The Influence of Helicobacter pylori Status on Circulating Levels of the Coagulation Factors Fibrinogen, von Willebrand Factor, Factor VII, and Factor VIII

Abstract The predominant procoagulant factor VIII (VIII:C) form in normal human plasma containing various combinations of anticoagulants and serine/cysteine protease inhibitors is a protein with mol wt 2.6 +/- 0.2 X 10(5). This protein can be detected by 125I-anti-VIII:C Fab binding and gel electrophoresis in the presence and absence of sodium dodecylsulfate (SDS) and is distinct from the subunit of factor VIII/von Willebrand factor (VIII:vWF) multimers. No larger VIII:C form is present in plasma from patients with severe congenital deficiencies of each of the coagulation factors, other than VIII:C. The mol wt approximately 2.6 X 10(5) VIII:C form is, therefore, likely to be the in vivo procoagulant form of VIII:C, rather than a partially proteolyzed, partially activated derivative of a larger precursor. About 60% of this procoagulant mol wt approximately 2.6 X 10(5) VIII:C form in plasma is present in noncovalent complexes with larger VIII:vWF multimers, which attach reversibly to platelet surfaces in the presence of ristocetin. This VIII:vWF-bound protein of mol wt approximately 2.6 X 10(5) may be the plasma procoagulant form of VIII:C which, after proteolytic activation, accelerates the IXa-mediated cleavage and activation of X postulated to occur on platelet surfaces.

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Effect of multimeric structure of the factor VIII/von Willebrand factor protein on binding to platelets

Blood ◽

10.1182/blood.v58.2.387.bloodjournal582387 ◽

1981 ◽

Vol 58 (2) ◽

pp. 387-397 ◽

Cited By ~ 2

Author(s):

HR Gralnick ◽

SB Williams ◽

DK Morisato

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Competitive Inhibition ◽

Human Platelets ◽

Factor Vii ◽

Variant Form ◽

Factor Binding ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

The characteristics of the intact factor VIII/von Willebrand factor protein binding to human platelets was compared to 2-mercaptoethanol- treated factor VIII/von Willebrand factor protein and to fractions of plasma factor VIII/von Willebrand factor protein that elute after the void volume. These studies indicate that the factor VIII/von Willebrand factor protein larger size oligomers bind preferentially with high affinity to low capacity sites on human platelets. The intermediate and smaller size oligomers bind with intermediate or low affinity to sites with a much greater capacity. The results from binding analysis are also paralleled by the competitive inhibition of the intact factor VIII/von Willebrand factor protein by the various 2-mercaptoethanol- treated materials. These studies indicate that the two classes of binding sites seen in previous reports of factor VII/von Willebrand factor binding reflect heterogeneity in the oligomer size of the factor VIII/von Willebrand factor protein used in these assays. This study provides a model for understanding some of the normal structure- function relationships of the normal factor VIII/von Willebrand factor protein and the defect(s) in a variant form of von Willebrand's disease. In this form of the disease, decreased factor VIII/von Willebrand factor binding to platelets is reflected in decreased von Willebrand factor activity but coagulant and/or antigen levels are normal or only slightly decreased.

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The complex multimeric composition of factor VIII/von Willebrand factor

Blood ◽

10.1182/blood.v57.6.1140.bloodjournal5761140 ◽

1981 ◽

Vol 57 (6) ◽

pp. 1140-1143 ◽

Cited By ~ 9

Author(s):

ZM Ruggeri ◽

TS Zimmerman

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Sodium Dodecyl ◽

Factor Vii ◽

Buffer System ◽

Type I ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Von Willebrand ◽

Willebrand Factor

We have analyzed the multimeric structure of factor VIII/von Willebrand factor in plasma by sodium dodecyl sulfate electrophoresis using gels of varying porosity and a discontinuous buffer system. Factor VIII/von Willebrand factor bands were identified by reaction with 125I-labeled affinity-purified antibody and subsequent autoradiography. In 1% agarose gels, normal plasma displayed a series of sharply defined oligomers. However, increasing the agarose concentration to 2.0% or utilizing mixtures of 0.8% agarose--1.75% acrylamide revealed two bands of lesser intensity interposed between the major bands. When the acrylamide concentration in the gels was increased to 2.5%, bands with a faster mobility than IgM and fibronectin were now evident. Type IIA von Willebrand's disease showed not only an absence of the larger multimers but also a relative increase in several of the newly identified bands as compared to type IIB, type I, and normal. These studies suggest that factor VII/von Willebrand factor in IIA von Willebrand's disease is structurally different from that in other forms of the disorder. They also indicate that the multimeric composition of factor VII/von Willebrand factor is more complex than can be explained by simple linear polymerization of a single protomer.

