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PubMed1987

Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation.

We have extended earlier studies (Blood 66:204, 1985) of a mechanism of inhibition of factor VIIa/tissue factor activity that requires a plasma component (called herein extrinsic pathway inhibitor or EPI) and factor Xa. An activated peptide release assay using 3H-factor IX as a substrate was used to evaluate inhibition. Increasing the tissue factor concentration from 20% to 40% (vol/vol) overcame the inhibitory mechanism in normal plasma but not in factor VII-deficient plasma supplemented with a low concentration of factor VII. A second wave of factor IX activation obtained by a second addition of tissue factor to plasma with a normal factor VII concentration was almost abolished by supplementing the reaction mixture with additional EPI and factor X. Factor Xa's active site was necessary for factor Xa's contribution to inhibition, but preliminary incubation of factor Xa with EPI in the absence of factor VIIa/tissue factor complex or of factor VIIa/tissue factor complex in the absence of EPI did not replace the need for the simultaneous presence of factor Xa, factor VIIa/tissue factor, calcium, and EPI in an inhibitory reaction mixture. Inhibition of factor VIIa/tissue factor was reversible; both tissue factor and factor VIIa activity could be recovered from a dissociated, inhibited factor VIIa/tissue factor complex. EPI appeared to bind to a factor VIIa/tissue factor complex formed in the presence of factor Xa but not to a factor VIIa/tissue factor complex formed in the absence of factor Xa.

Blood Coagulation↗
PubMed1997

[Effect of thrombolytic agents on platelets and blood coagulation system].

The effect of tissue-type plasminogen activator (tPA) on platelet aggregation and blood coagulation was investigated. Collagen-induced platelet aggregation in washed platelet suspension was significantly inhibited by the addition of tPA, but the effect was limited when platelet rich plasma was used instead of washed platelets because of the presence of alpha 2-antiplasmin in plasma. The diluted prothrombin time was significantly shortened by the addition of tPA to normal plasma, and although the levels of molecular markers of thrombin formation were increased compared to that of normal controls, the increase was diminished when factor VII-deficient plasma was used, suggesting that tPA enhances factor VII. The activated factor VII concentration was significantly increased by the addition of plasmin to factor VII solution. These findings suggest that tPA enhances the coagulation system by factor VII activation through the generation of plasmin in normal plasma. This enhancing effect of tPA on coagulation system may be partly related to vascular reocclusion after thrombolytic therapy.

Blood Coagulation↗
PubMed1987

Preliminary characterization of the procoagulant material in human ascites.

Disseminated intravascular coagulation invariably accompanies placement of peritoneovenous (LeVeen) shunts, which suggests that ascitic fluid contains procoagulant material capable of activating blood coagulation. In this study, we identified thrombogenic activity in human ascites and the hemostatic pathway by which it acts. Peritoneal fluid was removed percutaneously from patients with ascites due to various causes. Four fractions were prepared by centrifugation: cells, a low-speed, cell-free fluid, a high-speed supernatant, and the precipitate from the high-speed centrifugation. Cellular fractions from all ascitic fluids shortened a one-stage clotting time of normal pooled plasma by 68% in comparison with saline solution and endotoxin controls. Similarly, the cell-free fluids also shortened the clotting time of normal pooled plasma by 41%. The cellular and cell-free fractions shortened the clotting time of factor VIII-deficient plasma but failed to demonstrate procoagulant activity in factor VII-deficient plasma. These fractions had no effect on platelet aggregation or the platelet release reaction. The high-speed precipitate was dissociated by ethylenediaminetetra-acetate (EDTA) into fluid phase and precipitate, both of which demonstrated procoagulant activity. Furthermore, high-speed precipitate contained protein, phospholipid, and sterol in proportions similar to those of plasma membranes and contained membrane-bound vesicles as identified by means of electron microscopy. This material could be rendered inactive by heating to 100 degrees C for 2 minutes or by incubation with phospholipase C for 15 minutes. Finally, the ability of the high-speed precipitate to shorten the clotting time was prevented by preincubation with a monoclonal antibody, which is known to inhibit the procoagulant activity of human tissue factor. We suggest that several entities contribute to the procoagulant properties of human ascites, with procoagulant material deriving at least in part from peritoneal cells. The sedimentable procoagulant factor appears to be associated with cellular membranes or membrane fragments and is thromboplastin-like in its chemical composition, immunoreactivity, and substrate specificity.

Adult↗
PubMed1993

Procoagulant activity of the MC28 fibrosarcoma cell line in vitro and in vivo.

