Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0.74-34.40); early pregnancy loss (ORs, 1.40-6.25); late pregnancy loss (ORs, 1.31-20.09); pre-eclampsia (ORs, 1.37-3.49); placental abruption (ORs, 1.42-7.71) and intrauterine growth restriction (ORs, 1.24-2.92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1.62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

The interplay between inflammatory and hemostatic mechanisms may play a crucial role in the development and progression of atherosclerosis. The authors evaluated the separate and joint associations of hemostatic and inflammatory variables on peripheral atherosclerotic progression in the Edinburgh Artery Study, a population cohort study of 1,592 men and women aged 55-74 years that started in 1987. Levels of fibrinogen, fibrin D-dimer, von Willebrand factor, tissue plasminogen activator antigen, factor VII, prothrombin fragment 1 + 2, urinary fibrinopeptide A, C-reactive protein, and interleukin-6 were measured at baseline. Arm and ankle blood pressures were measured, and atherosclerotic progression was assessed by computing ankle brachial index (ABI) at baseline (1,582 participants) and after 12 years of follow-up (813 participants). Fibrinogen (p = 0.05) and D-dimer (p < or = 0.05) were significantly associated with ABI change independently of baseline ABI and cardiovascular disease risk factors. However, these associations were no longer significant when analyses were adjusted for either C-reactive protein or interleukin-6. Moreover, subjects with higher levels of both D-dimer and interleukin-6 at baseline had the greatest ABI decline. In conclusion, fibrinogen and D-dimer, but not other hemostatic factors, were associated with progressive peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation.

Objective: Abdominal aortic aneurysms often coexist with reduced lung function and chronic obstructive pulmonary disease (COPD). These conditions are each associated with cigarette smoking, cardiovascular disease, and evidence of increased inflammatory and hemostatic activity. The aim of this study was to determine if these factors accounted for the link between aneurysms and pulmonary disease.Methods. The design was a case-control study comparing patients with an asymptomatic abdominal aortic aneurysm with population-based controls without an aneurysm. Aneurysms were diagnosed by ultrasound scan, and pulmonary function was measured by respiratory questionnaire and spirometry. Activation of inflammation and hemostasis was measured by assay of plasma interleukin-6 (IL-6), fibrinogen, von Willebrand factor (vWF), tissue plasminogen activator (tPA) antigen, fibrin D-dimer, and plasmin antiplasmin complexes.Results. Cases with an abdominal aortic aneurysm (n = 89) had more COPD and worse expiratory lung function as measured by forced expiratory volume in I second (FEVI) and forced vital capacity C) than controls (n = 98) (FEVI, 1.9 vs 2.2 L, P < .01; FEVI/FVC, 0.67 vs 0.75, P < .001) and did not differ in restrictive function (FVC, 2.9 vs 3.0 L, P = .33). Cases also had higher levels of lifetime cigarette smoking (30 vs 24 pack-years, P < 0.01), cardiovascular disease (35% vs 18%, P = .01), plasma fibrinogen (3.5 vs 3.1 g/L, P = .02), IL-6 (2.8 vs 1.8, pg/mL, P < .001), plasmin antiplasmin complexes (596 vs 384 mu g/L, P = .01), and D-dimer (442 vs 93 ng/mL, P < .001). On multiple logistic regression analysis of lung function and COPD on the risk of aneurysm, both cigarette smoking and cardiovascular disease had little effect on the relationships. For the markers of activated inflammation and hemostasis, plasmin antiplasmin complexes and D-dimer had the most important confounding effect on the odds ratios. All markers combined had a substantial effect: odds ratio of aneurysm for a one standard deviation decrease in FEVI fell from 2.3 (95% confidence interval [CI], 1.5 to 3.5) (P <.01) to 1.3 (95% CI, 0.55 to 2.4) (P >= 1.05).Conclusion: The association between reduced respiratory function and abdominal aortic aneurysm was not accounted for by cigarette smoking or cardiovascular disease. We hypothesize that activation of inflammation and hemostasis in response to injury may be an important explanation of the association between aneurysm formation and reduced respiratory function. Further studies are required to test this hypothesis.

