Impaired Fibrinolytic Capacity Research Articles

Impaired Whole-Blood Fibrinolysis is a Predictor of Mortality in Intensive Care Patients.

Background Altered fibrinolysis is considered to play a crucial role in the development of coagulopathy in sepsis. However, routine laboratory tests for fibrinolysis are currently very limited, and the impact of fibrinolytic capacity on clinical outcome is poorly investigated. Objectives To assess whole-blood fibrinolysis in patients admitted to the intensive care unit (ICU) and compare fibrinolysis in sepsis patients with nonsepsis patients. Further, to investigate associations between fibrinolytic capacity and 30-day mortality and venous thromboembolism (VTE). Methods This study was designed as a prospective cohort study. Adult ICU patients were included at the Aarhus University Hospital, Denmark. All patients had a blood sample obtained the morning after admission. A modified thromboelastometry (ROTEM®) analysis with tissue plasminogen activator (ROTEM®-tPA) was used to assess fibrinolysis. The primary endpoint was difference in ROTEM®-tPA lysis time between sepsis patients and nonsepsis patients. Results ROTEM®-tPA revealed fibrinolytic impairment in sepsis patients ( n = 30) compared with nonsepsis ICU controls ( n = 129), with longer lysis time (median [interquartile range] 3,600 [3,352-3,600] vs. 3,374 seconds [2,175-3,600], p < 0.01), lower maximum lysis (23 [8-90] vs. 94% [14-100], p = 0.02), and lower fibrinolysis speed (0.41 [0.0-1.4] vs. 1.6 mm/min [0.1-2.7], p = 0.01). In the composite ICU population, 61% (97/159) demonstrated prolonged lysis time indicating impaired fibrinolytic capacity. These patients had higher 30-day mortality (adjusted odds ratio [OR]: 2.26 [0.83-6.69]) and VTE risk (OR: 3.84 [0.87-17.8]) than patients with normal lysis time. Conclusion Sepsis patients showed impaired fibrinolysis measured with ROTEM®-tPA compared with nonsepsis patients and ROTEM®-tPA lysis time was associated with 30-day mortality and VTE in the entire ICU cohort.

Predictive ability of viscoelastic testing using ClotPro® for short-term outcome in patients with severe Covid-19 ARDS with or without ECMO therapy: a retrospective study

BackgroundSARS-CoV-2 infections are suspected to trigger the coagulation system through various pathways leading to a high incidence of thromboembolic complications, hypercoagulation and impaired fibrinolytic capacity were previously identified as potentially mechanisms. A reliable diagnostic tool for detecting both is still under discussion. This retrospective study is aimed to examine the prognostic relevance of early viscoelastic testing compared to conventional laboratory tests in COVID-19 patients with acute respiratory distress syndrome (ARDS).MethodsAll mechanically ventilated patients with COVID-19 related ARDS treated in our intensive care unit (ICU) between January and March 2021 were included in this study. Viscoelastic testing (VET) was performed using the ClotPro® system after admission to our ICU. Prevalence of thromboembolic events was observed by standardized screening for venous and pulmonary thromboembolism using complete compression ultrasound and thoracic computed tomography pulmonary angiography at ICU admission, respectively. We examined associations between the severity of ARDS at admission to our ICU, in-hospital mortality and the incidence of thromboembolic events comparing conventional laboratory analysis and VET. ECMO related coagulopathy was investigated in a subgroup analysis. The data were analyzed using the Mann–Whitney U test.ResultsOf 55 patients enrolled in this study, 22 patients required treatment with ECMO. Thromboembolic complications occurred in 51% of all patients. Overall hospital mortality was 55%. In patients with thromboembolic complications, signs of reduced fibrinolytic capacity could be detected in the TPA assay with prolonged lysis time, median 460 s (IQR 350–560) vs 359 s (IQR 287–521, p = 0.073). Patients with moderate to severe ARDS at admission to our ICU showed increased maximum clot firmness as a sign of hypercoagulation in the EX-test (70 vs 67 mm, p < 0.05), FIB-test (35 vs 24 mm, p < 0.05) and TPA-test (52 vs 36 mm, p < 0.05) as well as higher values of inflammatory markers (CRP, PCT and IL6). ECMO patients suffered more frequently from bleeding complications (32% vs 15%).ConclusionAlthough, the predictive value for thromboembolic complications or mortality seems limited, point-of-care viscoelastic coagulation testing might be useful in detecting hypercoagulable states and impaired fibrinolysis in critically ill COVID-19 ARDS patients and could be helpful in identifying patients with a potentially very severe course of the disease.