Experimental evidence suggests that many tumours can activate blood coagulation and that such interaction is part of the pathology of metastatic tumour growth. This study aimed to study the procoagulant activity of the methylcholanthrene-induced (MC28) fibrosarcoma to determine whether coagulation activation by these cells could explain the previously reported effects of oral anticoagulants on lung seeding in this model. MC28 cells shortened the recalcification times of normal and factor VII-deficient plasma and directly activated factor X in a chromogenic assay, but did not aggregate platelets in vitro in either whole blood or platelet-rich plasma. Cellular coagulant activity was calcium-dependent, blocked by DFP and concanavalin A but not inhibited by iodoacetamide, E-64 or antibodies to human tissue factor or factor VII. Injection of viable MC28 cells into hooded Lister rats induced a decrease in platelet count (P < 0.001), plasma factor X (P < 0.001) and fibrinogen (P < 0.05) and a marked increase in plasma haemoglobin (P < 0.001). These effects were either not observed or were considerably less marked in heparinized or warfarinized animals. Injection of MC28 cells treated with concanavalin A in vitro completely abolished the clotting changes observed with untreated cells. In conclusion, MC28 cells possessed a potent factor X-activating serine proteinase procoagulant in vitro, which had some of the characteristics of a tissue factor/factor VIIa complex. In vivo, MC28 cells caused clotting activation and intravascular fibrin generation. Since thrombocytopenia was abolished by heparin and the cells lacked platelet aggregating activity in vitro, thrombocytopenia was probably secondary to intravascular coagulation and thrombin generation. The trigger for intravascular clotting activation appeared to be the cellular procoagulant activity since it was abolished by prior in vitro blockade of the latter with concanavalin A.

Animals↗
PubMed2006

The impact of tissue factor pathway inhibitor on coagulation kinetics determined by thrombelastography.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is a 40-kDa, endogenous protein that inhibits tissue factor (TF)-initiated coagulation by bonding with activated factor X (FXa). The TFPI/FXa complex then subsequently binds with TF/activated factor VII (FVIIa) complex, ultimately inhibiting thrombin generation. Heparin administration causes endothelial release of TFPI concentrations up to sixfold normal values. Thrombelastography (TEG) is often used to monitor hemostasis in the perioperative period, and TFPI could potentially affect the diagnostic interpretation of TEG-based data, given its inhibition of both common and TF coagulation pathways. Thus, in this study we characterized the effect of TFPI on coagulation kinetics via TEG. METHODS: Whole blood, Factor VII-deficient plasma, and normal plasma were exposed in vitro to various concentrations of TFPI, after which unmodified, celite-activated, and TF-activated TEG were performed. RESULTS: The addition of 87.5 ng/mL TFPI (twice normal concentration) was required to prolong clot propagation in whole blood, with propagation and strength only significantly affected by the addition of 175 ng/mL concentrations. Experiments with Factor VII-deficient plasma demonstrated that TFPI-mediated suppression of coagulation kinetics at these concentrations was secondary to FXa inhibition. Celite activation markedly attenuated TFPI-mediated effects on coagulation kinetics, whereas TF activation accentuated TFPI-mediated prolongation of clot initiation and diminution of propagation. CONCLUSIONS: In settings involving heparin administration (e.g., cardiopulmonary bypass), TFPI-mediated inhibition of coagulation should be considered during TEG-based hemostatic monitoring.

Blood Coagulation↗
PubMed1992

Congenital protein C deficiency and myocardial infarction:concomitant factor VII hyperactivity may play a role in the onset of arterial thrombosis.

A 29-year-old man with congenital protein C deficiency and acute myocardial infarction is reported. Four hours after the onset of chest pain, he was treated intravenously with tissue-type plasminogen activator. Subsequent coronary angiography revealed only slight stenosis of the left anterior descending coronary artery without any atherosclerosis. The propositus, his brother, and his mother, showed low levels of both protein C activity and antigen, while plasma thrombomodulin levels were normal. His grandfather had died from acute myocardial infarction at 38 years of age. We investigated several other risk factors for arterial thrombosis, including factor VII, fibrinogen, heparin cofactor II, lipoprotein (a), and anticardiolipin antibodies. No other haemostatic abnormalities apart from factor VII hyperactivity were detected in this family. To study the effects of protein C and factor VII on procoagulant activity, prothrombin time was measured after the addition of activated protein C and factor VII to protein C-deficient plasma. The prothrombin time ratio decreased along with an increase in the factor VII level. It also decreased with a decrease in the activated protein C level. These findings indicated that the procoagulant activity of factor VII was enhanced by low protein C levels, suggesting that concomitant factor VII hyperactivity may cause acute myocardial infarction in patients with protein C deficiency.

