(Circulation. 2000;101:372.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Relationships Between Homocysteine, Factor VIIa, and Thrombin Generation in Acute Coronary Syndromes
From the National Heart and Lung Institute, Cardiology and Haematology departments, Charing Cross Campus, Imperial College School of Medicine, London, UK.
Correspondence to Dr M Al-Obaidi, National Heart and Lung Institute, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, UK. E-mail m.al-obaidi{at}rbh.nthames.nhs.uk
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Background—It has been suggested by clinical, epidemiological, and experimental in vitro studies that homocysteine potentiates thrombin generation. This prothrombotic effect however has not previously been demonstrated in patients presenting with acute coronary syndromes (ACS).
Methods and Results—Patients with ACS (n =117) presenting with confirmed acute myocardial infarction (MI) (n =57) or unstable angina pectoris (UAP) (n =60) were consecutively recruited together with patients (n =18) in whom the presenting chest pain was not of cardiac origin (NCP), included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography, and both Factor VIIa and prothrombin fragment F1+2 were analyzed by ELISA. There were significant elevations in F1+2 in MI (P<0.001) and UAP (P=0.003), and modest elevations in Factor VIIa in UAP (P<0.05) compared with NCP but no differences in homocysteine levels among those groups. On dividing patients with ACS into quartiles of homocysteine, there was a stepwise increase in F1+2 (P<0.0001) and of Factor VIIa (P<0.05). There were significant correlations in ACS between homocysteine and F1+2 (r=0.46, P<0.0001), homocysteine and Factor VIIa (r=0.24, P<0.01), and F1+2 and Factor VIIa (r=0.41, P<0.0001). There was no correlation between homocysteine and either F1+2 (r=-0.15, P=0.57) or Factor VIIa (r=0.22, P=0.37) in the NCP patients.
Conclusions—Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS.
Key Words: coagulation • risk factors • heart disease • endothelium
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Recent epidemiological studies have shown that moderately elevated plasma homocysteine concentrations are associated with an increased risk for the development of atheromatous (cerebrovascular1 2 and peripheral vascular disease3 4 and thrombotic vascular diseases (deep vein thrombosis).5 Coronary artery disease may encompass both an atheromatous lesion and thrombosis during acute coronary events. There is a known association between elevated homocysteine levels and the development of coronary artery disease.6 7
Homocystinuria, the genetic form of hyperhomocystinemia, is associated with a marked rise of plasma homocysteine levels and an early risk of mortality from thrombotic vascular disease.8 Although the exact mechanism of atherothrombosis associated with hyperhomocystinemia is not clearly understood, several studies have pointed to an association with inhibition of thrombomodulin activity,9 reduction of protein C activation,10 11 increased platelet aggregation,12 and predisposition to endothelial cell injury.13 14 Most of these studies, however, were in vitro studies, where supraphysiological concentrations of homocysteine were used.
Disruption of coronary arterial atheromatous plaques is known to initiate a thrombotic process15 16 leading to complete or partial occlusion in the acute coronary syndromes (ACS) of myocardial infarction (MI) and unstable angina pectoris (UAP). Disrupted coronary plaques are thought to contain an abundance of tissue factor17 which, when exposed to circulating blood, forms a complex with Factor VII/VIIa initiating the coagulation cascade. Factor VIIa is generated by enzymatic cleavage of Factor VII by various circulating proteases, resulting in rapid generation of Factor IXa and Factor Xa. How these processes may be influenced by homocysteine in plasma in clinical syndromes characterized by artherothrombotic disease is uncertain.
We report an investigation of the relationship between plasma homocysteine and activation of coagulation in patients presenting with acute coronary ischemia, studied on admission and before clinical intervention.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Study Population
Consecutive patients (n=135) were recruited on admission to the Coronary Care Unit at Charing Cross Hospital in London between October 1995 and January 1997. Written informed consent was obtained from all the patients with the approval of the local ethical committee at Charing Cross Hospital. The patients were given a provisional diagnosis to guide appropriate treatment, but this diagnosis was subsequently reviewed during follow-up, and final diagnoses (MI, UAP and noncardiac chest pain [NCP]) were used in all analyses.
