A case-control comparison within the framework of the prospective, multidisciplinary PLAT Study was performed to assess whether altered baseline fibrinolytic variables were associated with an elevated risk of ischemic thrombotic events in patients with documented coronary, cerebral, and/or peripheral atherosclerotic disease. Fibrinogen, D-dimer, tissue plasminogen activator (t-PA) antigen, and fibrinolytic activity before and after venous stasis (A=difference between the two values), t-PA inhibitor, and lipid levels in 60 atherosclerotic patients with a thrombotic event during the first year of follow-up were compared with those in 94 atherosclerotic patients without such events, who were matched for age, sex, and diagnosis at enrollment. Events were associated with a higher release of A t-PA antigen (P=.O47), higher D-dimer (P=.O24), and higher t-PA inhibitor (P=.001) levels. A Fibrinolytic activity was correlated inversely with t-PA inhibitor (P<.01) and triglycerides (J*<.05). D-Dimer was also correlated with systolic blood pressure (P<.01). Atherosclerotic patients at higher risk of thrombotic ischemic events are characterized by increased fibrin turnover and impaired fibrinolytic activity due to high t-PA inhibitor levels. This hemostatic disequilibrium may participate with conventional risk factors such as elevated triglyceride levels and systolic blood pressure in the multifactorial mechanism of ischemic sequelae in patients with preexisting vascular atherothrombotic disease. (ArUrioscler Thromb. 1993;13:1412-1417.) KEY WORDS • atherothrombosis • ischemic events • fibrinolytic variables • plasminogen activator inhibitor • D-dimerR ecent clinical studies have reported decreases in fibrinolytic activity in patients with coronary artery disease. 15 The major mechanisms involved in the type of fibrinolytic impairment seen in these patients are an increase in plasma tissue-type plasminogen activator (t-PA) inhibitor, particularly in subjects with hypertriglyceridemia, and a selective depression of t-PA activity in euglobulins. The t-PA inhibitor (PAI-1) has also been shown to be an independent risk factor for reinfarction in young survivors of myocardial infarction (MI). 6The prospective, multidisciplinary PLAT Study, which was performed to investigate the associations between hemostatic variables and ischemic events in 953 patients with documented atherosclerotic disease, 79 afforded the opportunity of carrying out a nested casecontrol study, with the aim of assessing whether altered baseline fibrinolytic variables characterize subjects at a higher risk of ischemic sequelae, and we now report the results. Fibrinogen, fibrinolytic activity, and t-PA anti-

All-trans-retinoic acid (ATRA) induces complete remission (CR) in up to 90% of acute promyelocytic leukemia (APL) patients with rapid amelioration of the bleeding syndrome. Previous studies indicate that ATRA treatment in vitro of the APL NB4 cell line can affect their procoagulant activity (PCA). To assess whether ATRA has this effect also in vivo, we prospectively studied the PCA of bone marrow blasts from APL patients on therapy with ATRA alone or associated with chemotherapy. Samples were obtained before, during, and after ATRA. To characterize the coagulopathy, we measured a series of plasma hemostatic variables before and during the first two weeks of therapy, as follows: (1) markers of hypercoagulability; (2) natural anticoagulants; (3) fibrinolysis proteins; and (4) elastase. The results by enzymatic and immunologic methods show that both total (tissue factor-like) and factor VII-independent (cancer procoagulant- like) blast cell PCAs, present before therapy, were reduced during (69% and 65% decrement, respectively) and virtually undetectable after ATRA. The plasma hemostatic assessment of patients before treatment was elevated hypercoagulability markers, low mean protein C, normal fibrinolysis proteins, and increased elastase. After starting ATRA, hypercoagulability markers were reduced within 4 to 8 days, protein C augmented, the overall fibrinolytic balance was unmodified, and elastase remained elevated. These results were not different either with or without chemotherapy and are consistent with the clinical findings of rapid improvement of the coagulopathy.

SummaryMembrane glycoprotein IIb/IIIa plays a major role in platelet function. The gene encoding the glycoprotein IIIa shows a common polymorphism PlA1/PlA2 that was variably associated with vascular disease. To clarify the role of PlA1/PlA2 polymorphism in coronary risk, a meta-analysis of published data was conducted. Studies were identified both by MEDLINE searches, and hand searching of journals and abstract books.A total of 34 studies for coronary artery disease (CAD), and 6 for restenosis after revascularization were identified, for a total of 9,095 cases and 12,508 controls. In CAD, the overall odds ratio for carriers of the PlA2 allele was 1.10 (95% CI: 1.03 to 1.18), and it was 1.21 (95% CI: 1.05 to 1.38) in subjects younger than 60. Overall odds ratio was 1.31 (95% CI: 1.10 to 1.56) after revascularization procedures.The association of PlA2 status with overall cardiovascular disease in the general population is significant but weak; higher risk has been identified in less heterogeneous subgroups as in the younger cohorts and in the restenosis subset with stents.

