Factor VIIc Research Articles

Thrombophilia in patients with hypercholesterolemia

To investigate a possible interrelationship between hypercholesterolemia and the coagulation and fibrinolytic system, the Cardiovascular Disease Risk Factor Two-Township Study in Taiwan was undertaken as a longitudinal prospective study focusing on the evolution of cardiovascular disease risk factors, with an emphasis on hemostatic factors. Hemostatic parameters measured in this study included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, factor VIIc, factor VIIIc, antithrombin III, and plasminogen. Subjects of both sexes with hypercholesterolemia (> 6.2 mmol/L) also had significant elevations of diastolic blood pressure, plasma glucose, triglycerides, fibrinogen, and factor VIIc and reduced PT and APTT compared with subjects with lower cholesterol. The hypercholesterolemic women additionally had significant elevations of systolic blood pressure and factor VIIIc. Levels of the anticoagulant factors, antithrombin III and plasminogen, were also higher in both hypercholesterolemic men and women. In men, only factor VIIIc had no statistically significant elevation. In women, only PT showed no statistical difference. Established coronary risk factors such as fibrinogen and factor VIIc showed remarkable elevations in patients of both sexes. Using Pearson correlation and multiple regression, the most significant parameter related to cholesterol level was factor VIIc. The present results show that hemostatic abnormalities do exist in patients with hypercholesterolemia, and this thrombophilic phenomenon sheds further light on the study of higher cardiovascular mortality in these subjects.

Myocardial Revascularization in a Hemophiliac

The case of a mild hemophiliac who underwent a successful and uncomplicated myocardial revascularization is presented. The procedures was safely performed while the patient was receiving factor VIIIC.

Myocardial revascularization in a hemophiliac

The case of a mild hemophiliac who underwent a successful and uncomplicated myocardial revascularization is presented. The procedures was safely performed while the patient was receiving factor VIIIC. Copyright © 1996 The International Society for Cardiovascular Surgery.

Antithrombin and Atherosclerosis in the Rotterdam Study

Antithrombin is a potent inhibitor of thrombotic tendency. Whether atherosclerotic disease is associated with high or low antithrombin is unclear. Studies of the relation between antithrombin and presence of arterial disease have shown contrasting results. In the Rotterdam Study, a single-center, population-based cohort study of 7983 subjects aged 55 years and older, the association between atherosclerosis and antithrombin was evaluated. The ratio of ankle to arm blood pressure is a graded marker for atherosclerosis and provides the opportunity to investigate nonlinear associations. In the first 1427 participants of the Rotterdam Study who did not use anticoagulants, both antithrombin and the ratio of ankle to arm blood pressure were measured. In men the association between the two was quadratic: antithrombin activity was increased in men with moderate peripheral arterial atherosclerosis compared with those without, and in men with more severe atherosclerosis it was decreased. In women the association was linear: a decreased ratio of ankle to arm pressure was associated with increased antithrombin activity. These associations were independent of smoking, body mass index, serum lipids, fibrinogen, and factor VIIc. We propose that antithrombin activity rises in response to increased risk of cardiovascular disease and also in response to the presence of atherosclerosis, whereas antithrombin may decrease with increasing severity of the atherosclerotic process in men. This may explain the contrasting results found in previous studies. Changes in antithrombin over time might be useful in predicting the risk of cardiovascular disease and progression.

Vascular risk factors, atherosclerosis, cerebral white matter lesions and cerebral perfusion in a population-based study.

We studied risk factors for cerebral vascular disease (blood pressure and hypertension, factor VIIc, factor VIIIc, fibrinogen), indicators of atherosclerosis (intima-media thickness and plaques in the carotid artery) and cerebral white matter lesions in relation to regional cerebral blood flow (rCBF) in 60 persons (aged 65-85 years) recruited from a population-based study. rCBF was assessed with single-photon emission tomography using technetium-99m d, l-hexamethylpropylene amine oxime (99mTc-HMPAO). Statistical analysis was performed with multiple linear regression with adjustment for age, sex and ventricle-to-brain ratio. A significant positive association was found between systolic and diastolic blood pressure and temporo-parietal rCBF. In analysis with quartiles of the distribution, we found a threshold effect for the relation of low diastolic blood pressure (</=60 mmHg) and low temporo-parietal rCBF. Levels of plasma fibrinogen were inversely related to parietal rCBF, with a threshold effect of high fibrinogen levels (>3.2 g/l) and low rCBF. Increased atherosclerosis was related to low rCBF in all cortical regions, but these associations were not significant. No consistent relation was observed between severity of cerebral white matter lesions and rCBF. Our results may have implications for blood pressure control in the elderly population.

