Combined hereditary deficiency of factors VII and VIII: a distinct coagulation disorder due to the 'lack' of an autosomal gene controlling factor VII and VIII activation?

A patient with a combined hereditary deficiency of factors VII and VIII is presented together with a family study. The main bleeding manifestations were easy bruising and bleeding after tooth extractions. No hemarthrosis was ever observed. The main laboratory features consisted in a mild prolongation of prothrombin time and of partial thromboplastin time. TG test was abnormal and was corrected by the addition of adsorbed normal plasma. Specific assays revealed a moderate defect of factors VII and VIII. All other clotting factors were within normal limits. The factor VII antigen in the propositus was normal or nearly normal. The factor-VIII-associated antigen was also normal. Five additional family members presented the same coagulation pattern and were variably symptomatic. The hereditary transmission pattern seems to be autosomal dominant. The defect appears to be due to a structural abnormality of a gene controlling factors VII and VIII activation.     

Activation of factor VII during alimentary lipemia occurs in healthy adults and patients with congenital factor XII or factor XI deficiency, but not in patients with factor IX deficiency

Factor VII activity (FVIIc), a risk marker for coronary heart disease, is increased during postprandial lipemia. Factor VII activation accompanies lipolysis of triglyceride-rich lipoproteins, but the nature of this association and whether it is causal remain uncertain. To explore this issue, four patients with homozygous factor XII deficiency, four with complete factor XI deficiency, six with factor IX deficiency, and their respective age- and sex-matched controls were given two isocaloric dietary regimens, one providing on average 136 g fat and the other 19 g fat. Blood was taken before breakfast, immediately before lunch at 195 minutes, and at completion of the study at 390 minutes. All samples for each subject and matched control were assayed as one batch for FVIIc, activated factor VII, and factor VII antigen (FVIIag). Activation of factor VII was observed with the high-fat regimen but not with the low-fat regimen in all controls, factor XII-deficient patients, and factor XI-deficient patients. No factor VII activation was observed during either regimen in factor IX-deficient patients, but a normal postprandial responsiveness of factor VII to dietary fat was restored in one patient who replicated the study after factor IX therapy. Plasma FVIIag was not altered postprandially in either regimen in any group of patients or controls. Factor IX apparently plays an obligatory role in the postprandial activation of factor VII, although the mechanism remains to be determined.     

Postprandial coagulation factor VII activity: the effect of monounsaturated fatty acids

The present study investigated the effect of monounsaturated fatty acids (MUFA) on postprandial coagulation factor VII activity. Fifteen healthy male volunteers consumed three meals containing equal amounts (40 g) of fat, but providing different proportions of MUFA (12, 17 and 24% energy) in random order. Fasting and postprandial blood samples were drawn every hour for 9 h. The magnitude of the postprandial triacylglycerolaemic response and the postprandial plasma non-esterified fatty acid (NEFA) concentrations were not significantly different following the three meals. Coagulation factor VII was activated during postprandial triacylglycerolaemia but the area under the curve of postprandial coagulation factor VII activity was not significantly different following the three meals. Regression analysis showed that fasting factor VII activity was the single most important factor affecting postprandial factor VII activity, irrespective of plasma lipid concentrations and meal fat composition. Peak postprandial factor VII activity was attained significantly earlier following the high-MUFA meal compared with the low-MUFA meal (6.33 (SD 2.16)h, 3.60 (SD 1.81)h respectively; P = 0.016). Regression analysis showed that meal MUFA content was the primary determinant of time to peak postprandial factor VII activity. Although the magnitude of postprandial coagulation factor VII activity was not affected by meal MUFA content, peak postprandial factor VII activity occurred earlier and fasting activity levels were quickly restored following the high-MUFA meal. A short-lived increase in factor VII activity may be more beneficial than a prolonged thrombotic response.     

