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Binding of human factor VII and VIIa to monocytes.

Human coagulation Factors VII and VIIa bind with equal affinity to monocytes stimulated with endotoxin. Equilibrium binding studies performed at 0 degrees C using 125I-labeled Factor VII and VIIa showed the dissociation constant (Kd) to be congruent to 82 pM with congruent to 3,600 binding sites/monocyte. Ca++ was required for Factor VII and VIIa interaction with monocytes (optimal CaC12 concentration greater than or equal to 2.5 mM) and binding was reversed by the addition of EDTA. The rate of conversion of Factor X to Xa in mixtures containing Factor VIIa and monocytes was directly related to the quantity of Factor VIIa bound to the monocyte surface. Thus the monocyte binding sites appear to represent tissue factor. Competition experiments showed that Factor VII and VIIa bind to the same monocyte sites and further, that unlabeled Factor VII and VIIa have the same affinity for the binding sites as the 125I-labeled proteins.

Binding, Competitive↗

Congenital factor VII deficiency. A report of four new cases.

Four new cases with congenital homozygous factor VII deficiency are described. Factor VII levels were reduced to less than 1%, 3%, 8% and 10%, respectively. The incidence and severity of bleeding symptoms were well correlated with the measured factor VII activity. In the severe case of factor VII deficiency (less than 1%) a home treatment program was started because of severe recurrent hemarthroses. This entailed transfusions of 20 U/kg body weight prothrombin complex or factor VII concentrate in case of acute bleeding approximately every three weeks. These transfusions have been carried out successfully without any problems. In contradiction, two brothers with hypoproconvertinemia (factor VII 8% and 10% respectively) reached an age of more than 70 years. Despite replacement therapy postoperative bleeding followed one appendectomy, whereas no postoperative bleeding followed patients requiring Achilles tendon lengthening and an above knee amputation and only slight bleeding followed a tonsillectomy. Based on our experience we suggest that in patients with factor VII deficiency of less than 10%, when undergoing surgery, should be maintained a minimal factor VII activity of 10--15% during the first three postoperative days.

Adolescent↗

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↗

Molecular variant of factor VII.

Two patients with severe factor VII deficiency appeared to be different with respect to the presence of inactive factor VII-like material in their plasma. The inactive material, demonstrated in one patient's plasma and adsorbable onto BaSO4, inhibits the thrombotest-system and is capable of neutralizing a heterologous antibody against factor VII in a fluid phase system.

Cross Reactions↗

Treatment of congenital factor VII deficiency with a new concentrate.

A new factor VII concentrate, made from ACD plasma by a process involving successive absorptions of cryoprecipitate supernatant on DEAE Sephadex and of the resulting supernatant on A1(OH)3, was administered to 10 patients with severe factor VII deficiency. 5 patients received only one dose for treatment of a single bleeding episode, the remaining 5 were given multiple infusions (47) for spontaneous hemorrhages or for the prevention of surgical bleeding. In vivo factor VII recovery ranged from 43 to 126% (average 88%) of the assayed in vitro activity of the concentrate. A dose of 0.5 u/kg was found to produce a 1% rise of the plasma factor VII levels. The mean half-life on injected factor VII as assessed in 7 kinetic studies was 205 min (range 168--234). Spontaneous bleeding was easily controlled by the concentrate and major surgical procedures (two tonsillectomies) could be performed without complications. 1 patient developed HBSAg positive hepatitis, but otherwise no serious side effects were observed. Factor VII concentrate reduced the risk of precipitating circulatory overload associated with the use of plasma and avoids the unnecessary rise of factor II, IX and X which follows prothrombin complex concentrates.

Adolescent↗

Lipoprotein associated coagulation inhibitor, factor VII, antithrombin III, and monocyte tissue factor following surgery.

Fifteen patients undergoing major surgical procedures were evaluated for lipoprotein associated coagulation inhibitor (LACI) antigen, factor VII (F VII), antithrombin III (AT III), and peripheral blood monocyte tissue factor (TF) activity immediately before surgery and on following days. A peak in monocyte TF activity occurred between the first and fifth days after surgery in 10 of the patients, while LACI, F VII, and AT III levels dropped in a qualitatively parallel manner in 8 of these patients. LACI, F VII, and AT III levels decreased after surgery in two additional patients even though TF activity also decreased after surgery in these patients. In the remaining 3 patients who developed infections during the study, TF activity rose within 2 days of the diagnosis of infection in addition to the postoperative peak. In two of these patients, LACI levels increased dramatically near the end of the study period without concomitant changes in F VII and AT III. Overall, the presurgical TF levels in disrupted monocytes varied 52-fold and the maximal TF activity varied 24-fold among patients. The TF response following surgery is therefore heterogenous in both temporal occurrence and magnitude of the postsurgical peak. The patients also varied considerably in the presurgical levels of monocyte TF activity. A possible association between the level of presurgical TF activity and the magnitude of the postsurgical peak was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin III↗

Successful treatment of severe intra-abdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor VII.