448 Fibrinogen and factor VIIC levels after myocardial infarction and genetic variation

448 Fibrinogen and factor VIIC levels after myocardial infarction and genetic variation

Acquired von Willebrand disease in children with a Wilms' tumor

The association between acquired von Willebrand disease and Wilms' tumor has been reported in eight cases: four cases reports and one prospective study of Coppes et al. (J. Clin Oncol 10:422-427, 1992) who found this in four out of 50 patients. We retrospectively studied 73 children who were diagnosed with a Wilms' tumor between 1970 and 1993. All patients were treated according to the running international SIOP protocol. According to our local diagnostic workup protocol, blood samples for screening coagulation tests were obtained at diagnosis and during preoperative chemotherapy. Since 1984, factor VIII analysis was added. In four patients, no coagulation screen was done. Bleeding time and screening tests apart from APTT were normal in all 69 children tested before or within 2 days after starting therapy. In 47 out of 73 patients, an APTT was performed before starting therapy. In 19 patients (40%), it was prolonged (>33 sec). In 8 of them (17%), the prolongation was severe (> or = 40 sec). In 11 out of the 19 patients, factor VIIIc, factor VIIIag, and factor VIII RcoF determinations were done. In two children, all three factors were decreased suggestive for von Willebrand disease. One of the 19 patients with a prolonged APTT had hematuria. The others had no increased bleeding tendency or signs of bleeding in the tumor. In all patients, the prolonged APTT normalised during preoperative chemotherapy within 6 weeks. Frequent blood samples were obtained of the two children with acquired von Willebrand disease and showed normalisation of the coagulation disorder after 1 and 2 weeks, respectively. No specific therapy to correct the coagulation abnormalities was given to any patient.

Coagulation abnormalities in patients with Gaucher's disease: Effect of therapy

Various coagulation defects have been associated with Gaucher's disease, including factor IX deficiency and acquired von Willebrand's disease (VWD). We performed repeated coagulation assays in 9 patients with Gaucher's disease over a period of 2 years. The prothrombin time (PT) and fibrinogen levels were normal in 8 of 9 patients, while the partial thromboplastin time (PTT) was abnormal in 5 of 9; all mixing PTT tests showed correction. Factor IX was normal repeatedly in the 7 of 7 patients tested. In contrast, factor XI was decreased in 3 of 9 patients assayed. Anticardiolipin (ACL) IgM was normal in all patients. ACL IgG was highly variable; levels were abnormal at least once in 6 of 8 patients, but were also normal at least once in 7 of 8 patients. Factor VIII was also quite variable: levels were decreased at least once in 4 of 9 patients, and normal at least once in 8 of 9 patients. Von Willebrand factor antigen (VWF Ag) studies were normal in 7 of 8 patients, but VWF activity was decreased at least once in 4 of 8 patients. In some patients, these problems could be overcome by specimen dilution. In ony 1 patient was VWF Ag decreased; this patient had a factor VIIIC level of 13% , and VWF activity of 18.7%. Coagulation assays performed before and after alglucerase administration failed to demonstrate any significant improvement in these assays, and neither was there a consistent improvement over the duration of therapy. We suggest that previously reported decreases in factor IX and VWF may be secondary to the interfering presence of increased cerebroside levels. Caution must be used in the interpretation of clotting assays in the patient with Gaucher's disease.

Effects of unsaturated fatty acids on blood clotting and fibrinolysis.

The importance of factors influencing blood clotting and fibrinolysis in preventing coronary events is now established. Modification of these factors is likely to be of more immediate benefit to an elderly population than factors influencing the atherogenic process. Although good evidence shows that intake of long chain fatty acids (> C12) is a major determinant of factor VIIc, little evidence supports the importance of the degree of unsaturation. The role of unsaturated fatty acids in thrombogenesis still remains controversial.

