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PubMed1985

Deficiency of fibrinogen and factor VII following treatment of severe aplastic anaemia with anti-thymocyte globulin and high-dose methylprednisolone.

In 4 patients with SAA treated with ATG and high-dose MP, an as yet unrecognized acquired deficiency of fibrinogen and factor VII was observed. The plasma level of fibrinogen fell to 39% (34-51%) and of factor VII:C to 50% (31-55%) of the pretreatment value. The nadirs were between days 10 and 35 (fibrinogen) and d 3 and 11 (factor VII) after the 1st dose of ATG/MP. From additional clotting studies it is concluded that disseminated intravascular coagulation, fibrinolysis, liver cell damage and synthesis of abnormal clotting factors are unlikely causes of these clotting abnormalities. The most probable explanation seems to be a selective inhibition of the synthesis of fibrinogen and factor VII by an as yet unknown mechanism. These clotting abnormalities might, to some extent, increase the bleeding tendency in these patients, which up to now had been solely attributed to thrombocytopenia.

Adult↗
PubMedDate not supplied

White cell-associated procoagulant activity induced by ABO incompatibility.

BACKGROUND: Disseminated intravascular coagulation is an established complication of acute hemolytic transfusion reactions, particularly those involving the ABO red cell (RBC) antigen system. In addition, peripheral blood white cells, particularly monocytes, have demonstrated expression of procoagulant activity (PCA) in response to inflammatory stimuli. To better define the activation of coagulation in immune hemolysis, in vitro experiments were conducted to investigate the expression of PCA by peripheral blood white cells in ABO RBC incompatibility. STUDY DESIGN AND METHODS: Fresh group O heparinized whole blood was incubated with washed, packed group A or O RBCs. White cells were separated, washed, and lysed before assay of PCA, which was measured by a one-stage recalcified clotting time assay. Units of activity were calculated on the basis of a rabbit brain thromboplastin standard curve. Mechanisms of coagulation activation were investigated by using specific coagulation factor-deficient plasmas, blocking antibodies to tissue factor, and anti-CD11b. RESULTS: Significant levels of white cell-associated PCA were found at 2 to 6 hours in response to incompatible (group A) RBCs, but not in response to compatible (group O) RBCs. PCA was not correlated with numbers of platelets in whole blood. Nonimmune lysis of compatible RBCs did not induce PCA. When whole blood reconstituted from washed cells and heat-inactivated plasma was incubated with incompatible RBCs, PCA and hemolysis were abrogated, which suggests that complement is a required intermediate. Protein synthesis inhibition by the addition of cycloheximide (5 mg/mL) to whole blood incubated with RBCs prevented the expression of PCA. Substitution of factor VIII-deficient plasma for normal plasma in the recalcified clotting time assay had no effect, whereas PCA was reduced by 68 percent with factor VII-deficient plasma and was unmeasurable with factor X-deficient plasma. PCA was restored by a 1-to-1 mix of normal and factor VII-deficient plasma. Incubation of samples in the PCA assay with tissue factor antibodies resulted in up to 86-percent inhibition of measured PCA. Titration of the response to the amount of tissue factor antibodies added demonstrated that maximal inhibition occurred with 0.45 mg per mL, above which no further inhibition took place. However, the addition of anti-CD11b (0.75 mg/mL) concomitantly with anti-tissue factor abolished measurable activity. This effect was independent of the amount of added protein, and anti-CD11b alone had no effect on measured activity. The addition to whole blood concomitantly with RBCs of polyclonal antibodies to tumor necrosis factor, sufficient to neutralize 2000 pg per mL, did not alter PCA expression. CONCLUSION: These results indicate that white cell-associated PCA is generated in whole blood in response to ABO RBC incompatibility and may contribute to disseminated intravascular coagulation in acute hemolytic transfusion reactions. Two possible cellular mechanisms are suggested, which involve tissue factor expression and the activation of factor X by a CD11b-dependent mechanism.

ABO Blood-Group System↗
PubMed1960

The possible relationship between the antiheparin activity of serum and thrombosis.

Stored serum reduces the anticoagulant effect of heparin on the clotting times of normal plasma. This is also well marked with sera from patients with Christmas (factor IX) deficiency, with factor VII-deficient sera, and in sera derived from patients treated with phenindione with a gross defect in thromboplastin generation. The possible relationship between antiheparin activity of serum and heparin resistance in recent thrombosis is discussed. The antiheparin agent resembles factor VII and Christmas factor in being present in excess in serum, adsorbed and subsequently eluted from alumina. Unlike these, however, it does not appear to be appreciably reduced by phenindione treatment. It appears to have some properties in common with those described for the thrombotic agent of serum described by Wessler and his colleagues. It may play a part in the increased coagulability associated with thrombosis from the release of serum products into the circulation, although its relationship to the production of thrombosis in man remains to be established.

