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Title: Effects of exercise stress testing on blood coagulation and fibrinolysis in aortic valve stenosis


Calcific aortic stenosis (AS) is the most common form of valvular heart disease in adults. The early lesions in aortic valve leaflets are similar to those observed in atherosclerosis. It has been shown that AS is a prothrombotic state, characterized by increased thrombin formation and platelet activation, which is accompanied by systemic inflammation. Despite extensive research efforts, there is no effective treatment of the progression of AS. The presence of symptoms including heart failure, angina, dizziness and syncope in a patient with AS requires aortic valve replacement, because delay of the therapy worsens the prognosis. The management of asymptomatic AS patients is controversial. Several studies performed over the past decades have aimed to established the optimal treatment in this group of patients.In 2013, Natorska et al. have reported that hypofibrinolysis is more common in AS patients than in controls. Moreover, it is known that exercise can induce a prothrombotic state. It has been suggested that beneficial effects of physical activity on the risk of cardiovasculardisease may result at least in part from increased fibrinolysis. To our knowledge, there have been no published studies on the effect of exercise on blood coagulation and fibrinolysis in AS patients. The present study was performed to evaluate potential differences in the haemostatic response to exercise ; stress test in AS patients.The study included 33 adult patients with asymptomatic moderate-to-severe AS and 33 controls. The exclusion criteria were: history of angina, dizziness or syncope, heart failure, left ventricular (LV) ejection fraction (EF) <50%, history of myocardial infarction, stroke or venous thromboembolism, history or current atrial fibrillation, hyper- or hypothyroidism, diabetes treated with insulin, oral anticoagulant therapy, severe comorbidities and acute infection. Blood glucose, creatinine, lipid profile, aminotransferases, thyroid-stimulating hormone, high-sensitivity C-reactive protein and routine coagulation parameters (activated partial thromboplastin time, prothrombin time-international normalized ratio, fibrinogen) were determined on admission in all patients. Transthoracic echocardiography and stress echocardiography were performed in all subjects. We also measured intima-media thickness and ankle brachial pressure index to assess atherosclerotic vascular disease in other arteries. Markers of thrombin generation (prothrombin 1+2 fragments [F1+2], peak thrombin generated [Cmax], free tissue factor pathway inhibitor, platelet activation (soluble CD40 ligand [sCD40L]), fibrinolysis (PAI-1, TAFI antigen and activity, plasminogen, α2-antiplasmin, plasma soluble thrombomodulin [TM], tissue plasminogen activator [tPA] antigen, D-dimer, clot lysis time [CL ; T]), von Willebrand factor (vWF) antigen, vWF factor activity, VIII factor activity and troponin T were determined four times: at rest, at peak exercise, one hour and 24 hours after exercise.Measurement of the peak thrombin generated was performed using calibrated automated thrombography using the assay by Hemker et al.. Measurement of CLT with the modified method by Lisman et al. was based on the assessment of lysis efficiency mediated by tissue plasminogen activator (t-PA) after addition of tissue factor (TF) and phospholipids to plasma., Thirty-two AS patients and 32 controls were included in the finalanalysis; one subject from each group was excluded due to elevated blood white cell count and hypothyroidism respectively. Slightly lower hematocrit, hemoglobin, platelet count and more common hypercholesterolaemia were observed in AS patients, while other routine laboratory parameters were similar in both groups.The indices of the AS severity were: peak aortic velocity (Vmax)=3.8±0.59 m/s; peak pressure gradient (PPG)=59.4±19.8 mmHg; mean pressure gradient (MPG)=35.4±14.1 mmHg; aortic valve area (AVA)=1.08±0.23 cm2; AVA indexed to body surface area (AVA/BSA)=0.58±0.1 cm2/m2. Bicuspid aortic valves were found in 12 (37.5%) AS patients.The duration of stress test was shorter in AS group (p=0.008) and maximum workload was lower (p=0.002) and reached 81.3±21.1 W. During stress tes ; t 7 (21.8%) patients had dyspnea and 3 (9.3%) had angina without echocardiographic signs of ischemia in AS patients, while in the