Influence of Contraceptive Pill Use, Premenopause and Postmenopausal State on Hemostatic Parameters in Ethnic Chinese Women.

Background: Epidemiological studies has shown that increased fibrinogen and factor VIIc are two independent risk factors for cardiovascular disease (CVD). Postmenopausal women have a higher incidence of CVD than premenopausal women; one possible explanation is the increase of fibrinogen. Purpose: This study was undertaken to evaluate the influence of oral contraceptive pill use and postmenopausal status on coagulation factors in ethnic Chinese women. Patients and methods: This study included 1402 women aged 40-55 years, with 288 premenopausal women taking oral contraceptives and 364 postmenopausal women. All subjects underwent blood examination of prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIIc, factor VIIIc, plasminogen, and antithrombin III. Results: Data show that oral contraceptives users had a significant increase in plasminogen (91.7 +/- 40.7 vs. 80.0 +/- 26.5%; p < 0.01), while the levels of other hemostatic parameters were similar to non-contraceptive pill users. Postmenopausal women also had higher levels of plasminogen (113 +/- 36.2 vs. 108.7 +/- 30.7%; p = 0.06); the other parameters also show no statistical significance. Conclusions: Contrary to previous reports, which show elevation of fibrinogen and antithrombin III in menopause and in pill users, this study shows that only plasminogen levels exhibit a statistically significant contraceptive trend in Chinese women. Whether racial difference may account for the discrepancy in the present results needs further evaluation.

Hemostatic Disorder of Uremia: The Platelet Defect, Main Determinant of the Prolonged Bleeding Time, Is Correlated with Indices of Activation of Coagulation and Fibrinolysis

Several parameters of primary hemostasis and markers of activation of coagulation and fibrinolysis were measured in 48 patients with severe (creatinine clearance < 20 ml/min) chronic renal failure (CRF) without dialysis and disease or drugs affecting hemostasis. Bleeding time (BT) was prolonged in 25/48 patients, and was correlated with age of patients, severity of renal failure, hematocrit, impairment in platelet aggregation-secretion and decrease in platelet ATP content. Defects in von Willebrand factor played no role in the prolongation of the BT. Multivariate analysis showed that only platelet dysfunction and severity of renal disease were independent predictors of the BT in uremia. The platelet functional disorder was significantly correlated with a reduction in platelet ATP and ADP. High levels of plasma thrombin-antithrombin complexes (TAT), prothrombin fragment F1 + 2, fibrinogen and factor VIIc were observed in patients with CRF, as described in prethrombotic states. Plasmin-antiplasmin complexes (PAP), fibrinogen and fibrin degradation products (FgDP, FnDP) were significantly increased, and the activity of plasminogen activator inhibitor (PAI-1) was slightly reduced, denoting an activation of fibrinolysis. A negative correlation was found between platelet levels of ATP and ADP with plasma TAT, F1 + 2 and PAP. Furthermore, plasma PAI-1 activity was negatively correlated with the BT and was lower in patients with prolonged BT as compared with controls and patients with normal BT. These links between primary hemostasis and activation of coagulation and fibrinolysis suggest that increased intravascular generation of thrombin and/or plasmin is an important mediator of the defects in primary hemostasis, prolongation of the BT and, probably, bleeding in CRF.

Levels of Factor VIIc Associated With Decreased Tissue Factor Pathway Inhibitor and Increased Plasminogen Activator Inhibitor-1 in Dyslipidemias

