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PubMed2002

Clinical and laboratory features of 178 children with recurrent epistaxis.

PURPOSE: To determine the clinical and laboratory features of 178 children referred for the evaluation of recurrent epistaxis to an outpatient hematology clinic in a university medical center. PATIENTS AND METHODS: Medical records of 3681 outpatient pediatric hematology referrals were retrospectively review, and 178 children with recurrent epistaxis from 1985 to 1999 were identified. Historic (other bleeding symptoms: gingival bleeding, easy bruising, menorrhagia, and gross blood in the urine or stool: duration and severity of the epistaxis episodes; and family history of bleeding) and laboratory (complete blood count and coagulation tests) data were analyzed. RESULTS: There were 103 boys and 75 girls with a median age of 84 months (range 15-219 months). Sixty-seven percent (n = 119) did not have a coagulopathy diagnosed and 33% (n = 59) did. The diagnoses included von Willebrand disease in 33, platelet aggregation disorders in 10, thrombocytopenia in seven, mild factor VIII deficiency in three, Bernard-Soulier syndrome in two, factor VII deficiency in one, factor IX deficiency in one, and factor XI deficiency in one, and coagulation inhibitor in one. Of the historic data, only a family history of bleeding was predictive of diagnosing a coagulopathy (P = 0.023). The duration and severity of the epistaxis and the presence of other bleeding symptoms had no predictive value. Children with a coagulopathy diagnosed had a longer median partial thromboplastin time (PTT) (33.1 vs. 30.5 seconds; P = 0.012). CONCLUSIONS: One-third of children presenting with recurrent epistaxis have a diagnosable coagulopathy. A positive family history and a prolonged PPT are useful predictive data.

Adolescent↗
PubMed2000

Homozygous 2bp deletion in the human factor VII gene: a non-lethal mutation that is associated with a complete absence of circulating factor VII.

We report the case of a 5-year-old boy with severe factor VII deficiency. The affected child presented at the age of 8 months and again at 18 months with bleeding from the gastrointestinal tract but the diagnosis of factor VII deficiency was not made until the age of 3 years. He was treated with fresh frozen plasma and subsequently factor VII concentrates and to date remains well. To identify the causative mutation, the factor VII gene was screened by SSCP and direct sequence analysis. A single homozygous 2 bp deletion (-CT) mutation was identified in exon 1a removing nucleotides 27/28 (codons 52/53). Both parents, who were first cousins, were heterozygous for the mutation. The mutation located in the prepropeptide of factor VII, results in a complete absence of factor VII in plasma. This case indicates that a complete absence of plasma factor VII is not necessarily a lethal condition.

Child, Preschool↗
PubMed2001

Current therapy for rare factor deficiencies.

Haemophilia A and B and von Willebrand disease account for 80-85% of all inherited bleeding disorders. The other 15% are represented by deficiencies of fibrinogen, prothrombin, or factors V, VII, X, XI, or XIII. In addition, acquired factor deficiencies are seen in a variety of conditions ranging from malignancies to autoimmune disorders. The spectrum of symptoms in these conditions varies from severe and life-threatening haemorrhage to a mild bleeding diathesis. The diagnosis depends on demonstration of decreased activity of one of the clotting factors. Due to the rarity of each of the individual factor deficiencies, purified factor concentrates are not as readily available as they are for haemophilia A and B. Treatment of rare clotting factor deficiencies consists of the most purified blood product available that contains the missing factor. Depending on which factor is deficient, either purified concentrates, prothrombin complex concentrates, cryoprecipitate, or fresh frozen plasma can be used. In addition, recombinant factor VIIa is available for treating factor VII deficient patients.

Blood Coagulation Factors↗
PubMed1992

Factor IXa-factor VIIIa-cell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo.

