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PubMed2005

von Willebrand factor and factor VIII as risk factors for arterial and venous thrombosis.

Since the early 1990s attempts have been made to elucidate whether high concentrations of von Willebrand factor (VWF) and factor VIII (FVIII) in plasma are associated with an increased risk of thrombosis. Several prospective studies on the role of VWF in arterial thrombosis, mainly coronary heart disease, were performed in healthy individuals and patients with previous cardiovascular disease. Although the majority showed an association between high VWF levels and arterial thrombosis, others failed to confirm such findings. A smaller number of studies have evaluated FVIII, mainly for its association with venous thrombosis. Two prospective observations, together with several case-control studies, provided solid evidence of an association between high FVIII levels and a first or recurrent episode of venous thrombosis. On the whole, high levels of VWF and FVIII in plasma confer a moderately high risk of arterial and venous thrombosis, respectively. These findings have no therapeutic implication, but they should be taken into account in the assessment of the individual risk profile.

Animals↗

PubMed1993

A higher than expected incidence of factor VIII inhibitors in multitransfused haemophilia A patients treated with an intermediate purity pasteurized factor VIII concentrate.

In May 1990, 218 patients with haemophilia A regularly attending the Leuven Haemophilia Center were randomly assigned to a group receiving either of two newly introduced factor VIII concentrates: factor VIII-P, an intermediate purity pasteurized concentrate, or factor VIII-SD, a high purity concentrate treated with solvent-detergent for viral inactivation. Patients were followed from May 1990 until October 1991. Between August 1991 and October 1991 a clinically important factor VIII inhibitor was detected in five out of the 109 patients receiving factor VIII-P while none of the 109 patients receiving factor VIII-SD developed such antibodies. All patients acquiring an inhibitor had previously been clinically tolerant to transfused factor VIII with 200 to more than 1,000 days of exposure to factor VIII prior to May 1990. Patients with inhibitors were transfused daily with 30 U factor VIII-SD per kg body weight, which was associated with a gradual decline of the inhibitor level. In all patients the antibodies were relatively slow-acting and predominantly directed towards the light chain of factor VIII. This study demonstrates a higher than expected incidence of factor VIII inhibitors associated with the use of a specific factor VIII concentrate in multitransfused haemophilia A patients. It indicates the usefulness of evaluating newly introduced concentrates in prospective, randomized trials.

Adolescent↗

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

The use of porcine factor VIII concentrate (Hyate:C) in the treatment of patients with inhibitor antibodies to factor VIII. A multicenter US experience.

The response to a highly purified concentrate of porcine factor VIII was evaluated in 45 bleeding episodes in 38 patients with high responding inhibitor antibodies to factor VIII. A total of 437 infusions were given. The patients came from 25 hemophilia centers in the United States. The majority had a life- or limb-threatening hemorrhage for which other modalities had not been successful. In 32 of 45 episodes, a good to excellent response was obtained. Adverse reactions were minimal, occurring in 17 treatment episodes, and were mostly treated with antihistamines and/or hydrocortisone. No clear predictor of clinical response to porcine factor VIII concentrate was identified, including pretreatment human and porcine inhibitor levels, percentage of cross-reactivity between the human and porcine antibodies, and the presence of measurable levels of factor VIII after the porcine factor concentrate was given. Anamnesis to porcine factor VIII did occur in some instances. Porcine factor VIII is a valuable modality in the treatment of serious hemorrhages in patients with inhibitors to factor VIII. Its use should be considered early in the course of severe hemorrhage in these patients.

Adolescent↗

PubMed1995

Stability of canine factor VIII and von Willebrand factor antigen concentration in the frozen state.

The stability of factor VIII and von Willebrand factor antigen concentration in the frozen state was assessed. Citrated plasma was obtained from 10 healthy, mixed breed dogs and separated into 300 microliters aliquots. One aliquot was assayed immediately and the others were frozen at either -20 degrees C or -70 degrees C. The activity of factor VIII and the concentration of von Willebrand factor antigen were measured after one week and one, two, three, four, five, six, eight and 10 months of storage. There were minor changes in both variables, particularly after four months, resulting in a decrease in the activity of factor VIII and an increase in the concentration of von Willebrand factor antigen. The changes were more pronounced at -20 degrees C. However, both factors remained relatively stable for the whole period.

Animals↗

PubMed2001

A factor VIII minigene comprising the truncated intron I of factor IX highly improves the in vitro production of factor VIII.

