fibrin and Acute-Coronary-Syndrome

Acute coronary syndrome (ACS) encompasses a spectrum of diseases, ranging from ST-elevation myocardial infarction to non-ST-elevation myocardial infarction and unstable angina. A key initiating event in the pathology of ACS is atheromatous plaque disruption, in which the exposure of thrombogenic material triggers simultaneous activation of primary and secondary hemostatic pathways. Targeting platelet-mediated thrombus formation with dual antiplatelet therapy comprising acetylsalicylic acid and a P2Y12 antagonist is the current mainstay for management of ACS. However, a significant proportion of patients remain at risk of cardiovascular events. Fibrin is an important contributor to thrombogenesis and may account for the residual event rates. This review examines evidence for the role of the coagulation cascade in thrombus formation in ACS, which provides a rationale for the use of anticoagulation therapy. The current status of research with novel oral anticoagulants in combination with dual antiplatelet therapy for the secondary prevention of ACS is also discussed.

Topics: Acute Coronary Syndrome; Aspirin; Blood Coagulation; Fibrin; Humans; Plaque, Atherosclerotic; Platelet Aggregation Inhibitors; Receptors, Purinergic P2Y12; Thrombosis

Although mortality rates from coronary heart disease in the western countries have declined in the last few decades, morbidity caused by this disease is increasing and a substantial number of patients still suffer acute coronary syndrome (ACS) and sudden cardiac death. Acute coronary syndrome occurs as a result of myocardial ischaemia and its manifestations include acute myocardial infarction and unstable angina. Culprit plaque morphology in these patients varies from thrombosis with or without coronary occlusion to sudden narrowing of the lumen from intraplaque haemorrhage. The coronary artery plaque morphologies primarily responsible for thrombosis are plaque rupture, and plaque erosion, with plaque rupture being the most common cause of acute myocardial infarction, especially in men. Autopsy data demonstrate that women <50 years of age more frequently have erosion, whereas in older women, the frequency of rupture increases with each decade. Ruptured plaques are associated with positive (expansive) remodelling and characterized by a large necrotic core and a thin fibrous cap that is disrupted and infiltrated by foamy macrophages. Plaque erosion lesions are often negatively remodelled with the plaque itself being rich in smooth muscle cells and proteoglycans with minimal to absence of inflammation. Plaque haemorrhage may expand the plaque rapidly, leading to the development of unstable angina. Plaque haemorrhage may occur from plaque rupture (fissure) or from neovascularization (angiogenesis). Atherosclerosis is now recognized as an inflammatory disease with macrophages and T-lymphocytes playing a dominant role. Recently at least two subtypes of macrophages have been identified. M1 is a pro-inflammatory macrophage while M2 seems to play a role in dampening inflammation and promoting tissue repair. A third type of macrophage, termed by us as haemoglobin associated macrophage or M(Hb) which is observed at site of haemorrhage also can be demonstrated in human atherosclerosis. In order to further our understanding of the specific biological events which trigger plaque instability and as well as to monitor the effects of novel anti-atherosclerotic therapies newer imaging modalities in vivo are needed.

Topics: Acute Coronary Syndrome; Cardiac Imaging Techniques; Chronic Disease; Coronary Artery Disease; Coronary Thrombosis; Female; Fibrin; Hemorrhage; Humans; Macrophages; Male; Necrosis; Plaque, Atherosclerotic; Platelet Aggregation; Risk Factors; Rupture, Spontaneous; Vascular Calcification

The formation of blood clots--thrombosis--at sites of atherosclerotic plaque rupture is a major clinical problem despite ongoing improvements in antithrombotic therapy. Progress in identifying the pathogenic mechanisms regulating arterial thrombosis has led to the development of newer therapeutics, and there is general anticipation that these treatments will have greater efficacy and improved safety. However, major advances in this field require the identification of specific risk factors for arterial thrombosis in affected individuals and a rethink of the 'one size fits all' approach to antithrombotic therapy.

Topics: Acute Coronary Syndrome; Animals; Arteries; Atherosclerosis; Blood Platelets; Fibrin; Fibrinolytic Agents; Hemostasis; Humans; Plaque, Atherosclerotic; Thrombin; Thrombosis

Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = - 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.

