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Hereditary Factor VII deficiency is one of the rare congenital coagulopathies. Prolonged prothrombin time (PT) with normal partial prothrombin time (PTT) may be an indicator for Factor VII deficiency. A family with hereditary heterozygous Factor VII deficiency is presented in whom no symptoms of a bleeding disorder were clinically detectable. A discussion of the therapeutic options follows.
The activation of Factor IX by tissue factor-Factor VII has been studied in a bovine plasma system under conditions that minimize the activation of Factor VII. The plasma was defibrinated, then passed twice through a column of anti-Factor X coupled to Sepharose in order to lower the Factor X level below its limit of assay (ca. 5 ng/ml), and once through an anti-Factor IX column to remove Factor IX. Varying levels of tritium-labelled Factor IX were then added back to the plasma, permitting measurement of its activation upon the addition of tissue factor and Ca2+. Despite the absence of significant levels of Factor X in the system, the course of Factor IX activation was initially characterized by some upward curvature, which suggested activation of the plasma Factor VII during the incubation. In order to obtain linear activation of Factor IX three proteolytic inhibitors were added to the system: 1) a Factor Xa inhibitor, 1,2-bis-(5-amidinobenzimidazole)-ethane, 2) aprotinin, and 3) heparin. Under these conditions the apparent Km of non-activated Factor VII (+ tissue factor) on Factor IX was 17.3 +/- 2.5 nM (SE), and the maximum velocity was 0.12 nM/min. In parallel experiments the plasma Factor VII was activated by first treating the plasma with Factor Xa for 30 seconds before the addition of inhibitors and the final addition of substrate. Under these conditions the maximum velocity rose to 4.2 nM/min, and the Km increased to 53.3 +/- 6.0 nM (SE). This change in the Km is highly significant (P less than 0.002), and indicates that the activation of Factor IX by nonactivated plasma Factor VII cannot be due only to traces of Factor VIIa in the plasma. At least in part, activation of Factor IX in the presence of tissue factor is suggested to be a result of the action of Factor VII itself.
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We studied the effects of lipid membrane composition on factor VII autoactivation and observed that factor VII was activated in the presence of phospholipid vesicles containing sphingosine. The time course for the factor VII activation was sigmoidal and the duration of the initial lag phase was decreased by the addition of exogenous factor VIIA. Kinetic studies revealed that factor VII activation in the presence of sphingosine-containing phospholipids can be defined by a second-order reaction mechanism with an apparent second-order rate constant of 1.1x10(4) M(-1)s(-1). The sphingosine-mediated factor VII autoactivation rate was dependent on the concentration of calcium ions and sphingosine content of the vesicles. Neither bovine serum albumin-conjugated sphingosine nor sphingosine analogues (ceramide, sphingomyelin) affected the factor VII autoactivation rate.
Factor VII circulates as a single chain inactive zymogen (10 nmol/L) and a trace ( approximately 10-100 pmol/L) circulates as the 2-chain form, factor VIIa. Factor VII and factor VIIa were studied in a coagulation model using plasma concentrations of purified coagulation factors with reactions initiated with relipidated tissue factor (TF). Factor VII (10 nmol/L) extended the lag phase of thrombin generation initiated by 100 pmol/L factor VIIa and low TF. With the coagulation inhibitors TFPI and AT-III present, factor VII both extended the lag phase of the reaction and depressed the rate of thrombin generation. The inhibition of factor Xa generation by factor VII is consistent with its competition with factor VIIa for TF. Thrombin generation with TF concentrations >100 pmol/L was not inhibited by factor VII. At low tissue factor concentrations (<25 pmol/L) thrombin generation becomes sensitive to the absence of factor VIII. In the absence of factor VIII, factor VII significantly inhibits TF-initiated thrombin generation by 100 pmol/L factor VIIa. In this hemophilia A model, approximately 2 nmol/L factor VIIa is needed to overcome the inhibition of physiologic (10 nmol/L) factor VII. At 10 nmol/L, factor VIIa provided a thrombin generation response in the hemophilia model (0% factor VIII, 10 nmol/L factor VII) equivalent to that observed with normal plasma, (100% factor VIII, 10 nmol/L factor VII, 100 pmol/L factor VIIa). These results suggest that the therapeutic efficacy of factor VIIa in the medical treatment of hemophiliacs with inhibitors is, in part, based on overcoming the factor VII inhibitory effect. (Blood. 2000;95:1330-1335)