The biosynthesis of coagulation factor VIII (FVIII) is hampered by successive controls that limit its production. To improve this production, a truncated intron I sequence of factor IX (TFIXI1) was inserted in FVIII cDNA in place of FVIII introns 1, 12 and 13 and also as a combination between introns 1 and 12, and introns 1 and 13. The intron 12 and 13 locations were targeted because this region was previously shown to contain a transcriptional silencer. The expression of FVIII in CHO and HepG2 cells revealed important variations in the properties of the minigenes depending on the TFIXI1 insertion sites. In FVIII intron 13 location the TFIXI1 seemed to diminish the transcriptional silencer activity, whereas it was poorly spliced in intron 12 position. Among the five constructs, FVIII I1+13 leaded to a significant improvement in FVIII secretion (13 times) that was associated with a dramatic intracellular accumulation in cells. Therefore, the FVIII I1+13 minigene could represent a particular interest to produce recombinant FVIII in vitro as well as in the aim of gene therapy of haemophilia A.

Animals↗

PubMed2002

[High plasma levels of factor VIII and von Willebrand factor in a patient with portal vein thrombosis].

In portal vein thrombosis, various hypercoagulable conditions and inherited or acquired thrombophilias have already been described as predisposing factors. In a 33-year-old man admitted to a hospital with upper abdominal pain, a partial portal vein and upper mesenteric vein thrombosis, respectively, and a complete splenic vein thrombosis were diagnosed. Further diagnostic procedures showed no evidence for local precipitating factors or any underlying infectious, paraneoplastic or inflammatory disease. Thrombophilia screening demonstrated elevated factor VIII levels (206 %) and von Willebrand factor levels (> 440 %). An acute-phase reaction was excluded. Oral anticoagulant therapy with phenprocoumon was started. Factor VIII and von Willebrand factor were reproducibly elevated to high activity levels over a period of 12 months in absence of acute or chronic inflammatory reaction. Increased levels of factor VIII and von Willebrand factor may play a pathogenetic role in the development of portal, splenic, and mesenteric thrombosis.

Adult↗

PubMedDate not supplied

The mechanism of factor VIII inactivation by human antibodies. II. The effect of factor VIII R: antigen on the rate of interaction.

Factor VIII R:Ag by binding to the procoagulant component (VIII:C) inhibits the extent and rate of interaction of human antifactor VIII antibodies with VIII:C. When this reaction is examined under ionic strength conditions (0.24M CaCl) which dissociate the two factor VIII components, the extent of the reaction is increased approximately two fold and the initial rate of interaction is increased three to four fold for both intact IgG antibody and its Fab' derivative. With isolated procoagulant component, increased ionic strength conditions only influence the rate of interaction. These studies further explain the peculiar time-dependence of this interaction.

Antigens↗

PubMed1976

Factor VIII and human platelet aggregation. IV. Effect of proteolytic enzymes on platelet aggregation by factor VIII.

During digestion of highly purified bovine factor VIII or neuraminidase-treated human factor VIII by plasmin the procoagulant activity is destroyed more rapidly than the aggregating activity. At an intermediate stage, fragments are transiently formed, which inhibit platelet aggregation by the respective undigested materials, but without corssed inhibition. During proteolysis by plasmin, human factor VIII retains antigenic and restocetin cofactor properties. Contrary to previous observations obtained with less purified preparations, plasmin digest of human or bovine factor VIII do not inhibit ADP-induced platelet aggregation. Thrombin and reptilase do not modify the aggragating activities of bovine and neuraminidase-treated human factor VIII.

Animals↗

PubMed1999

Factor VIII, von Willebrand factor and the risk of major ischaemic heart disease in the Caerphilly Heart Study.

The relationships of three measurements of the factor VIII/von Willebrand factor (VWF) complex (factor VIII activity, FVIIIc (one-stage assay); VWF antigen, VWF Ag (ELISA); and VWF activity, VWF act, measured by a recently-developed ELISA) to major ischaemic heart disease (IHD) events were studied in 1997 men aged 49-65 years, in the second phase of the Caerphilly Heart Study. These variables were related using logistic regression analysis to myocardial infarction or IHD death, which occurred in 129 men during an average follow-up period of 61 months. All three measurements were highly correlated (r = 0.63-0.77), and each was significantly associated with incident major IHD on univariate analyses (relative odds in highest fifth compared to lowest fifth, 1.68-1.90; P = 0.028-0.006) and on multivariate analyses adjusting for major IHD risk factors and for baseline IHD. Neither FVIIIc nor VWF act was significantly related to incident IHD following adjustment for VWF Ag. We therefore suggest that the associations between these three measurements of the factor VIII/VWF complex and incident IHD might have at least three explanations: VWF Ag is a marker of arterial endothelial disturbance; VWF act promotes platelet adhesion/aggregation and hence the platelet component of arterial thrombosis; and FVIIIc promotes fibrin formation and hence the fibrin component of arterial thrombosis.