Ml was diagnosed according to the World Health Organization criteria.18 UAP was diagnosed if the WHO criteria for MI were not met, all enzyme measurements (creatine kinase, aspartate transaminase, hydroxybutyrate dehydrogenase) were below twice their upper reference range throughout the routine sampling period (daily for 3 days). Evidence of ischemic heart disease was demonstrated by either follow-up cardiac event (death, coronary revascularization, or Ml), a positive exercise treadmill test (>0.1 mV ST segment depression 80 ms after the J point) or demonstration of ischemia on thallium radio-isotopic scanning. NCP was diagnosed if angina was excluded by an alternative source of pain, a negative exercise treadmill test, or normal coronary anatomy on subsequent angiography. Patients were excluded from the study if they were receiving anticoagulant treatment before admission.
Clinical Data
Full clinical, biochemical, management and result of
investigations were recorded on all patients. Clinical
details included risk factor assessment for coronary artery
disease. Smoking status was classified as current smokers and
nonsmokers; current smokers included individuals who stopped <4 weeks
before enrollment in the study. A known history of hypertension and/or
diabetes mellitus and treatment received before admission were also
recorded. Routine lipid profile estimation was performed on
admission for all the patients documenting their total
cholesterol, triglycerides, and HDL levels.
Protocol
Venous blood samples were obtained on admission by trained
medical or senior nursing staff from a cuffed antecubital vein before
initiation of thrombolysis or anticoagulant treatment.
Care was taken to obtain this sample with a fresh needle and syringe.
Blood was transferred into bottles containing 0.105 mol/L sodium
citrate for Factor VIIa and F1+2 assay and bottles containing EDTA
(7.5%) for homocysteine assay (Becton Dickinson). Within 15 minutes of
collection, platelet-poor plasma was obtained by
centrifugation at room temperature for 15 minutes at
3000g, flash frozen on dry ice, and then transferred to a
-80°C freezer. Blind analysis of all samples was performed
in batches at completion of sample collection. The protocol for sample
collection and storage was formulated during a prior study published
elsewhere.19 Emphasis was put on clean
venipuncture to minimize artifacts. This was a particular
concern because sampling was performed in the environment of a busy
coronary care unit. To provide reassurance that artifactual
elevations in samples was minimal, blood samples were also taken from a
group (n =11) of age-matched healthy controls; these samples were
similarly processed and assayed. The results of the assay of these
samples were not significantly different from those of the NCP group
(which were collected in the coronary care unit and
subsequently assayed blind), suggesting that the sampling strategy
was adequate.
Homocysteine Measurements
Plasma total homocysteine, which includes the sum of
protein-bound and free homocysteine, was measured by
high-performance liquid chromatography with
fluorescence detection.20 21 The intra- and
interassay coefficients of variation were 
5%. Plasma homocysteine
was recorded in micromoles per liter.
Factor VIIa and Prothrombin Fragment F1+2 Measurements
These were performed with specific ELISAs (developed in-house
and fully reported elsewhere).19 22 23 The assay for F1+2
was performed as originally described23 and has intra- and
interassay coefficients of variation of 
10% and 15%,
respectively. The normal laboratory mean (±SEM) is 31.0±3.7 ng/mL,
which corresponds to 0.88±0.11 nmol/L. The Factor VIIa assay was
modified, as described22 by replacement of the standard,
which altered the normal mean to 0.25±0.10 ng/mL (0.005±0.003
nmol/L). The intra- and interassay coefficients of variation are 4%
and 10%, respectively. The ELISA to Factor VIIa measures free
Factor VIIa in plasma. Free Factor VIIa will have been generated and
released from a cell surface on which tissue factor has been expressed.
By its nature, the Factor VIIa ELISA cannot measure any Factor VIIa
still bound to the cell surface.
Statistical Methods
Because the distribution of values for plasma homocysteine,
F1+2, and Factor VIIa were positively skewed, the variables were
logarithmically transformed; geometric means (95% CI), unless
otherwise stated, are presented throughout the text, tables,
and figures. Median and interquartile (25th to 75th) ranges of plasma
homocysteine were used to categorize the patients into quartiles in MI
(12.7, 11.6 to 16.8 µmol/L), UAP (13.1, 10.2 to 16.5
µmol/L), and ACS (12.9, 10.9 to 16.5 µmol/L). Patients with a
final diagnosis of NCP were used as controls to establish that in those
patients with definite ACS, coagulation activation had occurred and
sampling artifacts had been kept to a minimum. The median homocysteine
level of 12.0 µmol/L was used to categorize the NCP patients
above and below this level. Group comparisons of the log-transformed
values were made by independent-sample Student’s t test for
2 groups and ANOVA for >2 groups. Bivariate correlations were tested
using Pearson’s method and correlation coefficients (r).
