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PubMed1971

A biological standard for measurement of blood coagulation Factor VIII activity.

Because of the instability of Factor VIII (antihaemophilic factor) in plasma in vitro, and since evidence has accumulated that the level of activity varies significantly between samples of "fresh normal plasma", it is apparent that a stable biological standard is required.Two freeze-dried preparations of Factor VIII, one plasma and one concentrate preparation, were prepared and have been assayed in a collaborative trial by 20 laboratories in 9 countries.The laboratories used their own methods and altogether 248 assays were carried out. Comparison of materials of similar type gave precise estimates with all the methods used, but when materials dissimilar in type and in Factor VIII content were compared less precise results were obtained. Sources of variation, such as differences in method, differences between operators, and day-to-day variations, were analysed.Accelerated degradation tests, carried out on the freeze-dried plasma and concentrate preparations, showed that Factor VIII activity was sufficiently stable in the concentrate for it to be used as a long-term standard but that the Factor VIII activity was less stable in the plasma preparation.

Biological Assay↗
PubMed1984

Studies on the procurement of coagulation factor VIII: selective precipitation of factor VIII with hydrophilic polymers.

Early work on the purification of factor VIII using polyethylene glycol (PEG) indicated that other polymers might also be used to precipitate factor VIII leaving fibrinogen in solution. Recently polyvinylpyrrolidone (PVP) has also been advocated for this purpose. In this study, different concentrations and molecular weights of hydroxyethyl starch, dextran, PEG, PVP, Ficoll, Percoll and albumin were examined for their ability to precipitate the factor VIII complex from cooled (not frozen) fresh CPD plasma. At optimal concentrations near quantitative recovery of VIIIR:Ag and VIII:CAg was achieved in 2 hr with minimal precipitation of fibrinogen or total protein. The best separations were observed with hydroxyethyl starch, albumin or Ficoll. PVP and PEG gave inferior purifications. Results for cryoprecipitate and intermediate-purity factor VIII concentrate were inferior to those obtained with plasma. Simple pre-concentration of plasma prior to chilling is an attractive alternative for large scale continuous production.

Chemical Precipitation↗
PubMed1980

[Determination of coagulation factor VIII inhibitors].

Factor VIII inhibitors represent a severe complication of the haemophilia A. Different methodical approach in the diagnostics of the laboratory and various definitions of the inhibitor unit render difficult the comparability of the results of examination. Methods for the unitary performance of the qualitative proof of inhibitors and the quantitative estimation of inhibitors are described and their application in the examination of two patients with factor VIII inhibitors are shown.

Antibodies↗
PubMed1993

Double strand conformation polymorphism (DSCP) detects two point mutations at codon 280 (AAC-->ATC) and at codon 431 (TAC-->AAC) of the blood coagulation factor VIII gene.

Hemophilia A is a hereditary, X-linked, bleeding disorder that is caused by a defect in the factor VIII gene. Here, we report two novel point mutations in the factor VIII gene that result in an aberrant electrophoretic mobility of double strand PCR fragments (double strand conformation polymorphism, DSCP). In exon 9 a TAC-->AAC mutation at codon 431, replacing Tyr by Asn, was observed in a family (A211) with moderately severe hemophilia A. A family with mild hemophilia A revealed an A-->T mutation in codon 280 (exon 7) that results in the replacement of Asn by Ile. One of these two mutations was not detected in an analysis based on single strand conformation polymorphisms (SSCP). At present we have no explanation for the effect of the nucleotide changes on the electrophoretic mobility of double strand DNA. Although DSCP is not able to detect all mutations the combination of DSCP analysis with SSCP analysis increases the sensitivity in a screening for factor VIII mutations.

Base Sequence↗
PubMed1996

[Acquired coagulation factor VIII deficiency. A 4-year survey of patients at the East Danish Hemophilia Center].

An East Danish population of acquired haemophilia A (factor VIII inhibitors) patients are described in a retrospective survey. Fifteen patients attended the centre during the period 1981-1994. The epidemiology, clinical presentation, time from début until diagnosis and response to treatment are presented. Acquired factor VIII inhibitors are rare and without treatment the disease has a high mortality and morbidity. Inhibitors mostly develop among the elderly, independent of sex and almost half have no known underlying disease. When the diagnosis is clear, bleedings may be controlled and the patient may be cured by treatment that eliminates the inhibitor. Time until diagnosis varies a lot, for some patients it takes years. It is therefore important to be aware of the disease, so that time with risk of fatal bleeding is shortened as much as possible.

