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PubMed1978

Factor VIII activity and factor VIII related antigen in newborns.

Factor VIII procoagulant activity and factor VIII related antigen were examined in 20 full-term and preterm newborn infants during the first days of life. The control group involved 15 adults volunteers. Factor VIII activity was estimated by a one-stage test and factor VIII related antigen was determined by immunelectrophoresis according to Laurell, using our own rabbit antiserum. The following results were obtained:--Factor VIII activity during the first 3 days of life did not differ from the normal range of the adult controls.--The concentration of factor VIII related antigen in newborns was markedly higher than in adults on the first, and to a lesser extent on the second, day of life.--The antigen concentration decreases on the second and following days of life to adult levels. The cause of this discrepancy cannot be completely explained but possible reasons are discussed.

Age Factors↗
PubMed1980

Characteristics of the factor VIII protein and Factor XIII in various factor VIII concentrates.

The in vitro properties of 5 factor VIII preparations (AHF-Kabi, Hemofil Hyland, AHF-Profilate Abbott, Kryobulin Immuno and Factorate High Purity Armour) and an ordinary cryoprecipitate were studied with reference to factor VIII clotting activity (VIII:C), factor VIII clotting antigen (VIII:CAg), factor VIII related antigen (VIIIR:Ag) (EI, IRMA, CIE), ristocetin cofactor activity (VIIIR:RCF), fibrinogen and factor XIII. All the preparations with the exception of Factorate had higher levels of VIII:CAg than VIII:C indicating inactivation of the biological activity of VIII:C during the procedure. AHF-Kabi (fraction I-0) and the cryoprecipitate, the only preparations capable of normalising the defect in patients with von Willebrand's disease, showed the same level of VIIIR:Ag determined by EI and by IRMA, while all the other preparations (i.e. cryoprecipitates purified further in different ways) had considerably lower levels of VIIIR:Ag determined by IRMA than by EI. Based on these in vitro techniques it seems to be possible to predict which preparations can be used successfully in patients with von Willebrand's disease, while no such conclusions can be made from VIIIR:RCF determinations. EI yielded similar concentrations of factor XIII a subunit in all the preparations tested. 3 functional assays showed high factor XIII activities in AHF-Kabi but low or no activities in the others. Thus, considerable differences were found on the in vitro properties of the proteins in 5 factor VIII concentrates and a cryoprecipitate. The action of proteases and the techniques used in the purification procedure are probably of crucial importance for the properties of the various factors.

Antigens↗
PubMed1988

Effects of contrast media on fibrinogen and factor VIII.

Factor VIII and fibrinogen play an important role in hemostasis and thrombosis because they help bridge functions between platelets, endothelial cells, and the soluble coagulation system. In the present study, we found that the various contrast media examined in concentrations adequate to cause marked anticoagulation did not markedly affect either factor VIII or fibrinogen. These media act predominantly as inhibitors of other fibrinogen functions, not as protein denaturation agents.

Antigens↗
PubMed1987

Virus safety of pasteurized factor VIII and factor IX concentrates: study in virgin patients.

In a long term surveillance study hemophilia A and B patients were treated with a Factor VIII HS and Factor IX HS concentrate respectively, both pasteurized by heating in solution: 10 hours at 60 degrees C. None of 31 virgin hemophiliacs treated with Factor VIII HS Behringwerke developed hepatitis B during a follow up between 6 to 60 months. One patient who received 379.280 IU Factor VIII by 977 applications showed a seroconversion after 961 days of treatment. Passive/active immunisation is suggested. 4 patients had moderate elevations of transaminases (less than 120 U/l) without clinical signs of liver disease. 2 patients suffered a non-icteric NA NB-hepatitis two months after synovectomy in the same hospital. 6 virgin hemophilia B patients who had been treated with Factor IX concentrate HS Behringwerke remained serologically negative and did not develop any symptoms indicative of a hepatic disease during a follow up between 11-29 months. The HTLV-III safety of Factor VIII HS and Factor IX HS Behringwerke is presently under investigation by determination of the corresponding antibody.

Adolescent↗
PubMed1982

In vivo interactions of autoantibodies to factor VIII with the factor VIII complex.