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A competitive enzyme-linked immunoadsorbent assay (ELISA) technique has been developed to facilitate quantitative analysis of the earliest step in the initiation of the extrinsic pathway of coagulation, i.e., complex formation of factor VII/VIIa with tissue factor. The ELISA measures the binding of biotinylated human plasma factor VII to relipidated recombinant human tissue factor. Quantitation of the relative affinity (expressed as IC50) of any factor VII molecular population or structural analogue for tissue factor can be determined by competitive binding. Subnanomolar concentrations of both wild-type recombinant human factor VII (rFVII) and rFVII(R152Q), a mutation at the FVII activation site, competed effectively with biotinylated plasma-derived factor VII in binding to tissue factor. In contrast, the affinity of rFVII(R79Q), a mutation in the first epidermal growth factor-like domain, was 12-fold lower. Following activation of rFVII(R79Q), its affinity for tissue factor and enzymatic activity increased 4-fold and 6-fold, respectively. For wild-type rFVII, enzymatic activity rose significantly following activation. However, its affinity for tissue factor was unchanged. We conclude that both the activation state of factor VII and the mutation of amino-acid residues within the first epidermal growth factor-like domain may alter the affinity of factor VII for tissue factor.     

Cryoglobulinemia: dilemma for the reconstructive surgeon

A close inter-relationship between raised factor VII clotting activity and elevated blood lipids, particularly serum triglycerides, is well established. A study of factor VII, its activation state and of plasma lipids has been undertaken in two groups of healthy middle-aged males to elucidate this mechanism. A control group with normal factor VII levels were closely matched for age and body-mass index with a second group with elevated levels. Factor VII assays, using rabbit and bovine thromboplastin and a factor VII Ag method, were employed. Triglycerides correlated with the rabbit factor VII thromboplastin assay and factor VII Ag (P < 0.05) but not with the bovine thromboplastin method. Higher HDL-cholesterol and apolipoprotein A-I levels were found in subjects with increased factor VII (P < 0.001) and appeared to be due to differences in alcohol consumption. Cholesterol levels were significantly higher with elevated factor VII. Differential testing suggests that higher factor VII is predominantly mediated through a rise in total VII, rather than an increase in its activity state.     

Factor VIIa's first epidermal growth factor-like domain's role in catalytic activity

Factor VIIa-tissue factor complex formation initiates the extrinsic blood coagulation pathway. We investigated factor VIIa's first epidermal growth factor-like (egf1) domain's role in the catalytic activity increase caused when factor VIIa binds tissue factor. Starting with a factor VIIa with factor IX's egf1 domain (factor VII(IXegf1)a), we made 4 proteins with egf1 residues changed to those in factor VIIa, including E51A, D64Q, FG74-75PA, and K79R. We measured each enzyme's affinity for tissue factor and determined the enzymes' kinetic constants with and without tissue factor. The Kd for factor VII(IXegf1)a binding to tissue factor was 60-200-fold higher than that of factor VIIa depending on the assay employed. Only factor VII(IXegf1)a with the K79R (K79Ra) mutation, among all the mutants, had an effect on binding with a Kd 3-8-fold lower than that of factor VII(IXegf1)a. In kinetic analyses with a small peptide substrate, in the absence of tissue factor, factor VIIa, factor VII(IXegf1)a, and K79Ra had similar kcat's and Km's. With tissue factor, due to a kcat decrease, factor VII(IXegf1)a's catalytic efficiency (kcat/Km) was 2-fold lower than factor VIIa's. K79Ra's catalytic efficiency was intermediate between those of factor VIIa and factor VII(IXegf1)a. With factor X as substrate, in the absence of tissue factor, K79Ra and factor VII(IXegf1)a had catalytic efficiencies 1.5-fold and 2-fold lower than that of factor VIIa. In contrast, with tissue factor and with factor X as substrate, due to higher Km's, factor VII(IXegf1)a and K79Ra had only 9% and 33% of factor VIIa's catalytic efficiency. Our results suggest the egf1 domain's role in tissue factor binding involves critical alignment of tissue factor with factor VIIa's catalytic domain. Proper alignment in turn promotes optimal catalytic activities.     

