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PubMed1996

Collaborative study on assays of activated FIX (FIXa). On behalf of the factor VIII and factor IX subcommittee of the ISTH. International Society on Thrombosis and Haemostasis.

A collaborative study has been organised by NIBSC to examine the performance of FIXa assays between laboratories, and to investigate the need for a standard. Ampoules of 3 materials, one monocomponent concentrate (coded C) and 2 different preparations of purified human FIXa (one proposed reference preparation, coded A and a test material coded B), have been assayed in 11 laboratories for FIXa using either the NIBSC method or a local method, with local standards (if available, coded D) to determine their potencies. The data showed high between assay variability; with the exception of one laboratory, most of the between assay variation expressed as %geometric coefficients of variation (gcv) were over 15%. The interlaboratory gcv when preparation B was assayed against the local standard was over 1700%, suggesting that most of the local standards are poorly calibrated. The %gcv was improved to 80% when reference A was used as the standard. These data clearly show that an international reference standard for FIXa would help to standardise FIXa preparations and would also improve in house assays for FIXa. However, an accelerated degradation study has shown that reference A is not suitable as a long term standard and another material with suitable stabilizers has to be established as an international standard for FIXa.

Factor IX↗
PubMed1995

Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study.

No studies have examined the associations of coagulation factor levels with measures of subclinical cardiovascular disease (CVD) in the elderly. The Cardiovascular Health Study (CHS) is a prospective, population-based cohort study of CVD in persons older than 65 years. At the baseline examination, we measured fibrinogen, factor VII, and factor VIII levels in 5024 of the 5201 participants of the CHS and examined the associations of these coagulation factors with measures of subclinical CVD in a cross-sectional analysis. Subclinical CVD measures were based on electrocardiography, carotid ultrasonography, echocardiography, and ankle-arm blood pressure measurements (AAI). For analyses, we used the full cohort as well as two mutually exclusive subgroups: those with prevalent clinical CVD at baseline and those without. Fibrinogen and to a lesser extent factor VIII showed positive associations with a variety of subclinical CVD measures. In age-adjusted analyses, fibrinogen and factor VIII were significantly associated with 8 of 10 measures. In multivariate analyses, fibrinogen was significantly associated with carotid artery stenosis, internal (but not common) carotid artery wall thickness, and AAI. Factor VIII was associated with abnormal wall motion and AAI in the full cohort only. Factor VII was not consistently associated with subclinical disease measures. In bivariate analyses that included data from all three groups, there were 5 positive subclinical disease associations and 5 negative associations for factor VII. In multivariate analyses, there were no significant associations between factor VII and subclinical CVD in the full cohort or in either subgroup. We conclude that in these cross-sectional analyses, fibrinogen and to a lesser extent factor VIII are associated with subclinical CVD in the elderly, even in those without symptoms or a history of clinical CVD. Factor VII, however, was not associated with subclinical CVD in the elderly.

Aged↗
PubMed1992

Standardisation of factor VIII--V. Calibration of the 2nd International Standard for Factor VIII and von Willebrand factor activities in plasma.

The proposed 2nd International Standard for Factor VIII and von Willebrand Factor activities in plasma, NIBSC code 87/718, was assayed against the 1st IRP, 80/511, and against fresh normal plasma, in 21 laboratories. There were no significant differences between the various assay methods for factor VIII antigen, von Willebrand factor antigen, and von Willebrand factor ristocetin co-factor activity. For factor VIII clotting activity there was a significant difference between the results of one-stage and two-stage assays. Plasma 87/718 has now been established by the WHO Expert Committee on Biological Standardisation as the 2nd IS for factor VIII and vWF in plasma with the following potencies: VIII:C 0.60 IU/ampoule; VIII:Ag 0.91 IU/ampoule; vWF:Ag 0.91 IU/ampoule; vWF/RCo 0.84 IU/ampoule.

Blood Chemical Analysis↗
PubMed2003

Binding of factor VIII inhibitors to discrete regions of the factor VIII C2 domain disrupt phospholipid binding.