We have infused recombinant factor VIIa into patients with hereditary factor VII deficiency with marked reductions in plasma concentrations of factor IX activation peptide (FIXP), factor X activation peptide (FXP), and prothrombin activation fragment F1+2. These investigations show substantial elevations in these markers of coagulation activation and thereby demonstrate that the factor VII-tissue factor pathway is largely responsible for the activation of factor IX as well as factor X in the basal state (ie, the absence of thrombosis or provocative stimuli). We have administered a monoclonal antibody purified factor IX concentrate to individuals with hemophilia B. These studies show an increase in the plasma levels of FIXP that were initially greatly decreased, but no change in FXP or F1+2. We have also infused highly purified factor VIII concentrate into patients with hemophilia A. The data demonstrate no significant changes in the plasma concentrations of FXP and F1+2. The above observations indicate that factor IXa generated by the factor VII-tissue factor pathway is unable to activate factor X under basal conditions. Based upon the above findings, we outline a model of blood coagulation system function under basal conditions, and suggest a process by which the generation of factor Xa and thrombin might be accelerated during normal hemostasis and in the setting of thrombotic disorders.

Adolescent↗
PubMed1979

Factor VII Padua 2: another factor VII abnormality with defective ox brain thromboplastin activation and a complex hereditary pattern.

A new factor VII abnormality is presented. The propositus was a 9-yr-old child who presented a mild bleeding tendency characterized by epistaxis and easy bruising. The parents were not consanguineous, but they came from the same area. The laboratory features were mild prolongation of prothrombin time and P.P. test and normal partial thromboplastin and Stypven cephalin clotting times. The Thrombotest was moderately prolonged. Factor VII was 40%-50% of normal using rabbit or human brain thromboplastin, but only 13%-24% using ox brain thromboplastin. Factor VII cross-reacting material (CRM) was about 50% of normal. The father, a paternal aunt, and a paternal cousin showed similar clinical and laboratory findings. The brother of the propositus, the mother, and other members of her family showed about 50% factor VII activity and CRM and were considered to be heterozygotes for true factor VII deficiency. Similar findings were also present in the father and in the brother of the affected cousin. The defect in the propositus seems to consist of a double heterozygosity between abnormal factor VII and heterozygous factor VII true deficiency. The factor VII abnormality appears to consist of abnormal reactivity toward ox brain tissue thromboplastins and appears to be different from previously described factor VII abnormalities. The name factor VII Paudua2 is proposed for this condition.

Adolescent↗
PubMed1998

[Genetic diagnosis of hereditary coagulation disorders].

Genomic abnormalities responsible for blood coagulation disorders have been the subject of extensive investigations for the last several years. Application of the methods of molecular biology had markedly increased the faculty of genetic diagnosis. Recently, we performed DNA sequence analysis of 7 families with type I antithrombin deficiency and 2 families with factor VII deficiency by polymerase chain reaction/direct DNA sequencing method. Here, we present the results of our studies. In addition, we address genetic basis of activated protein C resistance and a novel R485K polymorphism of the factor V gene in the Japanese.

Antithrombin III Deficiency↗
PubMed1994

Reduced thrombus formation in native blood of homozygous factor VII-deficient patients at high arterial wall shear rate.