Thromboembolic disease in hypercortisolism.

Endogenous Cushing's syndrome (CS) is associated with increased patient morbidity (hypertension, diabetes mellitus, dyslipidemia, visceral obesity, osteoporosis, cognitive alterations, and impaired quality of life). Both arterial and venous thromboembolic events (TE) due to alterations in the hemostatic system and prothrombotic state are widely reported in patients with CS, more so postoperatively. Increased mortality, if not appropriately treated, is largely due to cardiovascular events and infections. Patients with CS have markedly increased risk of thromboembolic episodes compared to the general population. The prothrombotic state is mediated by increased levels of procoagulant factors, but also by an impaired fibrinolytic capacity. All contribute to TE, atherosclerosis, and subsequent cardiovascular morbidity and mortality. Some abnormalities progressively improve after CS remission, but do not fully normalize for at least 1 year or more. Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in patients with CS and balanced with individual bleeding risk. However, a clear protocol of thromboprophylaxis is lacking and increased awareness regarding risks per se is needed. Large prospective trials will clarify, which patients with CS are at the highest risk and the optimal prevention protocol to minimize risks and maximize efficacy.

Increased fibrin formation and impaired fibrinolytic capacity in severe chronic kidney disease.

Chronic kidney disease (CKD) is associated with a concurrent increased risk of thrombosis and bleeding. We aimed to investigate whether CKD is associated with increased fibrin formation, impaired fibrin degradation, or both. Twenty-one patients with CKD stage 4 (CKD 4), 15 haemodialysis patients, and 13 controls (C) without kidney disease were studied. We used a global assay to determine fibrin formation and degradation in plasma. Fibrin turbidity was measured over time to obtain a value of the coagulation activation profile (Cp) and the fibrinolysis activation profile (Fp), and the amount of fibrin formed, termed fibrin optical density sum (fibrin OD-sum). We used scanning electron microscopy (SEM) to visualize the fibrin network. Plasminogen activator inhibitor type-1 antigen, thrombin-activatable fibrinolysis inhibitor activity, fibrinogen, von Willebrand factor, antithrombin, albumin, and C-reactive protein were measured in plasma. Fibrin OD-sum was significantly elevated in haemodialysis patients [312 a.u.; 278-435 (median; interquartile range); P < 0.0013] and in CKD 4 (293 a.u.; 169-434; P = 0.0119) compared with controls (115 a.u.; 82-234). SEM showed a tight fibrin network in haemodialysis and CKD 4 patients. Fp was lower in the haemodialysis group than in controls (P = 0.030). Plasminogen activator inhibitor type-1 was lower in haemodialysis patients (P = 0.034). Thrombin-activatable fibrinolysis inhibitor activity, Cp, antithrombin, and C-reactive protein did not differ between groups. Fibrinogen was significantly elevated and albumin decreased in both haemodialysis and CKD 4 patients compared with controls. Von Willebrand factor was elevated in haemodialysis patients compared with controls (P = 0.010). The prothrombotic state in severe CKD is characterized by impaired fibrinolysis in association with increased fibrin formation despite normal levels of endogenous fibrinolysis inhibitors.

Mechanisms in endocrinology: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect.

Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin-antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.

Adverse effects of glucocorticoids: coagulopathy.