Recombinant activated factor VII (rFVIIa) is indicated mainly for the treatment of patients with haemophilia and inhibitors. However, little information is available on the use of rFVIIa in the treatment of the severe bleeding associated with disseminated intravascular coagulation (DIC). We report a pregnant woman with DIC, who developed severe intra-abdominal bleeding after caesarean section. Despite treatment with fresh-frozen plasma, fibrinogen, platelet transfusions and surgery, the abdominal bleeding persisted and intravenous treatment with rFVIIa was initiated. The response to treatment was rapid, with control of the bleeding and resolution of the coagulopathy. No side-effects related to rFVIIa were noted. This case suggests a potential role for rFVIIa in the treatment of severe and refractory bleeding associated with DIC.

Acute Disease↗

Arthropathies in factor VII deficiency: a case report.

UNLABELLED: Factor VII deficiency (or hypoproconvertinemia) is a rare inherited bleeding disorder that can cause hemarthrosis similar to that seen in hemophilia. We report a case. CASE REPORT: A 28-year-old woman experienced recurrent spontaneous hemarthrosis in both elbows and one knee starting at 2 years of age. She sought advice for an episode of bleeding in the left knee. The prothrombin level was decreased to 15% and the activated partial thromboplastin time was normal. Radiographs disclosed advanced joint destruction in the right shoulder, both elbows, the left knee, and both ankles. She described similar joint symptoms in two cousins. Plasma factor VII was less than 10%. A diagnosis of arthropathy due to an inherited bleeding disorder was given. Triamcinolone hexacetonide was injected into the joint; fresh frozen plasma was given concomitantly as an intravenous infusion. DISCUSSION: Factor VII deficiency is an extremely uncommon bleeding disorder with an estimated prevalence of 1/300,000 to 1/500,000. Bleeding occurs only in homozygotes whose factor VII level is less than 20%. Hemarthrosis is less common than hemophilia, although the characteristics of joint destruction are similar in the two conditions.

Adult↗

The congenital factor VII abnormalities (dysproconvertinemias). The genetic plot thickens.

Congenital factor VII deficiency is a well known clotting disorder first identified in 1951. Several congenital abnormalities of factor VII have been described during the past decade. These abnormalities were all characterized by the presence of a discrepancy between factor VII clotting activity and factor VII cross reacting material or antigen. Recently other factor VII abnormalities have been described which showed peculiar sensitivities to ox-brain thromboplastins as compared to thromboplastins of other origin. These discoveries have complicated the differential diagnosis of prothrombin complex factors deficiences and abnormalities. A correct diagnosis may be reached only by means of a battery of tests which employ tissue thromboplastins of different origin.

Animals↗

Relationship between factor VII activity and clinical efficacy of recombinant factor VIIa given by continuous infusion to patients with factor VIII inhibitors.

A multicenter prospective study of recombinant activated factor VII (rFVIIa) given by continuous infusion (CI) to treat severe hemorrhages and to handle surgical procedures was carried out. Relations between clinical efficacy, dosages used and levels of FVII coagulant activity (FVII:C) achieved in plasma were also evaluated. Case material included 25 patients with hemophilia (9 children and 16 adults) with high-responding inhibitors and 3 patients with acquired factor VIII inhibitors. Overall, 35 CI courses were given for 10 spontaneous bleeding episodes, 11 major surgical procedures and 14 minor surgical procedures. Bolus doses of 90 to 150 microg/kg (median: 100) were followed by CI given at median rates of 20 microg/kg/h for major surgery and of 17 and 16 microg/kg/h for minor surgery and spontaneous hemorrhages. Satisfactory hemostasis was obtained in 30 of 35 courses (88%). rFVIIa CI was ineffective in 2 hemophiliacs undergoing surgical operations and in another hemophiliac with hemoperitoneum who had to be switched to other treatments (high doses of porcine or human factor VIII concentrates). rFVIIa CI was partially effective in 2 hemophiliacs who had mild local bleeding after minor surgery. The CI rates and the corresponding FVII:C levels in plasma were similar in effective, partially effective and ineffective courses (median rate: 17, 20 and 20 microg/kg/h, respectively; median FVII:C:14, 18 and 18 IU/ml, respectively). A single adverse event was observed, superficial thrombophlebitis. This study confirms that rFVIIa given by CI is effective in a high proportion of patients with factor VIII inhibitors. It also demonstrates that FVII:C levels attained in plasma do not always predict efficacy because similarly high levels were attained during successful treatments and in those that failed.

