Prophylaxis Using a Mixture of Plasma-Derived Activated Factor VII and Factor X (pdFVIIa/FX) in a Patient with Hemophilia B Complicated by Inhibitors and Allergy to Factor IX Concentrates: A Case Report

SummaryAbetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyce-ride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 μmol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients’ mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.

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Novel Insights and New Developments Regarding Coagulation Revealed by Studies of the Anti-Factor IXa (Activated Factor IX)/Factor X Bispecific Antibody, Emicizumab

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.312919 ◽

2020 ◽

Vol 40 (5) ◽

pp. 1148-1154

Author(s):

Koji Yada ◽

Keiji Nogami

Keyword(s):

Hemophilia A ◽

Activated Protein C ◽

Factor Ix ◽

Factor Vii ◽

Factor X ◽

New Developments ◽

Activated Factor Vii ◽

Factor Ixa ◽

Thrombin Activation ◽

No Activation

Emicizumab is a humanized anti-FIXa/FX (factor IXa/X) bispecific monoclonal antibody that mimics FVIIIa (activated factor VIII) cofactor function. The hemostatic efficacy of emicizumab has been confirmed in clinical studies of patients with hemophilia A, irrespective of the presence of FVIII inhibitors. Emicizumab differs in some properties from FVIIIa molecule. Emicizumab requires no activation by thrombin and is not inactivated by activated protein C, but emicizumab-mediated coagulation is regulatable and maintains hemostasis. A small amount of FIXa (activated factor IX) is required to initiate emicizumab-mediated hemostasis, whereas tissue factor/FVIIa (activated factor VII)-mediated FXa (activated factor X) and thrombin activation initiates FVIIIa-mediated hemostasis. Fibrin formation, followed by fibrinolysis, appears to be similar between emicizumab- and FVIIIa-mediated hemostasis. These results suggest possible future uses of emicizumab for treating hemorrhagic diseases other than hemophilia A and reveal previously unobservable behaviors of procoagulation and anticoagulation factors in conventional hemostasis. Here, we have reviewed novel insights and new developments regarding coagulation highlighted by emicizumab.

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Activation of human factor VII by activated factors IX and X

Blood ◽

10.1182/blood.v60.5.1143.bloodjournal6051143 ◽

1982 ◽

Vol 60 (5) ◽

pp. 1143-1150 ◽

Cited By ~ 1

Author(s):

DR Masys ◽

SP Bajaj ◽

SI Rapaport

Keyword(s):

Human Factors ◽

Factor Viii ◽

Active Site ◽

Human Factor ◽

Antithrombin Iii ◽

Factor Ix ◽

Factor Vii ◽

Activate Factor ◽

Factor X ◽

Activated Factor Vii

Factor VII clotting activity increases about five-fold when blood is clotted in glass. Prior studies suggested that this results from activation induced by activated factor IX (IXa). However, in purified systems containing phospholipid and calcium, activated factor X (Xa) is known to activate factor VII rapidly. Therefore, we studied activation of factor VII by IXa and X, in systems using purified human factors. Concentrations of IXa and Xa were calculated from total activated protein concentrations rather than from active site concentrations. In the presence of phospolipid and calcium, both IXa and Xa activated factor VII 25-fold; however, Xa was roughly 800 times more efficient than IXa. Without added phospholipid, activation of factor VII by both Xa and IXa was markedly slowed, and Xa was roughly 20 times more efficient than IXa. When both phospholipid and calcium were omitted, activation of factor VII by either enzyme was negligible. Adding normal prothrombin, but not decarboxylated prothrombin, substantially slowed activation of factor VII by both Xa and IXa. Adding thrombin-activated factor VIII and antithrombin-III did not change rates of factor VII activation by either enzyme. These results from purified systems do not provide an explanation for the prior data from plasma systems.

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Activation of human factor VII in the initiation of tissue factor- dependent coagulation

Blood ◽

10.1182/blood.v68.3.685.685 ◽

1986 ◽

Vol 68 (3) ◽

pp. 685-691 ◽

Cited By ~ 38

Author(s):

LV Rao ◽

SI Rapaport ◽

SP Bajaj

Keyword(s):