Two non-haemophilic elderly patients who had developed autoantibodies to factor VIII were studied over a period of 9 months to 5 years. Sequential measurements of antibody to factor VIII (anti-VII:C), factor VIII coagulant activity (VIII:C), factor VIII coagulant antigen (VIII:CAg), factor VIII-related antigen (VIIIR:Ag), and factor VIII ristocetin cofactor (VIII:WF) were performed. Before treatment, low VIII:C, normal or increased VIII:CAg and high VIIIR:Ag levels were found and were indicative of the presence of circulating immune complexes. Immunosuppressive therapy induced progressive correction of VIII:C and VIIIR:Ag values. High levels of VIII:CAg subsided in the patient who relapsed. It is suggested that antibodies to factor VIII bind and remove VIII:C from the circulation thereby inducing an increased synthesis of VIII:CAg which may be associated with an augmented release or production of VIIIR:Ag.

Aged↗
PubMed1982

Activation of factor VIII by factor IXa.

Thrombin causes an increase in factor VIII coagulant (VIII:C) activity, which is followed by a decay of VIII:C activity to below baseline levels. It has been suggested that a similar interaction of trace amounts of thrombin and factor VIII is a necessary prerequisite before factor VIII can participate in the coagulation cascade. In the current study, factor IXa, a serine protease with structural similarities to thrombin, is shown to cause an increase and subsequent fall in VIII:C in a manner qualitatively similar to the reaction with thrombin. The reaction is inhibited by a human inhibitor to factor IX and the interaction appears to involve only VIII:C, since factor-VIII-related protein (VIII:RP) is not changed on polyacrylamide gel electrophoresis (PAGE) or radioimmunoassay during the reaction. Phospholipid increases the activation of factor VIII by factor IXa, and high concentrations of diisopropylfluorophosphate and hirudin inhibit the reaction. The physiologic significance of the interaction of factor IXa with factor VIII is not entirely clear since the concentration of factor IXa needed for activation is much greater than the concentration of thrombin required for similar activation of factor VIII. Factor IXa is most likely to play a role in the intrinsic cascade acting as an initial activator of factor VIII, since factor IXa precedes thrombin in this clotting sequence. In addition, factor IXa may be important wherever relatively high local concentrations of factor IXa and factor VIII occur, particularly in the presence of phospholipid, which may serve to localize the coagulation factors.

Animals↗
PubMed1986

Factor VIII concentrates contain factor VIII procoagulant antigen bound to phospholipid.

Fractionation of a human antibody to factor VIII: Ag by immunoabsorption with factor VIII/phospholipid (PL) complex has produced two pools of labelled Fab' fragments which can be used in fluid-phase immunoradiometric assays (IRMAs). One pool binds only to the PL-binding sites on factor VIII:Ag (and thus measures only that factor VIII:Ag in a sample not bound to PL), while the second binds to other antigenic sites. Parallel assays of factor VIII-containing materials using these two pools provide estimates of the proportion of factor VIII: Ag bound to PL in those materials. Five batches each of nine brands of factor VIII concentrates from eight different manufacturers were tested for PL-bound factor VIII:Ag by this method: all contained substantial amounts, ranging from 28% to 54% of the total factor VIII:Ag present. In addition, varying amounts of the factor VIII:Ag present in both non-activated and activated prothrombin complex concentrates (PCCs) from four manufacturers were PL-bound.

Antigens↗
PubMed1995

Immunoblot cross-reactivity of factor VIII inhibitors with porcine factor VIII.

Porcine factor VIII has been used successfully to treat factor VIII inhibitor patients whose plasmas have minimal cross-reactivity to porcine factor VIII. However, some inhibitor plasmas do inhibit porcine factor VIII, and the extent of procoagulant inhibition often increases after treatment with porcine factor VIII. Because there is no information about the porcine factor VIII epitopes with which these antibodies react, we have compared the immunoblot and enzyme-linked immunosorbent assay (ELISA) reactivities with porcine and human factor VIII for 20 inhibitor plasmas (11 from hemophilia A patients and 9 autoantibodies). Immunoblots identified binding to porcine factor VIII for only 2 of the 12 plasmas from patients who had not received porcine factor VIII, but this reactivity could not be predicted from the inhibitor titer to porcine factor VIII. Immunoblot reactivity with porcine factor VIII was detected for 7 of 8 inhibitor plasmas from patients who had been previously treated with porcine factor VIII, and the strength of this reactivity was generally related to the inhibitor titer. Of the 5 plasmas that were immunoblot positive with the porcine factor VIII A2 domain, 4 had inhibitor titers greater than 45 Bethesda units when tested with porcine factor VIII, whereas only 1 of 15 of the other plasmas had this level of inhibitor activity with porcine factor VIII. In contrast, immunoblot reactivity to the porcine factor VIII A1 domain did not correlate with the antiporcine VIII inhibitor titer. We also determined the effect of preincubation with human or porcine factor VIII on immunoblot reactivity. In one case, immunoblot reactivity with porcine factor VIII was absorbed with porcine, but not human, factor VIII, which is consistent with antibody formation after treatment with porcine factor VIII. In no cases did human factor VIII reduce the reactivity of inhibitor plasmas with the porcine A1 domain, suggesting that these antibodies are directed at unique porcine factor VIII determinants. The reactivity to porcine A2 in 2 plasmas probably represented cross-reactivity of similar A2 determinants, because it was absorbed by both human and porcine factor VIII. Although the ELISA assays with porcine factor VIII detected antibodies in some plasmas that could not be identified by inhibitor assay or immunoblot, the level of ELISA reactivity was generally consistent with the titers of the other assays.