Enzyme-Linked Immunosorbent Assay↗

PubMed1976

[Treatment of haemophilia with factor VIII inhibitor by giving isoagglutinin-free factor VIII concentrate (author's transl)].

Two nine-year-old boys with haemophilia A and circulating inhibitor against factor VIII were given large doses of commercial AHG concentrates to control bleeding. But the isoagglutinins in the AHG concentrates caused haemolysis in both patients. When AHF (Immuno) from AB donors - a cryoprecipate without isoagglutinins - was used no further inhibitor activity was detectable, previously observed anaphylactoid reactions no longer occurred and usual doses of AHG were now sufficient to control bleeding.

Child↗

PubMed1981

HLA antigens and factor VIII antibody in classic hemophilia. European study group of factor VIII antibody.

Possible interrelations between the immune response factor VIII and the major histocompatibility system were investigated in 57 multi-transfused hemophilic brothers belonging to 26 families. Linkage appears very unlikely although formal proof of independence cannot be offered. The HLA system, therefore, does not provide markers predictive for the development of antibodies to factor VIII in severe hemophilia A.

Factor VIII↗

PubMed2006

Mechanisms of plasmin-catalyzed inactivation of factor VIII: a crucial role for proteolytic cleavage at Arg336 responsible for plasmin-catalyzed factor VIII inactivation.

Plasmin not only functions as a key enzyme in the fibrinolytic system but also directly inactivates factor VIII and other clotting factors such as factor V. However, the mechanisms of plasmin-catalyzed factor VIII inactivation are poorly understood. In this study, levels of factor VIII activity increased approximately 2-fold within 3 min in the presence of plasmin, and subsequently decreased to undetectable levels within 45 min. This time-dependent reaction was not affected by von Willebrand factor and phospholipid. The rate constant of plasmin-catalyzed factor VIIIa inactivation was approximately 12- and approximately 3.7-fold greater than those mediated by factor Xa and activated protein C, respectively. SDS-PAGE analysis showed that plasmin cleaved the heavy chain of factor VIII into two terminal products, A1(37-336) and A2 subunits, by limited proteolysis at Lys(36), Arg(336), Arg(372), and Arg(740). The 80-kDa light chain was converted into a 67-kDa subunit by cleavage at Arg(1689) and Arg(1721), identical to the pattern induced by factor Xa. Plasmin-catalyzed cleavage at Arg(336) proceeded faster than that at Arg(372), in contrast to proteolysis by factor Xa. Furthermore, breakdown was faster than that in the presence of activated protein C, consistent with rapid inactivation of factor VIII. The cleavages at Arg(336) and Lys(36) occurred rapidly in the presence of A2 and A3-C1-C2 subunits, respectively. These results strongly indicated that cleavage at Arg(336) was a central mechanism of plasmin-catalyzed factor VIII inactivation. Furthermore, the cleavages at Arg(336) and Lys(36) appeared to be selectively regulated by the A2 and A3-C1-C2 domains, respectively, interacting with plasmin.

Arginine↗

PubMed2005

The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels.

Elevated factor VIII (FVIII) levels are a recognized risk factor for venous thrombosis. Recently, family studies suggested that the G allele of the 3951C/G (D1241E) FVIII polymorphism is associated to lower FVIII activity. We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change. Among 145 healthy and 150 thrombotic women, not carriers of known thrombophilic defects, the 1241E allele was associated with 11% reduced (t-test, P<0.05) FVIII levels. The effect on activated protein C sensitivity ratio was not statistically significant. Carriership of the 1241E allele, potentially conferring protection from thrombosis, was found in 22.8% of controls and in 15.3% of cases. In an additional cohort of factor V Leiden carriers (n=283), carriership of the 1241E allele was 25.2% among 143 asymptomatic subjects and 17.1% among 140 thrombotic patients. Our data do not indicate a specific interaction with factor V Leiden. These genotype distributions suggest a mild protective effect from venous thrombosis conferred by 1241E FVIII, masked by other genetic and/or environmental components, and detectable only in very large population studies. Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors.

Activated Protein C Resistance↗

PubMedDate not supplied

Methods of assessing factor VIII content of stored fresh frozen plasma intended for preparation of factor VIII concentrates.

