[Congenital familial deficiency of factor VII with additional defect of thromboplastin formation].
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Factor VII↗
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Endotoxin release after antibiotic treatment and its potential pathogenetic role in coagulative disorders of patients with gram-negative sepsis.
The liberation of endotoxin by gram-negative bacteria upon antibiotic treatment might be of clinical relevance in terms of adverse effects of antibiotic therapy in patients with gram-negative infections. In this paper we have taken into consideration the endotoxic material released by Salmonella typhimurium SH9178 after treatment with either ofloxacin and norfloxacin (which act as DNA-gyrase inhibitors) or imipenem (which affects the bacterial cell wall) in its capacity to induce in-vitro production of procoagulant activity, tissue factor-like, by human mononuclear cells. Endotoxin released from Salmonella typhimurium after treatment with the above antibiotics behaves as the typical endotoxin of gram-negative bacteria in its capacity to induce procoagulant production. Indeed human mononuclear cells after prolonged incubation with supernatants of antibiotic-treated Salmonella were able to shorten the recalcification time of normal but not Factor VII deficient plasma (tissue factor-like activity). On this basis we hypothesize that this mechanism, leading to the activation of blood coagulation through the extrinsic pathway, might be closely involved in thrombohemorrhagic disorders sometimes complicating the antimicrobial therapy of gram-negative sepsis.
Anti-Infective Agents↗
[Observations in congenital deficiency of factor VII (hypoconvertinemia)].
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Child↗
[Hereditary factors in congenital deficiency of factor VII].
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Factor VII↗
Molecular mechanisms of FVII deficiency: expression of mutations clustered in the IVS7 donor splice site of factor VII gene.
In three Italian patients, two point mutations and a short deletion were found in the intron 7 of factor VII gene, clustered in the donor splice site and located in the first of several repeats. The mutation 9726+5G-->A, the most frequent cause of symptomatic factor VII deficiency in Italy, as well as the deletion (9729del4) gave rise in expression studies to abnormally spliced transcripts, which were exclusively produced from the cryptic site in the second repeat. The insertion in the mature mRNA of the first intronic repeat caused (9726+5G-->A) a reading frameshift, abolishing most of the factor VII catalytic domain, or produced (9729del4), an altered factor with 11 additional residues, the activity of which was not detectable in the cell medium after mutagenesis and expression studies. Studies of factor VII ectopic mRNA from leukocytes and expression studies indicated that the deleted gene produced 30% of normally spliced transcript. Differently, the 9726+5G-->A mutation permitted a very low level (0.2% to 1%) of correct splicing to occur, which could be of great importance to prevent the onset, in the homozygous patients, of most of the life-threatening bleeding symptoms. The 9726+7A-->G mutation was found to be a rare and functionally silent polymorphism. These findings, which provide further evidence of the interplay of sequence and position in the 5' splice site selection, throw light on the heterogeneous molecular bases and clinical phenotypes of FVII deficiency.
Animals↗
One-step chromogenic equivalent of activated partial thromboplastin time evaluated for clinical application.
We evaluated the clinical usefulness of a recently developed semi-automated one-step chromogenic equivalent of activated partial thromboplastin time (APTT; Behring). This simple test is easily adaptable for automation. Generally, the results with this chromogenic one-step APTT were at least as precise as those obtained with comparative coagulometric methods. The chromogenic one-step APTT showed, both in vitro and in vivo, adequate sensitivity to congenital intrinsic factor deficiency but no sensitivity to Factor VII deficiency. Unlike a two-step coagulometric APTT (Dade), the one-step chromogenic APTT seemed sensitive to activation products of the contact system, which are present in immunoadsorbed factor-deficient plasma. The in vitro sensitivity of the chromogenic APTT to heparin was comparable with that of a coagulometric APTT, but the sensitivity to heparin in patients' samples differed slightly. The chromogenic APTT is relatively insensitive to anomalies in the fibrinogen-fibrin conversion. Finally, we observed discrepancies between the chromogenic and coagulometric APTT results for plasma of patients with disseminated intravascular coagulation. We conclude that this one-step chromogenic APTT warrants further evaluation for possible use as a routine test for the clinical laboratory.
Amino Acid Sequence↗
The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding.