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To evaluate the feasibility efficaCy and safety of home treatment with recombinant activated factor VII (rFVIIa), 10 inhibitor patients (all haemophiliacs except one acquired post-partum) self-administered up to four doses of 90 microg/kg rFVIIa every 3+/-1 h. The response was rated by the patient as effective (haemorrhage stopped or decreased substantially), partially, effective (reduced) or ineffective (unchanged or worsened). 45 haemarthroses and eight haematomas were treated within a median time of 1.0 h (range 0.3-11.9) from the onset of bleeding, with a median of two rFVIIa doses per course (range 1-4). rFVIIa was effective in 42 episodes (79%), partially effective in six (11%) and failed in five (10%). Compared with partially effective and ineffective treatments, effective treatments started earlier (median time: 0.6 v 2.7 h, P=0.02) and required a smaller number of doses (median: 1.5 v 3, P=0.007). The risk of a partially effective or ineffective treatment was smaller for treatments started within 6 h from the onset of bleeding than for those which started later (OR 0.24, 95% CI 0.09-0.63). Mild side-effects were reported only after 3/113 self-infusions (2.6%). Early home treatment with rFVIIa is safe, feasible and effective, inducing and maintaining haemostasis with a small number of doses.
Factor VII deficiency is a rare disorder (1/500,000), with manifestations similar to those experienced by patients with haemophilia. Excessive bleeding during surgical procedure is prevented by factor VII administration. We report two cases of patients presenting a factor VII deficiency who were treated for oncological surgery. In the first patient with a severe congenital factor VII deficiency (8%), a continuous infusion of factor VII prevented the development of perioperative bleeding. In the second case, with a probably acquired factor VII deficiency (33%) related to a leiomyosarcoma, bleeding was prevented by a single preoperative factor VII injection.
The plasma levels of coagulation factor VII and fibrinogen are well known risk factors for arterial thrombosis. We tested the hypothesis that this association also exists for venous thrombosis. Additionally, MspI and HaeIII polymorphisms in the factor VII and fibrinogen genes have recently been reported to be associated with the concentration of both proteins in the plasma. However, no conclusion could be drawn with respect to an increase or decrease in thrombosis risk. We undertook a population-based case-control study, in which 199 patients with a population-based case-control study, in which 199 patients with a first, objectively confirmed episode of deep vein thrombosis, aged less than 70, and without a known malignant disorder were compared to 199 age- and sex-matched healthy controls, to evaluate the clinical importance of these reported findings. For fibrinogen we found a positive level-related association between the plasma fibrinogen level and thrombotic risk. Subjects with a plasma fibrinogen greater than 5 g/l had an almost 4-fold increase of thrombosis risk. The frequencies of the different HaeIII genotypes were out of balance only for the thrombosis patients, with a deficit of the H1H2 genotype. Possession of an H1H2 genotype was associated with a 40% reduction in thrombosis risk. For factor VII, neither the plasma level nor the MspI genotypes were related to deep vein thrombosis, although possession of a M2 allele was clearly associated with significantly lower factor VII levels. The frequencies of the MspI-genotypes were the same for patients and control subjects and exhibited Hardy-Weinberg equilibrium. (ABSTRACT TRUNCATED AT 250 WORDS)
To improve the standardization of the factor VII clotting activity (FVII:C) assay in patients treated with recombinant activated factor VII (rFVIIa), we conducted a multicentre study on plasma samples from four patients with haemophilia A, before and at various times after injection of a single dose of rFVIIa. FVII:C and prothrombin time were measured with the methods and reagents routinely used in each laboratory. Strong inter-laboratory variability of FVII:C values was found. The main source of variability was the type of thromboplastin. FVII:C values measured using rabbit thromboplastin were very close to activated factor VII clotting activity values (FVIIa:C) measured with a commercial assay (Staclot VIIa-TF). FVII:C values obtained with human placental thromboplastin were about three times lower than those obtained with rabbit and recombinant thromboplastins, and with the FVIIa:C assay. There was a good relationship between FVIIa:C and activated factor VII antigen values measured using a commercial immunoassay (Imubind FVIIa ELISA). In conclusion, rFVIIa at pharmacological concentrations can be easily monitored on the basis of FVII:C, using rabbit and probably also recombinant thromboplastin; equivalent results are obtained with a specific activated factor VII bioassay.
