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At least 19 recordsLinked to original sources
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↗
PubMed1977

Factor VIII coagulant activity and factor VIII-related antigen released from isolated perfused human spleens.

Eight human spleens were perfused for up to 65 h at normothermia and the coagulant Factor VIII activity measured in the perfusate. In addition, in three experiments Factor VIII-related antigen was determined in the perfusate. Although the spleens were pathologically enlarged and the normal structure involved by different diseases, all spleens released Factor VIII coagulant activity and Factor VIII-related antigen. On average the total amount of Factor VIII coagulant activity released was equivalent to that of 3.5 l of human plasma.

Antigens↗
PubMed1985

Abnormal factor VIII coagulant antigen in patients with renal dysfunction and in those with disseminated intravascular coagulation.

Factor VIII antigen (VIII:CAg) exhibits molecular weight heterogeneity in normal plasma. We have compared the relative quantities of VIII:CAg forms present in normal individuals (n = 22) with VIII:CAg forms in renal dysfunction patients (n = 19) and in patients with disseminated intravascular coagulation (DIC; n = 7). In normal plasma, the predominant VIII: CAg form, detectable by sodium dodecyl sulfate polyacrylamide gel electrophoresis, was of molecular weight 2.4 X 10(5), with minor forms ranging from 8 X 10(4) to 2.6 X 10(5) D. A high proportion of VIII:CAg in renal dysfunction patients, in contrast, was of 1 X 10(5) mol wt. The patients' high 1 X 10(5) mol wt VIII: CAg level correlated with increased concentrations of serum creatinine, F1+2 (a polypeptide released upon prothrombin activation), and with von Willebrand factor. Despite the high proportion of the 1 X 10(5) mol wt VIII:CAg form, which suggests VIII:CAg proteolysis, the ratio of Factor VIII coagulant activity to total VIII:CAg concentration was normal in renal dysfunction patients. These results could be simulated in vitro by thrombin treatment of normal plasma, which yielded similar VIII:CAg gel patterns and Factor VIII coagulant activity to antigen ratios. DIC patients with high F1+2 levels but no evidence of renal dysfunction had an VIII:CAg gel pattern distinct from renal dysfunction patients. DIC patients had elevated concentrations of both the 1 X 10(5) and 8 X 10(4) mol wt VIII:CAg forms. We conclude that an increase in a particular VIII:CAg form correlates with the severity of renal dysfunction. The antigen abnormality may be the result of VIII:CAg proteolysis by a thrombinlike enzyme and/or prolonged retention of proteolyzed VIII:CAg fragments.

Aged↗
PubMed1985

The functional defect of factor VIII Leiden, a genetic variant of coagulation factor VIII.

Factor VIII Leiden is a genetic variant of coagulation factor VIII which has been detected in the plasma of a patient with mild haemophilia A. In this patient's plasma factor VIII procoagulant antigen was in 5-fold excess over factor VIII procoagulant activity, indicating the presence of an abnormal factor VIII molecule. The variant factor VIII was isolated from the patient's plasma, and its functional properties were studied in a factor X-activating system consisting of purified components. The isolated factor VIII Leiden was normally activated by factor Xa and by thrombin, but the activity of the factor VIIIa was about 3% of normal. The defect of factor VIIIa Leiden was studied by comparison with normal factor VIIIa in kinetic experiments of factor Xa formation. The results support the hypothesis that factor VIIIa Leiden has a reduced affinity for phospholipid-bound factor IXa in the intrinsic factor X-activating complex.

Calcium↗
PubMed1985

Degradation of factor VIII coagulant antigen by proteolytic enzymes.

The factors responsible for the lability of factor VIII coagulant activity (VIII:C) and factor VIII coagulant antigen (VIII:CAg) are poorly understood. In this study the VIII:C and VIII:CAg are studied after incubation with plasmin, trypsin or alpha-chymotrypsin. Both isolated human VIII:CAg and VIII:CAg associated with factor VIII-related antigen (VIII R:Ag) are evaluated. The antigenic sites of the VIII:CAg are somewhat more stable to the action of these enzymes than the functional activity, although both follow a generally parallel degradation. A biphasic decay curve is seen in the initial time points. No stabilization of the functional or antigenic reactivity is observed in the presence of the VIII R:Ag. Lower concentrations of each enzyme cause an initial rise in the factor VIII:C in the presence of VIII R:Ag, but not in the isolated VIII:CAg. Higher concentrations of alpha-chymotrypsin cause activation of VIII:C and a slight decrease in the VIII:CAg values in both preparations. These enzymes may play a modulating role in the coagulation cascade through the activation and degradation of VIII:C and VIII:CAg.