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Effect of multimeric structure of the factor VIII/von Willebrand factor protein on binding to platelets

Blood ◽

10.1182/blood.v58.2.387.387 ◽

1981 ◽

Vol 58 (2) ◽

pp. 387-397 ◽

Cited By ~ 65

Author(s):

HR Gralnick ◽

SB Williams ◽

DK Morisato

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Competitive Inhibition ◽

Human Platelets ◽

Factor Vii ◽

Variant Form ◽

Factor Binding ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

Abstract The characteristics of the intact factor VIII/von Willebrand factor protein binding to human platelets was compared to 2-mercaptoethanol- treated factor VIII/von Willebrand factor protein and to fractions of plasma factor VIII/von Willebrand factor protein that elute after the void volume. These studies indicate that the factor VIII/von Willebrand factor protein larger size oligomers bind preferentially with high affinity to low capacity sites on human platelets. The intermediate and smaller size oligomers bind with intermediate or low affinity to sites with a much greater capacity. The results from binding analysis are also paralleled by the competitive inhibition of the intact factor VIII/von Willebrand factor protein by the various 2-mercaptoethanol- treated materials. These studies indicate that the two classes of binding sites seen in previous reports of factor VII/von Willebrand factor binding reflect heterogeneity in the oligomer size of the factor VIII/von Willebrand factor protein used in these assays. This study provides a model for understanding some of the normal structure- function relationships of the normal factor VIII/von Willebrand factor protein and the defect(s) in a variant form of von Willebrand's disease. In this form of the disease, decreased factor VIII/von Willebrand factor binding to platelets is reflected in decreased von Willebrand factor activity but coagulant and/or antigen levels are normal or only slightly decreased.

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Precipitating antibodies to factor VIII/von Willebrand factor in von Willebrand's disease: effects on replacement therapy

Blood ◽

10.1182/blood.v57.1.25.25 ◽

1981 ◽

Vol 57 (1) ◽

pp. 25-31 ◽

Cited By ~ 41

Author(s):

PM Mannucci ◽

ZM Ruggeri ◽

N Ciavarella ◽

MD Kazatchkine ◽

JF Mowbray

Keyword(s):

Factor Viii ◽

Replacement Therapy ◽

Antibody Titer ◽

Von Willebrand Factor ◽

Factor Vii ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

Abstract Precipitating antibodies to factor VII/von Willebrand factor can develop in patients with severe homozygous-like von Willebrand's disease following multiple transfusions with blood derivatives. This study of 4 patients treated with cryoprecipitate for 13 different bleeding episodes demonstrates that the occurrence of such antibodies interferes with the management of the disease. The control of mucosal bleeding was poor, whereas more favorable responses were obtained in soft-tissue hemorrhages. These findings probably relate to failure of replacement therapy to shorten the prolonged bleeding time. Immediately after treatment, measurement of plasma factor VIII/von Willebrand factor-related antigen and ristocetin cofactor showed either no increase, or very low values, depending on the pre-infusion antibody titer. Levels of the factor VIII/von Willebrand factor-related procoagulant activity in the circulation were also lower than predicted and usually there was no evidence of the delayed and sustained rise typically observed in uncomplicated von Willebrand's disease. An anamnestic rise in antibody titer appeared 6–15 days after treatment and showed no obvious relationship with the amount of cryoprecipitate infused. Replacement therapy invariably caused severe side effects during, or immediately after, concentrate infusion. The results of in vitro studies support the view that these reactions were due to the appearance of circulating immune complexes.

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Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor

Circulation ◽

10.1161/circulationaha.109.869156 ◽

2010 ◽

Vol 121 (12) ◽

pp. 1382-1392 ◽

Cited By ~ 228

Author(s):

Nicholas L. Smith ◽

Ming-Huei Chen ◽

Abbas Dehghan ◽

David P. Strachan ◽

Saonli Basu ◽

...