Topics: Acute Coronary Syndrome; Blood Specimen Collection; Fibrin; Fibrinolysis; Humans; Microscopy, Electron, Scanning; Point-of-Care Systems; Prognosis; Prospective Studies; ST Elevation Myocardial Infarction; Thrombosis

To determine whether fibrin clot properties are associated with clinical outcomes following acute coronary syndrome (ACS).. Plasma samples were collected at hospital discharge from 4354 ACS patients randomized to clopidogrel or ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. A validated turbidimetric assay was employed to study plasma clot lysis time and maximum turbidity (a measure of clot density). One-year rates of cardiovascular (CV) death, spontaneous myocardial infarction (MI) and PLATO-defined major bleeding events were assessed after sample collection. Hazard ratios (HRs) were estimated using Cox proportional hazards models. After adjusting for CV risk factors, each 50% increase in lysis time was associated with CV death/spontaneous MI [HR 1.17, 95% confidence interval (CI) 1.05-1.31; P < 0.01] and CV death alone (HR 1.36, 95% CI 1.17-1.59; P < 0.001). Similarly, each 50% increase in maximum turbidity was associated with increased risk of CV death (HR 1.24, 95% CI 1.03-1.50; P = 0.024). After adjustment for other prognostic biomarkers (leukocyte count, high-sensitivity C-reactive protein, high-sensitivity troponin T, cystatin C, N-terminal pro B-type natriuretic peptide, and growth differentiation factor-15), the association with CV death remained significant for lysis time (HR 1.2, 95% CI 1.01-1.42; P = 0.042) but not for maximum turbidity. These associations were consistent regardless of randomized antiplatelet treatment (all interaction P > 0.05). Neither lysis time nor maximum turbidity was associated with major bleeding events.. Fibrin clots that are resistant to lysis independently predict adverse outcome in ACS patients. Novel therapies targeting fibrin clot properties might be a new avenue for improving prognosis in patients with ACS.

Topics: Acute Coronary Syndrome; Aged; Blood Coagulation; Clopidogrel; Double-Blind Method; Female; Fibrin; Fibrin Clot Lysis Time; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Ticagrelor; Treatment Outcome

Topics: Acute Coronary Syndrome; Fibrin; Fibrinolysis; Humans; Thrombosis

Many studies have shown gender differences in the progress of acute coronary syndromes (ACS). These differences include, amongst others, processes involved in hemostasis and inflammation, and in the present study we put forward the hypothesis that these are the primary cause of other differences. The study included 66 ACS patients (27 women and 39 men) aged 43 - 83 years, 23 with non-ST-elevation myocardial infarction (NSTEMI) and 43 with ST-elevation myocardial infarction (STEMI). Blood samples were taken on day 3 (NSTEMI) or day 5 (STEMI) after hospitalization, and fibrinogen, D-dimers, von Willebrand factor, C-reactive protein and interleukin-6 levels measured. Men, compared to women, had significantly higher levels of fibrinogen (STEMI: P = 0.028; NSTEMI: P = 0.008), C-reactive protein (STEMI: P <0.0001; NSTEMI: P = 0.004) and interleukin-6 with STEMI (P = 0.015), but a lower D-dimer concentration with NSTEMI (P = 0.042). In women fibrinogen concentration was significantly higher with STEMI compared to NSTEMI (P = 0.052). Significant correlations were found between hemostatic and proinflammatory factors, especially in men, regardless of ACS type. In addition, correlations between fibrinogen and D-dimers were found: negative for women (r = -0.67) ) and positive for men (r = +0.60), as was that between C-reactive protein and interleukin-6: women (r = -0.72); men (r = +0.56). Based on these findings, we conclude that acute coronary syndromes in men may be potentially related to inflammatory processes, as indicated by strong associations between elevated C-reactive protein, interleukin-6 and hyperfibrinogenemia, most clearly shown in STEMI. By contrast in women, factors possibly most important for the course of acute coronary syndrome are D-dimer concentrations and an increased turnover of fibrin with NSTEMI and hyperfibrinogenemia with STEMI.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Reactive Protein; Female; Fibrin; Fibrinogen; Humans; Interleukin-6; Lipids; Male; Middle Aged; Pilot Projects; Sex Characteristics; von Willebrand Factor