Adult↗
PubMed1998

Improved blood preservation with 0.5CPD erythro-sol. Coagulation factor VIII activity and erythrocyte quality after delayed separation of blood.

BACKGROUND AND OBJECTIVES: Delay between blood collection and the separation of its components may result in lowered yield of factor VIII (FVIII) and loss of 2,3-biphosphoglycerate (2,3-BPG). This study was to see whether the use of 0.5 CPD resulted in better preservation of FVIII and maintenance of 2,3-BPG. MATERIALS AND METHODS: 55 units of blood were collected in 0.5CPD and 48 in CPD SAG-M. Ten of the collections were paired, so that the same donors were bled in a single session partly in an 0.5CPD system and partly in CPD SAG-M. After collection, the blood was promptly cooled to 20 degrees C and stored at that temperature for up to 24 h. RESULTS: Preservation of FVIII activity was significantly better in 0.5CPD compared with CPD. The content of von Willebrand factor was stable in the anticoagulant solutions for 24 h at that temperature. Plasma separated from both media had how levels of prothrombin fragment 1 + 2 and complement activation. Paired collections substantiated previous reports that red cell storage is significantly improved in 0.5CPD compared with CPD SAG-M with respect to 2,3-BPG and haemolysis. CONCLUSIONS: Red cell metabolism and oxygen-releasing capacity are kept at acceptable levels in 0.5CPD blood for 24 h at 20 degrees C before component separation. The concentration of red cell 2,3-BPG remained at normal or slightly subnormal levels during further storage in 0.5CPD at 4 degrees C for 2-4 weeks before gradual decay to an average of 39% at 48 days.

2,3-Diphosphoglycerate↗
PubMed1982

Megakaryocytic leukemia; identification utilizing anti-factor VIII immunoperoxidase.

Coagulation Factor VIII is produced by endothelial cells and megakaryocytes. Antibody directed against Factor VIII or its associated antigens has been shown to be a sensitive marker for both normal and neoplastic endothelial cells. Its use to identify neoplastic megakaryocytes has not been described. We used immunoperoxidase localization of Factor VIII to identify megakaryocytes and immature megakaryocytic precursors in a case of megakaryocytic leukemia.

Aged↗
PubMed1980

Coagulation factors in the human fetus of about 20 weeks of gestational age.

In plasma samples of 11 fetuses of about 20 weeks of gestational age the following coagulation factors have been determined (mean values found are given in parentheses): fibrinogen (0.30 U/ml), prothrombin (+/-0.17 U/ml), factor V (0.28 U/ml), factor VII (0.21 U/ml), factor VIII coagulant activity (factor VIII:C) (0.12 U/ml), factor VIII-related antigen (factor VIIIR:Ag) (1.04 U/ml), coagulant factor VIII-related antigen (factor VII:CAg) (0.19 U/ml), factor IX coagulant activity (0.05 U/ml), factor IX antigen (less than or equal to 0.03 U/ml), factor X (0,19 U/ml) and antithrombin III (AT-III) (0.23 U/ml). Our data support the evidence that prenatal diagnosis of haemophilia A is at present possible; less optimism is warranted where haemophilia B is concerned. the number of samples is sufficient to establish normal values for the age group. Means of quality control of the sample-which is often difficult to obtain-are disscussed.

Blood Coagulation Factors↗
PubMed2000

Retention of coagulation factors in plasma frozen after extended holding at 1-6 degrees C.