Adult↗
PubMed1997

Coagulation factor abnormalities after the Fontan procedure and its modifications.

OBJECTIVE: Recently we reported the prevalence of thromboembolism in patients who underwent the Fontan procedure and its modifications. Although hemodynamic factors may well contribute to thromboembolism, recent evidence suggests that coagulation factor abnormalities may also play a role. We therefore set out to investigate the coagulation status in a group of patients who had undergone the Fontan procedure. METHODS: The study population consists of 20 children who had undergone the Fontan procedure and its modifications. They were examined for coagulation factor abnormalities. Concentrations of serum albumin, total protein, and liver enzymes were also measured. The median age at the time of the operation was 6.2 years (17 months to 8 years) with a male/female ratio of 2.3:1. The median time from the Fontan repair was 4.9 years (18 to 76 months). RESULTS: Protein C (p < 0.001), protein S (p < 0.02), and factor VII (p < 0.001) were significantly lower than the normal range. The changes in serum albumin and total protein and factors II, IX, and X were not significant. CONCLUSIONS: It is possible that deficiency in protein C, protein S, and factor VII partly account for the prevalence of thromboembolism after Fontan-type repairs. The risk of long-term anticoagulation should be weighed against the best palliative procedure for these patients. We suggest that reduced protein C, protein S, and factor VII levels in this group of patients should be regarded as risk factors and that such patients should be treated with anticoagulants.

Child↗
PubMed2004

A patient homozygous for a Gly354Cys mutation in factor VII that results in severely impaired secretion of the molecule, but not complete deficiency.

We investigated the molecular basis of factor VII (FVII) deficiency in a Japanese woman who suffered occasional epistaxis. The patient had low levels of both FVII coagulant activity (FVII:C) and antigen (FVII:Ag) (5.0% and 7.3% of normal controls respectively). DNA sequence analysis of the FVII gene showed that the patient was homozygous for a mutation that resulted in a Cys for Gly354 substitution, a novel missense mutation in the catalytic domain. Haplotype analysis showed that this missense mutation was inherited from her consanguineous parents. Transient expression experiments showed that secreted FVII Cys354, FVII:C and FVII:Ag levels in conditioned media were reduced to 4% and 5%, respectively, of levels secreted from wild-type FVII. However, the intracellular FVII Cys354 was 67% that of normal recombinant protein. Immunohistochemical analysis showed that intracellular FVII:Ag from FVII 354Cys was present diffusely throughout the cytoplasm. Substitution of FVII 354Gly with amino acids other than Cys (Arg, Asp, Ser and Phe), did not produce a phenotype similar to FVII Cys354Gly. Molecular modelling indicated that FVII Gly354 was located outside the FVII heavy chain, and that Cys135 in the EGF2 domain, Cys262 in the catalytic domain and Cys127 all exist within 10 A of Gly354. Therefore, we propose that the introduction of an additional free cysteine residue in the FVII molecule results in the formation of illegitimate disulphide bonds and a mis-folded domain, leading to defective secretion.

Adult↗
PubMed1980

A factor VII concentrate for therapeutic use.

A concentrate of factor VII suitable for therapeutic use has been prepared from human plasma by a method forming part of a comprehensive scheme of large-scale plasma fractionation. Factor VIII was separated as cryoprecipitate and factors II, IX and X were adsorbed on DEAE-cellulose. Most of the factor VII remained in the supernatant. By batch adsorption on DEAE-Sepharose, followed by elution on a chromatographic column, factor VII was concentrated about 25-fold, and purified about 50-fold compared with original plasma, without the need for further dialysis or concentration steps. Data are presented from 10 batches, each from 80-120 kg plasma. Following doses of factor VII to six congenitally deficient patients, the mean rise in plasma factor VII was 95-100% of theoretical; the half-disappearance time was about 4 h. The treatment of four patients with acquired deficiency of factor VII is also described. No untoward side effects were observed.

Adult↗
PubMed1984

Congenital deficiency of vitamin K-dependent coagulation factors and protein C.