Factor VII levels have been studied in hemophilia A and B plasmas and normal controls in a controlled, prospective study. Three assay methods were used: a standard clotting assay (FVIIc-A); a modified clotting assay (FVIIc-B) (Seligsohn et al, Blood 52:978-988, 1978); and a coupled amidolytic assay. By the FVIIc-B assay, the hemophilic plasmas were significantly lower than in the normal group (68.2 +/- 3.3% [SE] and 83.5 +/- 3.8%, respectively; P less than .01). The amidolytic assay, however, which measures total factor VII regardless of its activity state (factor VII or VIIa), was higher in the patient group than in the control group (126.9 +/- 9.6% and 99.4 +/- 5.7%, respectively; P less than .01). Control experiments showed that the differences in FVIIc-B activity were not caused by artifactual activation of factor VII ex vivo in the control group. The mean FVIIc-A assay of hemophilic plasmas (126.3 +/- 6.5%) agreed closely with the amidolytic assay, suggesting that the FVIIc-A method is also insensitive to the factor VII activity state. These data support the hypothesis that the FVIIc-B assay is more sensitive to the presence of factor VIIa. The increased sensitivity of the FVIIc-B assay to factor VII activation was confirmed by comparison of the two clotting assays on plasma subjected to activation in glass at 4 degrees C. The results of this study indicate that factor VII in hemophilic plasma is less activated than in normal plasma. Whether this contributes to the bleeding diathesis of hemophilia is unknown. However, it does provide evidence for the idea that factor VII in vivo is normally subject to some degree of activation by an enzyme (or enzymes) generated by a turnover of the intrinsic pathway.
Tissue factor, the physiologic trigger of blood clotting, is the membrane-anchored protein cofactor for the plasma serine protease, factor VIIa. Tissue factor is hypothesized to position and align the active site of factor VIIa relative to the membrane surface for optimum proteolytic attack on the scissile bonds of membrane-bound protein substrates such as factor X. We tested this hypothesis by raising the factor VIIa binding site above the membrane surface by creating chimeras containing the tissue factor ectodomain linked to varying portions of the membrane-anchored protein, P-selectin. The tissue factor/P-selectin chimeras bound factor VIIa with high affinity and supported full allosteric activation of factor VIIa toward tripeptidyl-amide substrates. That the active site of factor VIIa was raised above the membrane surface when bound to tissue factor/P-selectin chimeras was confirmed using resonance energy transfer techniques in which appropriate fluorescent dyes were placed in the active site of factor VIIa and at the membrane surface. The chimeras were deficient in supporting factor X activation by factor VIIa due to decreased k(cat). The chimeras were also markedly deficient in clotting plasma, although incubating factor VII or VIIa with the chimeras prior to the addition of plasma restored much of their procoagulant activity. Interestingly, all chimeras fully supported tissue factor-dependent factor VII autoactivation. These studies indicate that proper positioning of the factor VII/VIIa binding site on tissue factor above the membrane surface is important for efficient rates of activation of factor X by this membrane-bound enzyme/cofactor complex.