Hypercortisolism is associated with various systemic manifestations, including central obesity, arterial hypertension, glucose intolerance/diabetes mellitus, dyslipidemia, nephrolithiasis, osteoporosis, gonadal dysfunction, susceptibility to infections, psychiatric disorders, and hypercoagulability. The activation of the hemostatic system contributes to the development of atherosclerosis and subsequent cardiovascular morbidity and mortality. Previous studies have identified an increased risk of both unprovoked and postoperative thromboembolic events in patients with endogenous and exogenous Cushing's syndrome (CS). The risk for postoperative venous thromboembolism in endogenous CS is comparable to the risk after total hip or knee replacement under short-term prophylaxis. The mechanisms that are involved in the thromboembolic complications in hypercortisolism include endothelial dysfunction, hypercoagulability, and stasis (Virchow's triad). It seems that at least two factors from Virchow's triad must be present for the occurrence of a thrombotic event in these patients. Most studies have demonstrated that this hypercoagulable state is explained by increased levels of procoagulant factors, mainly factors VIII, IX, and von Willebrand factor, and also by an impaired fibrinolytic capacity, which mainly results from an elevation in plasminogen activator inhibitor 1. Consequently, there is a shortening of activated partial thromboplastin time and increased thrombin generation. For these reasons, anticoagulant prophylaxis might be considered in patients with CS whenever they have concomitant prothrombotic risk factors. However, multicenter studies are needed to determine which patients will benefit from anticoagulant therapy and the dose and time of anticoagulation.

Residual perfusion defects in patients with pulmonary embolism are related to impaired fibrinolytic capacity

BackgroundFew studies investigated the relationship between fibrinolysis abnormalities and residual pulmonary perfusion defects after acute pulmonary embolism (PE). ObjectiveTo assess the fibrinolytic profile in patients with prior PE in relation to the extent of scintigraphically detectable residual perfusion abnormalities. Patients and methodsWe studied 71 consecutive patients with a prior episode of PE, who were examined after one year of the incident embolic event, and at least one month after anticoagulation withdrawal. They underwent lung scintigraphy to assess the recovery of pulmonary perfusion, echocardiography and chest radiography to look for signs of pulmonary hypertension. Clot formation and lysis were evaluated by two turbidimetric methods: Clot and Lysis Assay and Clot Lysis Time. We also measured the in vitro plasmin-mediated lysis of fibrin from purified fibrinogen, and the circulating levels of fibrinolytic inhibitors. The sample was split in two categories based on the extent of residual perfusion defects: <10% (n=53), ≥10% (n=18). ResultsPatients with perfusion defects >10% had significantly longer lysis time (p<0.05), and higher levels of plasminogen activator inhibitor-1 (p<0.01) than those with perfusion defects <10%. The time interval between symptoms onset and PE diagnosis (time-to-diagnosis) was significantly longer in patients with perfusion defects >10% than in the others (p=0.005). In multivariate logistic regression, both lysis time and time-to-diagnosis were independently associated with perfusion defects >10% (p<0.001). None of the sampled patients had echocardiographic or radiologic signs of pulmonary hypertension. ConclusionProlonged time-to-diagnosis and fibrinolysis imbalance are independent predictors of incomplete perfusion recovery after acute PE.

Hypercoagulability in Cushing's syndrome: prevalence, pathogenesis and treatment

Cushing's syndrome is not only accompanied by an increased prevalence of cardiovascular disease but also by a hypercoagulable state that is reflected by an increased incidence of venous thromboembolism. Overall, patients with CS have been reported to have a more than 10-fold increased risk of developing venous thromboembolism. Moreover, the incidence of postoperative thrombosis has been shown to be comparable to the risk after major orthopaedic surgery. Hypercoagulability in CS is due to both increased production of procoagulant factors with activation of the coagulation cascade and an impaired fibrinolytic capacity, resulting in a shortened activated partial thromboplastin time and an increased clot lysis time respectively. Although these abnormalities seem to improve 1 year following successful surgery, they do not yet normalize. Therefore, sustained biochemical remission might be required to fully resolve the hypercoagulable state in CS. Considering the risk of venous thromboembolism in uncontrolled CS there may be a rationale to give patients with active CS thromboprophylaxis. So far this seems warranted following surgical interventions. However, further studies are needed to determine the optimal dosage and duration of thromboprophylaxis.