Because fibrin is transparent and almost invisible by any conventional imaging methodologies, clinical examinations of coronary fibrin thrombus have been ignored, and little is known about its role in the genesis of acute coronary syndrome (ACS). The present study was performed to visualize coronary fibrin thrombus and to examine its role in ACS.. Dye-staining coronary angioscopy using Evans blue dye, which selectively stains fibrin blue but does not stain blood corpuscles, was performed for observation of globular coronary thrombi in 111 ACS patients. The thrombi were aspirated for histological examination. The thrombi were classified by visual appearance into 8 transparent, 3 light-red, 2 frosty glass-like and membranous, 32 white, 8 brown, 34 red, and 19 red-and-white in a mosaic pattern. Transparent thrombi that were not visible by conventional angioscopy were visualized as a blue structure by dye-staining angioscopy, and they were observed in patients with unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI). The thrombi caused total or subtotal coronary occlusion. The aspirated thrombi were composed of fibrin alone by histology. Fibrin-rich thrombi were visualized using dye-staining angioscopy in 60% of 50 patients with UA+NSTEMI and in 29% of 61 patients with ST-elevation myocardial infarction. By histology of the aspirated thrombi, fibrin-rich thrombi were observed in 71% of 33 patients with UA+NSTEMI and in 28% of 35 patients with ST-elevation myocardial infarction.. Fibrin-rich coronary thrombi were frequently observed by both dye-staining angioscopy and histology in ACS patients. Rarely, fibrin itself formed a globular thrombus and caused coronary occlusion.

Topics: Acute Coronary Syndrome; Aged; Angioscopy; Coloring Agents; Coronary Thrombosis; Female; Fibrin; Humans; Male; Middle Aged; Platelet Aggregation

In order to study coagulation and fibrinolysis in acute coronary syndrome (ACS) we used a recently developed assay, called OH-index, which provides simultaneous measurements of fibrin formation and fibrinolysis (fibrin degradation) in the patients' plasma. We also investigated thrombin generation using the calibrated automated thrombogram (CAT), and assessed thrombin generation in vivo by measuring F1+2 plasma concentrations. In addition, to better characterize the patients we also assessed markers of inflammation and endothelial function. Eighty-seven ACS patients were sampled at admission, within 24 hours during treatment with low molecular weight heparin (LMH), and 6 months later; 65 healthy controls were also sampled.. As assessed by OH-index fibrin formation was slightly depressed at admission, profoundly depressed during LMH treatment and comparable to controls at 6 months, whereas fibrin degradation was elevated, particularly during LMH treatment. F1+2 levels decreased during LMH treatment but did not deviate significantly from controls at admission or in convalescence. CAT data showed that peak thrombin was higher at admission and after 6 months compared to controls, whereas the endogenous thrombin potential only tended to be elevated. Both variables were strongly reduced during LMH treatment. Patients had elevated levels of markers of inflammation and endothelial function as expected.. ACS-patients have an increased capacity to generate thrombin and an enhanced capacity to degrade fibrin in the acute phase. Increased thrombin generation persists also 6 months after the event.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Coagulation; Case-Control Studies; Endothelium, Vascular; Female; Fibrin; Fibrinolysis; Humans; Inflammation; Male; Middle Aged; Thrombin

Topics: Acute Coronary Syndrome; Aged; Angina, Unstable; Angioscopy; Coronary Angiography; Coronary Thrombosis; Coronary Vessels; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Infarction