Tissue factor pathway inhibitor (TFPI), a kunitztype inhibitor of the extrinsic coagulation pathway, factor VII coagulant (FVIIc), FVIIa, and the fibrinolytic factors plasminogen activator inhibitor-1 (PA1-1) and tissue plasminogen activator (TPA) have been studied in various hyperlipidemias. Compared with a normal lipidic group, mean TFPI activity was 70% higher (P < .001) and 36% higher (P < .001) in type IIa and IIb hyperlipidemias, respectively, and was lower by 13% in type IV hyperlipidemia (P = .05). TFPI was correlated with LDL cholesterol (P < .001), total cholesterol (P < .001), HDL cholesterol (P < .01), apolipoproteins (apo) AI (P < .001) and B (P < .001) and lipoprotein a (P < .01). TFPI was negatively correlated with the triglyceride level (P < .05); the correlation was dependent on LDL cholesterol and HDL cholesterol levels, which were decreased in type IV hyperlipidemia. FVIIc activity (P < .001) was increased by 30% in both type IV and type IIb hyperlipidemia and was correlated with triglyceride levels. FVIIa was not significantly increased in any group compared with control group. FVIIc was correlated with triglyceride level (P < .001), while FVIIa was not. Interestingly, FVIIa was correlated with FVIIc (r = .5, P < .001) in the control group as well as in the hyperlipidemic groups (r = .32, P < .01). These results favor the hypothesis that higher FVIIc concentrations in hyperlipidemic patients are likely due to enhancement of synthesis of FVII and that a part of this FVII circulates in an activated chemical form. Compared with the control group, PAI-1 activity was twofold higher (P < .08) in type IIa hyperlipidemia, threefold higher (P < .001) in type IIb hyperlipidemia, and fourfold higher in type IV hyperlipidemia (P < .001). PAI-1 activity correlated with triglyceride levels (P < .001), apoB levels (P < .001) and total cholesterol levels (P < .05). These correlations were dependent on apoB and probably reflect the correlation between PAI-1 and VLDL. In contrast, TPA level was normal in the different hyperlipidemias. No correlation was found between TFPI, FVIIc, and PAI-1. Variation of TFPI activity appears to be related to the variations of its main lipoprotein carriers: LDL, HDL, and Lp (a). The association in hypertriglycemic patients of hypercoagulability (increased FVIIc and decreased TFPI) and hypofibrinolysis (increased PAI-1) may explain thrombosis predisposition of some of these patients. However, it would be interesting to study the increased levels of endothelium-derived TFPI in plasma induced by the injection of heparin.

Effect of marine oils supplementation on coagulation and cellular activation in whole blood

A study was performed to explore the effects of supplemental intake of various marine oils known to be part of the Eskimo diet. Healthy men and women (134) were randomly selected to consume 15 mL/d of oil from blubber of seal, cod liver, seal/cod liver, blubber of Minke whale, or no oil for ten weeks. Total cholesterol was unchanged in the oil groups, whereas high density lipoprotein cholesterol increased 7% in the seal/cod liver oil (CLO) group (P < 0.05) and 11% in the whale oil group (P < 0.005). Triacylglycerol was significantly reduced in the CLO group only. The concentration of prothrombin fragment 1 + 2 was reduced 25% (P < 0.05) after whale oil supplementation. No change in fibrinogen or factor VIIc was detected. Tumor necrosis factor generation in lipopolysaccharide (LPS)-stimulated blood was 30% reduced after whale oil (P < 0.05), but was unaffected by intake of seal or CLO. The LPS-induced tissue factor activity in monocytes was reduced to a significant degree only in the seal/CLO group (34%) and whale oil group (35%) (P < 0.05). The most dramatic change in thromboxane B2 in LPS-stimulated blood was seen after whale oil intake with 44% reduction (P < 0.01). Supplementation of a regular diet with a combination of seal oil and CLO and especially with whale oil seems to have beneficial effects on several products thought to be associated with cardiovascular and thrombotic diseases.

Acquired von Willebrand's Syndrome Causing a Hemorrhagic Diathesis in a Patient with Hypothyroidism

The occurrence of bleeding diathesis with menorrhagia and easy bruising may occur in patients with moderate to severe hypothyroidism sometimes linked to acquired von Willebrand's disease (VWD). We describe a patient with profound hypothyroidism in whom the diagnosis of hypothyroidism was established while evaluating uncontrolled gingival bleeding after a dental procedure. Thyroid hormone replacement led to a rise in von Willebrand factor, factor VIIIC, and a significant fall in the elevated bleeding time from 15 to 8 min. Acquired von Willebrand's disease is an unusual manifestation of hypothyroidism and is reversible.

Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease

To examine the hypothesis that the increase in fibrinogen concentration and respiratory infections in winter is related to seasonal variations in vitamin C status (assessed with serum ascorbate concentration). Longitudinal study of individuals seen at intervals of two months over one year. Cambridge. 96 men and women aged 65-74 years living in their own homes. Haemostatic factors fibrinogen and factor VIIC; acute phase proteins; respiratory symptoms; respiratory function. Mean dietary intake of vitamin C varied from about 65 mg/24 h in winter to 90 mg/24 h in summer; mean serum ascorbate concentration ranged from 50 mumol/l in winter to 60 mumol/l in summer. Serum ascorbate concentration was strongly inversely related to haemostatic factors fibrinogen and factor VIIC as well as to acute phase proteins but not to self reported respiratory symptoms or neutrophil count. Serum ascorbate concentration was also related positively to forced expiratory volume in one second. An increase in dietary vitamin C of 60 mg daily (about one orange) was associated with a decrease in fibrinogen concentrations of 0.15 g/l, equivalent (according to prospective studies) to a decline of approximately 10% in risk of ischaemic heart disease. High intake of vitamin C has been suggested as being protective both for respiratory infection and for cardiovascular disease. These findings support the hypothesis that vitamin C may protect against cardiovascular disease through an effect on haemostatic factors at least partly through the response to infection; this may have implications both for our understanding of the pathogenetic mechanisms in respiratory and cardiovascular disease and for the prevention of such conditions.

Coagulation activation in type 2 diabetes mellitus: the higher coronary risk of female diabetic patients.

Thrombophilia in diabetic patients is a well-recognized phenomenon which constitutes an additional risk of coronary heart disease. This study included 1980 ethnic Chinese people (835 male, 1145 female); age range: 45 to 69 years, including 280 Type 2 diabetic patients (male 125, female 155). Haemostatic parameters measured were fibrinogen, prothrombin time, activated partial thromboplastin time (APTT), factor VIIc, factor VIIIc, antithrombin III, and plasminogen. Compared with a control group, male diabetic patients showed significantly shorter APTT (25.6 +/- 3.7 vs 27.5 +/- 3.6 s, p < 0.001), and elevated factor VIIIc (171.1 +/- 77.48 vs 131.16 +/- 52.23%, p < 0.0001), whereas female diabetic patients showed significantly shorter APTT (24.9 +/- 4.2 vs 26.5 +/- 3.9 s, p < 0.001) and elevated fibrinogen (10.6 +/- 3.3 vs 9.8 +/- 2.6 mumol 1(-1), p < 0.05), factor VIIc (150.4 +/- 68.7 vs 135.3 +/- 32.3%, p < 0.001), factor VIIIc (190.1 +/- 92.6 vs 141.1 +/- 62.4%, p < 0.0001), and plasminogen (140.3 +/- 41.9 vs 128.4 +/- 38.7%, p < 0.01). This study showed that Chinese diabetic patients had coagulation activation, and that female diabetic patients seemed to constitute a higher risk group for coronary heart disease than males.

Haemostasis Factors in Angina Pectoris; Relation to Gender, Age and Acute-phase Reaction

The ECAT Angina Pectoris Study is a European multicentre study with the aim of investigating the pathogenetic and predictive role of haemostatic factors in the progression of coronary heart disease. It is the largest study performed up to now with regard to both the number of patients with angina pectoris (n = 3043) and the number of haemostasis assays (n = 23) included. The present paper presents baseline cross-sectional data with particular reference to the relationship of haemostatic factors with each other and with the coronary risk factors age, gender and acute-phase reaction (1). Two clusters of haemostatic factors could be distinguished in which each variable was correlated (P < 0.001) to every other variable: (a) Eight fibrinolysis assays including t-PA, PAI-1 and euglobulin clot lysis time (ECLT), for which PAI-1 appeared to be the dominating factor; (b) antithrombin III, protein C, alpha 2-antiplasmin and plasminogen, the interdependence of which has no obvious explanation. (2). Twelve out of the 23 haemostasis assays were associated (P < or = 0.01) with age. Except for alpha 2-antiplasmin, these relationships indicated an increased tendency to thrombosis with increasing age. (3). Gender differences found in 14 haemostasis parameters do not indicate a consistent difference in the tendency to thrombosis between men and women. Eight haemostasis parameters were on average higher in female than in male patients in the age group over 50 years. (4). C-reactive protein, an acute-phase reactant, was positively correlated (P < 0.001) with fibrinogen, factor VIIIc, von Willebrand factor, the fibrinolysis assays t-PA, PAI-1, ECLT and plasminogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic Determination of Coagulation Factor VIIc Levels among Healthy Middle-aged Women