All reported probability values are 2-sided. Analyses were
performed using SPSS for Windows (SPSS Inc).
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Clinical details of the 117 ACS and 18 NCP patients are given in Table 1
. Mean age, sex, and risk
factor distribution of the patients with ACS was not statistically
different from those with NCP.
|
The results for plasma homocysteine, Factor VIIa, and F1+2
concentration in ACS are presented in Table 2, stratified by age, sex, smoking
status, cholesterol, HDL, hypertension, and diabetes
mellitus. Homocysteine showed significant difference with increasing
age. Factor VIIa did not vary significantly with any of these factors.
There was a highly significant difference in F1+2 levels with age, a
finding that has been often reported. F1+2 was also noted to be
slightly higher in women and in patients with hypertension.
|
The respective relationships of Factor VIIa and F1+2 to final diagnosis
were examined. F1+2 levels were significantly (P<0.001)
higher in patients with MI (44.8, 37.0 to 53.4 ng/mL) than in patients
with NCP (25.1, 20.0 to 31.6 ng/mL), but not significantly different in
patients with UAP (39.3, 33.2 to 46.6 ng/mL), Figure 1a. Factor VIIa was significantly higher
in patients with UAP (0.38, 0.29 to 0.51 ng/mL) than in patients NCP
(0.22, 0.16 to 0.31 ng/mL) but not different in patients with MI (0.31,
0.23 to 0.41 ng/mL), Figure 1b. Evidence of a relationship
between changes in levels of F1+2 and Factor VIIa was then sought
through correlation analysis. There were significant
correlations between F1+2 and Factor VIIa levels when considering
results in MI (r=0.38, P=0.01, n =58), in UAP
(r=0.45, P=0.003, n =60), and when the ACS were
considered as one group (r=0.41, P<0.0001, n
=117). There was no correlation between F1+2 and Factor VIIa levels in
the NCP group (r=-0.06, P=0.59). These
observations confirm a hypercoagulable state in these patients
presenting with ACS but not in patients with NCP.
|
Plasma homocysteine concentrations were similar in both MI (13.8, 12.5
to 15.3 µmol/L) and UAP (13.3, 12.2 to 14.5 µmol/L), but
they were not significantly higher than NCP (12.0, 9.7 to 14.8
µmol/L), Figure 1c
.
The relationship between the coagulation activation markers (F1+2 and
Factor VIIa) and homocysteine was studied by dividing the latter into
quartiles. It can be seen from Figure 2a
that in MI there is a stepwise increase in F1+2 with increasing
quartiles (ANOVA, P=0.05): there is a significant difference
(P=0.007) between F1+2 levels in the lowest (33.5, 27.2 to
41.2 ng/mL) and highest (60.1, 40.4 to 89.4 ng/mL) homocysteine
quartiles. There was a similar stepwise increase in F1+2 levels (ANOVA,
P=0.01) in UAP, with a significant difference
(P<0.001) between lowest (32.1, 25.1 to 41.0 ng/mL) and
highest (68.4, 45.6 to 102.7 ng/mL) homocysteine quartiles, Figure 2b. When the results for all patients with ACS were combined (MI
plus UAP), there was a significant graded increase in F1+2 between the
homocysteine quartiles (ANOVA, P<0.0001). The difference
between the upper (63.4, 49.0 to 81.9 ng/mL) and lower (31.1, 27.1 to
35.7 ng/mL) homocysteine quartiles was highly significant
(P<0.0001; Figure 2c). When all results for
homocysteine and F1+2 in the ACS were compared by correlation
analysis, there was a significant correlation
(r=0.46, P<0.0001, n=117).