Chronic kidney disease (CKD), defined as a decreased estimated glomerular filtration rate (eGFR < 60 ml/min), is an independent risk factor for cardiovascular events. Both acute coronary syndrome (ACS) and end-stage renal disease have been shown to be associated with formation of compact fibrin clots relatively resistant to lysis. The aim of the current study was to evaluate the effect of CKD on fibrin clot properties in patients with ACS. In 30 ACS patients, aged 48-72 years, with CKD and 30 ACS patients with eGFR more than 60 ml/min, we investigated plasma fibrin clot properties using permeation and turbidity assays, including three different clot lysis assays. The ACS patients with eGFR less than 60 ml/min and those with normal filtration rate did not differ with regard to demographics, risk factors, medications and routine laboratory tests, including fibrinogen. The former group had higher plasminogen activator inhibitor-1 (P = 0.002) and tissue-type plasminogen activator (tPA) (P = 0.008). Compared with ACS patients with eGFR more than 60 ml/min, the ACS patients with CKD formed less porous fibrin clots (P = 0.004) and susceptible to fibrinolysis (P < 0.001), had thicker overall fibrin fibers (P = 0.007), earlier onset of fibrin clot formation (P = 0.004) and increased clot mass (P < 0.001). By multiple regression analysis, clot permeability was independently predicted by eGFR (P = 0.0005) and fibrinogen (P = 0.001), whereas the only predictors of lysis time were eGFR (P = 0.006) and tPA (P = 0.002). This study indicates that ACS patients with CKD display unfavorable fibrin clot properties including impaired fibrinolysis, which might contribute to worse outcome in this population.

Topics: Acute Coronary Syndrome; Aged; Blood Coagulation; Blood Coagulation Tests; Female; Fibrin; Fibrinolysis; Humans; Male; Middle Aged; Renal Insufficiency, Chronic

Web-like (W) and membrane-like (M) structures have been observed on coronary stent edges on angioscopy but their incidence and mechanisms remain obscure.. First, 26 patients [acute coronary syndromes (ACS) in 10 and stable angina (SA) in 16] underwent angioscopy of the stented coronary artery immediately after, and 32 patients (ACS in 18 and SA in 14) 6 months after insertion of bare-metal stents. Second, angioscopy of the stented coronary artery was performed in 4 beagles 5 h after, and in 9 beagles 1 month after stenting. W and M were observed in patients with ACS and those with SA (80.0% vs 18.7%; P<0.05) immediately after and 6 months after stenting (55.5% vs 28.5%; NS). They were stained with Evans blue that selectively stains fibrin immediately after stent insertion, but not 6 months later. In beagles, W and M were observed in 75.0% at 5 h and in 66.6% 1 month later. Histologically, W and M were composed of fibrin at 5 h, whereas they were composed of collagen fibers at 1 month.. W and M were frequently formed on the edges of coronary stents. They were formed with fibrin in the acute phase, whereas this fibrin was replaced by collagen fibers in the chronic phase.

Topics: Acute Coronary Syndrome; Angina Pectoris; Angioscopy; Animals; Collagen; Coronary Vessels; Dogs; Fibrin; Humans; Stents; Time Factors

We sought to test the prognostic performance of thrombus precursor protein (TpP) in patients presenting with an acute coronary syndrome (ACS).. Because thrombus formation is a critical step in the development of ACS, a measurement of activated coagulation could yield important information. Thrombus precursor protein is a biomarker that is used to measure soluble fibrin polymers, which are the penultimate products in fibrin formation.. We measured the levels of TpP in 284 healthy volunteers and in 2,349 patients with ACS.. Median TpP concentrations were 3.6 mug/ml (interquartile range 2.6 to 5.5) in the volunteers and 8.9 mug/ml (interquartile range 4.9 to 15.9) in the ACS patients (p < 0.001). Patients with ACS who had elevated TpP were older, more likely to be women, and more likely to have diabetes and pre-existing CAD (p < 0.02 for each). Thrombus precursor protein levels greater than the median were associated with a significantly increased risk for the composite of death, myocardial infarction (MI), or recurrent ischemia leading to rehospitalization or urgent revascularization through 10 months (hazard ratio [HR] 1.45, p < 0.001), as well as death or MI (HR 1.42, p = 0.02). We found that TpP correlated only weakly with cardiac troponin I, B-type natriuretic peptide, and high-sensitivity C-reactive protein (|r| <0.15 for each). After adjusting for clinical characteristics, cardiac troponin I, high-sensitivity C-reactive protein, and B-type natriuretic peptide, we found that patients with TpP levels greater than the median remained at significantly increased risk for the composite outcome (adjusted HR 1.51, p = 0.001) and death or MI (adjusted HR 1.58, p = 0.02).. In patients with ACS, increased levels of TpP are associated with an increased risk of death or ischemic complications. The incorporation of a marker of activated coagulation, such as TpP, with established cardiovascular risk factors may offer valuable complementary insight into risk assessment in ACS.