Blood Coagulation↗
PubMed1996

A Thr359Met mutation in factor VII of a patient with a hereditary deficiency causes defective secretion of the molecule.

We elucidated the genetic basis responsible for factor VII deficiency in an Italian woman with a severe bleeding diathesis. In the allele inherited from the patient's father, we identified a G to A mutation at nucleotide 6070 at the 5' splice site of intron 4 and a G to A substitution at nucleotide 10976 resulting in the Arg353Gln polymorphism. The maternal allele demonstrated a C to T substitution at nucleotide 10994 resulting in Thr359Met. The mutation at nucleotide 6070 alters an invariant GT dinucleotide and disrupts normal mRNA processing. To investigate the mechanism by which Thr359Met reduces factor VIl levels, we expressed wild type factor VII cDNA (FVIIwt) and a mutant factor VII cDNA containing the base substitution resulting in Met359 (FVII359M) in Chinese hamster ovary cells (CHO). In cells transfected with the mutant factor VII cDNA, FVII359M accumulated intracellularly, and no factor VII was detected in the media after 3 hours of chase. The carbohydrate side chains associated with FVII359M were sensitive to Endo H digestion, which indicates that the protein is retained in the endoplasmic reticulum. Analysis of cell lysates also showed that FVII359M was associated with the 78 kD protein corresponding to GRP78/BiP. We conclude that a Thr359Met mutation in factor VII results in a severe secretion defect that probably results from abnormal folding of the molecule.

Adult↗
PubMed1985

Monoclonal anti-human factor VII antibodies. Detection in plasma of a second protein antigenically and genetically related to factor VII.

Several murine monoclonal anti-human Factor VII antibodies were produced using hybridoma technology. Two noncompetitive monoclonal antibodies were used to examine by Western blotting the Factor VII cross-reactive material (CRM) in normal human plasma and three commercially available congenitally Factor VII-deficient plasmas, and to construct a facile "sandwich" immunoassay for plasma Factor VII. A second, previously undescribed, form of Factor VII CRM was detected in human plasma, which on Western blotting stained with an apparent intensity 5-8% that of Factor VII. This glycoprotein, tentatively called VII*, has a molecular weight 4,500 D less than Factor VII, lacks detectable Factor VII functional activity, does not bind to barium citrate, and is not recognized by a monoclonal antibody that recognizes Factor VII but not alpha-chymotrypsin-treated Factor VII. VII* was not proteolytically produced from Factor VII during in vitro coagulation or after infusion of human Factor VII into rabbits. As determined by Western blotting, the human hepatoma cell line, HepG2, cultured in the presence of vitamin K, secreted relatively greater levels of VII* in proportion to VII (75%) than that found in human plasma. Warfarin treatment of HepG2 cells decreased the quantity of VII secreted by 77%, whereas it only inhibited the secretion of VII* by 14%. Immunologic studies of the plasmas from a patient on chronic warfarin therapy and an individual given a short course of high dose warfarin therapy corroborated the in vitro synthetic studies obtained with HepG2 cells. The data are consistent with the production of VII* by posttranslational, proteolytic, modification of VII, that, at least in the HepG2 cells studied, occurs intracellularly. However, other mechanisms for the production of VII*, in particular, alternative RNA splicing of the transcript from a single gene, cannot be excluded.

Animals↗
PubMed2000

Successful use of recombinant VIIa (Novoseven) and endometrial ablation in a patient with intractable menorrhagia secondary to FVII deficiency.

Menorrhagia is a well-recognized complication of inherited bleeding disorders. In the past, the only viable option for women who were unresponsive to medical therapy was hysterectomy. Endometrial ablation has been recently developed as an alternative therapy for these patients and is associated with decreased morbidity. We report the successful use of activated recombinant factor VII (FVIIa) and endometrial ablation in the treatment of excessive menstrual blood loss in a 34-year-old women with severe factor VII (FVII) deficiency. Recombinant FVIIa (40 microg/kg) was administered pre-operatively and every 6 h (20 microg/kg) for 24 h postoperatively. The procedure was uncomplicated with a 200 ml surgical blood loss. FVIIa was used because it allowed FVII replacement with a recombinant product and also has the ability to bind to tissue factor expressed at the site of vascular injury, resulting in site-specific thrombin generation. We believe that endometrial ablation with recombinant VIIa should be considered in patients with severe FVII deficiency and menorrhagia unresponsive to medical therapy.