The influence of vascular space involvement on the prognosis of patients with stage IB cervical carcinoma: correlation of results from hematoxylin and eosin staining with results from immunostaining for factor VIII-related antigen

Factor VII is a trace protein required for normal haemostasis. Deficiency of factor VII comprises a highly heterogeneous disease group. Factor VII deficiency can cause bleeding, in particular if factor VII is extremely low, but a few cases lacking factor VII function entirely or subtotally may not present with a history of bleeding. Bleeding problems are not often reported in patients having a factor VII:C level at 10-15% of normal or more. Bleeding is frequently of mucocutaneous type, but the whole array of haemophilic bleeding may also occur. To control bleeding, during surgery in particular, substitution is required in the severe case of factor VII deficiency, but clinical studies documenting which correctional levels of factor VII:C to aim are lacking. It appears that a critical low level (trough) value at 10-15% may be anticipated, but clear documentation does not exist. Substitution programmes may include plasma or plasma derived factor IX concentrates of lower degrees of purity, so-called prothrombin complex concentrates that also are relatively impure, and pure factor VII concentrates. An alternative is a recombinant factor VIIa molecule. However, this concentrate has not received license in a number of countries. Thrombotic manifestations appear to occur more often than expected in the factor VII deficient patients, some have been linked to the use of impure concentrates, others to preexisting thrombophilic risk factors, but some are unexplained and may bear a relationship to the deficiency state of factor VII itself. Controlled clinical trials are highly warranted in this rare bleeding condition.     

Correlation of factor VIIa values with factor VII gene polymorphism, fasting and postprandial triglyceride levels, and subclinical carotid atherosclerosis

BACKGROUND: Factor VII plays a pivotal role in coagulation. Factor VIIc levels were reported to be a risk factor for fatal coronary heart disease (CHD). Factor VIIc and VIIag levels were noted to be positively associated with plasma triglyceride (TG) levels and influenced by a VII gene polymorphism. The purpose of this study is to determine whether these associations are related to activated factor VII (factor VIIa). METHODS AND RESULTS: Fasting and 3.5-hour postprandial samples from 216 cases with subclinical atherosclerosis and 341 matched controls selected from the ARIC cohort were assayed for levels of factors VIIa, VIIc, and VIIag and TG, and factor VII codon 353 gene polymorphism. The level of factor VIIa was higher in Arg/Arg than in Arg/Gln+Gln/Gln genotypes, and the difference was in accord with that of factors VIIag and VIIc. However, the factor VIIa difference was statistically insignificant. Factor VIIa values were not correlated with fasting or 3.5-hour postprandial TG levels, nor were they associated with subclinical atherosclerosis. CONCLUSIONS: Factor VIIa levels, like factor VIIag and VIIc levels, are influenced by factor VII gene codon 353 polymorphism. However, unlike factor VIIag or VIIc, factor VIIa is not influenced by TG levels; none of these is associated with subclinical atherosclerosis.     

Prophylaxis and therapy with factor VII concentrate (human) immuno, vapor heated in patients with congenital factor VII deficiency: a summary of case reports

Hereditary factor VII deficiency is a rare autosomal recessive condition, usually associated with normal or reduced levels of a functionally defective molecule. The available means of treating this condition in North America presents serious health risks to the patient. Transfusion with fresh frozen plasma carries a risk of volume overload and a significant risk for viral transmission. Sustained prothrombin complex therapy is associated with a high risk for thrombogenic complications. This communication describes the use of Factor VII Concentrate (Human) Immuno, Vapor Heated--an intermediate purity factor VII concentrate from Immuno A.G.--for the treatment of 13 patients with factor VII deficiency. Treatment regimens described include those for long-term prophylaxis (three children), acute hemorrhages (two children, one adult), peripartum prophylaxis (one patient), and surgical coverage (two children, four adults). Prophylaxis and therapy were successful in all cases, the medication was well-tolerated, and there were no complications. In the three cases of long-term prophylaxis in children, doses of 10-50 IU/kg were given one to three times a week; one patient has undergone long-term prophylaxis for approximately 8 years, one patient for 1 year, and one patient for 1 1/2 years. Three cases in which Factor VII Concentrate was principally used for treatment of acute episodes of bleeding are described. One infant received Factor VII Concentrate on about 50 occasions for treatment of mucosal bleeding; a correction to 40-100% resulted in cessation of bleeding within 15 min in all cases. For treatment of an episode of intracranial bleeding, an 8-year-old boy received a dose of 37 IU/kg Factor VII Concentrate every 6 hr for peak factor VII levels of approximately 100% and troughs as low as 4% over the 11-day treatment period. A 37-year-old adult male with intracranial bleeding received alternating doses of 16 IU/kg and 8 IU/kg every 6 hr for 10 days with peak factor VII levels in the upper thirties (%). The peak favor VII level during surgical coverage with Factor VII Concentrate (neurosurgery, open reduction of ankle bones, dental surgery, pituitary adenoma surgery, closed liver biopsy) was approximately 100% in all cases, with trough levels ranging from 8 to 65% over treatment periods of 24 hr to 16 days using treatment intervals of 6-12 hr.     