Tissue Factor ◽

Factor Ix ◽

Factor Vii ◽

Activate Factor ◽

Factor Xii ◽

Factor X ◽

Clotting Time ◽

Activated Factor Vii ◽

Peptide Release ◽

Minimal Generation

Abstract We have used activation peptide release assays to compare factor VII and activated factor VII (VIIa) activation of factor X, normal factor IX (IXN), and a variant factor IX (IXBmLE), which, after activation, is unable to back-activate factor VII. In purified systems, factor VII and VIIa each rapidly activated factor X, but after a one minute lag for factor VII. VIIa also readily activated both IXN and IXBmLE. Factor VII initially failed to activate substantial amounts of either IXN or IXBmLE; on further incubation factor VII activated IXN but not IXBmLE. Activation of IXN began when approximately 10% of factor VII had been converted to VIIa, as measured by 125I-factor VII radioactivity profiles. Adding factor VII to VIIa slowed its activation of IXBmLE. However, in the presence of factor X, factor VII alone rapidly activated IXBmLE. Unlike purified systems, 1 nmol/L VIIa added to factor VII-deficient plasma failed to activate factor IX. Increasing factor VII to 10 nmol/L (plasma concentration) either as native VII or VIIa yielded similar activation curves for factor IX and similar activation curves for factor X. Adding 5% VIIa to factor X-deficient plasma and to factor XII-deficient plasma substantially shortened the dilute tissue factor clotting time of only the former. These data support the hypothesis that factor VII/tissue factor complex initiates tissue factor-dependent clotting through a minimal generation of Xa. This Xa then rapidly back-activates a small amount of factor VII, following which the rates of activation of both factors IX and X increase dramatically.

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Activation of human factor VII in the initiation of tissue factor- dependent coagulation

Blood ◽

10.1182/blood.v68.3.685.bloodjournal683685 ◽

1986 ◽

Vol 68 (3) ◽

pp. 685-691 ◽

Cited By ~ 1

Author(s):

LV Rao ◽

SI Rapaport ◽

SP Bajaj

Keyword(s):

Tissue Factor ◽

Factor Ix ◽

Factor Vii ◽

Activate Factor ◽

Factor Xii ◽

Factor X ◽

Clotting Time ◽

Activated Factor Vii ◽

Peptide Release ◽

Minimal Generation

We have used activation peptide release assays to compare factor VII and activated factor VII (VIIa) activation of factor X, normal factor IX (IXN), and a variant factor IX (IXBmLE), which, after activation, is unable to back-activate factor VII. In purified systems, factor VII and VIIa each rapidly activated factor X, but after a one minute lag for factor VII. VIIa also readily activated both IXN and IXBmLE. Factor VII initially failed to activate substantial amounts of either IXN or IXBmLE; on further incubation factor VII activated IXN but not IXBmLE. Activation of IXN began when approximately 10% of factor VII had been converted to VIIa, as measured by 125I-factor VII radioactivity profiles. Adding factor VII to VIIa slowed its activation of IXBmLE. However, in the presence of factor X, factor VII alone rapidly activated IXBmLE. Unlike purified systems, 1 nmol/L VIIa added to factor VII-deficient plasma failed to activate factor IX. Increasing factor VII to 10 nmol/L (plasma concentration) either as native VII or VIIa yielded similar activation curves for factor IX and similar activation curves for factor X. Adding 5% VIIa to factor X-deficient plasma and to factor XII-deficient plasma substantially shortened the dilute tissue factor clotting time of only the former. These data support the hypothesis that factor VII/tissue factor complex initiates tissue factor-dependent clotting through a minimal generation of Xa. This Xa then rapidly back-activates a small amount of factor VII, following which the rates of activation of both factors IX and X increase dramatically.

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Activation of the Coagulant Pathway in Cigarette Smokers

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614942 ◽

1998 ◽

Vol 79 (03) ◽

pp. 549-553 ◽

Cited By ~ 60

Author(s):

K. A. Bauer ◽

J. A. Cooper ◽

R. D. Rosenberg ◽

G. J. Miller

Keyword(s):

Factor Ix ◽

Factor Vii ◽

Coagulation System ◽

Fibrinogen Concentration ◽

Factor X ◽

Activated Factor Vii ◽

Increased Risk ◽

Activation Peptide ◽

Factor X Activation ◽

Disease Factor

SummaryThe effects of chronic cigarette smoking on the coagulation system were examined in 2964 men aged 50 to 61 years and clinically free of cardiovascular disease. Factor VII activity (VIIc), factor VII antigen (VIIag), prothrombin fragment 1+2 (F1.2), fibrinopeptide A (FPA) and fibrinogen were measured in all participants, and activated factor VII (VIIa), factor IX activation peptide (IX pep) and factor X activation peptide (X pep) in a large sub-sample. The levels of all indices except FPA differed significantly between non-smokers, ex-smokers and current smokers. After adjustment for other conventional cardiovascular risk factors, mean VIIc was raised slightly by 3% in ex-smokers and current smokers as compared with non-smokers, owing to increases in VIIa and VIIag. Plasma IX pep, X pep, F1.2 and fibrinogen concentration were highest in current smokers, intermediate in ex-smokers and lowest in non-smokers. These findings accord with the increased risk of arterial thrombosis in smokers.