Impaired fibrinolytic capacity and increased fibrin formation associate with myocardial infarction

We assessed whether abnormality of haemostasis measured by a newly developed global method is associated with risk of a first myocardial infarction (MI). The global markers coagulation activation profile (Cp), fibrinolysis activation profile (Fp) and sum of fibrin optical density over time (Fibrin OD-sum) were determined in plasma from 800 MI cases and 1,123 controls included in the Stockholm Heart Epidemiology Program. Clot lysis time (CLT) was also determined based on raw data of fibrin OD from the global assay. Odds ratios (OR) of MI with 95% confidence intervals (CI) were calculated using logistic regression. A Fp value <10th percentile value in controls was significantly associated with increased MI risk; OR after multivariate adjustments for conventional cardiovascular risk factors 1.66 (95% CI 1.22-2.27). For an abnormally long CLT (>90th percentile value in controls) the adjusted OR of MI was 2.62 (95% CI 1.87-3.66) and for a high Fibrin OD-sum value (>90th percentile in controls) it was 1.86 (95% CI 1.37-2.53). A high Cp value was not significantly associated with MI. In conclusion, we found that abnormal haemostasis in platelet-poor plasma, reflected either as an attenuated fibrinolytic capacity or the resulting increase of fibrin formation, was associated with increased MI risk.

The impaired fibrinolytic capacity in hypertension is unaffected by acute blood pressure lowering

The endogenous fibrinolytic system and the ability of the endothelium to release tissue-plasminogen activator (t-PA) play a pivotal role to protect humans from atherothrombotic events. We have recently reported that the decreased capacity for t-PA release in hypertension is restored with chronic blood pressure lowering. Thus, we explored if acute blood pressure lowering has the same effect. The capacity for acute t-PA release was investigated in the perfused-forearm model during stimulation by intra-arterial substance P 8pmol/min in hypertensive subjects. The procedure was then repeated during acute blood pressure lowering (n=9) induced by sodium nitroprusside (SNP) infusion or during placebo infusion (n=3). SNP lowered mean arterial pressure from 108.6 (2.6) to 83.0 (2.6) (mean and SEM) mmHg (P<0.001). Substance P induced significant increase in t-PA release during both high- and low-pressure conditions (P<0.01, ANOVA). Peak t-PA release rate was 199 (77) and 167 (41) (mean and SEM) ng/min/l tissue, and accumulated t-PA release was 2,395 (750) and 2,394 (473) ng, during high- and low-pressure conditions, respectively. t-PA release and hemodynamic responses were almost identical during high- and low-pressure conditions (P=ns, for all). Acute blood pressure lowering does not restore stimulated t-PA release from the endothelium in hypertensive subjects. These findings are in contrast to previously described effects of chronic blood pressure treatment. Although data need to be confirmed in a larger study, they suggest that high blood pressure decreases the cellular t-PA pool rather than interferes with release mechanisms of the protein.

Coagulopathy in Cushing’s Syndrome

A hypercoagulable state and its consequent increased incidence of thromboembolic complications are reported in patients with Cushing’s syndrome (CS). These alterations are related to cortisol excess that induces prothrombotic changes in blood by several and complex mechanisms including increased levels of clotting factors, mainly factor VIII and von Willebrand factor (VWF) and impaired fibrinolytic capacity. However, it has recently been observed that the increase in VWF levels is not a constant feature of CS and that VWF response to glucocorticoids is genetically determined and depends on the presence of particular polymorphisms in the VWF gene promoter. The risk of venous thromboembolism is moreover enhanced in patients with CS by additional endogenous and exogenous risk factors such as obesity, bed rest, surgery and invasive diagnostic procedures like inferior petrosal sinus (IPS) sampling. In line with all these data, patients with active CS should be treated as having a prothrombotic disorder and undergo antithrombotic prophylaxis during IPS sampling. Special care should be taken in the immediate perioperative period in order to avoid thromboembolic events. In the absence of prospective randomized trials, preventive antithrombotic treatment (best with heparin) during IPS sampling and low-dose heparin treatment early after surgery should be suggested.

Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors.

Tissue plasminogen activator (tPA), a neuronal as well as the key fibrinolytic enzyme, is found concentrated on demyelinated axons in multiple sclerosis lesions together with fibrin(ogen) deposits. The decreased tPA activity in normal-appearing white and grey matter and lesions of multiple sclerosis is reflected in diminished fibrinolysis as measured by a clot lysis assay. Nonetheless, peptide products of fibrin, including D-dimer, accumulate on demyelinated axons-the result of fibrinogen entry through a compromised blood-brain barrier (BBB). Analysis of tissue samples on reducing and non-reducing polyacrylamide gels demonstrates complexes of tPA with plasminogen activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in grey matter. As total tPA protein remains unchanged in acute lesions and the concentration of PAI-1 rises several fold, complex formation is a probable cause of the impaired fibrinolysis. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, in inflammatory conditions with BBB disruption it has been demonstrated to have a protective role in removing fibrin, which exacerbates axonal injury. The impaired fibrinolytic capacity resulting from increased PAI-1 synthesis and complex formation with tPA, which is detectable prior to lesion formation, therefore has the potential to contribute to axonal damage in multiple sclerosis.

Influence of the Alu-Repeat I/D Polymorphism in t-PA Gene Intron 8 on the Stimulated t-PA Release After Venous Occlusion

Tissue type plasminogen activator (t-PA) is released from endothelium in both a constitutive and regulated fashion. In healthy subjects, an association between net t-PA release rate and a few t-PA gene polymorphisms, including the Alu-repeat I/D polymorphism in intron 8, was described. The possible influence of the Alu-repeat polymorphism on t-PA release was evaluated after a venous occlusion test (VO) in 82 patients showing an impaired fibrinolytic capacity associated with different arterial disease or with previous venous thrombosis, and in 50 healthy controls. Euglobulin lysis time, t-PA antigen (t-PA:Ag) and activity, PAI-1 antigen and activity plasma levels were assayed before and 20 minutes after VO; the Alu-repeat I/D polymorphism was determined by PCR. Defective fibrinolysis was due to reduced t-PA release in 40 patients (t-PA group) and to PAI-1 excess in 42 patients (PAI group). No differences in both genotype distribution and allele frequencies were observed between patients and controls. The t-PA:Ag increase after VO (20/0-minute levels ratio adjusted for hematocrit) was considerably higher both in controls and in PAI group patients carrying the I allele than in the DD genotype carriers (II, ID, DD: 3.77+/-0.62, 3.43+/-0.44, 2.06+/-0.32 in controls, and 3.67+/-0.23, 2.80+/-0.50, 1.62+/-0.29 in PAI group, respectively). The difference was significant between the DD and both the ID and II genotypes in controls (p<0.05), and between the DD and II genotypes in PAI-1 group (p<0.05). A slight and nonsignificant trend of association between genotype and t-PA:Ag 20/0 ratio was seen in the t-PA group patients. In conclusion, these data suggest a possible genetic modulation of t-PA-regulated secretion.

Coagulation and Fibrinolysis in Diabetes

The accelerated development of atherothrombotic cardiovascular disease in type 2 diabetes mellitus may be enhanced by the presence of a prothrombotic state. This prothrombotic state includes a diminished fibrinolytic capacity and an increased coagulability. Impaired fibrinolytic capacity appears to be a hallmark of the metabolic syndrome of type 2 diabetes and can be a direct consequence of visceral obesity. In addition, a chronic low inflammatory state with hyperinsulinemia and dyslipidemia may further influence the hemostatic balance. The characteristic dyslipidemia of type 2 diabetes, coined the atherogenic lipoprotein profile, with raised plasma levels of fasting and postprandial triglyceride lipoproteins, atherogenic low-density lipoproteins, and low high-density lipoproteins, is involved in promoting a hypercoagulable state. Lifestyle and pharmacologic interventions that reduce cardiovascular risk in the general population and that may improve the metabolic syndrome may also reduce the prothrombotic state.