|
A similar analysis of relationship between quartiles of
homocysteine and Factor VIIa levels showed no change in MI (Figure 3a). There was, however, a significant
increase overall in Factor VIIa levels in UAP (ANOVA,
P<0.05) and between lowest levels (0.25, 0.16 to 0.37
ng/mL) and highest levels (0.71, 0.44 to 1.13 ng/mL,
P<0.001; Figure 3b). When all results in the ACS
were included in a quartile analysis (Figure 3c), there
was a significant difference overall (P<0.05) and a
significant difference (P<0.001) between lowest quartile
Factor VIIa (0.22, 0.17 to 0.28 ng/mL) and highest quartile (0.49, 0.31
to 0.78 ng/mL). Correlation analysis of Factor VIIa with
homocysteine reflected these results: when UAP results were correlated,
there was a significant association (r=0.4,
P=0.007, n=60). This was weakened by combining results in MI
with UAP (r=0.24, P<0.01, n=118).
|
Because of the sample size of the NCP group, quartile analysis was inappropriate. Instead, F1+2 and Factor VIIa levels were grouped above and below the median homocysteine level of 12.0 µmol/L. F1+2 levels were not different between the groups (21.1, 15.2 to 29.2 and 30.0, 21.2 to 42.4 ng/mL, respectively, P=0.16). Similarly, there was no difference in Factor VIIa levels (0.29, 0.26 to 0.33 and 0.27, 0.21 to 0.34 ng/mL, respectively, P=0.59). Correlation analysis reflected these results with the absence of any correlation between homocysteine and F1+2 (r=-0.15, P=0.57, n=8) and Factor VIIa (r=0.22, P=0.37, n=8). It cannot be discounted, however, that this result could have been caused by the small sample size in this group.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The blood coagulation cascade is known to be activated in the acute phase of MI and UAP. Plasma levels of Fibrinopeptide A, F1+2, have been shown to be elevated, signaling activation of the end stages of the coagulation process. Plaque rupture and fissuring is thought to be a critical event in the pathogenesis of the ACS. This is associated with exposure of tissue factor, which can trigger the coagulation cascade via Factor VIIa generation. However, previous studies, which have investigated Factor VIIa levels, have generally failed to demonstrate changes that could be responsible for the readily detectable increase in thrombin generation (F1+2 elevation).24 An exception was a small previous study from this center, which showed elevated Factor VIIa levels, particularly in UAP.19
The design of our study differs from most investigations in that we have recruited all patients admitted to our coronary care unit and used patients diagnosed with NCP as a control group. This group was small because it comprised those patients who presented with suspected ACS but who were shown not to have the syndromes. It was mainly used as a control to establish that in those patients with definite ACS, coagulation activation had occurred and that sampling artifacts had been kept to a minimum. The main focus of this study was therefore not to study the relation between the ACS and NCP groups but the relationship between the degree of coagulation activation and homocysteine concentrations in patients in whom a thrombotic process had taken place. Although some formal analysis of results from the NCP group is presented, it must be stressed that the group size makes the interpretation of these results tentative.
We have been able to show a convincing association between Factor VIIa and F1+2 in the acute phase of the ACS. This association, manifest by correlation analysis, persists on subgroup analysis, despite the generally less clear elevation of Factor VIIa than F1+2 in MI. This latter finding could help explain the failure to demonstrate elevation of Factor VIIa in other studies of ACS. There is an important methodological aspect involved in the determination of Factor VIIa as an activation marker, which distinguishes it from other activation markers (eg, F1+2). Cellular expression of tissue factor is required for activation of Factor VII.15 16 17 An ability to detect Factor VIIa in plasma implies that sufficient Factor VIIa is released from the cell surface during the activation process to enable detection. Support for this possibility of detection in plasma is provided by results of in vitro activation experiments conducted in plasma. Addition of tissue factor and phospholipid vesicles to recalcified plasma results in generation in more Factor VIIa on a molar basis than the added tissue factor (H. Philippou, PhD, and D.A. Lane, PhD, unpublished observations, 1999). This suggests that each molecule of tissue factor can undergo multiple rounds of Factor VII activation, progressively releasing Factor VIIa. It might be that the low level activation of Factor VII observed in this clinical context might arise from the difficulty in its detection because of its slow release from the cell surface; this might also explain the lower levels of Factor VIIa observed in plasma in MI compared with UAP. There are additional methodological issues in the measurement of Factor VIIa levels. It is not clear whether our use of an ELISA for quantification of Factor VIIa levels was important for the demonstration of a relationship between Factor VIIa and F1+2 levels, because at the inception of this study we did not have available the functional assay for Factor VIIa. Regardless of these methodological points, our results provide an explanation for increased F1+2 levels in the ACS, by linking the initial cellular response (believed to be exposure of tissue factor) with the outcome (increased thrombin generation) through an essential proteinase (Factor VIIa) involved in activation of blood coagulation.