Background: Previous studies have suggested that several hemostatic and inflammatory variables, which are risk predictors for arterial or venous thrombosis, increase with age. However, there is a lack of data from large population studies for reliable estimates of reference ranges. Objectives: To establish reliable reference ranges of hemostatic and inflammatory variables for 5-year age groups in older men and their implications for pathogenesis and diagnosis. Patients and methods: A total of 3861 men aged 60-79 years at the 20 years follow-up of the British Regional Heart Study. Results: Several variables increased with age. The greatest median increases between 60-64 and 75-79 years age groups were observed for fibrin D-dimer (91%) and C-reactive protein (CRP) (57%). Significant median increases were also observed for von Willebrand factor antigen (23%), tissue plasminogen activator antigen (11%), factor VIII (10%), and fibrinogen (8%). In contrast, levels of classical cardiovascular risk factors neither decreased nor increased substantially with age, with the exception of systolic blood pressure (median increase 10%). Conclusions: The exponential increases in risk of arterial and venous thrombotic events in men between age 60 and 79 years (when most such events occur) may be related in part to increasing activation of blood coagulation, fibrinolysis, and inflammation; possibly related to the increasing inflammatory burden of both atherosclerotic and non-vascular disease. These increases also have implications for diagnosis of suspected acute venous thromboembolism (13-dimer), and recently proposed screening for prediction of coronary heart disease risk and detection of occult disease (CRP).

