Association of Variables of Coagulation, Fibrinolysis and Acute-phase with Atherosclerosis in Coronary and Peripheral Arteries and those Arteries Supplying the Brain

SummaryWe investigated the vessel status of coronary and peripheral arteries and those arteries supplying the brain in 929 consecutive male patients admitted to a coronary rehabilitation unit. The severity of coronary atherosclerosis was scored using coronary angiography. Changes in extracranial brain vessels and manifest cerebrovascular disease (CVD) were determined by B-mode ultrasound and Doppler examination. Peripheral arterial disease (PAD) was diagnosed using base-line and stress oscillography. We assessed variables of coagulation, fibrinolysis, and the acute phase response.There was a significant increase in plasma fibrinogen, plasminogen, d-dimer and C-reactive protein (CRP) with increasing severity of coronary heart disease. Compared to men with unaffected arteries, men with 3 diseased coronary arteries had 58% greater d-dimer concentrations. Patients with CVD and PAD, respectively, also had significantly higher fibrinogen, d-dimer and CRP concentrations. We did not find an association between plasminogen activator inhibitor activity and the severity of coronary atherosclerosis.In conclusion, plasma fibrinogen, d-dimer and CRP concentrations were significantly related to atherosclerosis in the coronary, peripheral and extracranial brain arteries.

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Use Of Fibrinogen and Fibrin D-Dimer in Prediction of Arterial Thrombotic Events

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615895 ◽

1999 ◽

Vol 82 (08) ◽

pp. 667-672 ◽

Cited By ~ 54

Author(s):

Ann Rumley ◽

Gordon D.O. Lowe

Keyword(s):

Blood Pressure ◽

Serum Cholesterol ◽

Prospective Studies ◽

Cardiovascular Events ◽

Arterial Disease ◽

Healthy People ◽

Plasma Fibrinogen ◽

Clinical Interest ◽

Risk Predictors ◽

D Dimer

IntroductionThere is increasing clinical and laboratory interest in the measurement of both plasma fibrinogen and fibrin D-dimer to predict arterial thrombotic events, such as cardiovascular death, myocardial infarction (MI), stroke, leg ischemia, arterial surgery (e.g., angioplasty, bypass grafting), and postsurgical arterial occlusion. There are several possible reasons for such interest.First, there is substantial evidence from prospective studies that the plasma fibrinogen level is a strong, consistent predictor of such cardiovascular events in people with or without clinically detectable arterial disease. Furthermore, fibrinogen adds to the predictive valve of major conventional risk predictors (e.g., smoking, blood pressure, serum cholesterol) in healthy people (Fig.1).1-7 Second, we and others have shown, in several prospective studies, that plasma fibrin D-dimer (measured quantitatively by enzyme-linked immunosorbent assays [ELISAs]) is also a strong, consistent predictor of such cardiovascular events in people with or without clinically detectable arterial disease.8-14 Again, fibrin D-dimer may add to the predictive value of major conventional risk predictors (e.g., smoking, blood pressure, serum cholesterol, plasma fibrinogen) in healthy people (Fig. 2).Third, there are several interactive, plausible, potential biological mechanisms through which increasing plasma fibrinogen levels, which are due to multiple gene-environment interactions, may promote ischemic events. These include increased blood viscosity, atherogenesis, and platelet-fibrin thrombogenesis (Fig. 3). Increased plasma D-dimer levels are a marker of turnover of cross-linked fibrin, whether vascular or extravascular (Fig. 3).Fourth, not only is there more evidence for fibrinogen and D-dimer as predictors of arterial thrombotic events than for other hemostatic or thrombotic variables, but these two assays are more stable and more practical to measure in clinical and epidemiological studies. These tests are also already available in many district hospitals for the diagnosis of disseminated intravascular coagulation (DIC) and, in the case of D-dimer, venous thromboembolism.15,16 As with other major cardiovascular risk factors (e.g., smoking, blood pressure, serum cholesterol), there is a need for standardization of both fibrinogen assays17-23 and D-dimer assays.24 Finally, clinical interest in plasma assays of fibrinogen also may increase in the event that ongoing clinical trials of plasma fibrinogen reduction (e.g., with certain fibrates or ancrod) show that such treatments are beneficial.25 Likewise, clinical interest in plasma assays of D-dimer may also increase if future studies show that oral anticoagulant prophylaxis is the most costeffective and risk-effective in people with elevated plasma D-dimer levels, who are normalized by full-dose warfarin.15,19,26-28 This review discusses each of these aspects of fibrinogen and fibrin D-dimer.