Stimulation in vivo of expression of intra-abdominal adipose tissue plasminogen activator inhibitor Type I by proinsulin.

Impaired fibrinolytic system capacity secondary to increased plasminogen activator inhibitor type-1 expression has been suggested as a pathogenetic link between insulin resistance and increased cardiovascular risk in patients with Type II (non-insulin-dependent) diabetes mellitus, obesity, or both. In patients with syndromes of insulin resistance including those with Type II diabetes, precursors of insulin such as proinsulin can constitute more than 50% of insulin-like molecules in blood. The aim of this study was to determine whether proinsulin can increase plasminogen activator inhibitor type-1 expression in intra-abdominal adipose tissue in vivo, potentially contributing to the increased PAI-1 seen with insulin resistance. Lightly sedated normal rabbits were given intravenous proinsulin, insulin, or vehicle alone under euglycaemic clamp conditions with serial sampling of blood and assessment of PAI-1 expression in visceral fat. Both proinsulin and insulin increased expression of plasminogen activator inhibitor type-1 in intra-abdominal adipose tissue, 5.3-fold (p = 0.006 vs control) and 2.5-fold (p = 0.031 vs control) respectively. PAI-1 inhibitor activity in blood peaked 3 h after administration of each, 5.1-fold, p = 0.020, and 3.4-fold, p = 0.004, respectively but did not change under control conditions. Hyperproinsulinaemia can contribute to increased expression of plasminogen activator inhibitor type-1 in intra-abdominal adipose tissue implicated in increasing PAI-1 activity in blood, impaired fibrinolysis, and accelerated atherogenesis typical of Type II diabetes.

Depression is associated with an impaired fibrinolytic capacity in coronary patients

Depression is associated with an impaired fibrinolytic capacity in coronary patients

Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients.

Long-term steroid immunosuppression has been associated with the prothrombotic state observed in renal transplant (RT) patients, in whom both hypercoagulability due to an increase of von Willebrand factor/factor VIII complex, and impaired fibrinolysis due to PAI-1 excess have been demonstrated. Our aim was to investigate the effect of steroid withdrawal on fibrinolytic capacity in a group of RT patients. The fibrinolytic study was performed in 28 RT patients under stable immunosuppression therapy with cyclosporine, azathioprine, and methylprednisolone; only 12 of these patients could repeat the study 6 months after steroid withdrawal. Euglobulin lysis time (ELT), tissue plasminogen activator activity (t-PA:act) and antigen (t-PA:Ag), PAI-1 activity (PAI-1:act), and antigen (PAI-1:Ag) were assayed on blood samples drawn before and 20 min after the venous occlusion test (VO). An hypofibrinolytic state due to a significant increase in PAI-1 levels was confirmed in RT patients receiving triple immunosuppression therapy. RT patient who stayed off steroids showed a significant shortening of ELT both before (P=0.01) and 20' after VO (P=0.005) at the 6-month control. Moreover, after steroid withdrawal, PAI-1:Ag levels decreased significantly (P=0.002) and normalized; in a similar manner PAI-1:act levels also showed a significant decrease both before (P=0.001), and after VO (P=0.0001). The prevalence of RT patients with impaired fibrinolytic capacity was as high as 83.3% during steroid treatment, and dropped to 16.7% after steroid withdrawal. Our findings confirm that steroid withdrawal may normalize impaired fibrinolytic capacity in RT patients; this improvement may further contribute to reduce the thrombotic risk associated with renal transplantation.

Work stress and metabolic and hemostatic risk factors.