Inhibition of thrombin formation in flowing native blood reduces thrombus formation on subendothelium, dacron, or collagen fibrils at arterial wall shear rates of 450 to 650 s-1. In the present study, we have investigated the role of low levels of factor VII (FVII) in thrombus formation on collagen fibrils at arterial wall shear rates of 650 s-1 (coronary arteries), 2,600 s-1 (mildly stenosed arteries), and 10,510 s-1 (severely stenosed arteries) in parallel-plate perfusion chambers. In the perfusion chamber with the highest wall shear rate, thrombus formation took place at the apex of an eccentric stenosis, which reduced the cross-sectional area of the blood flow channel by 80%, thus simulating thrombus formation at an atherosclerotic plaque rupture. Native blood from 21 healthy volunteers and 12 homozygous FVII-deficient patients was drawn by a pump directly from an antecubital vein over a surface of fibrillar collagen positioned in the respective perfusion chambers. The patients had FVII coagulant activities ranging from 1.3% to 4.5% and FVII antigen levels of 16% to 23% of normal. Immunoaffinity purification of the patients' FVII followed by electrophoresis (sodium dodecyl sulfate-polyacrylamide gel electrophoresis [SDS-PAGE]) and immunoblotting showed a protein with similar molecular mass as normal FVII. In the perfusion studies, a reduction in thrombus volume of 54% of normal (P < .007) at 10,510 s-1 was observed. The deposition of fibrin on the thrombogenic surface and the plasma level of fibrinopeptide A (FPA) in blood samples collected distal to the perfusion chamber were concomitantly reduced (P < .002 and P < .04, respectively). The plasma FPA level was also reduced at 2,600 s-1 (P < .04), but not at 650 s-1. However, at the lower shear conditions, the thrombus volume and the fibrin deposition were within the ranges observed in normal blood. The platelet-collagen adhesion was not affected at any of the three shear conditions. Thus, low plasma levels of FVII result in significantly less formation of thrombin and fibrin in and around growing platelet masses at high shear condition. This may weaken the thrombus stability and reduce platelet recruitment, thereby lowering thrombus volume. In support of this theory, one patient with afibrinogenemia had an 83% reduction in thrombus volume at this high shear condition.

Afibrinogenemia↗
PubMed1991

Activated factor IX-antithrombin III complexes in human blood: quantification by an enzyme-linked differential antibody immunoassay and determination of the in vivo half-life.

An enzyme-linked immunoassay has been developed to quantitate the activated human factor IX-antithrombin III complex (IXa-AT III). Test plasma was absorbed onto barium citrate and eluted to remove free antithrombin III (AT III). The IXa-AT III complex in the eluate was then measured by using polystyrene balls coated with immobilized rabbit anti-AT III antibody-binding fragments and anti-factor IX (anti-FIX) antibody-binding fragments labeled with beta-D-galactosidase. The assay was very sensitive, detecting a concentration as low as 0.15 fmol/assay/100 microliters plasma, which corresponds to as little as 0.002% of activated FIX in plasma. Experiments with purified FIX, IXa-alpha, AT III, IXa-AT III, normal plasma, AT III-depleted plasma, and FIX-deficient plasma demonstrated that the assay is specific. IXa-AT III generation could be detected in normal native whole blood within 2.0 minutes after venipuncture. The complex could not be detected in native whole blood from patients with severe hemophilia B even at 1 hour after venipuncture. The mean plasma level of IXa-AT III in healthy adults (n = 32, ages 23 to 54 years) was 9.67 +/- 2.86 pmol/L (mean +/- SD), whereas in eight patients with disseminated intravascular coagulation levels ranged from 11.7 to 35.0 pmol/L. The IXa-AT III titer was significantly reduced in three patients with severe factor VII deficiency (5.70 +/- 1.99 pmol/L) but was normal in three patients with severe factor XI deficiency (11.2 +/- 1.59 pmol/L). Purified IXa-AT III was cleared in vivo in rabbits with a half-life value of 30 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

[Assay of factor VII antigen by enzyme-linked immunosorbent assay (ELISA)].

This paper introduces a newly developed enzyme-linked immunosorbent assay (ELISA) method, using monospecific anti-human factor VII rabbit IgG, to quantify antigen levels of factor VII. The procedure is relatively simple, its method is remarkably specific and reproducible. Its sensitivity to detect factor VII antigen is as low as 0.015 U/ml, when factor VII antigen in 1 ml normal plasma is arbitrarily defined as 1 unit. The level of factor VII antigen in 4 patients with congenital factor VII deficiency and their family members was investigated through this ELISA and the results correlated well with those obtained by electroimmunoassay previously described. The significant correlation between the antigen levels and activity of factor VII was demonstrated in 4 patients with congenital factor VII deficiency and their family members, normal individuals and patients with liver disease. However, the level of factor VII antigen in patients treated with warfarin was higher than their coagulation activity.