All are now agreed that the plasma fibrinogen level is a strong and independent predictor of the risk of major episodes of coronary heart disease (CHD), i.e. coronary death and myocardial infarction. Those with fibrinogen levels in the highest third of the distribution of fibrinogen run about twice the risk of an event compared with those in the lowest third [1Danesh J. Collins R. Appleby P. Peto R. Association of fibrinogen, C‐reactive protein, albumin, or leukocyte count with coronary heart disease: meta‐analyses of prospective studies.JAMA. 1998; 279: 1477-82Crossref PubMed Scopus (1872) Google Scholar]. Another way of expressing the risk is that it increases by perhaps 50% or more for every standard deviation increase in fibrinogen [2Meade T.W. Mellows S. Brozovic M. Miller G.J. Chakrabarti R.R. North W.R. Haines A.P. Stirling Y. Imeson J.D. Thompson S.G. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.Lancet. 1986; 2: 533-7Abstract PubMed Scopus (1940) Google Scholar], which varies from about 0.5 to 0.8 g L−1. The association with stroke risk is less clear [3Baker I.A. Pickering J. Elwood P.C. Bayer A. Ebrahim S. Fibrinogen, viscosity and white blood cell count predict myocardial, but not cerebral infarction: evidence from the Caerphilly and Speedwell cohort.Thromb Haemost. 2002; 87: 421-5Crossref PubMed Scopus (40) Google Scholar], but it is probable that fibrinogen also predicts this [4Wilhelmsen L. Svardsudd K. Korsan‐Bengtsen K. Larsson B. Welin L. Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction.N Engl J Med. 1984; 311: 501-5Crossref PubMed Scopus (1580) Google Scholar, 5Smith F.B. Lee A.J. Fowkes F.G. Price J.F. Rumley A. Lowe G.D. Hemostatic factors as predictors of ischemic heart disease and stroke in the Edinburgh Artery Study.Arterioscler Thromb Vasc Biol. 1997; 17: 3321-5Crossref PubMed Scopus (336) Google Scholar, 6Smith F.B. Rumley A. Lee A.J. Leng G.C. Fowkes F.G. Lowe G.D. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants.Br J Haematol. 1998; 100: 758-63Crossref PubMed Scopus (99) Google Scholar, 7Tracy R.P. Arnold A.M. Ettinger W. Fried L. Meilahn E. Savage P. The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study.Arterioscler Thromb Vasc Biol. 1999; 19: 1776-83Crossref PubMed Scopus (205) Google Scholar]. Peripheral arterial disease and re‐occlusion of coronary arteries or veins after interventions such as angioplasty and bypass surgery [8Banerjee A.K. Pearson J. Gilliland E.L. Goss D. Lewis J.D. Stirling Y. Meade T.W. A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants.Thromb Haemost. 1992; 68: 261-3Crossref PubMed Scopus (98) Google Scholar, 9Wiseman S. Kenchington G. Dain R. Marshall C.E. McCollum C.N. Greenhalgh R.M. Powell J.T. Influence of smoking and plasma factors on patency of femoropopliteal vein grafts.BMJ. 1989; 299: 643-6Crossref PubMed Scopus (130) Google Scholar, 10Montalescot G. Ankri A. Vicaut E. Drobinski G. Grosgogeat Y. Thomas D. Fibrinogen after coronary angioplasty as a risk factor for restenosis.Circulation. 1995; : 31-8Crossref PubMed Scopus (125) Google Scholar] are other events of which the fibrinogen level does or may indicate the risk. The fibrinogen level may also be related to other conditions and causes of death, notably cancer. So it is not specific for arterial disease unless the explanation for its association with these other conditions is that fibrinogen affects the circulation in some way that hastens their onset or progression. However, this non‐specificity does not invalidate consideration of fibrinogen in arterial disease, particularly in view of its effects on pathways, such as viscosity, known to affect CHD risk. The ‘fibrinogen story’ started and has developed at least two decades after work on lipids and effective lipid‐lowering treatments, so the case for deciding when and in whom fibrinogen levels should be measured should be considered accordingly—there is a great deal of catching up to be done. Interest in studying fibrinogen and CHD developed in the early 1970s following the increasing awareness of the thrombotic contribution to major events [11Morris J.N. Recent history of coronary disease.Lancet. 1951; 1: 1-7Abstract PubMed Scopus (62) Google Scholar] (although much later after Morris's landmark publication than it should have done) and the need to take it into account as the immediate cause of most episodes [12Chandler A.B. Chapman I. Erhardt L.R. Roberts W.C. Schwartz C.J. Sinapius D. Spain D.M. Sherry S. Ness P.M. Simon T.L. Coronary thrombosis in myocardial infarction. Report of a workshop on the role of coronary thrombosis in the pathogenesis of acute myocardial infarction.Am J Cardiol. 1974; 34: 823-33Abstract Full Text PDF PubMed Scopus (182) Google Scholar, 13Davies M.J. Thomas A. Thrombosis and acute coronary‐artery lesions in sudden cardiac ischemic death.N Engl J Med. 1984; 310: 1137-40Crossref PubMed Scopus (1439) Google Scholar, 14Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death.Circulation. 71. 1985: 699-708Google Scholar, 15DeWood M.A. Stifter W.F. Simpson C.S. Spores J. Eugster G.S. Judge T.P. Hinnen M.L. Coronary arteriographic findings soon after non‐Q‐wave myocardial infarction.N Engl J Med. 1986; 315: 417-23Crossref PubMed Scopus (347) Google Scholar]. Until then—surprising as this now seems—the pathogenesis of CHD had been considered by most as due mainly or entirely to the consequence of the long‐term contribution of blood cholesterol to atherogenesis. Indeed, the widely used term ‘atherosclerosis’ to refer both to clinical episodes and to the atheromatous element of their pathology has been confusing, and has continued to limit full recognition of the thrombotic process. Assessing components of the haemostatic system and their possible contribution to the thrombotic component of CHD has been technically much more demanding than for lipids. There is still no satisfactory way of measuring platelet activity in individuals in large‐scale studies and most attention has hitherto been paid to the coagulation system. In this, the essential role of fibrinogen needs no further emphasis. Observational studies of CHD (as distinct from randomized controlled trials) have two main objectives. One is to help identify those at high risk of CHD. The other is to learn more about the causes and processes involved in its onset, in which case the implications for prevention and treatment are ultimately the chief aim. Of course, one approach overlaps with the other. If—to consider the extremes to make the point—the objective is simply to identify those at risk, it is entirely appropriate to place most emphasis on the fully independent contribution of a risk factor. If, on the other hand, the processes involved in CHD are the main interest, multivariate analyses should be the method of last, rather than first, resort. Putting fibrinogen and smoking straight into a multivariate analysis will underestimate the full contribution of fibrinogen to CHD, because smoking is a cause of high levels (and similarly for other determinants of fibrinogen). How do these considerations lead to rational decisions about measuring the fibrinogen level in individuals? Some have questioned the value of screening for the better‐known CHD risk factors [16Law M.R. Wald N.J. Morris J.K. The performance of blood pressure and other cardiovascular risk factors as screening tests for ischaemic heart disease and stroke.J Med Screen. 