The main novel feature of our study has been to relate homocysteine levels to coagulation activation. A significant association between plasma homocysteine levels and coagulation activation has been demonstrated both in relation to changes in F1+2 and Factor VIIa levels. F1+2 plasma levels correlated positively and in a concentration-related manner to plasma homocysteine levels. This pattern was seen in patients with MI and UAP but not in patients with NCP (however, note the caution about the sample size). The association between F1+2 levels and homocysteine has also previously been shown by Kyrle et al in patients with prior history of venous thromboembolism.25 In a similar patient group, Cattaneo et al did not find any correlation.26 In the latter study, however, blood samples were taken at least 4 months after the last thrombotic event. Furthermore, there was no difference in F1+2 levels between patients with prior history of thromboembolism and healthy controls, suggesting no obvious activation of coagulation. This contrasts to the present study, in which we have sampled on presentation and before any intervention in an attempt to study patients in the acute hypercoagulable state. The association between homocysteine and Factor VIIa levels is less prominent in the current study, possibly because of the relatively low elevation of Factor VIIa levels arising for the reasons discussed above.
How could homocysteine interact with coagulation to enhance activation? Fryer et al have suggested that high levels of plasma homocysteine may initiate coagulation by enhancing endothelial cell expression of tissue factor activity,27 and this certainly seems plausible in the light of the present observation of a correlation between homocysteine and Factor VIIa. Inhibition of protein C activation and downregulation of thrombomodulin is also well-documented.9
This study has limitations: its power is limited by its size, this has prevented a detailed statistical analysis of possible confounders. The size of the NCP group has prevented firm conclusions from being drawn on differences between ACS and NCP patients regarding associations between coagulation activation markers and homocysteine.
Despite these limitations, this study has shown for the first time that elevated plasma homocysteine in patients presenting with ACS appears to be associated with increased coagulation activation as judged by increases in F1+2 and Factor VIIa levels. Although there is plausible experimental evidence to suggest that these are causally related, further experimental and larger scale clinical studies are required to confirm our findings. If such confirmation is obtained, it would suggest therapeutic modulation of plasma homocysteine as a means of reducing increased thrombin generation in ACS.
|
Acknowledgments |
|---|
This study was supported by a Concerted Action Grant of the Biomed 1 Program of the European Commission (PL92005), and by a grant (PG/95128) from the British Heart Foundation.
Received June 4, 1999; revision received August 10, 1999; accepted August 26, 1999.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
-
Clarke R, Fitzgerald D, O’Brien C, O’Farrell C,
Roche G, Parker RA, Graham I. Hyperhomocysteinaemia: a risk factor for
extracranial carotid artery atherosclerosis. Ir
J Med Sci. 1992;161:61–65.[Medline]
[Order article via Infotrieve]
-
Selhub J, Jacques PF, Bostom AG, D’Agostino RB,
Wilson PW, Belanger AJ, O’Leary DH, Wolf PA, Schaefer EJ, Rosenberg
IH. Association between plasma homocysteine concentrations and
extracranial carotid-artery stenosis. N Engl J
Med. 1995;332:286–291.
[Abstract/Free Full Text]
-
Aronow WS, Ahn C. Association between plasma
homocysteine and peripheral arterial disease in
older persons. Coron Artery Dis. 1998;9:49–50.[Medline]
[Order article via Infotrieve]
-
Bergmark C, Mansoor MA, Swedenborg J, de Faire U,
Svardal AM, Ueland PM. Hyperhomocysteinemia in patients operated for
lower extremity ischaemia below the age of 50–effect of smoking and
extent of disease. Eur J Vasc Surg. 1993;7:391–396.[Medline]
[Order article via Infotrieve]
-
den Heijer M, Koster T, Blom HJ, Bos GM, Briet E,
Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a
risk factor for deep-vein thrombosis. N Engl J
Med. 1996;334:759–762.