We investigated the relation between clotting factor concentration, the parameters of the thrombin generation curve (the thrombogram) and the severity of clinically observed bleeding in patients with congenital deficiency of prothrombin (n = 21), factor V (n = 22), factor VII (n = 22), factor X (n = 10), factor XI (n = 7) and factor XII (n = 6). The parameters used were: area under the curve (endogenous thrombin potential, ETP), peak concentration of thrombin attained and lag time before manifest formation. Peak height and ETP varied linearly with the concentration of prothrombin. For the other factors these parameters hyperbolically approached to the 100% limit with increasing clotting factor concentration. Half normal ETP was seen at about the following concentrations: prothrombin (50%), factor V (1%), factor VII (2%), factor X (5%) and factor XI (1%). As a rule, the peak height was some-what more sensitive to clotting factor decrease than the ETP was. In all the patients with severe bleeding symptoms the ETP was less than 20% of normal. Bleeding tendency was absent or mild in patients with an ETP of 30% or higher. This value (except for prothrombin) is already obtained at concentrations of clotting factor of 1%-2%, which corroborates the clinical observation that a severe bleeding tendency is only seen in severe clotting factor deficiencies (less than 1%). The one exception was a patient with factor VII deficiency and severe bleeding, who showed a normal ETP value, albeit with a decreased peak height and a prolonged lag-time.
Blood Coagulation Tests↗
[Generalized pseudoxanthoma elasticum combined with vitamin K dependent clotting factors deficiency].
INTRODUCTION: Pseudoxanthoma elasticum is a connective tissue disease currently classed in 4 forms. Two forms are inherited via dominant autosomal transmission and the other two via recessive autosomal transmission. The generalized form of pseudoxanthoma elasticum is the most uncommon form and corresponds to recessive type II. Clinical manifestations include the typical generalized "peau d'orange" skin associated with hyperlaxity of the skin. Usually, there is no systemic manifestation. CASE REPORT: We report a case of a patient with generalized pseudoxanthoma elasticum associated with deficiency of vitamin-K dependent factors II, VII, IX, and X. A search for other causes of vitamin-K dependent factor deficiency was negative. DISCUSSION: The association of generalized pseudoxanthoma elasticum with deficiency of vitamin-K dependent clotting factors has been reported previously in very rare cases and is probably not fortuitous. It could led to the definition of a sub-group of recessive autosomal pseudoxanthoma elasticum.
Adult↗
Detection of two missense mutations and characterization of a repeat polymorphism in the factor VII gene (F7).
The 3' portion of the coagulation factor VII gene, containing the activation and serine protease domains, was investigated in four subjects with factor VII deficiency by temperature gradient gel electrophoresis and sequencing of polymerase chain reaction (PCR) products. Molecules displaying an altered melting behaviour were detected in three subjects, and direct sequencing showed two mutations. A G-to-T transversion causing a missense mutation, Cys-310 to Phe, suppresses a disulphide bond conserved in the catalytic domain of all serine proteases. This mutation, which in the homozygous form causes a severe reduction in protease activity (4%), was found in two patients from different Italian regions. A G-to-A transition, which gives rise to a missense mutation, Arg-304 to Gln, and is associated with the factor VII padua variant, was found in the heterozygous form in a subject also affected by von Willebrand disease. Two polymorphic alleles, which differ in one repeat monomer element, were precisely mapped in a region spanning the exon-intron 7 border of the factor VII gene and studied in families with factor VII or X deficiency.
Base Sequence↗
Prevalence of HIV infection in a cohort of patients with congenital coagulation defects of the prothrombin complex factors.
Twenty-seven patients suffering from congenital coagulation defects of the prothrombin complex factors were investigated: six had haemophilia B; 14, factor VII defect; four, factor X defect; and three, factor II defect. Nineteen patients (70.3%) had previously received plasma and/or clotting factors concentrates. Among these, markers of hepatitis B infection (HBV) were present in five cases (26.3%) and hepatitis C (HCV) antibodies were found in seven cases (36.8%). The HIV1 prevalence was similarly high. In fact, five patients (26.3%), previously infused with factor IX or prothrombin complex factors concentrates, developed HIV1 infection. No patient with factor VII deficiency became HIV1 positive, despite the administration of unheated factor VII concentrates and the consequent HBV and HCV contamination. In the HIV1 positive group, three patients showed a false positivity for HIV2 antibodies. Five years after seroconversion, three patients developed AIDS (stage IV) and died, one had persistent generalized lymphadenopathy (stage III), and one with post-hepatitis liver cirrhosis was asymptomatic (stage II) for HIV infection. The significant decrease in total white cells, T4 lymphocytes and platelet counts and increase of beta 2-microglobulin and neopterin levels confirmed the prognostic value of these markers for the progression of HIV1 disease. Only one HIV1 negative transfused patient developed anti-HTLV-I p19 antibodies.
Adult↗
Studies on a family with the factor VII defect.