Topics: Acute Coronary Syndrome; Adult; Biomarkers; Blood Coagulation; C-Reactive Protein; Case-Control Studies; Coronary Thrombosis; Female; Fibrin; Humans; Male; Middle Aged; Myocardial Ischemia; Odds Ratio; Prognosis; Risk Assessment; Treatment Outcome; Troponin I

Topics: Acute Coronary Syndrome; Biomarkers; Blood Coagulation; Fibrin; Humans; Myocardial Ischemia; Prognosis; Risk Assessment

D-dimer and fibrin monomer both reflect a prothrombotic potential. There are limited data available comparing these two markers of activated coagulation in a prospective manner in an unselected patient population presenting to the emergency department with chest pain. In addition, their role in risk stratification in patients with acute coronary syndrome is still under evaluation. Therefore, we wanted to assess the prognostic value of these markers with respect to long-term all-cause mortality in 871 patients admitted to the emergency department. Blood samples were obtained immediately following admission. After a follow-up period of 24 months, 123 patients had died. In the univariate analysis, both D-dimer and fibrin monomer predicted all-cause mortality within 2 years with an odds ratio of 7.78 (95% confidence interval, 3.95-15.33) and 4.19 (95% confidence interval, 2.42-7.28), respectively, in the highest quartile (Q4) compared with the lowest quartile (Q1). However, in the multivariable logistic regression model for death within 2 years, the odds ratio of D-dimer and fibrin monomer was 1.80 (95% confidence interval, 0.81 to 3.97) and 1.04 (95% confidence interval, 0.53 to 2.04) in Q4 compared with Q1, respectively, and added no prognostic information above and beyond age, known coronary heart disease, B-type natriuretic peptide and the index diagnoses of ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction and unstable angina pectoris. In an unselected patient population hospitalized with chest pain and potential acute coronary syndrome, neither D-dimer nor fibrin monomer provided complementary prognostic information to established risk determinants during long-term follow-up.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Female; Fibrin; Fibrin Fibrinogen Degradation Products; Hospitalization; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Risk Factors

Acute hyperglycemia on admission for acute coronary syndrome worsens the prognosis in patients with and without known diabetes. Postulated mechanisms of this observation include prothrombotic effects. The aim of this study was to evaluate the effect of elevated glucose levels on blood clotting in acute coronary syndrome patients.. We studied 60 acute coronary syndrome patients within the first 12 h after pain onset, including 20 subjects with type 2 diabetes, 20 subjects with no diagnosed diabetes but with glucose levels >7.0 mmol/l, and 20 subjects with glucose levels <7.0 mmol/l. We determined generation of thrombin-antithrombin complexes (TATs) and soluble CD40 ligand (sCD40L), a platelet activation marker, at the site of microvascular injury, together with ex vivo plasma fibrin clot permeability and lysis time.. The acute coronary syndrome patients with no prior diabetes but elevated glucose levels had increased maximum rates of formation and total production of TATs (by 42.9%, P < 0.0001, and by 25%, P < 0.0001, respectively) as well as sCD40L release (by 16.2%, P = 0.0011, and by 16.3%, P < 0.0001, respectively) compared with those with normoglycemia, whereas diabetic patients had the highest values of TATs and sCD40L variables (P < 0.0001 for all comparisons). Patients with hyperglycemia, with no previously diagnosed diabetes, had longer clot lysis time (by approximately 18%, P < 0.0001) similar to that in diabetic subjects, but not lower clot permeability compared with that in normoglycemic subjects.. Hyperglycemia in acute coronary syndrome is associated with enhanced local thrombin generation and platelet activation, as well as unfavorably altered clot features in patients with and without a previous history of diabetes.

Topics: Acute Coronary Syndrome; Acute Disease; Aged; Blood Coagulation; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fibrin; Fibrinolysis; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Myocardial Infarction; Platelet Activation; Prognosis; Thrombin