Antigen-Antibody Reactions↗
PubMed1986

Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity.

Human factor VIII was isolated from commercial factor VIII concentrates and found to consist of multiple polypeptides with molecular weights ranging from 80 000 to 210 000. Immunological and amino acid sequence data identified these polypeptides as subunits of factor VIII. N-Terminal amino acid sequence analysis determined that the Mr 210 000 and 80 000 proteins are derived from the N- and C-terminal portions of factor VIII, respectively; Mr 90 000-180 000 polypeptides are derived from the Mr 210 000 polypeptide by C-terminal cleavages. Treatment of purified factor VIII with thrombin resulted in proteolysis of Mr 80 000-210 000 proteins and the generation of polypeptides of Mr 73 000, 50 000, and 43 000. Maximum coagulant activity of thrombin-activated factor VIII was correlated with the generation of these polypeptides. The proteolysis as well as activation of factor VIII by thrombin was found to be markedly dependent on CaCl2 concentration. Proteolysis of factor VIII with activated protein C (APC) resulted in degradation of the Mr 90 000-210 000 proteins with the generation of an Mr 45 000 fragment. This cleavage correlated with inactivation of factor VIII by APC. The Mr 80 000 protein was not degraded by APC. Factor Xa cleaved the Mr 80 000-210 000 factor VIII proteins, resulting in the generation of fragments of Mr 73 000, 67 000, 50 000, 45 000, and 43 000. Factor Xa was found to initially activate and subsequently inactivate factor VIII.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1985

Crohn's disease activity: assessment by factor VIII coagulation proteins.

Twenty-eight patients (mean age 13.5 years) with proven Crohn's disease were examined for factor VIII coagulation activity (VIII:C), factor VIII-related antigen (VIII R:Ag), and factor VIII-related ristocetin cofactor activity (VIII R:RCF). The factor VIII coagulation proteins were correlated with disease activity index according to van Hees and were compared with inflammatory parameters such as erythrocyte sedimentation rate, c-reactive protein, and orosomucoid. Among the factor VIII proteins, factor VIII-related protein (VIII R:Ag) correlates best with van Hees disease activity index, orosomucoid, c-reactive protein, and erythrocyte sedimentation rate (p less than 0.001 for all parameters). Since acute phase proteins are produced by liver cells, whereas VIII R:Ag is synthesized by endothelial cells, we postulate that this coagulation factor is highly sensitive in reflecting the inflammatory process in the intestine.

Adolescent↗
PubMed1986

[Determination of factor VIII-coagulation antigen in factor VIII concentrates using an inhibitor test].

The method of determination of factor VIII coagulation antigen (VIIICAg) here described is based on the well established factor VIII inhibitor test. Highly concentrated inhibitors to factor VIII in factor VIII substituted hemophiliacs are the most frequent among inhibitors to clotting factors. If such an inhibitor is used in an inhibitor assay its reaction depends on the VIIICAg concentration in the test system. The slope of the reaction curve is proportional to VIIICAg if the inhibitor titer is known. VIIICAg was measured in one cryoprecipitate and 5 different factor VIII concentrates of medium to high purity using this assay. In addition factor VIII related antigen and factor VIII ristocetin cofactor were determined by routine methods. VIIICAg fairly corresponded to factor VIII coagulation activity. Only cryoprecipitate contained significantly more VIIICAg.

Antigens↗
PubMed1985

Use of segments for the quality control of the factor VIII: coagulant activity of fresh frozen plasma.