We characterized seven factor VIII inhibitors with epitopes in the C2 domain of factor VIII using a series of factor V C2 domain chimeras that substituted exon-sized fragments of the C2 domain of factor VIII for the corresponding regions of factor V. All inhibited co-factor activity of factor VIII and six inhibited binding of factor VIII to phosphatidylserine. Inhibitors Hz, JN and GK32 bound epitopes within amino acids S2173-K2281; inhibitors GK24 and TO bound epitopes within amino acids V2223-Y2332; and inhibitors UNC11 and UNC12 bound epitopes throughout the C2 domain (amino acids S2173-Y2332). Inhibitors Hz, JN and UNC12 inhibited the co-factor activity of chimera 5A, which substituted amino acids S2173-Q2222 of factor VIII for the corresponding region of factor V, in a prothrombinase assay. This inhibition could be partially reversed by pre-incubation of chimera 5A with phospholipid vesicles, suggesting that these antibodies interfered with phospholipid binding. Inhibitors UNC11 and UNC12, on the other hand, did not inhibit the binding of chimera 1 A to phosphatidylserine, suggesting that binding to the segment spanning amino acids V2282-Y2332 does not necessarily block phospholipid binding. These results agree with the model of the phospholipid-binding site determined by crystal structure of the C2 domain of factor VIII.

Antibodies, Monoclonal↗
PubMed1990

Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients.

We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the 'tolerant' antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the 'tolerant' antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

Antigen-Antibody Complex↗
PubMed1976

Infusion of human and canine factor VIII in dogs with von Willebrand's disease: studies of the von Willebrand and factor VIII synthesis stimulating factors.

Dogs with von Willebrand's disease (VWD) were infused with a highly purified human and canine factor VIII preparation. Control infusions were performed using isotonic saline solution. Following all of the concentrate infusions, the bleeding times were shortened to within the normal range for up to 4 h. Factor VIII activity rose immediately after infusion, rapidly returned to preinfusion levels, and then increased again at 18 h. The levels of factor VIII-related antigen (F VIII-RA) as measured with anticanine factor VIII also increased after infusion and then gradually declined. There was no further increase in F VIII-RA at 18 h, when the factor VIII activity showed the secondary increase characteristic of VWD. With antihuman factor VIII, two identifiable antigens were present in the plasma of the dogs given human factor VIII. The reduced platelet retention of these animals was not significantly altered following infusion, whereas ristocetin-induced platelet aggregation was corrected in one of the dogs given human factor VIII. These studies indicate that factor VIII procoagulalant and von Willebrand factor activities reside on a single molecule or form part of a molecular complex. In addition, the factor VIII preparations appeared to contain the factor VIII synthesis-stimulating factor and/or a precursor of factor VIII procoagulant activity.

Animals↗
PubMed1983

A comparison of "carrier screening" of hemophilia by the ratio of factor VIII coagulant activity or antigen to factor VIII related antigen.

The ratio of factor VIII coagulant activity (VIIIC) or antigen (VIIICAg) to that of factor VIII related antigen (VIIIRAg) was measured in 15 normals, 21 obligatory and 23 possible carriers of hemophilia. Factor VIII coagulant was measured on fresh plasma samples whereas antigenic properties were measured on frozen and thawed samples. In obligatory carriers only, the mean level of VIIICAg was significantly lower than VIIIC and there was a tendency for low VIIICAg levels to be associated with raised VIIIRAg levels. Using both ratios, 13 obligatory carriers were outside the normal tolerance ellipse. In possible carriers, neither ratio showed superior discriminating power. In reference laboratories that perform carrier studies on stored or transported specimens, measurement of VIIICAg/VIIIRAg is a suitable test for diagnosis of carriers.

Antigens↗
PubMed1982

Activation of human coagulation factor VIII by activated factor X, the common product of the intrinsic and the extrinsic pathway of blood coagulation.

The intrinsic activation of human factor X has been studied in a system consisting of purified factors and in plasma. In both these systems factor Xa stimulated the activation of factor X by factor IXa plus factor VIII. This is due to the activation of factor VIII by factor Xa. When this factor Xa is formed via the extrinsic pathway, the extrinsic factor X activator functions as a stimulator of the intrinsic factor X activator.

Blood Coagulation↗
PubMed2003

Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations: is it of clinical importance?

Factor VIII inhibitors may interfere with several important functional binding sites on the factor VIII molecule including that of von Willebrand factor, which binds to the C2 domain. There are in vitro and in vivo observations that inhibitors reacting against the factor VIII light-chain C2 domain may display a lower inhibitor titer against von Willebrand factor containing concentrates as compared to pure products. In low titer inhibitor patients it can be anticipated that von Willebrand factor containing concentrates give a better hemostatic effect. The role in immune tolerance induction is of great interest as an increased success rate and decreased treatment time may have a substantial impact on the cost of treatment. Case reports and treatment experience from some centers indicate a better success rate with von Willebrand factor containing concentrates. Even if formal, well-controlled studies are needed, it can already be recommended that inhibitor plasma should be tested against a panel of concentrates in order to select the less neutralized concentrate for use in inhibitor patients.

Antibodies↗