Investigations in a family with an isolated factor VII deficiency are reported. In one of the propositi VII Ag was reduced, in all other family members VII Ag was in the low normal range. Other investigators have observed various activation patterns of factor VII in four deficient families which were tested with thromboplastins from different sources. In contrast to most of these earlier studies the degree of activation with different thromboplastins was very similar regardless which thromboplastin was tested. These results confirm the heterogeneity of the factor VII defect. Platelet aggregation which was tested in one of the propositi with ADP, adrenaline, and collagen was found to be normal. No cold activation of factor VII was observed.
Antigens↗
Factor VII and haemostasis.
The role of factor VII in the haemostatic mechanism as well as thrombosis has recently gained new interest. Today's concept that factor VII may be a key regulator in the initiation of blood coagulation is based on studies that provide new evidence for a mandatory activation of factor VII to factor VIIa in blood. Exposure of thromboplastin to the circulation may not trigger activation of blood coagulation before the one chain factor VII is converted to the active two chain form of factor VIIa. A hypothetical model is proposed for the initiation and subsequent activation steps of the blood coagulation process. In this model, it is suggested that circulating activators of factor VII activate inactive complexes of thromboplastin-factor VII. Subsequently, newly generated factor Xa will accelerate this reaction and thereafter be the most potent activator of factor VII. This model would also fit with the clinical observation that moderate factor VII deficiency may be associated with thrombotic episodes discussed in this communication. This article also discusses the role of recombinant factor VIIa in the treatment of factor VIII deficiency patients with acquired factor VIII inhibitors, factor VII and ischemic heart disease and the factor VII-phospholipid complex, and the regulation of the thromboplastin-factor VIIa complex by factor Xa and extrinsic pathway inhibitor (EPI).
Blood Coagulation↗
Automated synthetic substrate assays for coagulopathies of dogs.
Automated synthetic substrate assays for factors II and VII in the extrinsic coagulation pathway have been developed in our laboratory. In both kinetic assays, p-nitroaniline (pNA) was cleaved from the substrate and measured spectrophotometrically at 405 nm. Plasma samples from 5-8 month old beagle dogs were analyzed for factors II and VII, and also for prothrombin times. A subpopulation considered abnormal (prothrombin times greater than 8 seconds) had slightly elevated factor II levels, but extremely low factor VII levels, relative to the normal group. Therefore, the prolonged prothrombin times of this abnormal group can now be confidently attributed to their decreased factor VII levels. The known genetic predisposition of beagle dogs to factor VII deficiency supports this conclusion. Thus, synthetic substrates are useful for the measurement of coagulation factors in dogs, and permit ready automation of the assay.
Animals↗
[Analysis of an inherited FVII deficiency pedigree caused by homozygosity of Thr359Met].
OBJECTIVE: To explore the gene mutation type of an inherited coagulation factor VII deficiency pedigree. METHODS: FVII:Ag, FVII:C, FVIIa were detected to classify deficiency type. FVII gene mutations were analysed in the proband and her family members by DNA directly sequencing. Biostructural pathology of the identified mutation was analysed by molecular modeling. RESULTS: Homozygosity of C-->T transition at position 11514 in exon 8 resulting in Thr359Met was identified in the proband, and heterozygosity for Thr359Met was confirmed in her parents, her son and some other family members. Thr359Met induces CRM-deficiency. It is found by computer simulated molecular model that the replacement of Thr by Met which has a larger and longer side chain might cause steric hindrance, and change the number of H-bonds. CONCLUSIONS: Homozygous missense mutation Thr359Met was found in a pedigree of hereditary FVII deficiency. This mutation might change the configuration of protein molecule and result in severe FVII deficiency.
Adolescent↗
Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants.
Hereditary combined deficiency of vitamin K-dependent factors is a rare entity. We report a 7-year-old girl of Arab origin with hereditary deficiency of the procoagulants factors II, VII, IX and X and the natural anticoagulants proteins C and S. The patient is the tenth offspring of a consanguinous marriage and presented at 6 weeks with spontaneous intracerebral haemorrhage. Symptoms improved following plasma infusion. A sibling died at 5 d from uncontrollable umbilical bleeding. Blood coagulation work-up at 6 years showed: factor II:C (activity) 12 U/dl, factor II:Ag (antigen) 40 U/dl; factor VII:C 12 U/dl; factor IX:C 36 U/dl, factor IX:Ag 57 U/dl; factor X:C 17 U/dl, factor X:Ag 54 U/dl; protein C activity 43 U/dl; protein C:Ag 45 U/dl; protein S:Ag 34 U/dl; levels of factors V:C and VIII:C were normal. Assays of coagulation factors in the parents and five of the siblings were within the normal range. Following acute infection and dilantin therapy procoagulant activity levels were reduced further and were partially increased after vitamin K infusion. Crossed immunoelectrophoresis of prothrombin in the presence of calcium lactate revealed a population of des-carboxyprothrombin. Serum vitamin K epoxide levels were undetectable. The data suggest that the defect in our patient stems from abnormal carboxylation of the vitamin K-dependent proteins and that the mode of inheritance is autosomal recessive.