The storage of fresh frozen plasma (FFP) for short periods at -20 degrees C for 6 weeks, -30 degrees C for 12 weeks, or -40 degrees C for 12 weeks, did not result in significant deterioration in factor VIII: coagulant (factor VIII:C) activity in the primary packs. In studies examining whether plasma segments could be used for quality control purposes, the mean factor VIII:C activity of the primary pack was found to be identical to that of the attached segments of plasma for units of FFP which were thawed within 2 h after preparation. This was also true for FFP units stored at -40 and -60 degrees C for up to 12 weeks. There was, however, a loss in factor VIII:C activity in the segments of FFP units stored at either -20 or -30 degrees C for 6 and 12 weeks, respectively. Thus for units of FFP stored at temperatures colder than -40 degrees C, segments are suitable for assessing the factor VIII:C activity in the primary pack but not for FFP units stored at -20 or -30 degrees C.

Factor VIII↗
PubMed1985

Combined factor V/VIII deficiency: a case report including levels of factor V and factor VIII coagulant and antigen as well as protein C inhibitor.

Comprehensive coagulation studies were performed on members of a family with combined factor V/VIII deficiency. The purpose of these studies was to investigate the hypothesis that combined factor V/VIII deficiency is due to a lack of the inhibitor to activated protein C. The analyses performed included routine APTT and PT, factor V and VIII coagulant activity and antigen levels, von Willebrand factor levels, protein C antigen assay, and both protein C inhibitor activity and antigen levels. Three of the 19 family members studied were found to have a deficiency of both factors V and VIII. These three individuals showed prolonged APTTs and PTs and decreased levels of factor V and factor VIII coagulant activity and antigen. Factor VIII related antigen and ristocetin cofactor (von Willebrand factor) levels were normal. Protein C and both protein C inhibitor activity and antigen levels were also found to be normal. These findings confirm the results of other recent investigators and indicate that the autosomal, inherited combined factor V/VIII deficiency is not due to a protein C inhibitor deficiency. The real defect in this combined deficiency remains to be determined.

Adult↗
PubMed1986

DDAVP-induced increases in coagulation factor VIII and von Willebrand factor in the plasma of conscious dogs.

Infusion of the vasopressin analogue DDAVP into five normal dogs at doses of 0.1-2.0 micrograms DDAVP per kg body weight induced dose-dependent increases in the plasma content of coagulation factor VIII and von Willebrand factor. Plasma concentrations of von Willebrand factor (determined antigenically as factor VIII-related antigen and functionally as coagglutinin cofactor activity) and coagulation factor VIII were measured immediately before and at 10, 30, and 120 min after 10-min intravenous infusions of DDAVP. The greatest increases in coagulation factor VIII were produced with the 2.0 micrograms/kg dose. Ten minutes after infusion the mean increase in coagulation factor VIII was 32 units/dl (concentrations of all indices were reported relative to concentrations in a standard canine plasma pool, arbitrarily assigned a concentration of 100 units/dl) and this increase did not change significantly throughout the duration of the experiment. At 10 min post-infusion, the mean factor VIII-related antigen concentration increased 81 units/dl (dose = 2.0 micrograms/kg) and did not change significantly for the duration of the experiment. The maximum mean increase in coagglutinin cofactor activity, 141 units/dl, occurred 10 min after infusion (dose = 1.0 microgram/kg). Coagglutinin cofactor activity decreased significantly from peak activity by 120 min post-infusion.

Animals↗
PubMed1989

Inhibition of human coagulation factor VIII by monoclonal antibodies. Mapping of functional epitopes with the use of recombinant factor VIII fragments.