[Abstract/Free Full Text]
-
Clarke R, Daly L, Robinson K, Naughten E, Cahalane S,
Fowler B, Graham I. Hyperhomocysteinemia: an independent risk factor
for vascular disease. N Engl J Med. 1991;324:1149–1155.[Abstract]
-
Stampfer MJ, Malinow MR, Willett WC, Newcomer LM,
Upson B, Ullmann D, Tishler PV, Hennekens CH. A prospective study of
plasma homocyst(e)ine and risk of myocardial infarction in US
physicians. JAMA. 1992;268:877–881.[Abstract]
-
Mudd S, Levy H, Skovby F. Disorders of
transsulfuration. In: Scriver C, Beaudet A, Sly W, eds.
Metabolic and Molecular Basis of Inherited
Disease. New York: McGraw-Hill; 1995:1279–1327.
-
Hayashi T, Honda G, Suzuki K. An atherogenic stimulus
homocysteine inhibits cofactor activity of thrombomodulin and enhances
thrombomodulin expression in human umbilical vein
endothelial cells. Blood. 1992;79:2930–2936.
[Abstract/Free Full Text]
-
Lentz SR, Sadler JE. Inhibition of thrombomodulin
surface expression and protein C activation by the thrombogenic agent
homocysteine. J Clin Invest. 1991;88:1906–1914.
-
Rodgers GM, Conn MT. Homocysteine, an atherogenic
stimulus, reduces protein C activation by arterial and
venous endothelial cells. Blood. 1990;75:895–901.
[Abstract/Free Full Text]
-
Durand P, Lussier-Cacan S, Blache D. Acute methionine
load-induced hyperhomocysteinemia enhances platelet aggregation,
thromboxane biosynthesis, and
macrophage-derived tissue factor activity in rats.
FASEB J. 1997;11:1157–1168.[Abstract]
-
Starkebaum G, Harlan JM. Endothelial
cell injury due to copper-catalyzed hydrogen peroxide generation from
homocysteine. J Clin Invest. 1986;77:1370–1376.
-
Dudman NP, Hicks C, Wang J, Wilcken DE. Human
arterial endothelial cell detachment in
vitro: its promotion by homocysteine and cysteine.
Atherosclerosis. 1991;91:77–83.[Medline]
[Order article via Infotrieve]
-
Fuster V, Badimon L, Badimon JJ, Chesebro JH. The
pathogenesis of coronary artery disease and the acute
coronary syndromes (1). N Engl J Med. 1992;326:242–250.[Medline]
[Order article via Infotrieve]
-
Fuster V, Badimon L, Badimon JJ, Chesebro JH. The
pathogenesis of coronary artery disease and the acute
coronary syndromes (2). N Engl J Med. 1992;326:310–318.[Medline]
[Order article via Infotrieve]
-
Toschi V, Gallo R, Lettino M, Fallon JT, Gertz SD,
Fernandez-Ortiz A, Chesebro JH, Badimon L, Nemerson Y, Fuster V,
Badimon JJ. Tissue factor modulates the thrombogenicity of human
atherosclerotic plaques. Circulation. 1997;95:594–599.
[Abstract/Free Full Text]
-
WHO. Report No. Eur 8201 (5). 1971. Working group on
the establishment of ischaemic heart disease registers: report of the
fifth working group.
-
Philippou H, Adami A, Amersey RA, Stubbs PJ, Lane DA. A
novel specific immunoassay for plasma two-chain factor VIIa:
investigation of FVIIa levels in normal individuals and in patients
with acute coronary syndromes. Blood. 1997;89:767–775.
[Abstract/Free Full Text]
-
Fiskerstrand T, Refsum H, Kvalheim G, Ueland PM.
Homocysteine and other thiols in plasma and urine: automated
determination and sample stability. Clin Chem. 1993;39:263–271.[Abstract]
-
Refsum H, Ueland PM, Svardal AM. Fully automated
fluorescence assay for determining total homocysteine in
plasma. Clin Chem. 1989;35:1921–1927.
[Abstract/Free Full Text]
-
Philippou H, Davidson S, Mole M, Pepper J, Burman J,
Lane DA. Two chain factor VIIa generated in the pericardium during
surgery with cardiopulmonary bypass: relationship to increased
thrombin generation and to heparin concentration. Atheroscler
Thromb Vasc Biol. 1998;19:248–254.
[Abstract/Free Full Text]
-
Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B.
