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

Abstract

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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“…Functionally, patients with PAD and highest D-dimers had the worst walking distance [23] and venous occlusion resulted in impaired fibrinolytic response in patients with PAD versus those without PAD [47]. Significant and independent associations between D-dimer and clinically relevant endpoints were also found in several studies in patients with PAD [15,18,25,48], in line with observations in other groups of patients with atherosclerotic manifestations.…”

Antithrombotic treatment for peripheral arterial disease

“…Many studies have suggested that patients with PAD manifest platelet hyperaggregability, increased levels of soluble platelet activation markers, enhanced thrombin generation and altered fibrinolytic potential (summarised in table 1). [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] These findings, which are consistent across the different stages of PAD, have important ramifications. Individually, many of the markers characterising the prothrombotic environment of PAD are predictive of future cardiovascular events.…”

“…Higher TM levels Cortellaro 11 50 PAD/58 CAD or CVD controls without PAD Higher D-dimer and lower tPA antigen and fibrinolytic capacity; D-dimer and fibrinolytic capacity predictive of subsequent vascular events Devine 12 29 PAD/10 controls Higher anti-factor XIII a-chain binding to platelets Gosk-Bierska 13 59 PAD/26 controls Higher vWF, fibrinogen, TAT and PF4 Gresele 14 63 PAD/18 controls Higher urinary 11-dehydro-thromboxane B2 levels Handa 15 18 PAD/19 controls Higher TM, fibrinogen, a1-AT and TAT; lower a2-PI levels Killewich 16 69 PAD/11 controls Higher PAI-1 and tPA antigen; lower tPA activity Koksch 17 50 PAD/50 controls Higher fibrinogen, vWF, PAI-1, tPA, P-selectin on both stimulated and non-stimulated platelets; lower PAI-1/tPA ratio Lowe 18 388 PAD/1581 controls Higher blood viscosity, hematocrit, fibrinogen, leucocyte elastase, and uric acid; haematocrit and viscosity directly correlated with PAD severity Makin 19 234 PAD/50 controls Higher soluble P-selectin, vWF, TF and fibrinogen; fibrinogen directly correlated with PAD severity McDermott 20 346 PAD/203 controls D-dimer and hsCRP inversely correlated with limb function in both PAD and controls Reininger 21 92 PAD/70 controls Higher platelet adhesion and aggregation, fibrinogen, fibrin monomer, d-dimer and TAT Robless 22 20 PAD/20 controls Higher spontaneous and induced platelet aggregation Zeiger 23 50 PAD/50 controls Higher P-selectin expression on platelets, platelet aggregates and platelet-derived microparticles a1-AT, a 1-antitrypsin; a2-PI, a 2-plasmin inhibitor; CAD, cardiovascular disease; CVD, cerebrovascular disease; hsCRP, highly sensitive C reactive protein; PAI-1, plasminogen activator inhibitor 1; PF4, platelet factor 4; TAT, thrombin-antithrombin complex; TM, thrombomodulin; tPA, tissue plasminogen activator; vWF, von Willebrand Factor. Overall 9% reduction favouring clopidogrel (p = 0.043); 24% reduction in PAD subgroup (p = 0.003) CHARISMA 33 Clopidogrel + ASA v ASA 15 603 with atherosclerosis including 2838 with PAD Overall 7% reduction favouring clopidogrel (p = 0.22); 13% reduction in PAD subgroup (p = 0.29) CREDO 34 Clopidogrel + ASA v ASA 2116 patients including 272 with PAD or CVD Overall 27% reduction favouring clopidogrel (p = 0.02); 48% reduction in PAD/CVD subgroup (p = 0.06) EMATAP 35 Ticlopidine v placebo 615 patients with claudication 74% reduction favouring ticlodipine (p = 0.002) STIMS 36 Ticlopidine v placebo 687 patients with claudication Non-significant 11% reduction favouring ticlopidine (p = 0.24); 29% reduction in all-cause mortality (p = 0.015) Thromboxane inhibitors ADEP 37 Picotamide v placebo 2304 patients with claudication Non-significant 19% reduction favouring picotamide (p = 0.056) DAVID …”

Physical Exertion Induces Thrombin Formation and Fibrin Degradation in Patients With Peripheral Atherosclerosis

“…[17][18][19] Increased PAI-1 is associated with all forms of atherothrombosis, 20 -22 and continuous fibrin deposition on the atherosclerotic vessel wall appears to stimulate endogenous fibrinolysis, reflected in elevated t-PA levels. 17 We also found that there was no difference between the patients and healthy age-, sex-, medication-, and cardiovascular risk factor-matched control subjects in resting levels of t-PA to PAI-1 Ag ratio, t-PA-activity, or PAP.…”

“…29 At rest, depending on the severity of PAOD in the patients involved, various degrees of activation of the coagulation cascade have been reported previously by our group and others. 17,18 The effect of exercise on hemostasis in patients with peripheral arterial disease has also been studied previously. 19 In contrast to our results, the PAOD patients in the study by Herren et al 19 showed enhanced thrombin formation (TAT) at rest compared with the age-and sex-matched healthy control group.…”