Animals↗
PubMedDate not supplied

Standardization of assays of factor VIII and factor IX.

The development of international standards over the last 15-20 years has led to improved interlaboratory agreement on assays of factor VIII and factor IX. In the most recent international collaborative study, the coefficient of variation for one-stage assays (26 laboratories) was 5.6%. However, in quality assurance surveys, carried out in the UK and USA, agreement between laboratories is much less good, with coefficients of variation ranging from 30% to over 50%. Improvements in agreement between clinical laboratories could be obtained by increasing the amount of testing on each sample, especially the number of dilutions, and reducing the number of reagent systems used. A large number of laboratories now use immunodepleted plasmas instead of congenitally deficient plasmas as substrates for one-stage assays. These plasmas may give satisfactory assays, but many of them have not been thoroughly evaluated in comparison with congenitally deficient plasma. In assessment of potency of very high purity (VHP) factor VIII concentrates, some immunodepleted plasmas were found to give lower potencies than hemophilic plasma. This is partly due to the fact that VHP concentrates contain little or no von Willebrand factor (vWF), and most immunodepleted plasmas are also deficient in vWF. In recent collaborative studies, assays of VHP factor VIII concentrate were much more variable, both within and between laboratories, than assays of intermediate purity concentrates. Standardization of these new products will require careful attention to methodological detail.

Factor IX↗
PubMed1985

Elevation of Factor VIII coagulant activity over Factor VIII coagulant antigen in diabetic children without vascular disease. A sign of activation of the Factor VIII coagulant moiety during poor diabetes control.

To investigate whether the elevation of factor VIII coagulant activity observed in children with poor control of diabetes is due to increased levels of the factor VIII coagulant moiety of the factor VIII complex or reflects activation of the factor VIII coagulant moiety, factor VIII coagulant activity (VIII C), factor VIII coagulant antigen (VIII C:Ag), and factor VIII-related antigen (VIII R:Ag) were determined in 75 insulin-dependent children. All children were without signs of vascular disease based on negative funduscopy, negative fluorescein angiography, normal serum creatinine levels, and absence of proteinuria. Children with poor actual control of diabetes had significantly higher VIII C values than did children with good actual control of diabetes based on HbA1 values, but VIII C:Ag values did not differ in children with good or poor actual control of diabetes. A significant elevation of VIII C over VIII C:Ag values was observed in children with poor actual control of diabetes, but no elevation of VIII C over VIII C:Ag was found in children with good actual control. VIII R:Ag values were higher in children with poor actual control. VIII C, VIII C:Ag, and VIII R:Ag did not differ significantly in children with short or long duration of clinical diabetes. Our observation of significantly higher VIII C values than VIII C:Ag levels strongly suggests intravascular activation of the factor VIII coagulant moiety during poor diabetes control. The process leading to activation of the coagulant moiety seems to be different from the process leading to the elevation of the other moiety of the factor VIII complex, the factor VIII-related antigen, in diabetic subjects.

Adolescent↗
PubMed1979

Factor VIII procoagulant activity, factor VIII related antigen and von Willebrand factor in newborn cord blood.