2004; 11: 3-7Crossref PubMed Scopus (40) Google Scholar], but this begs the question of whether newer risk factors may help. Fibrinogen probably does, as we now have additional clues about hitherto less well‐known pathways that may lead to CHD. For several years there has been a largely sterile debate as to whether fibrinogen is a cause or simply a marker of CHD risk. Very probably, the answer is both. Figure 1 shows various characteristics influencing the fibrinogen level and several pathways that are either known to contribute to CHD or may do so [17Meade T.W. The epidemiology of atheroma, thrombosis and ischaemic heart disease.in: Bloom AL Forbes CD Thomas DP Tuddenham EGD Haemostasis and Thrombosis. Churchill Livingstone, 1994: 1199-227Google Scholar]. One of these pathways is the effect of the fibrinogen level on the development of atheroma in the arterial wall, presumably in the long term, while the other mechanisms are likely to promote the much more acute, short‐term complication of thrombosis. Atheroma is an inflammatory process which may lead to an increase in fibrinogen as a chronic or acute‐phase protein, so in this sense a high level would indeed be a marker of underlying vessel wall pathology. There may even be a sequence in which fibrinogen contributes to atheroma, which leads in turn to a further increase in fibrinogen and thus to a higher level of the activity of the pathways through which fibrinogen increases the risk of a major CHD event. For fibrinogen, this is a more helpful way of thinking about the ‘marker or cause’ explanation than ‘reverse causality’, an ambiguous term which may or may not imply direct causality and which many do not understand properly anyway. It seems probable that high fibrinogen levels, whatever their explanation to begin with, are likely to be involved in the causation of the acute thrombotic event. (Whether C‐reactive protein or fibrinogen is associated more closely with CHD is debated, but at present at least as much, if not more, is known about the ways through which fibrinogen contributes to CHD. It may, of course, be that both are valuable, but it is fibrinogen that is under consideration here.) However, another argument against a causal role for fibrinogen has been advanced. The theory of ‘Mendelian randomization’ is that a genetic marker associated with the fibrinogen level should also be associated with the occurrence of clinical CHD events. It has been used to question the role of fibrinogen in causation, as in one study there was no clear association with CHD of one of the polymorphisms associated with the fibrinogen level [18Youngman L.D. Keavney B.D. Palmer A. Parish S. Clark S. Danesh J. Delepine M. Lathrop M. Peto R. Collins R. Plasma fibrinogen and fibrinogen genotypes in 4685 cases of myocardial infarction and in 6002 controls: test of causality by ‘Mendelian randomisation’.Circulation. 2000; 102: 31-2Google Scholar]. For a variety of statistical and other technical reasons, the question remains open. Very recently, however, the failure of the Mendelian approach to show clear associations with clinical events of polymorphisms for lipid fractions contributing to CHD shows that there are problems with the Mendelian approach that remain to be explained [19Keavney B. Palmer A. Parish S. Clark S. Youngman L. Danesh J. McKenzie C. Delepine M. Lathrop M. Peto R. Collins R. and the International Studies of Infarct Survival (ISIS) Collaborators.Lipid‐related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk.Int J Epidemiol. 2004; 33: 1002-13Crossref PubMed Scopus (58) Google Scholar]. The balance of evidence does seem to favour a causal role (as well as that of a marker). Therefore, as with the cholesterol debate several years ago, what would be the effects of lowering the fibrinogen level? It is a desirable condition for screening that there should be an effective treatment for the risk factor involved [20Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. Public Health Papers, no. 34. Geneva: WHO, 1968.Google Scholar]. At present, there are no selective oral agents for lowering fibrinogen. Fibrates such as bezafibrate do so by an amount that would be expected to lead to a worthwhile reduction in CHD, particularly as they also have beneficial lipid‐modifying properties. However, trials of bezafibrate and similar fibrates show mostly only modest reductions of around 10% in major events [21Meade T. Zuhrie R. Cook C. Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial.BMJ. 2002; 325: 1139Crossref PubMed Google Scholar], and it may be that the rise in homocyst(e)ine caused by these fibrates offsets much of their potentially beneficial effect [22MacCallum P.K. Cooper J.A. Rumley A. Lowe G.D. Meade T.W. Effect of bezafibrate on plasma homocysteine concentration in men with lower extremity arterial disease.J Thromb Haemost. 2004; 2: 364-5Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. Is it justifiable still to measure fibrinogen? (Gemfibrozil, which does reduce CHD [23Frick M.H. Elo O. Haapa K. Heinonen O.P. Heinsalmi P. Helo P. Huttunen J.K. Kaitaniemi P. Koskinen P. Manninen V. et al.Helsinki Heart Study: primary‐prevention trial with gemfibrozil in middle‐aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.N Engl J Med. 1987; 317: 1237-45Crossref PubMed Scopus (3520) Google Scholar, 24Rubins H.B. Robins S.J. Collins D. Fye C.L. Anderson J.W. Elam M.B. Faas F.H. Linares E. Schaefer E.J. Schectman G. Wilt T.J. Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high‐density lipoprotein cholesterol.N Engl J Med. 1999; : 410-18Crossref PubMed Scopus (3241) Google Scholar], differs biochemically from other fibrates and tends to raise fibrinogen [25Wilkes H.C. Meade T.W. Barzegar S. Foley A.J. Hughes L.O. Bauer K.A. Rosenberg R.D. Miller G.J. Gemfibrozil reduces plasma prothrombin fragment F1+2 concentration, a marker of coagulability, in patients with coronary heart disease.Thromb Haemost. 1992; 67: 503-6Crossref PubMed Scopus (66) Google Scholar].) Although formal research remains to be conducted, clinical experience shows that high fibrinogen is sometimes the only risk factor in someone who has previously not had an event but who may be at risk of one. (Patients who have already had events are at high risk for that reason alone, and should be taking statins and aspirin and perhaps other agents.) Consider a 45‐year‐old man who has an uncertain family history but a fibrinogen level in the top 10% of the distribution. Low‐dose aspirin might well be indicated (provided his annual risk of a major event is more than 1% because, at lower risk, hazards may well outweigh benefit [26Sanmuganathan P.S. Ghahramani P. Jackson P.R. Wallis E.J. Ramsay L.E. Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta‐analysis of randomised trials.Heart. 2001; 85: 265-71Crossref PubMed Scopus (373) Google Scholar]—an important consideration not generally recognized) even though (pace Wilson and Jungner) there is at present no effective agent for lowering fibrinogen itself. This scenario draws on several only partly satisfied requirements—the number of people with high fibrinogen levels but no other obvious risk factors, having the resources to measure levels more than once (as with any characteristic such as cholesterol on which clinical decisions may be based), being able to use the fibrinogen level in a reliable risk scoring system, and laboratories with good quality control that can say what their reference ranges are, for example. It will also be particularly valuable to be able to allow for the regression dilution effect [27MacMahon S. Peto R. Cutler J. Collins R. Sorlie P. Neaton J. Abbott R. Godwin J. Dyer A. Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure. prospective observational studies corrected for the regression dilution bias.Lancet. 1990; 335: 765-74.Abstract PubMed Scopus (3945) Google Scholar], which depends on having more than a single value for individuals in order to avoid underestimating the strength of the fibrinogen/CHD association. The case for answering all these questions is a strong one, and closely resembles the questions about cholesterol 20 or 30 years ago. They will be clarified only by measuring the fibrinogen level in many people in different settings and for different reasons, and with increasingly helpful clinical decisions in mind. In fact, there is, as already suggested, the single individual who should be considered. Ask yourself whether, not so far having had a myocardial infarct but concerned about marginal or uncertain ‘conventional’ risk factors (perhaps your cholesterol level and your family history), you would completely forgo measurement of your fibrinogen level, even if you regard it only as a marker, to help you make a rational decision about taking low‐dose aspirin or some other prophylactic measure? I am grateful to Dr Peter MacCallum for helpful discussion about this paper.