BACKGROUND AND OBJECTIVES: The ability to use plasma, isolated from units of whole blood and frozen within 24 h of phlebotomy, as a substitute for plasma frozen within 8 h of phlebotomy would have several advantages for blood centers. It should provide increased flexibility pertaining to the freezing of plasma for clinical use. We have conducted studies to assess the influence of an extended holding time for separated plasma, prior to freezing, on the retention of coagulation factor activity. STUDY DESIGN AND METHODS: Freshly harvested plasma from each of 10 units of CPD-whole blood was divided into four equal aliquots. These aliquots were held in plastic packs at 1-6 degrees C for a total of 0, 8, 15 and 24 h. Subsequently, the plasma aliquots were frozen rapidly and stored at -20 degrees C for 4 months. The thawed plasma was tested for coagulant factors V and IX, factor VIII coagulant activity (factor VIII:C), von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor of von Willebrand factor. RESULTS: The levels of factor V, factor vWF:Ag, factor IX and ristocetin cofactor were not influenced by holding the plasma for up to 24 h prior to freezing. Factor VIII:C activity was reduced with extended holding at 1-6 degrees C; the percentage at time zero activity was 75.9+/-2.4% for samples frozen immediately after a 24-hour period. CONCLUSIONS: The data indicate that coagulation factor properties of harvested plasma are retained except for factor VIII for at least 24 h prior to freezing.

Antigens↗
PubMed1985

Factor VIII and factor IX in a twin population. Evidence for a major effect of ABO locus on factor VIII level.

In order to establish the relative importance of genetic factors on the variation in plasma concentration of coagulation factors VIII and IX, these parameters were determined in 74 monozygotic and 84 like-sexed dizygotic twin pairs. The twins belonged to two age groups: 33-39 years and 57-62 years. Factor VIII was determined as factor VIII coagulant antigen (VIIICAg) and as factor VIII-related antigen (VIIIRAg). Factor IX was determined as factor IX antigen (IXAg). A higher value for each coagulation factor was found in the older-age group compared to the younger group, whereas no difference was found between the sexes. A significant correlation was found between values for VIIIRAg and VIIICAg (r = .56). For VIIICAg, it could be demonstrated that the age effect was secondary to the age effect on VIIIRAg. The concentration of VIIICAg and VIIIRAg varied among ABO blood types, being lowest in type O individuals, higher in A2 individuals, and highest in A1 and B individuals. The effect of the ABO locus on VIIICAg was secondary to an effect on VIIIRAg. Analysis of variance revealed a significant genetic influence on the variance of VIIICAg and VIIIRAg with a heritability estimate of .57 for VIIICAg and .66 for VIIIRAg. This is in agreement with a previous hypothesis of an effect of several autosomal genes on factor VIII concentration. Thirty percent of the genetic variance of VIIIRAg was due to the effect of ABO blood type. The ABO locus is therefore a major locus for the determination of factor VIII concentration. No significant genetic effect on the variation in plasma concentration of IXAg could be detected.

ABO Blood-Group System↗
PubMed2005

Effect of levothyroxine replacement therapy on coagulation and fibrinolysis in severe hypothyroidism.

OBJECTIVE: We previously demonstrated that patients suffering from moderate hypothyroidism were at increased risk of thrombosis contrasting with the bleeding tendency of those presenting severe hypothyroidism. The latter state is associated with hemostatic anomalies including von Willebrand type 1 disease and increased fibrinolytic capacity. With the exception of von Willebrand type 1 disease, reversibility of hemostatic changes is not established after levothyroxine replacement therapy. Therefore our objective was to analyze the reversibility of these anomalies. MATERIALS AND METHODS: We analyzed the impact of levothyroxine treatment on lipid parameters, fibrinogen, platelet count, D-dimers, alpha2 antiplasmin activity, plasminogen activity, tissue plasminogen activator antigen (t-PA Ag), plasminogen activator inhibitor type 1 antigen (PAI-1 Ag) and coagulation factors (factor VIII coagulant, von Willebrand factor antigen, von Willebrand factor and factor IX) in 23 patients with severe hypothyroidism (TSH level > 50 mU/ I). RESULTS: Mean fibrinogen levels increased by 14.2% while t-PA Ag and PAI-1 Ag increased by 42.6 and 69%, respectively, after correction of hypothyroidism. Interestingly, post-treatment PAI-1 Ag levels tended to be higher in patients with normal-high final TSH levels than in patients with normal-low final TSH levels. Our results suggest that normalization of fibrinolysis is obtained after a transient decrease of fibrinolytic activity. We also confirmed the correction of coagulation factor abnormalities upon levothyroxine replacement therapy. CONCLUSIONS: We demonstrated that the coagulation disorders and the hyperfibrinolytic status of severe hypothyroid patients were corrected upon levothyroxine therapy. However, the clinical consequences of the transient decrease of the fibrinolytic activity during the course of TSH normalization need further studies.