Adult↗

Metabolism of rabbit plasma-derived factor VII in relation to prothrombin in rabbits.

In the human circulation, factor VII is present in relatively low plasma concentration (0.01 microM) and has been reported to have a short half-life (t(1/2); 6 h). In contrast, prothrombin is present in a relatively high plasma concentration (2 microM) and has a relatively long catabolic half-life (t(1/2) = approximately 2-3 days). This report examines the metabolic characteristics of purified rabbit plasma factor VII and prothrombin, radiolabeled with (125)I and (131)I, respectively, in healthy young rabbits. From the plasma clearance curves of protein-bound radioactivities, fractional catabolic rates and compartmental distributions were calculated using a three-compartment model. Turnover of factor VII within the intravascular space (2.95 days) exceeded that of prothrombin (1.9 days). However, the whole body fractional catabolic rate of factor VII (0.34 days(-1); catabolic t(1/2) = 2.04 days) was significantly slower than that of prothrombin (0.53 days(-1); t(1/2) = 1.31 days). Furthermore, the fractional distributions of factor VII in the intravascular (0.14) and extravascular compartments (0.76) differed from those of prothrombin (0.29 and 0.53). Absolute quantities of factor VII and prothrombin catabolized by a 3-kg rabbit amounted to 0.18 and 24.0 mg/day, respectively (molar ratio of prothrombin to factor VII = 100). The molar ratio of catabolism was compared with the release rates of factor VII and prothrombin from rabbit livers perfused ex vivo. After correction for uptake of factor VII and prothrombin by the liver, the molar ratio of released prothrombin to factor VII in the perfusate was approximately 293:1 over a 0.25- to 3-h interval. These results indicate that, compared with prothrombin, factor VII in the healthy rabbit circulates as a relatively long-lived protein. This behavior does not reflect that reported for factor VII in the human circulation.

Animals↗

Monoclonal antibodies to human factor VII: production of immunodepleted plasma for VII:C assays.

A high affinity monoclonal antibody to factor VII (RFF-VII/1), coupled to sepharose, was used to immunodeplete factor VII from normal plasma. The plasma could be used as a substrate in a one stage coagulation assay and performed as well as, or better than, commercially available factor VII deficient plasma or plasma from congenitally deficient factor VII patients. Plasma from normal donors (n = 20), patients with liver disease (n = 20), and patients receiving warfarin (n = 20), or congenitally factor VII deficient patients (n = 7) was assayed for VII:C concentration in a one stage coagulation assay. The concentration of VII:C detected with the immunodepleted plasma substrate was comparable in all cases with that seen with a commercially available substrate (r = 0.95).

Antibodies, Monoclonal↗

Factor VII deficiency and surgery. Is preoperative replacement therapy necessary?

A patient with congenital factor VII deficiency (factor VII was 12%) had gynecologic surgery performed without prophylactic blood-product replacement therapy. Blood loss was not excessive. A review of 12 additional patients with factor VII deficiency who underwent surgery without replacement therapy showed that surgical bleeding was uncommon and that there was no relationship between factor VII levels and hemorrhage. It is proposed that patients who bleed may be those who also have a prolonged bleeding time or who have ingested aspirin shortly before surgery. It is all proposed that replacement therapy be available for use if required, but that its routine preoperative use is probably unnecessary in this disorder.

Adolescent↗

A new approach to treatment of bleeding episodes in young hemophilia patients: a single bolus megadose of recombinant activated factor VII (NovoSeven).

Recombinant activated factor VII (rFVIIa, NovoSeven) represents an effective treatment for hemophilia patients with inhibitors, but no consensus as to the best dosing regimen exists. We assessed the efficacy and safety of a rFVIIa 'megadose' (300 micro g kg(-1) bolus) as treatment for bleeds in three young inhibitor patients. Of 114 bleeds, 95 responded to a single dose. Pain relief was faster and therapy duration significantly shorter than with continuous infusion (CI) regimens or standard boluses (90 micro g kg(-1) every 3 h). Rebleeding occurred in 9.6% of cases and 19/114 episodes required a second bolus injection. Although rFVIIa consumption per bleed (median: 300 micro g kg(-1)) was higher than with standard boluses (180-270 micro g kg(-1)), patients found single bolus administration more convenient than recurrent injections or CI. With two exceptions, no complications occurred within 3 h of treatment, despite high FVII:C levels (median: 27.4 U mL(-1); range: 19.8-54 U mL(-1)). Treatment of bleeds with a rFVIIa megadose in young inhibitor patients is effective and well tolerated.