The mean level of factor VIII procoagulant acitivity (VIII:C) and factor VIII related antigen (VIIIR:AG) was normal in 100 newborn cord plasmas, whereas that of von Willebrand factor (VIIIR:WF) activity was slightly lower than normal. On crossed immunoelectrophoresis, 20 of 50 newborn infants had an increased anodal mobility of VIIIR:AG. When the cord plasma showing an abnormal electrophoretic pattern was mixed with normal plasma, two precipitation peaks with a broad base were found. Similar mixing experiments with the abnormal cord plasma and plasma from a patient with atypical von Willebrand's disease did not normalize the electrophoretic mobility of VIIIR:AG. Gel filtration of the cord plasma with an abnormal electrophoretic pattern of VIII:AG, showed that the three activities were all detected at the position corresponding to a molecular weight of about 800 000. The results suggest the presence of qualitative abnormalities of the factor VIII molecule in half of full-term newborn cord plasma.

Adult↗
PubMed1977

[Factor VIII activity and factor VIII associated antigen in newborns (author's transl)].

Factor VIII activity and factor VIII associated antigen were determined in healthy term newborns. On the first day of life factor VIII activity was higher than in adults. The activity reached the adult level at about the tenth day. The factor VIII associated antigen was found higher than the activity and did not decrease in the first ten days. Studies of the factor VIII associated antigen of newborns by the two-dimensional immunoelectrophoresis showed the same pattern as compared to adults.

Antigens↗
PubMed1980

Preparation and properties of bovine factor VIII (antihemophilic factor).

Factor VIII has been purified approximately 300000-fold from bovine plasma by ammonium sulfate fractionation, glycine precipitation, DEAE-Sephadex column chromatography, sulfate--Sepharose column chromatography, Sephadex G-200 gel filtration, and factor X--Sepharose column chromatography. The highly purified preparation migrated as a triplet on sodium dodecyl sulfate/urea--polyacrylamide gel electrophoresis with apparent molecular weights of 93000, 88000, and 85000. The coagulant activity of the purified preparations was inhibited by antibodies raised in rabbits against either the purified factor VIII protein or a preparation of factor VIII/von Willebrand factor. Antibodies to the purified protein also inhibited the coagulant activity of factor VIII/von Willebrand factor preparations. The purified factor VIII contained no platelet-aggregating activity, as measured in human platelet-rich plasma. The purified preparation of factor VIII was required for the activation of factor X in the presence of factor IXa, calcium, and phospholipid. It was activated about 30-fold by thrombin or factor Xa plus calcium and phospholipid, and each of these reactions was accompanied by a change in the sodium dodecyl sulfate/urea--polyacrylamide gel electrophoresis pattern of the protein. Factor VIII was rapidly inactivated by bovine-activated protein C in a reaction requiring calcium and phospholipid. This reaction was also associated with a change in the sodium dodecyl sulfate/urea--polyacrylamide gel electrophoresis pattern of the highly purified protein. These experiments involving three highly specific serine proteases support the conclusion that the triplet observed on polyacrylamide gels is factor VIII.

Animals↗
PubMed1986

Hemophilic patients with an inhibitor to factor VIII treated with high dose factor VIII concentrate. Results of a collaborative study for the evaluation of factor VIII inhibitor titer, recovery and half life of infused factor VIII.

The long term treatment of hemophilic patients with an inhibitor to Factor VIII has been difficult although some success with immunosuppressive agents has been reported. Eighteen hemophilic patients, mainly from Bonn in Germany, but also from other countries, have completed a high dose Factor VIII treatment in an attempt to reduce their inhibitor titer and induce "immune tolerance" to Factor VIII. Plasma samples from the 18 patients collected before and after infusion of 50 units Factor VIII/kg body weight were sent to five laboratories to evaluate inhibitor titer, Factor VIII recovery and half life. This collaborative study demonstrated a close correlation from one laboratory to another concerning inhibitor titration and Factor VIII recovery. The conclusion of the study is that all patients treated with this protocol showed an undetectable or low inhibitor titer against Factor VIII indicating that they can be efficiently treated with Factor VIII.

Adolescent↗
PubMed1991

Restriction fragment length polymorphisms associated with the factor VIII and factor IX genes in Polynesians.

New Zealand Maoris (72 X chromosomes) have been compared with Pacific Island Polynesians (121 X chromosomes) and Caucasian New Zealanders (51 X chromosomes) as a control group to determine the allelic frequency of six RFLPs associated with the genes for two X linked diseases (haemophilia A and haemophilia B). RFLPs examined were BclI, XbaI, and BglI within the factor VIII gene, the factor VIII extragenic TaqI system, and the factor IX intragenic TaqI and XmnI sites. The information obtained facilitates the design of strategies for both carrier detection and prenatal diagnosis of haemophilia A within these groups. Strong linkage disequilibrium was observed between the factor VIII BclI and XbaI sites in Polynesians. Genetic counselling for Polynesians with haemophilia B continues, however, to rely on phenotypic diagnosis. The RFLP data from the two separate loci on the X chromosome in Polynesians show similarities with Chinese and Japanese populations, reinforcing theories of an early Polynesian ancestry originating in east Asia.