A high level of work stress has been associated with cardiovascular disease. However, the pathophysiological mechanisms underlying this association remain unclear. This study examined the effect of work stress on a cluster of metabolic and hemostatic risk factors. Blood was collected three times, on the first, third, and fifth day of a work week, from 124 middle-aged, white-collar workers. Metabolic measures were insulin, glucose, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and total cholesterol. Hemostatic measures were fibrinogen, tissue-type plasminogen activator activity, tissue-type plasminogen activator antigen, and type 1 plasminogen activator inhibitor antigen. Chronic work stress was defined according to Siegrist's model as 1) a combination of high effort and low reward at work (effort-reward imbalance) or 2) high overcommitment (an exhaustive work-related coping style). Overcommitment, but not imbalance or the imbalance-overcommitment interaction, was associated with an impaired fibrinolytic system, as reflected in decreased tissue-type plasminogen activator activity levels and increased type 1 plasminogen activator inhibitor antigen levels on all three measurement occasions. After controlling for body mass index, total cholesterol, triglycerides, high-density lipoprotein/low-density lipoprotein cholesterol ratio, glucose, and insulin, the relation between overcom-mitment and the fibrinolytic factors was attenuated but remained significant. The results suggest that individuals with an exhaustive coping style at work have an impaired fibrinolytic capacity that is possibly due to the effects of chronic stress on insulin resistance.

Insulin resistance and thrombosis: a cardiologist’s view

Atherogenesis in the vasculature is accelerated by changes in the dynamic equilibrium between endogenous tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1). Increased expression of PAI-1, decreased expression of tissue plasminogen activator, or both can lead to decreased fibrinolytic activity and predispose to thrombosis. Increased concentrations of insulin (and proinsulin) in the plasma increase plasma PAI-1, although the mechanisms of this effect are not known. In addition, it has been observed that basal fibrinolytic activity is decreased in patients with type 2 diabetes; this may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi. Abnormalities in the vessel wall appear to contribute to the increased risk. There is also evidence that PAI-1 content is increased in atherosclerotic lesions of patients with type 2 diabetes, suggesting that interventions to reduce insulin resistance and improve glycemic control may improve the fibrinolytic response. Clinical studies in patients with polycystic ovary syndrome (characterized by insulin resistance, hyperinsulinemia, ovarian androgen overproduction, and impaired fibrinolytic capacity) demonstrated that treatment with troglitazone, an insulin-sensitizing agent, can markedly reduce blood levels of PAI-1. There is also clinical evidence that these agents may contribute to regression of intimal medial thickness in patients with type 2 diabetes, providing further indication that antidiabetic interventions may help inhibit the progression of early atherosclerotic lesions.

Relationship of blood coagulation and fibrinolysis to vital exhaustion.

Acute physical and psychological stressors affect blood coagulation and fibrinolysis, but little is known about hemostatic factors associated with chronic psychological stress. Prolonged psychological stress may end in a state of vital exhaustion, which has been shown to be a risk factor for first myocardial infarction and recurrent events after coronary angioplasty. The present study tested the hypothesis that vital exhaustion resulting from chronic psychological stress is associated with impaired fibrinolytic capacity and increased coagulation factors. On the basis of a validated questionnaire and subsequent structured interview, a well-defined group of otherwise healthy exhausted men was recruited (N = 15) and compared with age-matched not-exhausted controls (N = 15). Fibrinolytic measures included tissue plasminogen activator (TPA) antigen and plasminogen activator inhibitor (PAI-1) activity, and as coagulation factors we examined factors VIIc, factor VIIIc, and fibrinogen. Control variables were: blood pressure, smoking status, triglycerides, cholesterol, and standard hematological measures. Samples were collected twice to correct for intraindividual fluctuations. Statistical analyses were performed using 2 x 2 mixed model analysis of variance with subsequent univariate testing. Vital exhaustion was associated with significantly elevated levels of PAI-1 activity (p = .023). The higher PAI-1 activity in exhausted subjects (median = 13.0 U/ml vs. 6.0 U/ml) was not accounted for by smoking status or serum lipids. No significant differences were observed in TPA antigen, factor VIIc, factor VIIIc, and fibrinogen. The groups did not differ in blood pressure, smoking status, triglycerides, cholesterol, or standard hematological measures. These data suggest a reduced fibrinolytic capacity in exhausted individuals. Therefore, the relationship between vital exhaustion and risk of myocardial infarction may be mediated in part by an imbalance between blood coagulation and fibrinolysis.