Adult↗

A new form of coagulation factor VII in plasma.

We have reported the existence of a novel form of coagulation factor VII - probably a factor VII-phospholipid complex - in plasma from pregnant women and men at risk for cardiovascular disease. We report here further observations on the presence and characteristics of this complex. Some apparently healthy individuals who, on testing by standard methods, have normal levels of factor VII activity achieve such levels by means of a phospholipase C-sensitive modification of (some of) their factor VII molecules. Their residual factor VII activity after phospholipase C treatment of plasma may be as low as 10-20 U/ml. Antiserum to the protein component of thromboplastin (apoprotein III) had no effect on the factor VII activity, whereas antiserum to factor VII effectively blocked both the total factor VII activity and the residual activity of factor VII after treatment of plasma with phospholipase C. These factor VII complexes precipitate with the VLDL/LDL fraction in lipoprotein precipitations.

Adolescent↗

Recombinant activated factor VII and the anaesthetist.

Recombinant activated factor VII is a safe and effective for the treatment and prevention of haemorrhage in haemophiliacs with circulating inhibitors to replacement factors, and patients with Glanzmann's thrombasthenia refractory to platelet transfusion. By restoring thrombin generation on the surface of tissue factor bearing cells, such as activated platelets and monocytes, recombinant activated factor VII has the potential to effect haemostasis in the setting of many coagulopathic states encountered by the anaesthetist in the operating theatre or the intensive care unit. Case reports of successful rescue therapy make up the majority of the literature covering other, numerous, off-label uses of recombinant activated factor VII, although some randomised, controlled studies, mostly underpowered to address safety concerns, have been performed. However, off-label use is becoming increasingly popular judging by the number of published case reports. Additional randomised, controlled trials to determine the safe and appropriate use of this potentially valuable therapy in broader patient groups are eagerly awaited.

Blood Loss, Surgical↗

Factor VII congenital deficiency. Clinical picture and classification of the variants.

In congenital factor VII deficiency the clinical picture is related to the levels of factor VII coagulant activity; when factor VII:C levels are very low the bleeding episodes can occur frequently. The most frequent bleedings are menorrhagia and metrorrhagia in females and hemarthrosis in both sexes. There are 3 immunological variants of factor VII deficiency: VII-, VIIR and VII+. Conversely, the genetic variants are 2: one characterized by no discrepancy between VII:C and VII:Ag (found in the heterozygotes of VII- and VIIR variants) and the other, in which a discrepancy between VII:C and VII:Ag is found (heterozygotes from VII+ kindreds). In factor VII deficiency, most commonly the human and ox tissue factors show the highest sensitivity to the coagulation defect, whereas the one extracted from rabbits is definitely less sensitive; the definition of functional variants is based upon a different reactivity to homologous and/or heterologous tissue thromboplastins. In no case was a PIVKA-VII-like protein found and none of the factor VII defective molecules reacted to the generation of important kallikrein activity.

Animals↗

Activation of coagulation factor VII during alimentary lipemia.

Dietary studies have established a connection between plasma lipoproteins and coagulation factor VII. The present study was undertaken to specifically examine whether factor VII is activated during alimentary lipemia and to investigate the relations of factor VII mass and activity state with fasting and postprandial lipoproteins and free fatty acids (FFAs). Factor VII levels were therefore determined in plasma samples taken before and after intake of a standardized, oral fat load of a mixed-meal type in 33 men (mean age +/- SD, 48.8 +/- 3.2 years) with a previous myocardial infarction at a young age and 10 healthy, age-matched control subjects. A panel of methods for factor VII determination was used to ensure that changes in all potentially existing forms of the factor during alimentary lipemia would be included. Substantial activation of factor VII was found to occur during alimentary lipemia, whereas the number of factor VII molecules remained constant or even appeared to decrease after the test meal. Activation of factor VII was more pronounced in control subjects than patients, and the proportion of activated factor VII molecules was higher in control subjects. Interestingly, factor VII activation, which correlated quantitatively with the degree of postprandial triglyceridemia, seemed to be related to FFA production during lipolysis of triglyceride-rich lipoproteins that were generated in response to fat intake. Postheparin plasma lipoprotein lipase activity was lower in patients, which could offer one explanation why factor VII activity was lower during alimentary lipemia in these subjects despite their exaggerated postprandial triglyceridemia. Thus, activation of coagulation factor VII during alimentary lipemia may result in a procoagulant state that is likely to promote the formation of a coronary thrombus in individuals with established coronary artery disease.

Adult↗