AIMS:To examine the associations between cigarette smoking, pipe/cigar smoking, and years since quitting smoking, and inflammatory and haemostatic markers.METHODS AND RESULTS:A study in 2920 men aged 60-79 with no history of myocardial infarction, angina, stroke, or diabetes, and who were not on warfarin, from general practices in 24 British towns. After adjustment for other major cardiovascular risk factors, compared with never smokers, current cigarette smokers showed significantly higher levels of C-reactive protein (2.53 vs. 1.35 mg/L), white cell count (7.92 vs. 6.42 x 10(9)/L), and fibrinogen (3.51 vs. 3.13 g/L). They also showed higher levels of haematocrit, blood and plasma viscosity, tissue plasminogen activator antigen, and fibrin D-dimer, and lower levels of albumin. Primary pipe/cigar smokers showed levels similar to never smokers. Ex-cigarette smokers and secondary pipe/cigar smokers showed intermediate levels although secondary pipe/cigar smokers showed higher odds of having elevated white cell count and fibrinogen than ex-cigarette smokers. Most inflammatory and haemostatic levels improved within 5 years of smoking cessation but took over 20 years to revert to levels of never smokers.CONCLUSION:These findings suggest that activation of inflammation and haemostasis may be potential mechanisms by which cigarette and pipe/cigar smoking increase cardiovascular risk.

