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Coagulation studies in uraemia.
Bleeding diathesis is an important complication of advanced uraemia and has assumed more significance during recent years. Riesmann,[24] was the first to recognise renal disease as the cause of haemorrhagic diathesis. This fact is now a well established entity but its pathogenesis is still baffling. The frequency of haemorrhagic disorder in renal failure appears to be related to the degree of uraemia. Although the haemostatic defect in uraemia often is complex and may include thrombocytopenia and minor coagulation abnormalities, it is possible that platelet dysfunction is most consistent and a clinically important feature.[20] The disorders of coagulation and fibrinolysis have also aroused interest because of their possible pathogenic effect in renal disease with glomerular fibrin deposits and by consequent clinical trials with anticoagulant therapy with beneficial results.[13] Plasma fibrinogen was found to be elevated in uraemic patients.[25] Decreased fibrinolytic activity and increased content of inhibitors of plasminogen activators were found to be common in conservatively treated chronic uraemia.[16] The evidence of decreased fibrinolytic activity in chronic renal disease was first described by Jacobsson.[12] The objectives of this study were: (1) to delineate the coagulation abnormalities in various grades of renal failure, (2) to note the effects of short term hemodialysis and peritoneal dialysis on the coagulation abnormalities in cases of acute and chronic renal failure, (3) to find out the alterations in coagulation parameters on long term basis in patients undergoing rehabilitation by regular dialysis treatment and transplantation, and (4) to note the differences between bleeders and non-bleeders with respect to various coagulation parameters.
A total number of 304 patients of either sex was taken for this study. A similar observation was done on 35 normal subjects for comparison. All the patients of renal failure were admitted to the Artificial Kidney Unit, K.E.M. Hospital, Bombay for the management of renal failure. Clinical details of each patient including details of renal disease, drug therapy, and bleeding tendency were noted. The patients were observed for any abnormal bleeding, skin petechiae, ecchymosis in addition to a complete clinical examination. Based on the clinical diagnosis, these 304 patients were classified into three major groups (a) acute (total 164, bleeders-76 and non-bleeders-88) (b) chronic (total 113, bleeders-39, nonbleeders-74) and (c) acute on chronic (total 27, bleeders 13 and non-bleeders 14). Dialysis was given to 136 out of 164 cases of ARF (haemodialysis to 28, Peritoneal dialysis to 67 and both dialyses to 41), to 95 out of 113 cases of CRF (haemodialysis to 24, peritoneal dialysis to 28 and both to 43) and to 25 out of 27 cases of acute on chronic renal failure (haemodialysis to 4, peritoneal dialysis to 15 and both to 6). Coagulation studies in these patients were done prior to dialysis. Blood was collected by venepuncture and then transferred to different containers containing different anticoagulants. Heparinised blood was used for BUN and creatinine estimation, oxalated blood for fibrinogen estimation and citrated blood for the other coagulation parameters. The degree of renal failure was measured by their renal chemistry as estimated by plasma urea nitrogen and creatinine. All the patients had their ESR estimated by Westergren method and read at the end of one hour. The various parameters studied for coagulation data with their normal values are listed below. 1. Bleeding time (BT) (Ivy's method)[11]: 2-5 minutes. 2. Clotting time (CT) (Lee and White's method)[17]: 5-10 minutes. 3. Prothrombin time (FT) (Quick's one stage method)[22]: upto ± 3 seconds of normal. 4. Partial thromboplastin time with Kaolin (PTTK) (Biggs)[1]: 45-60 seconds. 5. Platelet count (Brecher et al method)[2]: 1.5-4.5 lakhs /cmm. 6. Fibrinogen (Tyrosine method) (Lempart)[18]: 200-400 mg%. 7. Euglobulin lysis time (ELT) (Buckell's method)[3]: 90-180 minutes. All the patients were hospitalised and were treated either conservatively or by haemodialysis and/or peritoneal dialysis. Follow up was done on patients who were on long-term dialysis therapy and recoverable renal failure who were given short term dialysis.
The causative factors responsible for the occurrence of renal failure have been presented groupwise in [Table 1]. The hematological and biochemical values for different parameters in normal persons and in patients in the 3 groups of renal failure and their statistical comparison with normals is presented in [Table 2]. All the parameters were abnormal in renal failure patients when compared with the normals and these differences were statistically significant. All the three groups of renal failure were further divided into bleeders and non-bleeders and their values for all the parameters are as shown in [Table 2]. There was not much difference in the average values of bleeders and nonbleeders for all the parameters except platelet count where it was found to be low and significant in acute renal failure. Plasma creatinine values were correlated with some of the coagulation parameters as presented in [Table 3]. A good correlation was possible between fibrinogen and creatinine in acute renal failure patients. Partial thromboplastin time however, showed significant values in both chronic and acute on chronic renal failure groups when correlated with plasma creatinine. Plasma creatinine values in acute renal failure patients could be correlated with euglobulin lysis time. Statistically significant correlation was possible between ESR and fibrinogen in all three groups of renal failure [Table 3]. Recoverable renal failure patients on short term dialysis, and chronic renal failure patients due to end stage renal disease who were on long term dialysis treatment were studied during their illness. Values for the coagulation parameters through the follow up period are presented in [Table 4] and [Table 5]. Chronic renal failure patients themselves were followed up through their disease [Table 4]. Evaluation of the pre and post-transplant coagulation parameters is presented in [Table 6.]