Adult↗
PubMed2003

Coinheritance of Factor V (FV) Leiden enhances thrombin formation and is associated with a mild bleeding phenotype in patients homozygous for the FVII 9726+5G>A (FVII Lazio) mutation.

We investigated the role of thrombophilic mutations as possible modifiers of the clinical phenotype in severe factor VII (FVII) deficiency. Among 7 patients homozygous for a cross-reacting material-negative (CRM-) FVII defect (9726+5G>A, FVII Lazio), the only asymptomatic individual carried FV Leiden. Differential modulation of FVII levels by intragenic polymorphisms was excluded by a FVII to factor X (FX) gene haplotype analysis. The coagulation efficiency in the FV Leiden carrier and a noncarrier was evaluated by measuring FXa, FVa, and thrombin generation after extrinsic activation of plasma in the absence and presence of activated protein C (APC). In both patients coagulation factor activation was much slower and resulted in significantly lower amounts of FXa and thrombin than in a normal control. However, more FXa and thrombin were formed in the plasma of the patient carrying FV Leiden than in the noncarrier, especially in the presence of APC. These results were confirmed in FV-FVII doubly deficient plasma reconstituted with purified normal FV or FV Leiden. The difference in thrombin generation between plasmas reconstituted with normal FV or FV Leiden gradually decreased at increasing FVII concentration. We conclude that coinheritance of FV Leiden increases thrombin formation and can improve the clinical phenotype in patients with severe FVII deficiency.

Adult↗
PubMed1996

Characterisation of platelet aggregation induced by PC-3 human prostate adenocarcinoma cells and inhibited by venom peptides, trigramin and rhodostomin.

PC-3 cells, a metastatic human prostate adenocarcinoma line, caused dose-dependent platelet aggregation in heparinised human platelet-rich plasma (PRP). PC-3 tumour cell-induced platelet aggregation (TCIPA) was completely inhibited by hirudin (5 U/ml) and limited by increasing concentrations of apyrase. This TCIPA was unaffected by cysteine proteinase inhibition with E-64 (10 microM), but was limited by cell pretreatment with phospholipase A2. PC-3 cell suspension caused marked, dose-dependent decreases in plasma recalcification times using normal, Factor VIII-deficient and Factor IX-deficient, but not Factor VII-deficient, human plasma. This effect was potentiated in cell lysates, but was inhibited in intact cells preincubated with sphingosine. Overall, these data suggest that PC-3 TCIPA arises from PC-3 tissue factor activity expression. Trigramin and rhodostomin, RGD-containing snake venom peptides which antagonise the binding of fibrinogen to platelet membrane glycoprotein IIb-IIIa, prevented PC-3 TCIPA. Similarly, synthetic peptide GRGDS as well as monoclonal antibodies against platelet membrane glycoproteins IIb-IIIa and Ib prevented PC-3 TCIPA, which was unaffected by control peptide GRGDS. On a molar basis, trigramin (IC50, 0.11 microM) and rhodostomin (IC50, 0.03 microM) were approximately 5000 and 18000 times, respectively, more potent than GRGDS (IC50, 0.56 mM).

Adenocarcinoma↗
PubMed1979

Evidence that cells from experimental tumours can activate coagulation factor X.

The procoagulant activity of cells from some experimental tumours isolated in culture or in single-cell suspensions from ascitic fluid was investigated. Cells from Lewis lung carcinoma (primary and metastasis), Ehrlich carcinoma ascites and JW sarcoma ascites were able to shorten markedly the recalcification time of normal, Factor VIII- and Factor VII-deficient but not of Factor X-deficient human plasma. The same cells generated thrombin when mixed with a source of prothrombin and Factor X, absorbed bovine serum (as a source of Factor V), phospholipid and calcium chloride. Thrombin formation was not influenced by the presence of Factor VII. Cells from Sarcoma 180 ascites were completely inactive in both test systems. It is concluded that cells from some experimental tumours have the capacity to activate Coagulation Factor X directly. These findings suggest the existence of an alternative "cellular" pathway in the initiation of blood clotting distinct from both the intrinsic and extrinsic mechanisms.

Animals↗
PubMed2005

Potential predictors of bleeding risk in inherited factorVII deficiency. Clinical, biological and molecular criteria.

