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Fibrin formation and degradation in patients with arteriosclerotic disease
T Herren1, H Stricker, A Haeberli
1Laboratory for Thrombosis Research, University Hospital, Inselspital, Bern, Switzerland.
Insights
Patients with peripheral arterial disease (PAD) show increased thrombin formation, indicated by higher prothrombin fragment F1+2 and thrombin-antithrombin complexes. While fibrin formation markers were not elevated, D-dimers suggest fibrinolysis occurs in PAD patients.
Area of Science:
- Cardiovascular Medicine
- Hematology
- Biochemistry
Background:
- Peripheral arterial disease (PAD) is associated with activated blood coagulation.
- Previous studies had potential limitations in control group selection.
- This study investigates coagulation markers in PAD patients versus a rigorously screened control group.
Purpose of the Study:
- To measure markers of blood coagulation activation in PAD patients and healthy controls.
- To assess the impact of exercise on coagulation markers in PAD.
- To correlate coagulation markers with disease severity and ischemic changes.
Main Methods:
- Recruited 22 PAD patients (Fontaine grade II) and 13 healthy controls with no arteriosclerosis.
- Measured prothrombin fragment F1+2, TAT, FPA, and D-dimers before and after a treadmill stress test.
- Assessed PAD severity using ankle-brachial pressure index (ABPI) and ECG for ischemic changes.
Main Results:
- PAD patients had significantly higher baseline F1+2, TAT, and D-dimers than controls.
- Fibrinopeptide A (FPA) levels were not significantly different between groups.
- Exercise did not further activate coagulation, but post-exercise F1+2 and TAT correlated with ECG ischemic changes.
Conclusions:
- PAD patients exhibit enhanced thrombin generation, mostly neutralized by antithrombin III.
- Elevated D-dimers in PAD patients indicate in vivo fibrinolysis, suggesting some fibrin formation.
- Coagulation markers correlate with PAD severity and exercise-induced ischemia.
Background:
The blood coagulation cascade was reported to be activated in patients with arteriosclerotic disease of the lower limbs (peripheral arterial disease, PAD). There is more thrombin and fibrin formation compared with healthy control subjects. In many studies, however, the presence of arteriosclerotic disease had not been thoroughly ruled out in the control group. Therefore, markers of the activation of the blood coagulation cascade were measured in patients with PAD and in a carefully defined control group, both groups being subjected to an exercise test.
Methods And Results:
Twenty-two patients with angiographically documented PAD of grade II (Fontaine classification) and 13 control subjects in whom the presence of arteriosclerotic lesions was ruled out by noninvasive means in the carotid arteries, abdominal aorta, leg arteries, and coronary arteries took part in the study. Before and immediately after a treadmill stress test, the concentrations of prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin III complexes (TAT), fibrinopeptide A (FPA; this peptide was measured in spot urine also), and D-dimers were measured. Before exercise, the concentrations of F1 + 2 (1.0 +/- 0.6 versus 0.7 +/- 0.3 nmol/L), TAT (2.9 +/- 2.1 versus 1.9 +/- 0.8 micrograms/L), and D-dimers (318.2 +/- 270.1 versus 150.0 +/- 91.4 micrograms/L) were significantly higher in the patients with PAD compared with the healthy control subjects. FPA concentrations in plasma (1.9 +/- 1.0 versus 1.4 +/- 0.6 micrograms/L) and spot urine were not different, however. F1 + 2, FPA, and D-dimer concentrations correlated with the severity of the PAD as assessed by the ankle systolic blood pressure index (ABPI). The symptom-limited stress test did not lead to further activation of the blood coagulation cascade. However, concentrations of F1 + 2 (P < .001) and TAT (P < .01) after exercise correlated with the presence of ischemic changes in the stress-test ECG.
Conclusions:
There is evidence of enhanced thrombin formation in patients with PAD compared with an age- and sex-matched control group without clinical and sonographic evidence of arteriosclerosis. The thrombin formed, however, appears to be almost completely neutralized by antithrombin III. No direct evidence of fibrin formation was obtained, since the FPA concentrations were not different. In the patients with PAD, the higher concentrations of D-dimers are indicative of in vivo fibrinolysis. Thus, some fibrin formation must be postulated to occur in patients with arteriosclerosis.