The precise cause of bleeding in uraemia still remains ill-understood and probably varies from person to person. Bleeding time Willoughby and Crouch[28] found the bleeding time to be prolonged in uraemic patients contrary to the findings of a normal bleeding time as reported by Castaldi et al.[4] Clotting time Normal or near-normal clotting times were obtained by Kuhlback[14] in his studies while Guild and co-workers[9] and Larrain and Adelson[15] found prolonged clotting times in uraemic patients. In the present study, bleeding and clotting times were within the normal range (2.08 ± 0.795 minutes and 9.23 ± 7.603 minutes respectively). In both acute and chronic renal failure cases, prolonged bleeding times were obtained. Prolonged clotting times were a feature of all the three groups of renal failure being highly significant for acute and chronic renal failure and of moderate significance in acute on chronic renal failure group. No differences existed, however, between the bleeders and nonbleeders in each group. Prothrombin time An abnormal prothrombin time was reported in approximately 25 to 50% of uraemic patients.[5] Since it was only slightly prolonged, it was not likely to result in a haemorrhagic tendency. Rath et al[23] found increased prothrombin time in 23 out of 45 cases and these normalised following dialysis. Partial thromboplastin time Majority of the uraemic patients studied by Sanchez-Avalos et al,[25] showed shortened partial thromboplastin times. In the present study, both prothrombin and partial thromboplastin times were found to be prolonged when compared to normals. Comparison of the three groups with normals revealed highly significant differences. Acute renal failure patients had a prolonged partial thromboplastin time of 66.51 ± 15.16 seconds when compared with that of acute on chronic renal failure patients who had a partial thromboplastin time of 58.96 ± 10.76 seconds. Bleeders and non-bleeders did not show any difference in both these parameters. A moderately significant negative correlation was discernible between plasma creatinine levels and partial thromboplastin times in chronic and acute on chronic renal failure groups. Platelet count Thrombocytopenia has been mostly incriminated as an important cause of haemorrhagic diathesis in uraemia.[10] This was however, not found to be significantly so, by Chenny and Bonnin.[5] It is now known that there is a qualitative platelet defect in patients with chronic renal failure which is a consequence of the abnormal biochemical environment.[4] [19], [23] That this platelet defect is improved by haemodialysis[27] suggests that low molecular weight compounds usually retained in uraemic subjects play an important role here. In the present study, significantly low platelet counts (1.83 ± 0.348 lakhs/cmm.) were found in renal failure patients when compared with normals (2.69 ± 0.296 lakhs/cmm). Each individual group had significantly lowered counts. Between themselves, no significant difference existed. Only in the acute renal failure group, the bleeders showed a lower platelet count when compared with the nonbleeders. This probably means that a lowered platelet count could be the cause for a bleeding tendency in acute renal failure whereas a qualitative platelet defect probably predisposes to bleeding in other groups. No correlation was possible between platelet counts and creatinine in any group. Euglobulin lysis time Decreased fibrinolytic activity in uraemic patients is a known finding.[6], [26] Elevated fibrinogen levels due to depressed fibrinolytic activity are obtained in uraemia. This depressed fibrinolytic activity could be due to decreased production of urokinase or other fibrinolytic activators in the damaged kidney.[21] This study has found elevated euglobulin lysis time of 267.39 ± 63.109 minutes when compared to that of normals (mean of 189 ± 27.29 minutes). Highly significant differences were noted in the 3 groups as compared with normals. No distinction was possible between the bleeders and non-bleeders. A linear correlation between euglobulin lysis time and fibrinogen was obtained. Correlation was possible between euglobulin lysis time and plasma creatinine only in acute renal failure group. Euglobulin lysis time was seen to normalise with normalisation of fibrinogen in cases of recoverable renal failure, end stage renal disease on dialysis and in the post transplant stage. Fibrinogen In chronic renal failure, raised fibrinogen leves[7], [8] with normal plasminogen levels have been reported. This study highlights the elevated fibrinogen levels (662.04 ± 197.94 mg%) in cases of renal failure when compared with the normal levels of 403.17 ± 62.85 mg%. All the three groups had highly significant elevations. Lower values of fibrinogen were noted in acute renal failure group as compared to acute on chronic renal failure group. No difference existed between the bleeders and non-bleeders. Correlation was possible between the fibrinogen and plasma creatinine, only in acute renal failure group. Levels increased with increasing azotemia. This was so in acute renal failure group till creatinine reached 20 mg%. Thereafter, fibrinogen levels fell off. At the level of more than 20 mg%, the non-creatinine chromogens are likely to be adding to the true creatinine and this discrepancy may be due to this factor. In cases of chronic renal failure, fibrinogen increased with creatinine levels till a level of 15 mg% and then it showed a decrease as the creatinine levels increased further. In cases of acute on chronic renal failure, till the level of 10 mg% of creatinine, fibrinogen increased and then fell off and showed a second rise only after creatinine levels exceeded 20 mg%. Recoverable renal failure patients showed decreasing fibrinogen levels paralleling the correction of renal failure. End stage renal disease patients on regular dialysis therapy showed a fall in fibrinogen levels to normal after a varying period of 3-4 months and remained at a higher level of normal throughout the interdialysis phase. A successful transplant also showed a similar fall in fibrinogen to normal levels. Fibrinogen and fibrinolytic activity after dialysis and transplantation returned to normal. Increased inhibitors of plasminogen activators or antiplasmins may be responsible for the hyperfibrinogenemia in renal failure patients. Adequate dialysis removes these inhibitors. In the present study, coagulation investigations performed at varying intervals from diagnosis showed a disturbed coagulation pattern with a definite hyperfibrinogenemia varying with the degree of azotemia and decreased fibrinolytic activity. The possible causes of defective haemostasis in this situation are numerous and multiple mechanisms may be simultaneously involved. However, the result of various coagulation tests commonly used in the present study were of enormous value in supporting the abnormality and in the management of any individual case.
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