Antigens↗
PubMed1986

[Effect of the C1q complement subcomponent on blood coagulability and fibrinolysis].

The in vitro experiments on human plasma have shown that C1q addition in a concentration of 120 micrograms/ml led to a substantial shortening of coagulation time of test-plasma, as well as kaolin- and cephalin time. The effect is preserved in plasma deficient in factors V, X and VII. It is assumed that C1q has properties similar to those of thromboplastin.

Blood Coagulation↗
PubMed1989

Detection of factor X activation in humans.

A sensitive radioimmunoassay (RIA) for the fragment that is liberated from factor X when this zymogen is activated by factor VII/VIIa-tissue factor or factor IXa was developed. Antisera were raised in rabbits to a synthetic 15 amino acid peptide containing the COOH-terminal sequence of the activation fragment coupled to bovine serum albumin with glutaraldehyde. The reactivity of the antibody population obtained toward the factor X zymogen was negligible (less than 1/36,000 that of the activation peptide on a molar basis). However, because other plasma constituents contributed to a nonspecific basal signal in the RIA, a procedure by which the peptide could be reproducibly extracted from plasma was developed. The mean level of this species in normal individuals younger than the age of 40 was 66.4 pmol/L, and elevations up to 550 pmol/L were observed in patients with evidence of disseminated intravascular coagulation. The validity of these measurements of factor X activation is supported by the fact that the RIA signal migrates on reverse-phase high pressure liquid chromatography in a manner identical to that of the native peptide and can be quantitatively recovered. The mean concentration of the activation fragment was markedly decreased to 25.7 pmol/L in patients with hereditary factor VII deficiency (P = .0001 v normal controls), whereas the mean level in subjects with factor VIII deficiency was 61.1 pmol/L (P greater than .1 v normal controls). These data indicate that the basal (ie, in the absence of thrombosis or provocative stimuli) levels of FXP under in vivo conditions result mainly from the activity of the extrinsic pathway.

Animals↗
PubMed2005

Recombinant factor VIIa (Eptacog Alfa): a review of its use in congenital or acquired haemophilia and other congenital bleeding disorders.

Recombinant factor VIIa (NovoSeven) [also known as recombinant activated factor VII or eptacog alfa] is a vitamin K-dependent glycoprotein that is structurally similar to human plasma-derived factor VIIa. It is a recombinant product, manufactured using DNA biotechnology. Intravenous recombinant factor VIIa has been evaluated in the treatment of bleeding episodes and for providing haemostasis cover during surgery in patients with certain bleeding disorders. Large, well controlled trials of recombinant factor VIIa have not been performed because of the rarity of these bleeding disorders. However, the efficacy of recombinant factor VIIa has been investigated in these patients in double-blind dose-finding or noncomparative clinical trials and worldwide compassionate-use programmes. Recombinant factor VIIa is effective and generally well tolerated in patients with haemophilia A or B with inhibitors, those with acquired haemophilia or Glanzmann's thrombasthenia. Also, recombinant factor VIIa is a treatment of choice in patients with haemophilia B with high-responding inhibitors and those with factor VII deficiency. Direct head-to-head comparisons and robust pharmacoeconomic data are required to fully determine the position of recombinant factor VIIa in relation to other therapies. Importantly though, the product appears to be relatively free of antigenicity, thrombogenicity and risk of viral transmission that, in the past, have limited the utility of blood products. Given that these characteristics are important determinants of the place of a treatment in bleeding disorders, recombinant factor VIIa provides a valuable treatment alternative in patients with haemophilia with inhibitors, platelet-refractory Glanzmann's thrombasthenia or congenital factor VII deficiency.

Factor VIIa↗