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Hypercoagulability Markers in Patients with Peripheral Arterial Disease: Association to Ankle-brachial Index

Angiology ◽

10.1177/0003319708325444 ◽

2008 ◽

Vol 60 (5) ◽

pp. 529-535 ◽

Cited By ~ 7

Author(s):

Mota Ana Paula Lucas ◽

Castro Santos Maria Elizabeth Rennó de ◽

Limae Silva Francisco das Chagas ◽

Carvalho Schachnik Natalia Castro de ◽

Sousa Marinez de Oliveira ◽

...

Keyword(s):

Peripheral Arterial Disease ◽

Plasminogen Activator ◽

Ankle Brachial Index ◽

Plasminogen Activator Inhibitor ◽

Arterial Disease ◽

Plasminogen Activator Inhibitor Type ◽

Peripheral Arterial ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

D Dimer

Peripheral arterial disease is diagnosed by measuring the ankle-brachial index. Values lower than 0.90 define the disease being usually related to its severity. Patients with peripheral arterial disease may show a hypercoagulability state. The aim of this study was to assess hemostatic variables and to correlate them with the presence of peripheral arterial disease and its severity as assessed by ankle-brachial index values. Plasma levels of D dimer, plasminogen, prothrombin fragment 1+2, plasminogen activator inhibitor and thrombomodulin were measured in 36 patients with peripheral arterial disease (group 1) and 30 without disease (group 2). Significant differences for D dimer, plasminogen, prothrombin fragment 1+2 and plasminogen activator inhibitor type 1 between the 2 groups were found ( P<0.05). Significant and inverse correlations were also observed (Pearson correlation, P<0.05) between ankle-brachial index values and levels of both plasminogen and plasminogen activator inhibitor type 1. Although there was no significant correlation between ankle-brachial index and levels of D dimer, higher D dimer values were observed in patients with lower ankle-brachial index values. The results confirm a trend to hypercoagulability and hypofibrinolysis in patients with peripheral arterial disease. Increased levels of plasminogen activator inhibitor type 1 seem to be associated with the severity of the disease, considering the inverse correlation between this inhibitor and ankle-brachial index.

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APC Resistance and other Haemostatic Variables during Pregnancy and Puerperium

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614518 ◽

1999 ◽

Vol 81 (04) ◽

pp. 527-531 ◽

Cited By ~ 114

Author(s):

U. Kjellberg ◽

N.-E. Andersson ◽

S. Rosén ◽

L. Tengborn ◽

M. Hellgren

Keyword(s):

Factor Viii ◽

Plasminogen Activator ◽

Protein C ◽

Activated Protein C ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Reference Level ◽

Soluble Fibrin ◽

Prothrombin Fragment ◽

D Dimer

SummaryForty-eight healthy pregnant women were studied prospectively and longitudinally. Blood sampling was performed at 10-15, 23-25, 32-34 and 38-40 weeks of gestation, within one week and at eight weeks postpartum. Classic and modified activated protein C ratio decreased as pregnancy progressed. In the third trimester 92% of the ratios measured with the classic test were above the lower reference level whereas all modified test ratios were normal. Slight activation of blood coagulation was shown with increased levels of prothrombin fragment 1+2, soluble fibrin and D-dimer. Fibrinogen, factor VIII and plasminogen activator inhibitor type 1 and type 2 increased. Protein S and tissue plasminogen activator activity decreased. Protein C remained unchanged. No correlation was found between the decrease in classic APC ratio and changes in factor VIII, fibrinogen, protein S, prothrombin fragment 1+2 or soluble fibrin, nor between the increase in soluble fibrin and changes in prothrombin fragment 1+2, fibrinogen and D-dimer.