Due to the wide molecular and clinical heterogeneities of inherited factor VII (FVII) deficiency, consensus guidelines for management of this coagulation disorder are not currently well established. Therefore, potential clinical, plasmatic or genetic criteria, that could be predictive for bleeding tendency in this condition, have been evaluated. Genotypic criteria including FVII genotypes and thrombophilic mutations are of particular interest to better understand some of the variations observed in bleeding phenotypes but they are still poorly informative for the management of surgery in FVII-deficient patients. Up to now, no plasma parameters have been found to be reliable predictors of bleeding risk. Nevertheless, tissue factor and platelet pathways remain to be explored. Finally, clinical history appears to be the best predictor of bleeding risk after haemostatic challenges in inherited FVII deficiencies. Furthermore, the absence of history of bleeding or mild bleeding phenotypes including menorrhagia, bruises and epistaxis (not inducing iron deficiency anaemia or requiring blood substitutive treatment) could enable minor surgery to be performed in FVII-deficient patients without blood replacement therapy.

Consensus↗
PubMed1998

Characterization of a factor VII molecule carrying a mutation in the second epidermal growth factor-like domain.

A missense mutation at codon 100 in the second epidermal growth factor-like domain, resulting in Gln100-->Arg, was detected in 19 out of 21 available severely factor VII (FVII) deficient patients in Norway. Seventeen patients were homozygous, and the two remaining were compound heterozygotes. In the homozygous patients, FVII antigen was measured to 10-28%, and activity to 0.6-6.5% of that in normal pooled plasma. Recombinant FVII containing the mutation was expressed transiently in CHO cells to a mean antigen level of 57% of the wild type FVII protein, and with a specific activity of 6% of wild type. The mutant protein had a 14-fold reduction in affinity for tissue factor (TF), whereas binding of FX seemed unaffected. In line with the experimental data, molecular modelling of the mutation based on the coordinates of the tissue factor/FVIIa complex showed that substituting arginine for glutamine disrupts the interface between the catalytic and second epidermal growth factor-like domains.

Adolescent↗
PubMed1998

Effect of a novel covalent antithrombin-heparin complex on thrombin generation on fetal distal lung epithelium.

Respiratory distress syndrome is characterized by fibrin deposition in the lung. Fibrin adversely affects surfactant function and stimulates proliferation of fibroblasts. There is evidence that these properties may be important to the development of bronchopulmonary dysplasia. Despite successful initial treatment of neonatal respiratory distress syndrome with surfactant, the incidence of bronchopulmonary dysplasia has not decreased. In previous studies, it has been demonstrated that rat fetal distal lung epithelium (FDLE) possesses both procoagulant and anticoagulant properties. In this report, we have demonstrated (using factor VII-deficient plasma) that tissue factor is expressed on the FDLE surface and promotes thrombin generation. To regulate thrombin within this procoagulant environment, we have developed a novel anticoagulant, antithrombin-heparin covalent complex (ATH) that can be retained within the lung after intrapulmonary instillation. We have demonstrated that ATH was superior to antithrombin plus standard heparin in suppressing thrombin generation (P < 0.001) and prothrombin consumption (P < 0.01) in recalcified defibrinated plasma on the surface of FDLE. Further studies with ATH in vivo need to be performed.

Adult↗
PubMed2006

Arterial and venous thrombosis in rare congenital bleeding disorders: a critical review.

A thorough review of the literature and of personal files has allowed the gathering of 81 patients with rare congenital bleeding disorders and thrombotic phenomena. Sixteen of these patients had congenital afibrinogenemia, eight involved factor V deficiency, 20 factor VII defects, 33 factor XI deficiencies and only one, a factor XIII defect. Altogether 42 patients showed arterial thrombosis (myocardial infarction [MI] in 28 cases; ischemic stroke in 4; arterial occlusion in 8; 2 patients with disseminated intravascular coagulation (DIC)). Ages varied between 13 and 74. Twenty-two patients were males and 16 females. In four cases, sex was not reported. There were three fatalities: two after a MI and one because of heart failure. With regard to venous thrombosis: 9 patients had pulmonary embolism, 15 patients had deep vein thrombosis, 9 patients had both pulmonary embolism and deep vein thrombosis; 1 patient had superficial vein thrombosis, whereas, 5 cases had an unusual site venous thrombosis (two portal systems, two cerebral sinuses, one inferior vena cava) for a total of 39 cases. Age varied between 3 and 86. In this case, 20 patients were males and 17 were females. In two cases, sex was not reported. There were three fatalities: two because of pulmonary embolism and one because of inferior vena cava thrombosis. The fact that thrombosis has never been described in patients with factor II or factor X seems to underscore the central antithrombotic role that these two factors have in the coagulation system.

Adolescent↗