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

There is current interest in the associations of circulating inflammatory markers (C-reactive protein, fibrinogen, white cell count, albumin, erythrocyte sedimentation rate, the factor VIII:von Willebrand factor complex, the tissue plasminogen activator:plasminogen activator inhibitor type 1 complex, fibrin D-dimer) not only with prognosis in acute coronary syndromes and acute stroke, but also in prediction of cardiovascular events in the general population. Recent meta-analyses of long-term prospective studies have established their associations with coronary heart disease (CHD) events, which may be cause, consequence or coincidence. These markers are also associated in epidemiologic studies of general populations with many cardiovascular risk factors (which may confound their associations with CHD risk), and also with asymptomatic arterial disease (of which they be consequences: 'reverse causality'). The causality of their associations with cardiovascular events is questioned by their lack of specificity for risk of cardiovascular events; and by the lack of association of their functional genotypes with CHD in 'Mendelian randomized trials'. Hence, proof of causality awaits testing in randomized-controlled trials of long-term selective reduction by future agents. Markers are of little additional predictive value to current cardiovascular risk scores, and it is premature to advocate their use in screening for cardiovascular risk prior to careful evaluation of costs, risks, and benefits.

BACKGROUND AND PURPOSE:Several prospective studies have shown significant associations between plasma fibrinogen, viscosity, C-reactive protein (CRP), fibrin D-dimer, or tissue plasminogen activator (tPA) antigen and the risk of primary cardiovascular events. Little has been published on the associations of these variables with recurrent stroke. We studied such associations in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).METHODS:Nested case-control study of ischemic (n=472) and hemorrhagic (n=83) strokes occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial.RESULTS:Fibrinogen and CRP were associated with an increased risk of recurrent ischemic stroke after accounting for the matching variables and adjusting for systolic blood pressure, smoking, peripheral vascular disease, and statin and antiplatelet therapy. The odds ratio for the last compared with the first third of fibrinogen was 1.34 (95% CI, 1.01 to 1.78) and for CRP was 1.39 (95% CI, 1.05 to 1.85). After additional adjustment for each other, these 2 odds ratios stayed virtually unchanged. Plasma viscosity, tPA, and d-dimer showed no relationship with recurrent ischemic stroke, although tPA was significant for lacunar and large artery subtypes. Although each of these variables showed a negative relationship with recurrent hemorrhagic stroke, none of these relationships achieved statistical significance.CONCLUSIONS:Fibrinogen and CRP are risk predictors for ischemic but not hemorrhagic stroke, independent of potential confounders.

Aims: We have examined the cross-sectional relationship between insulin resistance, the metabolic syndrome and haemostatic and inflammatory markers.Methods and results: We carried out the study in 2722 non-diabetic men aged 60-79 years with no history of coronary heart disease or stroke and who were not on warfarin treatment, drawn from general practices in 24 British towns. Insulin resistance (HONIA) was significantly associated with increased inflammatory markers (C-reactive protein (CRP), white cell count), coagulation factors VII-IX, von Willebrand factor (VWF) and tissue plasminogen activator (t-PA) antigens (markers of endothelial dysfunction) and blood viscosity after adjustment for age, smoking, physical activity, alcohol intake and waist circumference. Relationships with fibrinogen and fibrin D-dimer were weak. The relationship between HOMA and CRP was abolished after adjustment for t-PA. The prevalence of the metabolic syndrome was similar using World Health Organization (WHO) and National Cholesterol Education Program definitions (26.7% and 27.0%) but associations between the metabolic syndrome and increased haemostatic markers, particularly for raised factor VIII and VWF were stronger using WHO criteria.Conclusion: Insulin resistance and the metabolic syndrome showed significant associations with markers of haemostasis and inflammation, which may be relevant to their associations with cardiovascular disease. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Background and Aims: We wanted to determine the prevalence of atrial fibrillation (AF) in a community based cross sectional study in greater Glasgow and how current anti thrombotic management compares to published guidelines. Methods: 1466 patients with AF were identified in General Practices in our community and 1008 consented to take part. Their demographic details and medical history were recorded. Results: 1466 patients (mean age 73.4; 55% female) with AF were identified, in our community, giving a prevalence of 1%. 53% of patients were on warfarin therapy. Of those not receiving warfarin, only one third had a putative contra-indication. The proportion of AF patients on warfarin increased with increasing stroke risk, and over the period of the study. Conclusions: Prevalence of AF was in keeping with previous estimates. The proportion of patients with AF receiving warfarin therapy appears to be increasing. In the moderate risk group, there was a tendency to use more warfarin in the younger age groups compared to the elderly. It was in the moderate and low risk groups that there was still evidence of deviation from published guidelines.