Minimally destructive methods were sought to assess the factor VIII content of fresh frozen plasma intended for large-scale fractionation and stored in five-liter polyethylene packs after pooling approximately 23 plasma donations. Although factor VII distribution in the frozen pack was not perfectly homogenous, a central "core" through the frozen pack gave a representative sampel of the entire contents of the pack. Coring was compared with other methods of pack sampling before large-scale cryoprecipitation. The survival of factor VIII was studied in three grades of stored plasma which had been separated and frozen within 4 hours, 8 hours, and 18 hours of blood donation. Plasma frozen after overnight storage of blood is a satisfacory starting material for the preparation of factor VIII and factor IX concentrates.

Blood Banks↗

PubMed1987

A component of factor VIII preparations which can be separated from factor VIII activity down modulates human monocyte functions.

In this study we investigated different aspects of monocyte functions following interaction of monocytes (Mo) with therapeutic concentrations of factor VIII (F VIII) concentrate. A short (one-hour) treatment of normal Mo with F VIII concentrates led to a significant (P less than 0.001) down modulation of Fc receptors expressed in the Mo plasma membrane. This down modulation was accompanied by a decrease of Mo effector functions that was expressed by a reduced capacity of F VIII-treated Mo to release O2 radicals (40% of controls) and to kill bacteria (% killing: control Mo, 65%; F VIII-treated Mo, 24% to 51%). Further studies showed that the modulating activity was due to a contaminant present in F VIII concentrates (immune complexes or IgG aggregates). Fractionation using molecular sieving revealed that the modulatory activity was confined to a high-molecular range fraction (Mr greater than 1,270,000 daltons), while the fraction containing monomeric IgG had no effect. Further fractionation by affinity chromatography on protein A-Sepharose separated the coagulation activity (effluent) from the Mo function-modulating activity (eluate). We conclude that treatment with F VIII concentrates might contribute to an immunocompromised state in some hemophiliacs and facilitate opportunistic infections in these patients.

Antigen-Antibody Complex↗

PubMed1988

Normal response of factor VIII and von Willebrand factor to 1-deamino-8D-arginine vasopressin in nephrogenic diabetes insipidus.

The effects of 1-deamino-8D-arginine vasopressin (DDAVP) on plasma factor VIII and von Willebrand factor (vWF) levels were studied in four patients with nephrogenic diabetes insipidus (NDI) from two unrelated families. While the urine osmolality remained low, the plasma levels of factor VIII and vWF rose 2- to 3-fold after infusion of 0.3 micrograms/kg DDAVP, compared to preinfusion levels. The degree of increase was similar in both NDI patients and normal subjects. We conclude that in NDI patients the end-organ resistance to DDAVP is confined to the kidneys and does not involve the sites from which factor VIII and vWF are released.

Adult↗

PubMed2001

Domain specific monoclonal anti-factor VIII antibodies generated by inclusion body-renatured factor VIII peptides.

Production of monoclonal anti-factor VIII (FVIII) antibodies was hampered by the availability of FVIII proteins devoid of albumin and the von Willebrand factor (vWF). We showed a successful way to generate domain specific anti-FVIII antibodies by using a series of Escherichia coli expressed FVIII fusion peptides. A total of eight fusion peptides were synthesized to cover almost the entire coding region of FVIII. All except one of the fusion peptides were insoluble and became aggregated as inclusion bodies. Purification and refolding of the peptides were accomplished by solublizing them with denaturants and dialyzing them in appropriate buffers, this being followed by chromatography of the refolded fractions on a metal-ion chelating column. These purified FVIII fusion peptides were used individually or as a pool to immunize mice and generate antibodies. Three monoclonal antibodies, D2, E6 and B12, were obtained. D2 recognizes a region (residues 1680-1703) of the light chain of FVIII, E6 recognizes a fragment (residues 744-1021) in the heavy chain, and B12, the A1 domain (residues 89-326). Both D2 and B12 inhibited >80% FVIII function. The affinities (k(A)) of the antibodies for FVIII were 1.62x10(7) M(-1) for D2 and 2.2x10(8) M(-1) for E6. Although B12 is inhibitory, it did not show a strong binding affinity with FVIII. The specificity of D2 and E6 for FVIII was demonstrated by immunoprecipitation of the FVIII protein in full-length recombinant FVIII (rFVIII) supplemented FVIII-deficient plasma, but not in FVIII-deficient plasma alone. An enzyme-linked immunosorbant assay (ELISA) using D2 or E6 was designed to detect plasma FVIII. The system may be useful in monitoring FVIII in cultured supernatants and in mouse models for gene therapy experiments.

Animals↗