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-

, and the PLAT Study Group* The Progetto Lombardo Atero-Trombosi (PLAT) Study was a prospective, multicenter, multidisciplinary study of the association among hemostatic variables, conventional risk factors, and atherothrombotic events in four groups of patients with preexisting vascular ischemic disease (335 myocardial infarction survivors, 123 patients with stable angina pectoris, 160 with transient ischemic attacks, and 335 with peripheral vascular disease). In the myocardial infarction group, univariate analysis showed that atherothrombotic events were associated with high fibrinogen (p=0.001), factor VIII C (p<0.001), and von Willebrand factor antigen (vWF:Ag) (p=0.004) levels and with low high density lipoprotein cholesterol (p=0.043), factor VII (p=0.019), and protein C (p=0.044) levels; multivariate analysis produced associations with high fibrinogen and factor VIII: C levels and low protein C levels. By both univariate and multivariate analysis, events in the angina pectoris group were associated with high vWF:Ag (i=0.026) and leukocyte (p=0.033) levels and the presence of carotid arterial stenosis (p=0.063); associations with high leukocyte (p=0.037) and factor VIII :C (p=0.186) levels, family history (p=0.031), and diabetes (p=0.061) were also found in the group with transient ischemic attacks. In those with peripheral vascular disease, events were associated with Fontaine stage allB (p =0.024), high factor Vm:C levels (p=0.073), and low protein C (p=0.028), fibrinogen (p=0.030), antithrombin m (p=0.054), and factor VII (p=0.057) levels by univariate analysis and with Fontaine stage and low fibrinogen levels by multivariate analysis. In conclusion, the different associations observed in the four groups of patients may reflect a different hemostatic system involvement in the development of atherosclerosis and/or its clinical sequelae. (

Summary Background. Despite prophylaxis, deep vein thrombosis (DVT) after hip surgery continues to occur frequently. Thus it would be helpful if before surgery patients at higher risk of DVT could be identified and more adequate prophylaxis given. As part of an international study on the prevention of DVT after total hip replacement, we investigated whether preoperative levels of three coagulation activation markers, prothrombin fragment F1+2 (F1+2), thrombin-antithrombin III complexes (TAT) and D-dimer, correlate with results of postoperative venography. Methods. 159 patients undergoing total hip replacement were randomized to receive 10, 15 or 20 mg desirudin bid or 5000 IU unfractionated heparin tid immediately before surgery and then for 11 days, until bilateral venography was performed. Preoperative F1+2, TAT and D-dimer plasma levels were measured using ELISA procedures. As no difference among anticoagulant treatments or in the interaction between treatments and DVT was detected for any of the three variables, results are reported as pooled data. Findings. The frequency of DVT was 18.8% in the low (0.75-1.33 nM) vs 65.7% in the high third of distribution (1.77-3.47 nM) of F1+2 (p ˂.001), 27.3% in the low (2.00-2.50 μg/1) vs 57% in the high third (5.10-61.00 μg/l) of TAT (p = .042), and 29.4% in the low (39-59 μg/1) vs 57.1% in the high third (129-651 μg/1) of D-dimer (p = .051). Interpretation. Preoperative F1+2, TAT and D-dimer levels are associated with the risk of development of DVT after total hip replacement.

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.

SummaryBackground: Measurements of prothrombin fragment 1+2 (F1+2), thrombin antithrombin III complexes (TAT) and D-dimer plasma levels have been proposed as non-invasive screening tests to exclude postoperative deep venous thrombosis (DVT). We investigated the diagnostic efficacy of these coagulation activation markers to rule out postoperative DVT in patients undergoing hip surgery under antithrombotic prophylaxis. Methods: In this substudy of a randomized double-blind thrombosis prophylaxis trial comparing three doses of desirudin (10, 15 or 20 mg b.i.d.) with unfractionated heparin (5000 IU t.i.d.) we used ELISA procedures to measure F1+2, TAT and D-dimer in 159 patients undergoing total hip replacement at baseline (day 0) and on postoperative days 1, 3 and 6. Bilateral venography was performed in all cases 8-11 days after surgery. Results: For the F1+2 assay sensitivity ranged from 73 to 83% in the three postoperative days investigated, and negative predictive value (NPV) from 68 to 74%. For TAT and D-dimer sensitivity ranged from 71 to 73% and from 71 to 83% and NPV from 61 to 65% and from 61 to 74% respectively. Interpretation: In terms of sensitivity and NPV F1+2 and D-dimer are equivalent and are superior to TAT. However, their accuracy is too low to rule out the presence of DVT after hip surgery under antithrombotic prophylaxis.