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Modulation of Plasma Fibrinogen Levels by Ticlopidine in Healthy Volunteers and Patients with Stable Angina Pectoris

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650547 ◽

1996 ◽

Vol 76 (02) ◽

pp. 166-170 ◽

Cited By ~ 11

Author(s):

Moniek P M de Maat ◽

Alf E R Arnold ◽

Stef van Buuren ◽

J H Paul Wilson ◽

Cornells Kluft

Keyword(s):

Angina Pectoris ◽

Healthy Volunteers ◽

Acute Phase ◽

Stable Angina ◽

Gene Polymorphisms ◽

Acute Phase Reaction ◽

Plasma Fibrinogen ◽

Phase Reaction ◽

Stable Angina Pectoris ◽

Lowering Effect

SummaryElevated plasma fibrinogen levels are associated with an increased risk for cardiac events. Ticlopidine is a drug that inhibits the ADP-induced aggregation of blood platelets and it also has been described that ticlopidine can decrease the plasma fibrinogen level in patients with vascular diseases. The mechanism of this decrease has not yet been elucidated and therefore mechanisms that are known to affect fibrinogen levels were studied, viz. the acute phase reaction, total fibrin plus fibrinogen degradation (TDP) levels and the polymorphisms of the fibrinogen β-gene.The fibrinogen lowering effect of ticlopidine was studied in 26 healthy volunteers, selected on genotype of the BclI polymorphism of the fibrinogen β-gene, and in 26 patients with stable angina pectoris in a double blind, randomized cross-over study. Functional plasma fibrinogen levels were measured with the Clauss assay. Fibrinogen antigen, C-reactive protein (CRP) and TDP levels were measured using an enzyme immuno assay (EIA).In the healthy volunteers the functional fibrinogen levels had decreased by 0.20 g/l (9%, p = 0.005 using the paired Student t-test) after 4 weeks of 250 mg bid ticlopidine administration, whereas fibrinogen antigen, CRP and TDP levels were not significantly changed. In the stable angina pectoris patients the pre-treatment fibrinogen, CRP and TDP levels were significantly higher than in the volunteer group. After four weeks 250 mg bid ticlopidine administration the functional fibrinogen levels had decreased by 0.38 g/l (11%, p < 0.005), whereas the fibrinogen antigen, CRP and TDP levels were not significantly changed. The levels of functional and antigen fibrinogen, CRP and TDP did not change significantly during the placebo period in the volunteers or the patients. Neither in the volunteers nor in the patients was the effect of ticlopidine on the fibrinogen levels associated with the fibrinogen β-gene polymorphisms.Therefore, the fibrinogen lowering effect of ticlopidine is likely to be a modulation of the functionality of the molecule and unlikely to be modulated by the acute phase reaction, TDP-levels or the fibrinogen β-gene polymorphisms.

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Association of Increased Fibrin Turnover and Defective Fibrinolytic Capacity with Leg Atherosclerosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648855 ◽

1994 ◽

Vol 72 (02) ◽

pp. 292-296 ◽

Cited By ~ 24

Author(s):

M Cortellaro ◽

E Cofrancesco ◽

C Boschetti ◽

L Mussoni ◽

M B Donati ◽

...

