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Plasma fibrinolytic activity and fibrinogen : their relationship in cardiac injury.
A dynamic equilibrium between coagulation and fibrinolysis exists in order to maintain fluidity of blood. However, in certain pathological states fibrinolytic system undergoes abnormal deviations.[5], [19] Plasma fibrinolytic activity (PFA) has generally been reported to be diminished and fibrinogen (PF) raised following myocardial damage in laboratory animals[15], [18] as well as in human beings.[3], [11] Moreover, these changes in PFA and PF have been shown to be related in graded fashion with increasing severity of myocardial necrosis in rats.[14], [16] In view of these observations it seems logical to speculate some kind of relationship between the two. However, some workers have concluded that though there are definite changes in PFA and PF following myocardial infarction, they are not reflected in each other.[3], [9], [10] Therefore, to confirm our speculation it seemed worthwhile to undertake the present work.
Present study was conducted in rats, dogs and patients with myocardial infarction. (a) Study in rats Male Porter strain rats weighing between 250 and 270 g were divided in five groups of ten animals each and were challenged with isoprenaline hydrochloride subcutaneously (s.c.) for two consecutive days to induce myocardial necrosis. The doses selected for different groups were 85.0, 10.63, 1.33, 0.17 and 0.02 mg/kg so as to induce myocardial necrosis of variable grades.[13] One group of ten rats was treated with matching volume of saline and served as control. Forty eight hours after the first injection of isoprenaline/saline, rats were anaesthetized with pentobarbitone sodium (40.0 mg/kg, i.p.) and blood was collected from the abdominal aorta for estimation of plasma fibrinolytic activity (PFA) by noting the euglobulin clot lysis time (ELT)[2] and plasma fibrinogen (PF).[17] The animals were then sacrificed by severing the diaphragm and their hearts were autopsied. Frontal sections of the heart including both auricles, ventricles and interventricular septum (5 um) were stained with haematoxylin and eosin. Based on the gross and microscopic appearances, the heart lesions were graded on a five point scale from grade zero to four.[13] (b) Study in dogs Eighteen adult mongrel dogs of either sex weighing between 8 and 16 kg were subjected to coronary artery ligation (CAL) by the method of Harris.[8] The animals were divided in three groups containing six dogs each. Anterior descending branch of the left coronary artery was ligated at three different places in different groups. The distances of site of ligation the origin of the anterior descending branch were 1.0-2.0 cm, 2.1-3.0 cm and 3.1-5.0 cm to produce infarcts of variable size and severity. Corresponding three groups of two dogs each, subjected to sham operation served as control for respective sites of ligation. Blood samples were collected from each dog from saphenous vein after CAL daily for five consecutive days for the measurement of ELT and PF. The dogs were sacrificed on the fifth post-operative day. Heart was taken out, cleaned, dried with blotting paper and weighed. Quantification of ischaemic area of heart was done by the method of Nachlas et al.[12] The infarcted myocardium, thus identified, was removed with the help of a knife and weighed. Percentage of infarcted myocardium was calculated. (c) Study in patients Thirty patients of either sex, aged between 35 and 75 years, admitted to the intensive therapy ward of SX.B.P. Hospital, Meerut with the diagnosis of acute myocardial infarction were included. Blood samples were collected from the antecubital vein of these patients for five consecutive days following their admission to the hospital for estimating PF, ELT and serum creatine phosphokinase (CPK).[4]
(a) Study in rats The distribution of grades of lesions, ELT and PF following isoprenaline challenge are summarized in [Table 1]. The changes in ELT and PF observed exhibited a steady increase with the severity of necrosis. Pearson's coefficient of correlation (r) between PF and ELT was found to be +0.882 (p < 0.001). Regression line between these parameters plotted by the method of least square demonstrated a linear correlation [Fig. 1]. (b) Study in dogs Coronary artery ligation at different levels produced variable sizes of myocardial infarction. Amount of infarcted cardiac tissue in CAL animals ranged from 3.5-20.0%, while no infarction could be detected in sham operated animals. Variable values of PF and ELT were obtained for different size of infarcted myocardium [Table 2]. Observed changes in PF and ELT showed a steady increase with increasing size of myocardial infarction. Pearson's coefficient of correlation (r) between PF and ELT was + 0.501 (p < 0.05), and the regression line plotted demonstrated a linear correlation [Fig. 1]. (c) Study in patients Different values of CPK ranging from 2.0 to 9.6 I.U. per litre were obtained in patients showing variable severity of myocardial infarction. Plasma fibrinogen and ELT also rose to different extents in accordance with CPK [Table 3]. Correlation coefficient (r) between PF and ELT in these patients was + 0.458 (p < 0.50). Similar to rats and dogs, a linear correlation was demonstrated on plotting the regression line between ELT and PF.
The present study revealed the reaction pattern of fibrinolytic system following experimental as well as clinical myocardial damage. The results unequivocally demonstrate that plasma fibrinolytic activity is reduced (as judged by increase in ELT) and fibrinogen raised consistently following myocardial damage irrespective of its aetiology. Moreover, it also became evident that the prolongation of ELT (depression in PFA) is related to PF levels as a strong positive correlation [Fig. 1] was found between these two parameters in all the three models. However, this finding is at variance from the observations of Chakrabarti et al[3] who concluded that the changes in PFA were not a reflection of PF levels. Tissue injury and stressful situations are supposed to be the stimulating factors for excessive production of fibrinogen by livers.[6], [7] On the other hand, PFA is known to be affected primarily by stress which may be as mild as exercise.[1] It seems probable that PF is not always influenced by stress viz. electroplexy, which exercises pronounced effect on fibrinolytic activity.[3] Hence in such situations PFA ought to be independent of PF levels as noticed by Chakrabarti et al.[3] On the other hand both the parameters i.e. PFA and PF levels have been found to be affected in the present study which dealt with myocardial injury which is a stressful situation also. Hence, it is not unreasonable to believe that in the stressful conditions associated with tissue damage changes in PFA are related to changes in PF levels.
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