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Region of Factor IXa Protease Domain that Interacts with Factor VIIIa: Analysis of Select Hemophilia B Mutants

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615836 ◽

1999 ◽

Vol 82 (08) ◽

pp. 218-225 ◽

Cited By ~ 13

Author(s):

S. Paul Bajaj

Keyword(s):

X Chromosome ◽

Coagulation Factor ◽

Factor Ix ◽

Hemophilia B ◽

Coagulation Cascade ◽

Factor Vii ◽

Factor X ◽

Homologous Proteins ◽

Dependent Protein ◽

Factor Ix Deficiency

IntroductionThe identification of coagulation factor IX as a substance required for blood coagulation was first established by Pavlovsky, who reported that a mixture of blood from two hemophiliacs clotted normally.1 Based on this discovery and subsequent observations,2 hemophilia was divided into two conditions-hemophilia A or factor VIII deficiency, the most prevalent condition, and hemophilia B or factor IX deficiency, a less common condition. Since then, much has been learned about the molecular and structural biology of factor IX. It is a vitamin K-dependent protein that participates in the middle phase of the intrinsic as well as the extrinsic coagulation cascade.3 The gene for factor IX consists of eight exons and seven introns, is approximately 34 kb long, and located on the long arm of the X-chromosome at band Xq27.1.4,5 The positions of the introns in the factor IX gene are essentially identical to those of the other three homologous proteins, namely, factor VII, factor X, and protein C;3 the genes for the latter three proteins, however, are not located on the X-chromosome.

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Recombinant human factor VIIa (rFVIIa) in hemophilia: mode of action and evidence to date

Therapeutic Advances in Hematology ◽

10.1177/2040620717737701 ◽

2017 ◽

Vol 8 (12) ◽

pp. 345-352 ◽

Cited By ~ 5

Author(s):

Muriel Giansily-Blaizot ◽

Jean-François Schved

Keyword(s):

Tissue Factor ◽

Factor Viia ◽

Factor Ix ◽

Factor Vii ◽

Factor X ◽

Independent Manner ◽

Recombinant Activated Factor Vii ◽

Platelet Surface ◽

Activated Factor Vii ◽

Treatment And Prevention

Recombinant activated factor VII (rFVIIa) is a bypassing agent widely used both in the treatment and prevention of hemorrhagic complications due to hemophilia with inhibitor. In such cases, antihemophilic factors cannot be used. The normal physiology of factor VII/ factor VIIa (FVII/FVIIa) in the hemostatic process requires the presence of tissue factor (TF) that links to FVII leading to a FVIIa-TF complex which activates both factor X and factor IX. The therapeutic use of rFVIIa requires high amount of FVIIa. Some studies demonstrate that FVIIa at high doses still requires tissue factor for function, whereas others suggest that FVIIa activates FX directly on the platelet surface, in a TF-independent manner. In the present article, we discuss the arguments supporting both TF-dependent and TF-independent modes of action. Finally, the coexistence of both TF-dependent and TF-independent mechanisms cannot be excluded.

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Activation of human factor VII by activated factors IX and X

Blood ◽

10.1182/blood.v60.5.1143.1143 ◽

1982 ◽

Vol 60 (5) ◽

pp. 1143-1150 ◽

Cited By ~ 47

Author(s):

DR Masys ◽

SP Bajaj ◽

SI Rapaport

Keyword(s):

Human Factors ◽

Factor Viii ◽

Active Site ◽

Human Factor ◽

Antithrombin Iii ◽

Factor Ix ◽

Factor Vii ◽

Activate Factor ◽

Factor X ◽

Activated Factor Vii

Abstract Factor VII clotting activity increases about five-fold when blood is clotted in glass. Prior studies suggested that this results from activation induced by activated factor IX (IXa). However, in purified systems containing phospholipid and calcium, activated factor X (Xa) is known to activate factor VII rapidly. Therefore, we studied activation of factor VII by IXa and X, in systems using purified human factors. Concentrations of IXa and Xa were calculated from total activated protein concentrations rather than from active site concentrations. In the presence of phospolipid and calcium, both IXa and Xa activated factor VII 25-fold; however, Xa was roughly 800 times more efficient than IXa. Without added phospholipid, activation of factor VII by both Xa and IXa was markedly slowed, and Xa was roughly 20 times more efficient than IXa. When both phospholipid and calcium were omitted, activation of factor VII by either enzyme was negligible. Adding normal prothrombin, but not decarboxylated prothrombin, substantially slowed activation of factor VII by both Xa and IXa. Adding thrombin-activated factor VIII and antithrombin-III did not change rates of factor VII activation by either enzyme. These results from purified systems do not provide an explanation for the prior data from plasma systems.

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