Keyword(s):

Arterial Disease ◽

Venous Stasis ◽

Stepwise Discriminant Analysis ◽

Predisposing Factor ◽

Risk Of Death ◽

Peripheral Arterial ◽

Fibrinolytic Potential ◽

Fibrinolytic Capacity ◽

Control Study ◽

D Dimer

SummaryPatients with peripheral arterial disease have a high risk of death from cardiovascular events. As defective fibrinolysis associated with leg atherosclerosis has been suggested as a predisposing factor, we sought a relation among decreased fibrinolysis, the presence of leg atherosclerosis and the incidence of thrombotic events in a case control study nested in the PLAT.Fifty-eight patients with coronary and/or cerebral atherothrombotic disease, free of leg atherosclerosis at Doppler examination, were compared with 50 atherosclerotic patients with leg involvement. High D-dimer (153.0 vs 81.3 ng/ml, p <0.001) and tPA antigen before venous stasis (14.4 vs 11.8 ng/ml, p <0.03), and low tPA antigen (6.7 vs 15.6 ng/ml, p <0.01) and fibrinolytic activity released after venous stasis (fibrinolytic capacity: 113.2 vs 281.4 mm2, p <0.001) were found in patients with leg atherosclerosis. D-dimer and fibrinolytic capacity, in addition to age, were selected by stepwise discriminant analysis as characterizing patients with leg atherosclerosis. Moreover, higher D-dimer and tPA inhibitor characterized patients with leg atherosclerosis who subsequently experienced thrombotic events.These findings constitute evidence of high fibrin turnover and impaired fibrinolytic potential in patients with leg atherosclerosis. Thus impaired fibrinolysis may contribute to the prothrombotic state in these patients.

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A Six Year Prospective Study of Fibrinogen and Other Risk Factors Associated with Mortality in Stable Claudicants

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656361 ◽

1992 ◽

Vol 68 (03) ◽

pp. 261-263 ◽

Cited By ~ 71

Author(s):

A K Banerjee ◽

J Pearson ◽

E L Gilliland ◽

D Goss ◽

J D Lewis ◽

...

Keyword(s):

Risk Factors ◽

Intermittent Claudication ◽

Fibrinogen Level ◽

Past History ◽

Fold Increase ◽

Arterial Disease ◽

Plasma Fibrinogen ◽

Plasma Fibrinogen Level ◽

Factors Associated ◽

Probability Of Death

SummaryA total of 333 patients with stable intermittent claudication at recruitment were followed up for 6 years to determine risk factors associated with subsequent mortality. Cardiovascular diseases were the underlying cause of death in 78% of the 114 patients who died. The strongest independent predictor of death during the follow-up period was the plasma fibrinogen level, an increase of 1 g/l being associated with a nearly two-fold increase in the probability of death within the next 6 years. Age, low ankle/brachial pressure index and a past history of myocardial infarction also increased the probability of death during the study period. The plasma fibrinogen level is a valuable index of those patients with stable intermittent claudication at high risk of early mortality. The results also provide further evidence for the involvement of fibrinogen in the pathogenesis of arterial disease.

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Increased Plasma Fibrinogen and Platelet-Aggregates in Type II Hyperlipoproteinaemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657051 ◽

1979 ◽

Vol 42 (05) ◽

pp. 1503-1507 ◽

Cited By ~ 41

Author(s):

G D O Lowe ◽

Maureen M Drummond ◽

Jane L H C Third ◽

W F Bremner ◽

C D Forbes ◽

...

Keyword(s):

Plasma Lipids ◽

Young Patients ◽

Adult Life ◽

Arterial Disease ◽

Arterial Injury ◽

Plasma Fibrinogen ◽

Type Ii ◽

Familial Type ◽

Platelet Aggregate ◽

Platelet Aggregates

SummaryPlasma fibrinogen and platelet-aggregates (method of Wu and Hoak) were measured in 21 patients with familial Type II hyperlipoproteinaemia and 21 matched control subjects. Patients with hyperlipoproteinaemia had increased levels of fibrinogen and platelet- aggregates (p<0.01). Young patients with hyperlipoproteinaemia had prematurely high fibrinogen levels, and the normal rise in fibrinogen during adult life was abolished. There were no statistically significant correlations within the patient group between fibrinogen, platelet-aggregates, and plasma lipids. High fibrinogen and platelet-aggregate levels may play a part in the development of the premature arterial disease associated with Type II hyperlipoproteinaemia, or may be markers of arterial injury.

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