Background Levels of C-reactive protein (CRP), serum amyloid A protein (SAA), and interleukin-6 (IL-6) can predict coronary restenosis following angioplasty and stent deployment in patients with unstable angina. We investigated whether measurement of periprocedural inflammatory markers predicted the angiographic outcome at 6 months in stable angina patients undergoing coronary stenting.Methods We prospectively studied 182 patients; 152 patients underwent elective and successful stenting procedure. for de novo lesions in native and nongrafted coronary arteries and 30 individuals in the control group underwent diagnostic angiography alone. CRP, SAA, and IL-6 were determined by high-sensitivity immunoassays.Results At 6 months, quantitative computer-assisted angiographic analysis in 133 patients with stents showed a binary restenosis rate of 33.8%. Statins were being taken by 80% of the patients. There were no significant differences between the pre- or postprocedure values of CRP, SAA, or IL-6 in patients with or without in-stent restenosis.Conclusions Preprocedural inflammatory markers in stable angina subjects undergoing coronary artery stent deployment did not correlate with the development of in-stern restenosis. Differences in pathobiology between stable and unstable coronary syndromes, the widespread use of statins with anti-inflammatory activity in our cohort of patients, along with different mechanisms underlying the early angiographic appearances of restenosis as compared to clinical end points, most likely explain our findings.

BACKGROUND:The epidemiology of plasma lipid peroxides, which may play a role in atherogenesis, has not been well defined.AIM:To study the relationships of plasma lipid peroxides to cardiovascular risk factors in a random population sample.DESIGN:Random, age- and sex-stratified population sample.METHODS:We studied 739 men and women aged 25-74 years. Lipid peroxides were assayed by the thiobarbituric acid (TBA) assay for malondialdehyde (MDA) in stored plasma samples.RESULTS:Lipid peroxide levels increased with age. In men, lipid peroxides were significantly associated with smoking habit. Lipid peroxides correlated with non-fasting serum triglycerides (r = 0.33; p < 0.0001) in both sexes. Weaker associations were observed for cholesterol, high-density lipoprotein cholesterol (inversely), body mass index, fibrinogen and white cell count; as well as an inverse association with serum vitamin C in men.DISCUSSION:These findings clarify the relationships of plasma lipid peroxides to cardiovascular risk factors; and are consistent with the hypothesis that lipid peroxidation may be one mechanism through which several risk factors may promote cardiovascular disease.

Background Imprecision in measurement of risk factors leads to underestimation of associations with disease outcomes (through regression dilution bias). We examine the extent of this bias for established and novel risk factors for coronary heart disease (CHD) and consider the consequences for CHD prevention. Design Prospective cardiovascular study of middle-aged British men followed up over 20 years. Methods Repeated measurements of blood lipids, blood pressure and insulin were available at intervals of 1 week, 4, 16 and 20 years; repeated measurements of homocysteine and haemostatic factors were available over 1 week and 4 years. Results The use of single baseline measures of both established and novel risk factors in analysis results in marked underestimation of risk associations, increasing over time. The use of a single baseline measurement of total cholesterol results in a 47% (95% confidence interval 44 to 50%) underestimation of its association with CHD risk during the third decade of follow-up; for diastolic blood pressure the corresponding underestimation is 76% (95% confidence interval 73 to 78%). Ignoring the consequences of regression dilution can also lead to error in the assessment of other risk markers, even those measured precisely. Conclusions The importance of risk factors for CHD can be greatly underestimated by using a single baseline measure in prospective study analyses. Studies that wish to estimate associations between disease risk and usual exposure levels need to take regression dilution effects into account. Failure to do so can lead to serious misinterpretation of the importance of CHD risk factors. Eur J Cardiovasc Prevention Rehab 11:125–134 © 2004 The European Society of Cardiology.