Dietary fatty acids and blood coagulation

Factor VII coagulant activity (VIIc) is a risk factor for coronary heart disease (CHD). Plasma VIIc is positively associated with dietary fat intake, suggesting that fat-rich diets are accompanied by a hypercoagulable state. Reduction in total fat consumption is followed by a decrease in VIIc within 24 h. In adults taking diets rich in long-chain saturated fatty acids, a postprandial increase in VIIc occurs after a fatty meal irrespective of its fat composition. This effect has dose-response characteristics, persists for several hours, and is due to activation of factor VII. There is no acute effect of dietary fat on factor VII antigen (VIIag) concentration, but VIIag is positively related to dietary fat intake. More studies are needed on the effects of dietary fat composition on fasting and postprandial factor VII. Dietary fat appears to influence both the atherosclerotic and thrombogenic components of CHD.     

Lipoproteins and the haemostatic system in atherothrombotic disorders

The early belief that the haemostatic system has no active role in the formation of the atheromatous plaque is no longer tenable. Rather, the association between hypercholesterolaemia and atherosclerosis appears to arise in part because of various effects of high concentrations of LDL and VLDL particles on the cellular and humoral components of the system, thereby promoting plaque growth and thrombosis. These may be summarized as follows: 1. High concentrations of native LDL have been reported to promote the adhesion of monocytes to the endothelial cell, suggesting that the latter undergoes a form of activation upon such exposure. Oxidized LDL is more potent in this respect, and persistent exposure of endothelium to such particles can eventually lead to cell injury. 2. Activated endothelial cells acquire characteristics on their luminal surface conducive to thrombin generation and fibrin production. Thrombin has several actions on the endothelial cell, monocyte, smooth muscle cell and platelet which in the presence of hypercholesterolaemia will promote the formation of atheroma. 3. Oxidatively modified LDL can activate circulating monocytes, when they also acquire procoagulant properties which favour thrombin production. 4. Platelets show an increased tendency to aggregate when exposed to hypercholesterolaemic plasma. This effect may arise in part because the platelet of the hypercholesterolaemic patient expresses an increased number of fibrinogen binding sites on its surface following activation by agonists such as ADP. These hyperaggregable platelets adhere to activated endothelial cells which express von Willebrand factor on their surface, and to subendothelial proteins exposed in the gaps that open between injured endothelial cells. Platelets exposed to raised LDL levels also show a reduced sensitivity to prostacyclin, an antiaggregatory agent. Oxidatively modified LDL has been reported to stimulate aggregation of platelets in the absence of other agonists such as ADP or thrombin (spontaneous aggregation). 5. Platelet aggregation and fibrin deposition at sites of endothelial injury will create microthrombi which become incorporated into the lesion by organization, thereby increasing the fibrous and cellular content of the atheromatous plaque. 6. Lipolysis of triglyceride-rich lipoproteins at the endothelial cell surface leads to transient activation of the coagulation mechanism with activation of factor VII. Activated factor VII is a potent procoagulant when it forms a complex with tissue factor in the atheromatous lesion. Persistent hypertriglyceridaemia is accompanied by raised concentrations of factor X, factor IX, factor VII and prothrombin. 7. Hypertriglyceridaemia is associated with an increased plasma concentration of PAI-1 and a reduction in plasma fibrinolytic activity.(ABSTRACT TRUNCATED AT 400 WORDS)     

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A case of acquired hemophilia A in a 65-year-old woman is presented. The patient had been subjected to cholecystectomy 2 months before the bleeding tendency appeared. On admission, she had easy bruising and prolonged activated partial thromboplastin time, but during hospitalization she had severe hemorrhage into the right gluteal and femoral muscles. An inhibitor of the factor VIII coagulant protein (FVIII:C) of high Bethesda titer was found in her serum. The patient was successfully treated with activated recombinant human factor VII (rhFVIIa) and immunosuppression. We conclude that rhFVIIa is a safe, effective, and fast-acting preparation for the treatment of severe hemorrhage in patients with acquired hemophilia A, and that the simultaneous administration of azathioprine and corticosteroids may suppress production of the inhibitor.     