Adult↗
PubMed1986

The effects of desmopressin on hemostatic parameters in the normal dog.

Seven normal unanesthetized dogs were infused with desmopressin in saline (doses 0.2, 0.4 and 0.6 micrograms/kg i.v.) or saline alone, on separate occasions in order to determine the effects of desmopressin on circulating factor VIII coagulant and factor VIII-related antigen activities, on partial thromboplastin times and prothrombin times, on blood platelet count and packed cell volume, and on serum osmolarity. Desmopressin caused a rapid dose-dependent elevation in both factor VIII activities peaking at 30-60 minutes postinfusion. At a dosage of 0.6 microgram/kg desmopressin induced rises in factor VIII coagulant activity and factor VIII-related antigen of 150% and 198% of the preinfusion levels respectively, while the half disappearance times were approximately five and six hours respectively. The other parameters were not significantly affected by even the highest dose of desmopressin used. These results indicate that normal dogs respond to desmopressin in a manner similar to man. The major differences are in the dosage required to produce comparable effects (higher in dogs), and in the fact that the factor VIII-related antigen activity consistently responds to a greater degree than the coagulant activity. It is concluded that desmopressin may have particular value in stimulating elevations in plasma factor VIII-related antigen in dogs deficient in this plasma protein. Six dogs were pretreated with the endorphin inhibitor, naloxone, (0.04 mg/kg I.V.) or sterile saline, three minutes prior to infusion with desmopressin at a dose of 0.6 microgram/kg i.v.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Postoperative changes in coagulant and anticoagulant factors following abdominal aortic surgery.

The extent and time course of changes in selected procoagulant and anticoagulant factors were investigated in 19 patients undergoing elective abdominal aortic surgery. The coagulation factors were measured preoperatively, and on days two, four, and six postoperatively. It was found that there were no significant changes outside the normal range in prothrombin time, partial thromboplastin time, or thrombin clotting time. However, there were large increases in the procoagulants, fibrinogen, factor VIII coagulant, factor VIIIRag/von Willebrand factor, and in alpha 1-antitrypsin. Over the same time there were marked decreases in the naturally occurring anticoagulants, protein C and antithrombin III, and in alpha 2-macroglobulin. These changes implied that the patients were "hypercoagulable" in the postoperative period. The maximum changes in the procoagulants occurred on either postoperative day two or day four. The maximum changes in the natural anticoagulants occurred on postoperative day two. There were no significant changes in factor V, factor X, alpha 2-antiplasmin, or platelet aggregability. The timing of the changes coincided with a period of high risk of perioperative myocardial infarction in this group of patients. Thus, it is possible that postoperative hypercoagulability contributes to the development of coronary artery thrombosis and myocardial infarction following abdominal aortic surgery.

Aged↗
PubMed1994

[Hemophilia A: molecular biology and carrier diagnosis].

OBJECTIVE: Within this review we give an overview of haemophilia A research concentrating on molecular biology and carrier diagnosis. Haemophilia A, located on X-chromosome and transmitted recessively, is caused by deficiency or functional abnormality of coagulation factor VIII. DATA SOURCES: For this review we used original papers as main sources, but also review articles as well as study results of our group. SELECTION CRITERIA: This review describes factor VIII synthesis and its posttranslational modification, and it discusses the known functional domains of factor VIII protein on the basis of mutations identified and protein studies. Additionally, the significance of mutations concerning carrier diagnosis of haemophilia A affected families is described. RESULTS: Only a few functional domains within factor VIII protein are found, so far. Using newly available prescreening methods, mutations are now identified within factor VIII gene in about 60% of all patients studied. This is an excellent completion of the already available carrier diagnosis by polymorphisms and factor VIII coagulation data. CONCLUSION: The new mutations identified using prescreening methods will improve the results of factor VIII protein studies. In spite of this progress, mutation screening should be intensified, thus allowing to diagnose each female who could be a carrier of haemophilia A.

Factor VIII↗