Aim Anti-inflammatory effects of moderate alcohol consumption have been proposed to explain why moderate alcohol intake lowers coronary heart disease risk. We investigated the relationship between overall alcohol, beer or wine consumption and markers of systemic inflammation in three different geographical areas in Europe.Methods and results Cross-sectional samples, each representative of the general population from Germany, Scotland, and France (MONICA Augsburg 1994/95, 2275 men and 2186 women, 25-74 years; Glasgow MONICA 1994/95, 561/616, 25-74 years, and MONICA Lille 1994/95, 581/574, 35-64 years) were studied. Alcohol intake was assessed by standardized interview. Adjusted means of C-reactive protein (CRP), fibrinogen, white blood cell (WBC) count, plasma viscosity (PV), and albumin were calculated among categories of alcohol intake, and separately for beer or wine consumption, by multiple linear regression. Self-reported moderate daily alcohol intake up to 40 g was associated with lower concentrations of CRP, fibrinogen, PV and WBC count, compared to non-drinking and heavy drinking, even after adjustment for various potential confounders.Conclusions Moderate consumption of either wine or beer is associated with lower levels of systemic inflammatory markers in three different European areas, suggesting that ethanol itself might be largely responsible for the potential anti-inflammatory effects of these beverages. (C) 2004 Published by Elsevier Ltd on behalf of The European Society of Cardiology.

Aims To determine whether circulating tissue plasminogen activator (t-PA) antigen concentrations are prospectively related to risk of coronary heart disease (CHD) in the general population Methods and results We measured baseline concentrations of t-PA antigen in the stored serum samples of 606 CHD cases and 1227 controls ‘nested’ in a prospective cohort of 5661 men monitored for 16 years, and conducted a meta-analysis of previous relevant studies to place our findings in context. Tissue plasminogen activator antigen values were strongly correlated with several vascular risk factors, including serum lipids, body mass index, alcohol consumption, and markers of systemic inflammation. In a comparison of men in the top third compared with those in the bottom third of baseline t-PA antigen values, the odds ratio for CHD was 2.20 (95% confidence interval (CI) 1.70–2.85) after adjustment for age and town only, but this fell to 1.48 (1.09–2.01) after further adjustment. Analysis of t-PA as a continuous variable gave similar results. Similarly, when published information on all seven available prospective cohort studies in general populations (2119 cases and 8832 controls in total) was synthesized, the combined odds ratio was 2.18 (1.77–2.69) after adjustment for age and sex only, and this fell to 1.47 (1.19–1.81) after further adjustment. Conclusion Although there is a statistically significant association between circulating concentrations of t-PA antigen and subsequent CHD, additional studies are needed to determine to what extent this is independent from more established risk factors. © 2003 Published by Elsevier Ltd on behalf of The European Society of Cardiology.

BACKGROUND AND PURPOSE:Plasma d-dimer levels, measured using a research laboratory assay, independently predict progressing ischemic stroke. We wished to confirm these findings using commercially available assays and to provide data to allow the design of intervention studies.METHODS:We studied 219 consecutive acute ischemic stroke admissions of whom 54 (25%) met criteria for progressing stroke.RESULTS:There were strong correlations between d-dimer results as measured by the Biopool AB, MDA and VIDAS assays; correlation coefficients r=0.91 to 0.94; all P<0.001. In binary logistic regression analyses, d-dimer, as measured by the 3 different assays, was an independent predictor of progressing stroke (odds ratios, 1.87 to 2.45; all P<0.001). This confirms the results of our original analysis (Biopool AB) using 2 commercial d-dimer assays, demonstrating the potential usefulness of d-dimer in providing early prognostic information after ischemic stroke in different clinical settings. We also provide information on the performance of the 3 assays in predicting progressing stroke at a variety of cutoff values.CONCLUSIONS:Ischemic stroke patients at high risk of early progression can be identified using commercial d-dimer measurements. This could allow selection of high-risk patients for inclusion in randomized trials of early antithrombotic treatments.