Thrombin production, inactivation and expression during open
heart surgery measured by assays for activation fragments including a
new ELISA for prothrombin fragment F1 + 2. Thromb Haemost. 1993;70:253–258.[Medline]
[Order article via Infotrieve]
-
Merlini PA, Ardissino D, Oltrona L, Broccolino M,
Coppola R, Mannucci PM. Heightened thrombin formation but normal plasma
levels of activated factor VII in patients with acute
coronary syndromes. Arterioscler Thromb Vasc Biol. 1995;15:1675–1679.
[Abstract/Free Full Text]
-
Kyrle PA, Stumpflen A, Hirschl M, Bialonczyk C, Herkner
K, Speiser W, Weltermann A, Kaider A, Pabinger I, Lechner K, Eichinger
S. Levels of prothrombin fragment F1+2 in patients with
hyperhomocysteinemia and a history of venous thromboembolism.
Thromb Haemost. 1997;78:1327–1331.[Medline]
[Order article via Infotrieve]
-
Cattaneo M, Franchi F, Zighetti ML, Martinelli I, Asti
D, Mannucci PM. Plasma levels of activated protein C in healthy
subjects and patients with previous venous thromboembolism:
relationships with plasma homocysteine levels. Arterioscler
Thromb Vasc Biol. 1998;18:1371–1375.
[Abstract/Free Full Text]
-
Fryer RH, Wilson BD, Gubler DB, Fitzgerald LA, Rodgers
GM. Homocysteine, a risk factor for premature vascular disease and
thrombosis, induces tissue factor activity in
endothelial cells. Arterioscler Thromb. 1993;13:1327–1333.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  N. Tyagi, K. C. Sedoris, M. Steed, A. V. Ovechkin, K. S. Moshal, and S. C. Tyagi Mechanisms of homocysteine-induced oxidative stress Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2649 - H2656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. H. Samson, Z. Yungst, and D. P. Showalter Homocysteine, a Risk Factor for Carotid Atherosclerosis, Is Not a Risk Factor for Early Recurrent Carotid Stenosis Following Carotid Endarterectomy Vascular and Endovascular Surgery, July 1, 2004; 38(4): 345 - 348. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Soinio, J. Marniemi, M. Laakso, S. Lehto, and T. Ronnemaa Elevated Plasma Homocysteine Level Is an Independent Predictor of Coronary Heart Disease Events in Patients with Type 2 Diabetes Mellitus Ann Intern Med, January 20, 2004; 140(2): 94 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matetzky, D. Freimark, S. Ben-Ami, I. Goldenberg, J. Leor, R. Doolman, I. Novikov, M. Eldar, and H. Hod Association of Elevated Homocysteine Levels With a Higher Risk of Recurrent Coronary Events and Mortality in Patients With Acute Myocardial Infarction Arch Intern Med, September 8, 2003; 163(16): 1933 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Maseri and D. Cianflone Inflammation in acute coronary syndromes Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B8 - B13. [Abstract] [PDF]
|
|
|
|
 |
|
 B Chandrasekaran and A S Kurbaan Myocardial infarction with angiographically normal coronary arteries J R Soc Med, January 8, 2002; 95(8): 398 - 400. [Full Text] [PDF]
|
|
|
|
 |
|
 M K Al-Obaidi, P J Stubbs, R Amersey, and M I M Noble Acute and convalescent changes in plasma homocysteine concentrations in acute coronary syndromes Heart, April 1, 2001; 85(4): 380 - 384. [Abstract] [Full Text]
|
|
|
|
 |
|
 N. H. Badner, W. S. Beattie, D. Freeman, and J. D. Spence Nitrous Oxide-Induced Increased Homocysteine Concentrations Are Associated with Increased Postoperative Myocardial Ischemia in Patients Undergoing Carotid Endarterectomy Anesth. Analg., November 1, 2000; 91(5): 1073 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Al-Obaidi, P. J. Stubbs, P. Collinson, R. Conroy, I. Graham, and M. I. M. Noble Elevated homocysteine levels are associated with increased ischemic myocardial injury in acute coronary syndromes J. Am. Coll. Cardiol., October 1, 2000; 36(4): 1217 - 1222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Stubbs, M. K. Al-Obaidi, R. M. Conroy, MusB, P. O. Collinson, MRCPath, I. M. Graham, FRCPI, and M. I. M. Noble Effect of Plasma Homocysteine Concentration on Early and Late Events in Patients With Acute Coronary Syndromes Circulation, August 8, 2000; 102(6): 605 - 610. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||