A 15-month-old girl from Coimbra (Portugal) had a history of numerous hemorrhagic episodes with multiple bruises, hematomas but not hemarthroses. On serial testing she showed deficiency of factors II, VII, IX, X and protein C. Malabsorption-induced vitamin K deficiency, liver disease or ingestion of a coumarin compound were excluded. An absence of detectable abnormalities was found among her relatives. Consanguinity was not present. The immunologic assay, immunoelectrophoresis or antibody neutralization, revealed much higher levels of these factors than the clotting assay. The non-physiological activator (Echis carinatus venom) produced higher levels of prothrombin activation than those detected by physiological activation. Two-dimensional immunoelectrophoresis of the patient's plasma in calcium showed that prothrombin had the same mobility as acarboxyprothrombin. No significant response to large doses of intravenous vitamin K3 (6 mg) was observed. Transfusion of 120 ml of frozen fresh plasma led to an immediate increase in the procoagulant activities of vitamin K dependent protein, similar to that found after perfusion of plasma plus vitamin K3. The results obtained from this patient suggest a defect in the gammacarboxylation mechanism inside the hepatocyte.

Blood Coagulation Disorders↗
PubMed1992

Enzyme-linked immunosorbent assay of human factor VII based upon a monoclonal antibody that recognizes the native conformation of the protein.

An enzyme-linked immunoassay (ELISA) was developed for measuring human factor VII antigen using two monoclonal antibodies, one of them reacting only with fully carboxylated factor VII. This assay permits to measure factor VII antigen in concentrations ranging from 0.78 to 100 ng/ml, with within- and between-assay coefficients of variation of less than 7%. In 53 normal subjects, 32 patients with liver cirrhosis, 21 pregnant women and 53 patients on oral anticoagulant therapy the plasma levels of FVII antigen were very similar to those of factor VII coagulant activity measured with a bioassay. The ELISA also gave very similar values of factor VII antigen in plasma and in serum, and in plasma before and after exposure to cold, indicating that the assay is not affected by factor VII activation. In five of 8 patients with severe congenital deficiency of factor VII values of factor VII antigen were higher than those of factor VII activity. The close concordance of factor VII values obtained by ELISA and bioassay in the majority of plasmas, including those from patients on oral anticoagulant therapy, indicates that the assay measures native factor VII and can perhaps replace the bioassay systems in clinical conditions associated with normal or high levels of factor VII.

Adult↗
PubMed1999

Characterization of two naturally occurring mutations in the second epidermal growth factor-like domain of factor VII.

We investigated the mechanisms responsible for severe factor VII (FVII) deficiency in homozygous Italian patients with either Gly97Cys or Gln100Arg mutations in the second epidermal growth factor domain of FVII. Transient expression of complementary DNA coding for the mutations in COS-1 cells showed impaired secretion of the mutant molecules. Using stably transfected Chinese hamster ovary (CHO) cells, we performed pulse-chase labeling studies, immunohistochemistry, and experiments with inhibitors of protein degradation, showing that FVII-Cys97 did not accumulate intracellularly but was degraded in a pre-Golgi, nonlysosomal compartment by a cysteine protease. In stably transfected CHO cells expressing FVII-Arg100, the level of intracellular FVII was not increased by several inhibitors of protein degradation, but FVII-Arg100 was retained in the endoplasmic reticulum for a longer period of time than wild-type FVII. FVII-Arg100 had a lower apparent molecular weight than did wild-type FVII under nondenaturing conditions, which is attributable to misfolding due to abnormal disulfide bond formation.

Animals↗
PubMed2006

Intracellular readthrough of nonsense mutations by aminoglycosides in coagulation factor VII.

BACKGROUND: Nonsense mutations in coagulation factor (F) VII potentially cause a lethal hemorrhagic diathesis. Readthrough of nonsense mutations by aminoglycosides has been studied in a few human disease models with variable results. OBJECTIVES: We investigated the K316X and W364X FVII mutations, associated with intracranial hemorrhage, and their correction by aminoglycosides. The rare nonsense mutations in FVII represent favorite models to test this strategy, because even tiny increases in the amount of functional full-length protein in patients could ameliorate hemorrhagic phenotypes. RESULTS: A FVII-green fluorescent protein (GFP) chimaera provided us with a fluorescent model of FVII expression in living cells. Appreciable fluorescence in cells transfected with nonsense FVII-GFP mutants was detected upon geneticin treatment, thus demonstrating suppression of premature translation termination. To investigate the rescue of FVII function, nonsense variants of the native FVII without GFP (p316X-FVII and p364X-FVII) were transfected and found to secrete low amounts of FVII (approximately 1% of Wt-FVII activity), thus suggesting a spontaneous stop codon readthrough. Geneticin treatment of cells resulted in a significant and dose-dependent increase of secreted FVII molecules (p316X-FVII, 24 +/- 12 ng mL(-1), 3.6 +/- 0.8% of Wt-FVII activity; p364X-FVII, 26 +/- 10 ng mL(-1), 3.7+/-0.6%) characterized by reduced specific activity, thus indicating the synthesis of dysfunctional proteins. Similar results were observed with gentamicin, a commonly used aminoglycoside of potential interest for patient treatment. CONCLUSIONS: Our approach, extendable to other coagulation factors, represents an effective tool for a systematic study of the effects of aminoglycosides and neighboring sequences on nonsense codon readthrough. These results provide the rationale for a mutation-specific therapeutic approach in FVII deficiency.