The epitopes of four monoclonal antibodies against coagulation Factor VIII were mapped with the use of recombinant DNA techniques. Full-length Factor VIII cDNA and parts thereof were inserted into the vector pSP64, permitting transcription in vitro with the use of a promoter specific for SP6 RNA polymerase. Factor VIII DNA inserts were truncated from their 3'-ends by selective restriction-enzyme digestion and used as templates for 'run-off' mRNA synthesis. Translation in vitro with rabbit reticulocyte lysate provided defined radiolabelled Factor VIII fragments for immunoprecipitation studies. Two antibodies are shown to be directed against epitopes on the 90 kDa chain of Factor VIII, between residues 712 and 741. The 80 kDa chain appeared to contain the epitopes of the other two antibodies, within the sequences 1649-1778 and 1779-1840 respectively. The effect of antibody binding to these sequences was evaluated at two distinct levels within the coagulation cascade. Both Factor VIII procoagulant activity and Factor VIII cofactor function in Factor Xa generation were neutralized upon binding to the region 1779-1840. The antibodies recognizing the region 713-740 or 1649-1778, though interfering with Factor VIII procoagulant activity, did not inhibit in Factor Xa generation. These findings demonstrate that antibodies that virtually inhibit Factor VIII in coagulation in vitro are not necessarily directed against epitopes involved in Factor VIII cofactor function. Inhibition of procoagulant activity rather than of cofactor function itself may be explained by interference in proteolytic activation of Factor VIII. This hypothesis is in agreement with the localization of the epitopes in the proximity of thrombin-cleavage or Factor Xa-cleavage sites.

Antibodies, Monoclonal↗
PubMed1978

Factor VIII coagulant activity in an African population in relation to a recognized standard.

The normal range of factor VIII coagulant activity (derived from log potency ratio) in some sections of the Nigerian population has been established at 0.65--5.55 iu/ml with a geometric mean of 1.90 iu/ml. This was determined against an acceptable standard (MRC Human 68/413 with activity o.66 iu/ml). The distribution of the potency ratio was log normal. The level was not affected by age or an abnormal haemoglobin (Hb A + S or A + C). The mean activity in females was significantly higher than the mean value in male subjects. With the use of a stable standard, our results show that the conclusions of some previous studies in respect of some of the parameters such as population distribution but which did not use a recognized standard, were valid. Within the age limits of our subjects, age did not affect the population level of factor VIII coagulant activity.

Adolescent↗
PubMed1987

Factor VIII coagulant moiety binds to platelets by binding to phospholipids of the platelet membrane.

Washed human platelets were incubated with commercial factor VIII concentrate, or with purified factor VIII coagulant moiety. Platelets were then washed again and lysed by sonication. VIII:Ag and vWf:Ag were measured in the platelet lysate prior to and after incubation of the lysate with phospholipase C (PL-C). Platelet bound VIII:Ag was significantly higher after incubation of washed platelets with factor VIII concentrate than after incubation with buffer. Platelet bound VIII:Ag was further increased when platelets had been incubated with concentrate in the presence of thrombin and collagen. In contrast, only a slight increase in platelet bound vWf:Ag was observed after incubation of platelets with concentrate. When washed platelets had been incubated with factor VIII coagulant moiety, also significantly more platelet bound VIII:Ag was observed than after incubation with buffer. Measurable VIII:Ag, but not vWf:Ag, increased significantly after incubation of the platelet lysate with PL-C. When intact washed platelets had been treated with PL-C prior to the incubation with concentrate, binding of VIII:Ag to platelets was nearly completely abolished. Our data suggest that the factor VIII coagulant moiety binds to phospholipids of the platelet membrane and thereby contributes to the assembly of the factor X activating complex on the platelet surface.

Blood Platelets↗
PubMed1986

Characterization of four monoclonal antibodies to factor VIII coagulant protein and their use in immunopurification of factor VIII.

Four monoclonal anti-VIII:C antibodies were obtained from the fusion of the splenocytes of one Balb/C mouse with a specific activity ranging from 2.3 to 45,000 U/mg when purified from ascitic fluid. Only one antibody was able to inhibit completely Factor VIII:C in normal plasma. The four antibodies could bind Factor VIII:CAg in plasma and commercial concentrate both in liquid and solid phase, and were suitable for immunopurification of Factor VIII:C. Three antibodies competed with polyclonal anti-VIII:CAg Fab' in a liquid phase IRMA, and all of them were able to displace their own binding to Factor VIII:CAg. Competition studies between monoclonal antibodies for the binding to Factor VIII:CAg were performed and showed the recognition of different epitopes and various functional impact. These studies indicate that at least one antibody, with the lowest anti-VIII:C titer clearly recognizes a different epitope of VIII:C than those recognized by the others. Affinity constants ranged from 10(9) to 10(10) l/mole.

Animals↗