Blood Coagulation Disorders↗
Abnormalities in liver function and coagulation profile following the Fontan procedure.
OBJECTIVE: To investigate liver function and coagulation disorders in patients with a Fontan circulation at different time intervals after surgery. DESIGN: Retrospective analysis of clinical data and cross sectional study relating liver function and coagulation profile to time since surgery, in 28 surviving patients after the modified Fontan procedure. PATIENTS: 20 patients (71%) with atriopulmonary anastomosis, seven (25%) with atrioventricular anastomosis, and one (4%) with total cavopulmonary connection. Follow up ranged from 2.0 to 21.8 years (mean 11.1). RESULTS: Abnormal liver function tests, mainly reflecting cholestasis, were present in 21 patients who had a significantly longer follow up (p < 0.01). Protein synthesis was normal in almost all patients. Coagulation profile showed abnormalities in 22 patients. "Procoagulant" abnormalities-that is, decreased plasminogen and protein C activity-were found in 11 and five patients, respectively. The extent of these abnormalities was less in patients with a longer follow up. Anticoagulant abnormalities were factor V deficiency in 16 patients and factor VII deficiency in 17, resulting in a prolonged prothrombin time in 19 patients. Thirteen patients had both pro- and anticoagulant abnormalities. A prethrombotic state was present in five patients, with a significantly longer mean time interval since surgery (p = 0.05). Thus, although the individual procoagulant indices decreased with increasing time intervals since surgery, a prethrombotic state was found particularly in patients with a long term follow up. CONCLUSIONS: Mild cholestasis was mainly present in Fontan patients with a long duration of follow up. Along with laboratory procoagulant abnormalities indicating a prethrombotic state, anticoagulant abnormalities were also present. The coagulation profile varied at different time intervals after surgery. Thus detailed evaluation should be performed regularly, and the use of anticoagulants should be considered in every patient. Long term prospective studies are needed to evaluate the individual fluctuations of coagulation profile over time following a Fontan procedure.
Adolescent↗
The structural gene for human coagulation factor X is located on chromosome 13q34.
The gene coding for coagulation factor X was studied in a family segregating chromosomal abnormalities involving chromosomes 13 and 6. An individual monosomic for 13q34 was deficient in levels of clotting factors VII and X, while her brother, who is trisomic for 13q34, had elevated levels. DNA dosage studies with a cloned human factor X gene demonstrated that the low levels of factor X expression in the individual with the chromosome 13q34 deletion were due to the absence of one copy of the factor X structural gene. This confirms the assignment of the human gene coding for factor X to 13q34.
Blood Coagulation Factors↗
Resistance to activated protein C: evaluation of three functional assays.
Resistance to Activated Protein C (APC) was evaluated using 3 different methods: two of them were based on the prolongation of the Activated Partial Thromboplastin Time (APTT) using 2 different APTT reagents in the presence of APC, whereas the third method was based on the prolongation of prothrombin time when APC is added. The three methods were significantly correlated. APTT-based assays were sensitive to factor XII deficiency, whereas thromboplastin-based assay was sensitive to factor VII deficiency (< 0.5 UI/ml), which surestimates the response to APC. In contrast, an increase in factor VIII (F. VIII) level is associated with a decreased response to APC, when APTT-based assays are used, whereas thromboplastin-based assay is unmodified. During pregnancy, a decreased response to APC is observed, which is not only due to the increase in F. VIII, since thromboplastin-based assay is also modified. In Protein S (PS) immuno-depleted plasma, the low response to APC is corrected by addition of free PS: the thromboplastin-based assay was the most sensitive one to PS deficiency. However, in patients with congenital PS deficiency, there was no correlation between APC-resistance and free PS level. In patients with lupus anticoagulant, discrepancies were observed between the 3 methods, but with a high frequency of low response to APC. For the 3 assays, there was a good differentiation and correlation between normal and pathological results, the thromboplastin-based assay being perhaps the most discriminating. However, 3 unrelated thrombophilic patients showed normal results using thromboplastin-based assay, although they were APC-resistant using APTT-based assays. For 2 patients, this discrepancy can be explained by high levels of F. VIII. For the last patient, an abnormal F. VIII, resistant to APC can be suspected.
Adult↗