Cisplatin based chemotherapy in testicular cancer patients: long term platinum excretion and clinical effects

The authors have evaluated the behaviour of protein C activity, factor X and factor VII coagulant activity, and serum lipoprotein(a) before and after haemodialytic treatment in the plasma of patients on maintenance haemodialysis. The plasma level of protein C activity, depressed before haemodialysis, significantly increased during the course of haemodialysis; factor X and factor VII increased as well despite heparinization; serum lipoprotein(a) was abnormally elevated before haemodialysis and did not change after haemodialysis. In vitro incubation (30' at 37 degrees C) of uremic and healthy blood samples resulted in a decrease of serum lipoprotein(a) concentration. After heparin addition (final concentration 0.5 U/ml) lipoprotein(a) became higher in uremic blood only.     

Successful hemostasis during a major orthopedic operation by using recombinant activated factor VII in a patient with severe hemophilia A and a potent inhibitor

The treatment of bleeding episodes and the provision of perioperative hemostasis in patients with hemophilia in whom coagulation factor inhibitors have developed are a major therapeutic challenge because ordinary replacement therapy is usually ineffective. Herein we report the use of recombinant activated factor VII (rFVIIa) in providing successful hemostasis in a patient with hemophilia A and a high-titer inhibitor to factor VIII during a major orthopedic operation. rFVIIa (102 micrograms/kg) was administered intravenously every 2 to 3 hours for a total of 9 days. No excessive bleeding occurred intraoperatively or postoperatively, and no adverse effects attributable to rFVIIa were observed. This surgical procedure probably represented a greater hemostatic challenge than any previously reported operation in which rFVIIa was used. Thus, this article adds considerably to the growing body of literature that suggests the safety and efficacy of rFVIIa in providing perioperative hemostasis and treating severe bleeding episodes in patients with hemophilia and inhibitors refractory to other treatment modalities.     

Erythropoietin-induced recurrent veno-occlusive priapism associated with end-stage renal disease

A longitudinal study of 21 pregnant women has been undertaken using a variety of factor VII assays, including factor VIIa, to investigate the increase of factor VIIc. All assays demonstrated significant rises (p <0.001), most marked for factor VIIa (82%) and factor VIIc rabbit (81%). Smaller rises were seen for factor VIIc bovine (50%) and VII antigen (40%). Three indirect measures of activity state, factor VIIc rabbit:antigen, bovine:antigen and bovine:rabbit, provided conflicting data. Factor VIIa:antigen showed a significant increase of 36% (p <0.001). Within individual pregnancies the change in factor VIIc rabbit and antigen correlated with maternal weight gain (p < 0.05). Two activity state measures, bovine:rabbit and bovine:antigen, showed negative correlation with birthweight. The increases in both zymogen and in activity state appear to contribute to the factor VIIc rise. The extent of this rise appears to be influenced by maternal weight gain. Increased factor VII activation is associated with reduced foetal growth.     

Effect of long-term olive oil dietary intervention on postprandial triacylglycerol and factor VII metabolism