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Plasma Levels ◽

Factor Vii ◽

Genetic Loci ◽

Von Willebrand ◽

Willebrand Factor ◽

Novel Associations

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Decreased factor VIII levels during acetaminophen-induced murine fulminant hepatic failure

Blood ◽

10.1182/blood-2003-03-0826 ◽

2003 ◽

Vol 102 (5) ◽

pp. 1743-1744 ◽

Cited By ~ 5

Author(s):

Christopher B. Doering ◽

Ernest T. Parker ◽

Christopher E. Nichols ◽

Pete Lollar

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Fulminant Hepatic Failure ◽

Hepatic Failure ◽

Elevated Plasma ◽

Fviii Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Circulating Levels ◽

Factor Antigen

Abstract During human fulminant hepatic failure (FHF) circulating levels of most hemostatic proteins fall dramatically. Concurrently, factor VIII (fVIII) procoagulant activity rises despite destruction of the hepatocytes considered responsible for fVIII synthesis. This observation suggests a role for cells other than hepatocytes in fVIII biosynthesis during FHF. We have attempted to identify nonhepatocytic sites of fVIII biosynthesis by inducing FHF in mice using acetaminophen overdose, a common cause of human FHF. Acetaminophen-treated mice consistently displayed signs characteristic of FHF, including elevated plasma aminotransferase activity. However, acetaminophen-treated mice demonstrated markedly reduced fVIII activity, contrary to the observation in human FHF. von Willebrand factor antigen levels were only mildly reduced, suggesting that the decrease in fVIII is not secondary to loss of von Willebrand factor. These results imply that there are fundamental differences in the regulation of plasma fVIII levels between humans and mice.

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Epitope Specific Discrepancies Between Antibody Mediated Inhibition Of Recombinant Factor VIII and Plasma Derived Factor VIII Containing Von Willebrand Factor Affecting All Domains Of Factor VIII

Blood ◽

10.1182/blood.v122.21.1089.1089 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1089-1089

Author(s):

Tami Livnat ◽

Amy L. Dunn ◽

Shirley Azar-Avivi ◽

Wallace Hunter Baldwin ◽

Gili Kenet ◽

...

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Conflicts Of Interest ◽

The Other ◽

Factor Vii ◽

Specific Response ◽

Fviii Activity ◽

Von Willebrand ◽

Willebrand Factor ◽

Kinetics Of

Abstract Background Previous results from our laboratory demonstrate an epitope specific response to high doses of FVIII within anti-C2 antibodies that was independent of antibody titer. In addition, for a panel of monoclonal antibodies (MAbs) directed against all FVIII domains the kinetics of inhibition influenced response to combinations of FVIII and recombinant factor VII (rFVIIa). The influence of inhibitor kinetics on response to treatment has also been demonstrated in inhibitor patient plasmas. The Bethesda assay detects the inhibitory capacity of anti-factor VIII (FVIII) antibodies to neutralize FVIII after 2 hours of incubation with pooled normal plasma (PNP). In this assay patient antibody is added to PNP as compared to the clinical scenario where recombinant FVIII (rFVIII) or plasma derived FVIII containing von Willebrand Factor (pdFVIII/VWF) is infused into the patient where antibody is already present. In this case the infused product is immediately available to interact with both VWF and anti-FVIII antibodies as compared to the Bethesda assay where VWF is already bound to FVIII when the antibody is added. Methods In this study we investigated the inhibitory kinetics of a panel of 20 anti-FVIII MAbs (Table) with known epitope specificity and inhibitory activity in a standard Bethesda assay. Inhibitor plasma consisted of a single MAb added to FVIII deficient plasma at 5 µg/ml. rFVIII and pd-FVIII/VWF were added to each inhibitor plasma and samples were sequentially removed at intervals between 5 and 90 minutes. FVIII activity was measured by a one-stage aPTT based assay. Results Of the MAb panel, 2 anti-A2 MAbs, 1D4 and 4A4, and the anti-A3 MAb F147 had full neutralization of both rFVIII and pd-FVIII/VWF. All 3 of these MAbs exhibit high inhibitory titers in the Bethesda assay. The majority of the other MAbs had improved neutralization kinetics and thus higher residual FVIII activity with pd-FVIII/VWF when compared to rFVIII. The figure below shows the residual FVIII activity at 15 minutes following the addition of rFVIII or pdFVIII/VWF into the inhibitor plasmas. Similar patterns were seen at the other time points. Three MAbs from the panel, two anti-A2 (4C7 and B157) and one anti-C2 (2-117), had significant inhibition of FVIII activity when rFVIII was added to the inhibitor plasma. This was not demonstrated in the standard Bethesda assay or when pd-FVIII/VWF was added to the inhibitor plasma. This demonstrates that the order of binding of VWF and anti-FVIII antibodies may be clinically relevant for a subset of FVIII epitopes. Conclusion The Bethesda assay in isolation neither predicts inhibitory kinetics nor defines response to various FVIII sources. FVIII source dependent neutralization kinetics and epitope mapping may be applied as additional tools for tailoring therapy in patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.

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