control group 5 patients had dyspnea (15.6%). In the AS group at maximum workload PPG rose to 75.3±26.1 mmHg, MPG to 45.3±15.9 mmHg and EF to 73±6.5% (all p<0.05). There was no intergroup difference in post exercise increase in EF.There was no differences in baselins levels of Cmax, F1+2 and TFPI between the two groups. Cmax during peak workload in AS group increased by 25% (p<0.001) and was higher than in controls (p<0.001). Interestingly, Cmax in AS patients reached its peak 24 hours after exercise, while it followed a different pattern in controls, i.e. it decreased reaching its nadir 24 hours post exercise (p<0.001).Baseline plasma sCD40L was similar in both groups without any exercise-related changes.Baseline CLT was 13% longer among AS patients (p=0.006) compared with controls. CLT remained unaltered at peak exercise in AS group and it decreased in controls (intergroup difference of 28%, p<0.001). One hour after exercise test CLT decreased in AS patients to the level similar to the control group, and then increased 24 hours later, being 15% higher than in controls (p<0.001). Exercise showed no effect on D-dimer in either group., TAFI antigen remained unaltered during stress test in the AS group. Interestingly, in all four time points, TAFI acti ; vity was higher in ASgroup than in controls (all p<0.001). In AS patients TAFI activity remained unaltered at peak exercise, but then after a decrease after one hour it rose above the baseline value (p=0.003). In controls TAFI activity was reduced during the test and after its completion compared to the baseline (all p<0.01,). Of note there was a weak association between TAFI antigen and Vmax (r=0.36, p=0.042). Importantly, in AS patients CLT at baseline, but not in three other time points, correlated with TAFI activity (r=0.69, p<0.001), α2-AP (r=0.47, p=0.007) and plasminogen (r=-0.55, p=0.001). In controls CLT correlated with TAFI activity in all time points (r=0.65, p<0.001; r= 0.54, p=0.001; r=0.42, p=0.015; r=0.50, p=0.003, respectively).Plasminogen was similar at baseline in both groups, but then plasminogen became higher in AS group (all p<0.05, respectively). There were no differences in PAI-1 antigen between the two groups in any time point. Although α2- antiplasmin remained unaltered during exercise test in the AS group, it was higher than in the control group at baseline (p=0.024), similar at peak exercise, and lower at one and 24 hours post exercise (both p<0.05). Importantly, in AS patients CLT at baseline, but not in three other time points, correlated with TAFI activity (r=0.69, p<0.001), α2- antiplasmin (r=0.47, p=0.007) and plasminogen (r=-0.55, p=0.001). In c ; ontrols CLT correlated with TAFI activity in all time points (r=0.65, p<0.001; r=0.54, p=0.001; r=0.42, p=0.015; r=0.50, p=0.003, respectively).Soluble TM in both groups at baseline was similar, but it was higher than in the control group both at peak exercise (p<0.001), one (p<0.001) and 24 hours after exercise (p=0.034). Pre-exercise CLT, but not other fibrinolytic variables, correlated with TM in the AS group (r=0.55, p=0.001).There were no differences in tPA antigen between the AS and control groups.There were no intergroups differences and post-exercise changes in troponin levels in both.The current study shows that during exercise moderate-to-severe AS patients display a specific pattern of prothrombotic changes in coagulation and fibrinolysis markers, quite different from that observed in age- and sex-matched controls. Patients with AS respondto physical activity with a marked increase in maximum concentration of thrombin generated and a decrease in fibrinolytic capacity. The present data suggest that exercise-induced prothrombotic alterations in AS patients may promote fibrin deposition on aortic valve leaflets, leading to the progression of this disease. It might be speculated that intense exercise could contribute to faster progression of valvular lesions and higher risk of cardiovascular events. Our observations apply to patients with moderate-to-severe AS, and canno ; t possibly be extended to the early stages of this disease.

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2 - studia doktoranckie

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Wydział Lekarski


Undas, Anetta

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Mar 15, 2023

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ZB-122315 Mar 15, 2023


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