Activated factor VII (factor VIIa) is a vitamin K-dependent plasma serine protease that participates in a cascade of reactions leading to the coagulation of blood. Two overlapping genomic clones containing sequences encoding human factor VII were isolated and characterized. The complete sequence of the gene was determined and found to span about 12.8 kilobases. The mRNA for factor VII as demonstrated by cDNA cloning is polyadenylylated at multiple sites but contains only one AAUAAA poly(A) signal sequence. The mRNA can undergo alternative splicing, forming one transcript containing eight segments as exons and another with an additional exon that encodes a larger prepro leader sequence. The latter transcript has no known counterpart in the other vitamin K-dependent proteins. The positions of the introns with respect to the amino acid sequence encoded by the eight essential exons of factor VII are the same as those present in factor IX, factor X, protein C, and the first three exons of prothrombin. These exons code for domains generally conserved among members of this gene family. The comparable introns in these genes, however, are dissimilar with respect to size and sequence, with the exception of intron C in factor VII and protein C. The gene for factor VII also contains five regions made up of tandem repeats of oligonucleotide monomer elements. More than a quarter of the intron sequences and more than a third of the 3' untranslated portion of the mRNA transcript consist of these minisatellite tandem repeats.
Factor (F)VII plays a critical role in initiation of coagulation. Several segments within the 5' flanking region of the FVII gene were previously demonstrated to recognize hepatic nuclear proteins, but few have been identified. To identify a regulatory protein binding the nuclear hormone response region (-237 to -200) of the FVII 5' flanking region and demonstrate that the interaction is functional. Electrophoretic mobility shift assays and mutation analysis showed that ARP1, an orphan nuclear hormone receptor, interacted with two regions of the FVII 5' flanking region, the hepatic nuclear factor 4 binding region (-77 to -47) and the nuclear hormone response region (-237 to -200). Transfection experiments demonstrated that reporter gene expression was decreased from vectors including the nuclear hormone response segment compared with that containing only the minimal promoter between positions -109 and +1, and that ARP1 also repressed expression through an interaction with the minimal promoter. These data indicate a role for ARP1 in transcriptional modulation of the FVII gene.
Thirty obligate and 28 possible carriers of factor VII congenital deficiency, belonging to 16 families, were studied in relation to the immunological variants to which the kindreds belonged, namely, VII+, VIIR and VII-. Factor VII activity and antigen determinations in these subjects formed two phenotypical patterns: a discrepant pattern characterized by a low ratio activity/antigen present in VII+ heterozygotes, and a non-discrepant pattern (normal ratio activity/antigen) which is present in the VII- and VIIR variants. In the first genetic variant the detection of carriers can be performed using the ratio VII:C/VII:Ag. In the other variant, which accounts for the vast majority of heterozygotes, the distribution of the carriers' factor VII is so widespread that a large overlap results between these subjects and the normals. The application of a probabilistic calculation performed by combining the actual values of factor VII:C and the genetic probability of carriership using Fisher's linear discriminant analysis, makes discrimination between carriers and normals easier.
This study was aimed to investigate coagulation factor VII level in uremic patients with chronic renal failure and to explore theirs influence factors. The plasma levels of coagulation factor VII were detected in 30 uremic patients with chronic renal failure before and after hemodialysis for 1 month, the factor VII activity (FVII:C) was determined by one-stage coagulation method, while activated factor VII (FVIIa) was measured by one-stage coagulation method using recombinant soluble tissue factor, and factor VII antigen was detected by ELISA. The results showed that: (1) The FVIIa, FVII:C and FVIIAg levels in chronic uremic patients before hemodialysis were 4.00 +/- 0.86 microg/L, (148.5 +/- 40.4)% and (99.8 +/- 21.1)% respectively, which were significantly increased, as compared with healthy controls [2.77 +/- 1.02 microg/L, (113.1 +/- 33.0)% and (73.7 +/- 18.3)% respectively, P < 0.05]. (2) After hemodialysis the FVIIa, FVII:C and FVIIAg levels in uremic patients significantly enhanced to 5.56 +/- 1.45 microg/L, (200.8 +/- 68.7)% and (124.1 +/- 19.3)% respectively (P < 0.05). (3) The abnormal increase of coagulation factor VII was positively correlated with levels of blood uria nitrogen and serum creatinine before hemodialysis but not after hemodialysis. It is concluded that the enhanced levels of coagulation factor VII in chronic uremic patients suggested abnormal activated state, herperactivity and elevated production of factor VII which correlated with renal functional injury. The abnormality of factor VII in uremia may be aggravated by hemodialysis. Coagulation factor (FVII) may be a risk factor for cardiovascular events in uremic patients who especially had been accepted long-term hemodialysis.