Adolescent↗
PubMed1992

Evidence that an Arg79-->Gln substitution in human factor VII is not associated with a reduction in coagulant activity.

A recent report hypothesized that an Arg79-->Gln mutation in the first epidermal growth factor-like domain of human factor VII is the molecular basis for a severe (< 1%) factor VII functional deficiency. In the present study, a site-specific mutant human factor VII cDNA (Arg79-->Gln) was constructed, subcloned and expressed in baby hamster kidney cells. Mutant factor VII was purified to homogeneity and characterized with respect to gamma-carboxyglutamic acid content, ability to activate, tissue factor-dependent amidolytic activity and expression of factor VIIa proteolytic activity on tissue factor-bearing cells. Mutant factor VII was fully carboxylated and exhibited the same molecular weight and coagulant activity as plasma factor VII. Mutant factor VII was activated by factor Xa at the same rate, and to the same extent, as plasma factor VII. In the presence of tissue factor, mutant factor VII was converted to factor VIIa in an autocatalytic manner at a rate indistinguishable from that observed with plasma factor VII. In addition, the amidolytic activities of mutant factor VIIa and plasma factor VIIa towards S-2288 in the presence of relipidated tissue factor were identical. Finally, following complex formation with cell surface tissue factor, mutant factor VIIa activated factor X at essentially the same rate as plasma factor VIIa under comparable conditions. These results are not consistent with the notion that the arginine-79 residue in the first epidermal growth factor-like domain of human factor VII is essential for the expression of tissue factor-dependent factor VIIa proteolytic activity.

Animals↗
PubMed1997

Factor VII Toyama (Thr 359 Met): a homozygous missense mutation causing severe type I deficiency.

We performed a DNA analysis on a patient with severe type I factor VII deficiency by the polymerase chain reaction amplification and a direct DNA sequencing method. The proband was a 66-year-old Japanese woman who had recurrent episodes of excessive bleeding after dental extraction. The functional and antigenic levels of plasma factor VII markedly reduced to 1.6% and 2% of normal, respectively. However, she had no serious symptoms such as intracranial or intraarticular hemorrhage. The analysis revealed that the patient was homozygous for a missense mutation, Thr (ACG) to Met (ATG) at codon 359 in the catalytic domain. Her deceased parents were first cousins, and their consanguineous marriage presumably resulted in the homozygosity in her. This patient was the first case of homozygote for the Thr359Met mutation, though heterozygotes for the mutation were previously found in an Italian family.

Adult↗
PubMedDate not supplied

Coagulation abnormalities in type 1 Gaucher disease in children.

Gaucher disease is the most prevalent inherited lysosomal storage disorder caused by deficiency of beta-glucocerebrosidase enzyme. Clinically, 3 forms of Gaucher disease are recognized, of which type 1 is the mild to moderately severe, slowly progressive, nonneuropathic form. Bleeding disorders in Gaucher disease are believed to be due to thrombocytopenia but there may be additional factors that influence coagulation and fibrinolysis in Gaucher disease patients. The aim of the present work was to study some coagulation parameters in the Egyptian children with type 1 Gaucher disease. Five newly diagnosed patients and another 5 patients on enzyme replacement therapy (ERT) were enrolled in the study. Their coagulation profile, including coagulation factors, was evaluated. The results showed that in newly diagnosed cases factors II and VII were deficient in 40%, factor V was deficient in 20%, and all the cases had low levels of serum fibrinogen. In patients on ERT, factors VII and VIII were deficient in 60%, factor XI was deficient in 40% and factors V, X, and XII were deficient in 20% of cases. In conclusion, Egyptian patients with type 1 Gaucher disease, whether newly diagnosed or receiving enzyme replacement therapy, experience coagulation factor abnormalities regardless the clinical expression of bleeding diathesis. This should be taken into consideration before these patients are subjected to surgery for, e.g., splenectomy, which is common in these patients.

Blood Coagulation Disorders↗