Although the beneficial effects of Mediterranean-type diets, which are rich in olive oil, a good source of monounsaturated fatty acids (MUFAs), are generally accepted, little is known about the effects of long-term dietary MUFA intake on postprandial lipoprotein metabolism and hemostasis. This study used a single-blind, randomized, crossover design to investigate the relative effects of a long-term dietary olive oil intervention and a control [saturated fatty acid (SFA)-enriched] diet on postprandial triacylglycerol metabolism and factor VII activity. The postprandial response to a standard test meal was investigated in 23 healthy men who adhered to both diets for 8 wk. cis-MUFAs were successfully substituted for SFAs in the MUFA diet without affecting total dietary fat or energy intakes. The long-term dietary MUFA intervention significantly reduced plasma and LDL-cholesterol concentrations (P = 0.01). Postprandial triacylglycerol concentrations were significantly greater in the early postprandial period after the MUFA diet (P = 0.003). Postprandial factor VII activation and the concentration of the factor VII antigen were significantly lower after the MUFA diet (P = 0.04 and P = 0.006, respectively). This study showed that isoenergetic substitution of MUFAs for SFAs reduces plasma cholesterol and reduces the degree of postprandial factor VII activation. The alterations in the postprandial triacylglycerol response suggest a greater rate of dietary fat absorption and postprandial triacylglycerol metabolism after a diet rich in MUFAs. This study presents new insights into the biochemical basis of the beneficial effects associated with long-term dietary MUFA consumption, which may explain the lower rates of coronary mortality in Mediterranean regions.     

Hemostasis in normotensive and hypertensive men: results of the PROCAM study. The prospective cardiovascular Münster study

BACKGROUND: The greater than normal cardiovascular risk of hypertensive patients could be partly due to an impairment of hemostatic balance found in such individuals. OBJECTIVE: To examine the relationship between hemostatic variables and blood pressures in 1950 apparently healthy male participants in the prospective cardiovascular Münster study aged 40-65 years. METHODS: Blood pressure and other variables were determined, including fibrinogen level, coagulation factor VII clotting activity, protein C level, antithrombin III level, plasminogen activator inhibitor-1 level, euglobulin fibrinolytic activity, and von Willebrand factor level. RESULTS: Age-adjusted mean values of coagulation factor VII clotting activity, plasminogen activator inhibitor-1 level, antithrombin III level, and protein C level in hypertensives and borderline hypertensives were significantly higher than those in normotensive men (e.g. for hypertensive versus normotensive men, coagulation factor VII clotting factor activity 111.5 versus 106.1%, plasminogen activator inhibitor-1 level 5.05 versus 3.22 arbitrary units/ml, and protein C level 111.1 versus 107.0%, P < 0.05-0.01). For most of the hemostatic variables we found positive bivariate correlations to blood pressure (P < or = 0.05). Exceptions were von Willebrand factor level (no correlation to blood pressure), and euglobulin fibrinolytic activity (a negative correlation to systolic blood pressure and no correlation to diastolic blood pressure). Significance persisted in the multiple logistic regression analysis with the exception of the relationships between systolic and diastolic blood pressures and fibrinogen level as well as euglobin fibrinolytic activity after adjustment for age. After adjustment for age and body mass index significance for relationships between systolic blood pressure and coagulation factor VII clotting activity as well as protein C level was also lost. CONCLUSIONS: We conclude that the greater than normal cardiovascular risk of hypertensive patients is partly due to an imbalance in hemostasis.     

The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0

Vitamin K antagonists are most commonly used in long-term thrombosis prophylaxis and the use in patients with cardiovascular disease seems to be increasing. By interfering with the normal hemostatic mechanism, an increased risk of bleeding will arise and administration of human plasma or prothrombin complex concentrates may be necessary. It can be difficult to normalize hemostasis using plasma and prothrombin complex concentrates, because these may be associated with thromboembolic side-effects. The level of factor VII, one of the vitamin-K-dependent coagulation factors, decreases during oral anticoagulant therapy and the administration of recombinant factor VIIa normalizes the prolonged prothrombin time in warfarin-treated rats. After administration of acenocoumarol (International Normalized Ratio > 2), decreased levels of factor X and factor IX (19-46%), protein C (2-20%) and factor VII (4-17%) were found in 28 healthy volunteers. After one dose of recombinant factor VIIa (5, 10, 20, 40, 80, 120, 160, 240, or 320 microg/kg) the International Normalized Ratio and prothrombin time normalized, which may imply an effect on bleeding in individuals receiving oral anticoagulant therapy. The lowest dose (5 microg/kg) normalized the International Normalized Ratio for 12 h and doses > 120 microg/kg normalized it for 24 h. Fragment 1+2 stayed within its normal range in all dose groups, indicating that no systemic coagulation occurred.