Human blood coagulation factor VII has unique carbohydrate moieties O-glycosidically linked to serine 52 and serine 60 residues in its first epidermal growth factor-like domain. To study the functional role of these glycosyl moieties in factor VII, we constructed, expressed, and purified site-specific recombinant mutants of human factor VII in which serine 52 and serine 60 were conservatively replaced with alanine residues. S52A factor VIIa (Ser-52-->Ala), S60A factor VIIa (Ser-60-->Ala), and S52,60A factor VIIa (Ser-52, Ser-60-->Ala) exhibited 56, 73, and 44%, respectively, of the clotting activity of wild-type factor VIIa using human brain thromboplastin as a source of tissue factor/phospholipids and 32, 43, and 14% of wild-type factor VIIa using a mixture of recombinant soluble tissue factor and mixed brain phospholipids. The tissue factor-dependent and -independent amidolytic activities of these mutants were essentially indistinguishable from that of wild-type factor VIIa. In addition, equilibrium dialysis experiments indicated that the profiles of 45Ca2+ binding to these mutants were identical with that of wild-type factor VII. In the presence of either Ca2+ or EGTA, the Kd values for the interaction of the three factor VIIa mutants to full-length tissue factor were 2- to 5-fold higher than that of wild-type factor VIIa, while the Kd values for the interaction of these mutants to soluble tissue factor were 4- to 15-fold higher than that of wild-type factor VIIa. Measurement of the association and dissociation rate constants for factor VIIa binding to relipidated tissue factor apoprotein revealed that the association rate constants of the three factor VII mutants were decreased in comparison with that of wild-type factor VIIa, while the dissociation rate constants of these three mutants were virtually identical to that of wild-type factor VIIa. These findings strongly suggest that glycosyl moieties attached to Ser-52 and Ser-60 in factor VII/VIIa provide unique structural elements that are important for the rapid association of factor VII/VIIa with its cellular receptor and cofactor.
Factor VII can be activated, to a molecule giving shorter clotting times with tissue factor, by incubating plasma with kaolin or by clotting plasma. The mechanisms of activation differ. With kaolin, activated Factor XII (XII(a)) was the apparent principal activator. Thus, Factor VII was not activated in Factor XII-deficient plasma, was partially activated in prekallikrein and high-molecular weight kininogen (HMW kininogen)-deficient plasmas, but was activated in other deficient plasmas. After clotting, activated Factor IX (IX(a)) was the apparent principal activator. Thus, Factor VII was not activated in Factor XII-,HMW kininogen-, XI-, and IX-deficient plasmas, but was activated in Factor VIII-, X-, and V-deficient plasmas. In further studies, purified small-fragment Factor XII(a) (beta-XII(a)), kallikrein, and Factor IX(a) were added to partially purified Factor VII and to plasma. High concentrations of beta-XII(a) activated Factor VII in a purified system; much lower concentrations of beta-XII(a) activated Factor VII in normal plasma but not in prekallikrein or HWM kininogen-deficient plasmas. Kallikrein alone failed to activate partially purified Factor VII but did so when purified Factor IX was added. Kallikrein also activated Factor VII in normal, Factor XII-, and Factor IX-deficient plasmas. Purified Factor IX(a) activated partially purified Factor VII and had no additional indirect activating effect in the presence of plasma. These results demonstrate that both Factor XII(a) and Factor IX(a) directly activate human Factor VII, whereas kallikrein, through generation of Factor XII(a) and Factor IX(a), functions as an indirect activator of Factor VII.