Alleles↗
PubMed1976

Importance of protease inhibition in studies on purified factor VIII (antihaemophilic factor).

According to some authors factor VIII procoagulant activity may be dissociable from carrier protein (MW approximately 2 X 10(6) by agarose gel filtration, e.g. at high ionic strength. We were able to reproduce this phenomenon. However, addition of protease inhibitor (Trasylol) prevented the appearance of low molecular weight peak of factor VIII procoagulant activity both at high ionic strength and elevated temperature (37 degrees C). We conclude from our results that procoagulant activity and carrier protein (von Willebrand factor, factor VIII antigen) are closely associated functional sites of native factor VIII macromolecule. Consequently, proteolytic degradation should be avoided in functional and structural studies on factor VIII and especially in preparing factor VIII concentrate for therapeutic use.

Antigens↗
PubMed1997

Subunit structure and function of porcine factor Xa-activated factor VIII.

Factor Xa and thrombin (factor IIa) activate factor VIII (fVIII) by different proteolytic pathways. Thrombin cleaves fVIII at Arg372 between the A1 and A2 domains, at Arg740 between the A2 and B domains, and at Arg1689 between the B and A3 domains to form an A1/A2/A3-C1-C2 heterotrimer. We now report a stable porcine fVIIIaXa preparation obtained by Mono S HPLC at pH 6. NH2-terminal sequence analysis of purified subunits of fVIIIaXa revealed that factor Xa cleaves fVIII at Arg219 within the A1 domain and at Arg490 within the A2 domain, as well as at Arg372, Arg740, and Arg1689. Analytical ultracentrifugation of the fVIIIaXa preparation yielded results consistent with a single, 148 kDa species, similar to previous results with fVIIIaIIa [Lollar, P., & Parker, C. G. (1989) Biochemistry 28, 666-674]. Thus, the major species in the fVIIIaXa preparation contains five subunits, including fragments of the A1 and A2 domains that remain noncovalently bound. Fluorescence anisotropy measurements indicated there was no difference in the affinity of fVIIIaXa and fVIIIaIIa for a fluorescent dye-labeled, active-site-blocked derivative of porcine factor IXa. Additionally, the fVIIIaXa preparation bound dye-labeled factor IXa with 1:1 stoichiometry, indicating that all fVIIIaXa molecules in the preparation can bind factor IXa. However, fVIIIaXa had 4-fold less procoagulant activity than fVIIIaIIa. Kinetic analysis of fVIIIa cofactor activity using purified factor IXa and factor X suggested this difference is due to greater activity of fVIIIaIIa relative to fVIIIaXa within the intrinsic fXase complex, rather than a difference in their stabilities.

Amino Acid Sequence↗
PubMed1993

[Effect of substrate and diluent for factor VIII activity in highly purified factor VIII concentrate and patient plasma infused factor VIII concentrate].

We studied the difference between congenital factor VIII deficient plasma and factor VIII immuno-depleted plasma on the effect of pre-dilution for factor VIII activity determined by the one-stage assay. When standard curves of one-stage assay for factor VIII: C by GEORGE KING factor VIII deficient plasma (frozen at -80 degrees C), BEHRING factor VIII deficient plasma (lyophilized), DADE factor VIII depleted plasma (lyophilized, von Willebrand factor antigen 0.2 U/ml) and DADE factor VIII depleted plasma (lyophilized, von Willebrand factor antigen 1.0 U/ml) were compared, the difference between the clotting times for 100% and 6.25% of activity in each reagent were 39.5, 29.5, 25.0, 23.0 seconds respectively. Potency values in concentrates without albumin or von Willebrand factor showed a discrepancy between pre-dilution in Owren-Koller buffer and pre-dilution in factor VIII deficient plasma. Potencies of those products pre-diluted in Owren-Koller buffer were 40-60% lower than potencies pre-diluted in factor VIII deficient plasma. These results showed substrate and pre-diluent must be chosen carefully for the accurate assay of factor VIII activity in vitro for the highly purified factor VIII concentrates.

Adult↗