A recent study (1) reported variation among men in clotting factor VIIc levels is associated with a genetic polymorphism detected by the restriction enzyme Msp I. The present study determined the Msp I genotype (Arg353, Gln353 alleles) for 189 women (mean age 53) who were subjects in the Healthy Women Study, a population study of CHD risk factor change at menopause. Women with the Arg/Arg genotype (n = 147) had an 16% higher (geometric) mean FVIIc level than those with the Arg/Gln (n = 41) genotype (1.21 vs 1.04 U/ml, p < 0.01), while the one subject with the Gln/Gln genotype had an FVIIc level of 1.00 U/ml. These results are consistent with those previously found in healthy men (1). In addition, women carrying the Gln allele did not exhibit the elevation in FVIIc with menopause and use of hormone therapy found among those with the Arg allele, suggesting that genotype may modify the observed rise in factor VIIc at menopause. Possibly because of the small sample size this interaction did not reach conventional levels of statistical significance. Results of multiple linear regression analyses controlling for age, hormone use, obesity, (ln) triglyceride levels, and family history of CHD found FVIIc levels to be significantly (p < 0.001) related to genotype. Thus, genotype appears to be a major determinant of FVIIc levels among women.

Alpha interferon for hepatitis C virus infection in haemophilic patients.

We have conducted a controlled trial in 20 haemophilic patients in which intravenous recombinant interferon alpha-2a, 3 mega units thrice weekly, was used to treat chronic hepatitis C infection. The study endpoints included complete and paritial normalization of serum ALT, and loss of serum HCV RNA as determined by polymerase chain reaction (PCR). Interferon treatment was effective, and resulted in improvement in ALT in nine (45%) and a loss of HCV RNA in five patients (26%), but a sustained normalization of ALT has been seen in only one case. Responses were poor in those with HIV coinfection or with HCV genotype 1 (Simmonds classification). Troublesome side-effects were reported in 80%. The occurrence of a factor VIIIc inhibitor during the study was possibly an autoimmune complication of interferon. In conclusion, we have shown lower response rates than those seen in post-transfusion hepatitis C infection and suspect that current interferon regimes are unlikely to influence the natural history of HCV infection in haemophilia. Consideration should be given to trials of higher dosage interferon, and of long-term maintenance therapy for those who relapse.

Definition of the Bleeding Tendency in Factor XI-Deficient Kindreds–A Clinical and Laboratory Study

Individuals with severe factor XI deficiency are prone to excessive bleeding after injury or surgery, but the existence of a haemorrhagic tendency in partial factor XI deficiency is controversial. In this study, 172 members of 30 kindreds (20 non-Jewish) transmitting factor XI deficiency in North West England were interviewed and a bleeding history questionnaire completed. Blood was taken for coagulation assays. The questionnaires were categorised independently by two assessors to determine presence or absence of a bleeding tendency, in the absence of information about the factor XI level or family history. Analysis shows that 48% of heterozygotes have a bleeding tendency. Eighteen (60%) families came to attention because of bleeding problems in heterozygotes. Comparison of histories between partially deficient and non-deficient individuals demonstrated a higher incidence of menstrual problems, an increase in significant bruising, and an increased likelihood of excessive bleeding after tonsillectomy and dental extractions. The incidence of von Willebrand's disease was not increased, but individuals with heterozygous factor XI deficiency who were bleeders tended to have lower levels of factor VIIIc and von Willebrand factor, and were more commonly of blood group 0. These features may contribute to the bleeding tendency. There was no evidence of alteration in factor VII activity (as defined by the ratio of activity to antigen) between the bleeders and non-bleeders. This is convincing evidence for abnormal bleeding in factor XI deficiency which is not confined to severely deficient patients.