The aim of this study was to investigate the association of the Bcl I beta-chain fibrinogen polymorphism with the risk of acute myocardial infarction (AMI) and its relationship with fibrinogen levels in the Italian population. We studied 102 AMI patients, selected within the framework of the GISSI-2 trial, who had a familial history of arterial thrombosis (at least one first-degree relative suffering from AMI or stroke before 65 years) and 173 control subjects (with neither AMI nor personal or familial history of arterial thrombosis). All subjects were Italian. Patients showed fibrinogen levels higher than control subjects. There was a highly significant difference in allele frequency in cases versus control subjects, the B2 allele frequencies being respectively 0.28 versus 0.17 (P = .002). In multivariate analysis, adjusted for sex, age, smoking habits, and history of hyperlipidemia, hypertension, or diabetes, the (B1B2 + B2B2) genotype was associated with a higher risk of AMI (odds ratio 2.4, 95% confidence interval, 1.2 to 4.6). The Bcl I genotype was also associated with fibrinogen levels, independently of gender and smoking habits, the (B1B2 + B2B2) subjects showing the highest levels in both cases and control subjects. The difference in fibrinogen levels between cases and control subjects was significantly influenced by the genotype (significant interaction, P = .042). The B2 allele of the Bcl I polymorphism in the beta-chain of the fibrinogen gene is a new factor associated with the risk of familial AMI through its association with fibrinogen levels. These data provide evidence for a causal role of fibrinogen in familial AMI.

Mental health modulates the risk of common chronic conditions like cardiovascular disease, cancer and diabetes. Although inflammation is thought to partly explain this link, its relation with mental health is still unclear and largely unexplored.We investigated three scales assessing psychological resilience (CD-RISC), depression symptoms (PHQ8) and mental wellbeing (SF36-MCS) in an Italian adult population cohort (N max =16,952). We performed stepwise generalized linear models to test the association between each scale and INFLA-score, a composite blood-based inflammation index. At each step, a class of potential mediators was included in the model, namely health conditions, lifestyle factors, or both (full model). Full model analysis was also conducted on single blood markers involved in the inflammatory process.In the baseline model, we observed significant associations of PHQ8 (standardized β =0.024, p=8.9x10 -3 ) and SF36-MCS (β=-0.021, p=7x10 -3 ) with INFLA-score. These associations survived adjustment for health conditions but not for lifestyle factors, which explained 81% and 17% of the association with PHQ8 and SF36-MCS, respectively. Significant associations (p<4.2x10 -3 ) after mediator adjustment were observed for single low-grade inflammation markers, including platelet distribution width (with PHQ8 and CD-RISC), granulocyte-and neutrophil-to-lymphocyte ratios, monocyte and lymphocyte fractions (with SF36-MCS).These findings suggest that the relationship between mental health and low-grade inflammation is largely influenced by lifestyle. However, the associations with specific biomarkers related to inflammation are partly independent and might be explained by biological factors. Interestingly, these associations are in line with recent blood transcriptomic analyses of depressed subjects, reporting up-and down-regulation of genes related to innate and adaptive immunity, respectively.

SummaryBlast cell extracts from patients with acute non lymphoid leukemia (ANLL) express cancer procoagulant (cp). Thii factor X (FX) activator is distinct from tissue factor (TF) in that it does not require factor VII (FVII) to trigger blood coagulation, it acts as a cysteine proteinase and is not present in normal mononuclear cells. Tb assess whether there is any relationship between the presence of CP and the status of the disease, ANLL patients have been studied at diagnosis, during remission, at relapse. The procoagulant activity in either the presence or absence of F VII and sensitivity to cysteine proteinaie inhibitors were tested on cell extracts. Immunoreactivity was explored with an anti-cP polyclonal antibody. Data obtained in gL newlydiagnosed ANLL patients (subtypes M1 to M5, EAB classification) confirmed the presence of cp in M1- to M4 groups (mean + sE Fvll-independent activity: M1 = 2.1 ± 0.7 unit/mg; M2 = 5.7 ± 1.7 unit/mg; M3 = 31.5 ± 8 unit/mg M4 = 1.6 ± 1.2 unit/mg; CP was absent in the M5 type. In eight patients analy zedin a subsequent phase of partial remission, specific activity had dropped from 26.9 ± 7.8 to 10.5 ± 4.0 unit/mg. Activiiy was virtually absent (0−0.05 unit/mg) in the bone marrow of 37 patients studied at complete remission. Bone marrow samples from six subjects tested at different intervals after complete remission were repeatedly negative for CP but became positive 2 to 5 months before relapse. Upon relapse, the FVII indbpendent activity rose to 24.2 ± 8.2 unit/mg.These results suggest that CP activity may be closely associated with the presence of myeloid malignant cells in the bone marrow, a finding of potential relevance not only to the coagulation disorders of acute leukemia, but also to the early deteition of blast cells in ANLL.

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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