The expression of plasma hFVIII reached 30 ng/mL (15% of normal) but was transient as the plasma levels fell concomitant with the formation of anti-hFVIII antibodies. However, hFVIII levels were persistent in immunodeficient C57Bl/6 scid mice, suggesting humoral immunity-limited gene expression in immunocompetent mice. This study demonstrates that lentiviral vectors can produce therapeutic levels of coagulation factors in vivo, which can be enhanced with hepatocellular proliferation.

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Use of a non-depleting anti-CD4 antibody to modulate the immune response to coagulation factors VIII and IX

British Journal of Haematology ◽

10.1046/j.1365-2141.2002.03666.x ◽

2002 ◽

Vol 118 (3) ◽

pp. 839-842 ◽

Cited By ~ 13

Author(s):

Nina Salooja ◽

Geoffrey Kemball-Cook ◽

Edward G. D. Tuddenham ◽

Julian Dyson

Keyword(s):

Immune Response ◽

Coagulation Factors ◽

Viii And Ix

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The Global Need and Availability of Plasma Coagulation Factors VIII and IX in Hemophilia Context: A Global Health Estimate Reporting

SSRN Electronic Journal ◽

10.2139/ssrn.3787451 ◽

2021 ◽

Author(s):

Elisângela César dos Santos Anjos ◽

Fabiano Romanholo Ferreira ◽

Paulo Henrique de Souza Bermejo ◽

Marina Figueiredo Moreira ◽

David Nadler Prata

Keyword(s):

Global Health ◽

Coagulation Factors ◽

Plasma Coagulation ◽

Viii And Ix

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Inhibition of Extrinsic Pathway Inhibitor Shortens the Coagulation Time of Normal Plasma and of Hemophilia Plasma

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646439 ◽

1991 ◽

Vol 66 (04) ◽

pp. 464-467 ◽

Cited By ~ 40

Author(s):

Ole Nordfang ◽

Sanne Valentin ◽

Thomas C Beck ◽

Ulla Hedner

Keyword(s):

Coagulation Factors ◽

Inhibitory Antibody ◽

Extrinsic Pathway ◽

Coagulation Time ◽

Plasma Analysis ◽

Normal Plasma ◽

Low Concentrations ◽

Viii And Ix ◽

Dependent Pathway ◽

Individual Donor

SummaryAn increasing amount of evidence suggests that coagulation factors VIII and IX play a role not only in the intrinsic but also in the extrinsic pathway of coagulation. In this context the influence of the Extrinsic Pathway Inhibitor (EPI) on the coagulation time of hemophilia plasma lacking FVIII or FIX has been investigated. The coagulation time was measured in a dilute thromboplastin assay. Addition of recombinant EPI (rEPI) prolonged the coagulation time of normal plasma while the addition of an inhibitory antibody against EPI shortened the coagulation time. At low concentrations of thromboplastin the coagulation time of hemophilia plasma was prolonged and at all dilutions of thromboplastin, addition of anti-EPI IgG normalized the coagulation time of a hemophilia plasma. Analysis of 10 individual donor plasma samples and 8 individual hemophilia samples showed that addition of anti-EPI IgG shortened the coagulation time more in hemophilia plasma than in normal plasma. This illustrates the importance of a powerful extrinsic FVII dependent pathway to achieve hemostasis in the case of FVIII or FIX deficiency (hemophilia A and B).

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Efleet of Endotoxin on the Activity of Coagulation Factors VII, VIII and IX Produced during Organ Perfusion

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647721 ◽

1974 ◽

Vol 32 (02/03) ◽

pp. 528-537

Author(s):

W Jean Dodds ◽

Stein A. Evensen

Keyword(s):

Factor Viii ◽

Actinomycin D ◽

Platelet Rich Plasma ◽

Coagulation Factors ◽

Factor Vii ◽

Protein Synthesis Inhibitors ◽

Factor Viii Activity ◽

Coagulation Activity ◽

Viii And Ix ◽

Initial Perfusion

SummaryThe effect of bacterial endotoxin on the production of factor VII, VIII and IX activities in isolated rabbit livers, spleens and kidneys was investigated. The organs were perfused for 4 hours with fluid devoid of coagulation activity and containing either endotoxin or glucose-saline diluent. A series of parallel experiments included an initial hour of perfusion to ensure removal of tissue-stored coagulation activity, and perfusion with platelet-rich plasma and protein synthesis inhibitors. Endotoxin increased factor VII production in all organs but especially in livers not subjected to the initial perfusion; this effect was abolished by actinomycin D and puromycin. Endotoxin had little effect on hepatic factor VIII and IX activities but it inhibited production of both factors in the kidney and of factor VIII in the spleen. Initial perfusion prevented this inhibition of splenic factor VIII activity. These data suggest that endotoxin increases factor VII synthesis and causes consumption of factors VIII and IX in perfused kidneys and, to a lesser extent, spleens. Also, initial perfusion appears to prevent the subsequent consumption of splenic factor VIII by endotoxin. This response may involve activation of some tissue-bound or stored factor(s) or may be due to removal of an inhibitor substance.

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The Adsorption of Coagulation Factors onto Phospholipids

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654227 ◽

1970 ◽

Vol 24 (01/02) ◽

pp. 214-223 ◽

Cited By ~ 11

Author(s):

H. C Hemker ◽

M. J. P Kahn ◽

P. P Devilee

Keyword(s):

Reaction Mechanism ◽

Blood Coagulation ◽

Coagulation Factors ◽

Factor X ◽

Intrinsic Pathway ◽

Viii And Ix ◽

Complex Enzymes

SummaryIt is shown that factors VIII and IX react with phospholipid in a way fully analogous to the reaction of factors V and X. From this it is concluded that a complex of factors VIII and IX adsorbed onto a phospholipid micelle may be the entity that activates factor X in the intrinsic pathway. The implications of this finding for the concepts of the reaction mechanism of blood coagulation are discussed. It is shown that instead of the original 7-step cascade of Macfarlane, a 4-step cascade consisting partly of complex enzymes is more probable.

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