International Urology and Nephrology 23 (1), pp. 89--96 (1991)
Effect of Heparin and Prostacyclin-heparin Infusion on Blood Coagulation in Haemodialysed Patients M . KU:~NIFWSKI,* W. SULOWICZ,* J. LISIEWICZ** Departments of *Nephrology an d ** Haematology, Institute of Internal Medicine, Copernicus Medical Academy, Cracow, Poland (Received January 11, 1990) In 10 patients (8 men and 2 women) aged 28 to 58 years (mean 44.4 years) treated by repeated haemodialysis due to end-stage renal failure, the bleeding time, whole-blood coagulation time, one-stage prothrombin time, thrombin time of plasma, activated partial thromboplastin time (APTT), fibrinogen level and euglobulin lysis time have been determined (1) during a 4-hour haemodialysis using heparin as an antithrombotic agent, and (2) one week later in the course of another haemodialysis using prostacyclin-heparin. The values for any of the above parameters with both anticoagulant treatment types did not differ. Plasma fibrinogen level after haemodialysis was significantly lower after administration of heparin alone as compared with the group treated by prostacyclin-heparin infusion. During haemodialysis performed with prostacyclin-heparin infusion, activation of the blood fibrinolytic system was manifested by a significant shortening of euglobulin lysis time, observed after 1.5 hours and after the end of haemodialysis. The above phenomenon did not occur when haemodialysis was performed with heparin alone.
Introduction
In patients with uraemia several disturbances of haemostasis occur, among which decreased platelet adhesion and aggregation, lowered availability of platelet factor 3 and prolonged bleeding time may be mentioned [3, 8, 10]. Mechanisms of these disturbances are not known in detail, however, there is a general opinion that they result from an inhibition of platelet function due to increased concentrations of such metabolites as guanidine succinic and phenolic acids [9, 22], parathormone [24], or defect of factor VIII platelets and platelet vascular endothelium binding, mediated by the factor VIII complex [15]. Moreover, mechanisms involving disturbed interaction between platelets and ~essel wall caused by anaemia [13 ], diminished platelet pool [33 ], defect of fibrinogen-platelet binding [5], increased prostacyclin synthesis in vessel walls [26, 33] or abnormal metabolism of arachidonic acid in platelets [25] are discussed in this regard. The treatment with haemodialysis may result in elimination of certain metabolites disturbing the haemostatic balance from the blood on the one hand, and in additional damage to platelets Changed by the uraemic process, on the other [23, 26]. The Contact of blood with the haemodialyzer membrane results in an VSP, Utrecht Akaddrniai Kiad6, Budapest
90
K u 2 n i e w s k i e t al. : B l o o d c o a g u l a t i o n
instant activation of the blood coagulation system including platelets [12, 41]. Moreover, adsorption of several plasma proteins, first of all of fibrinogen, to the artificial surface devoid of endothelium takes place [11, 21 ]. The artificial surface induces adhesion of platelets with subsequent release of the platelet coagulation factors [12, 16]. The role of activation of factor XII by artificial surface is also emphasized [17, 37] and heparin used during haemodialysis does not prevent that activation [28]. Antithrombotic activity of heparin is, among others, associated with binding and activation of natural coagulation inhibitor, antithrombin III [1, 27]. Furthermore, heparin inhibits the aggregating effect of thrombin on blood platelets, changing no other platelet functions [31]. It does not prevent the activation of platelets and their adhesion to artificial surfaces [12, 16]. There are data indicating that a continuous infusion of exogenous prostacyclin during haemodialysis could prevent some disturbances of the blood coagulation system accompanying that treatment [32, 34, 42]. The aim of this study was to compare the effects of haemodialysis-associated heparin and prostacyclin-heparin infusions on selected plasma blood coagulation indices in patients with end-stage renal failure.
Material and methods
The study comprised 10 patients (8 men and 2 women) aged 28 to 58 years (mean 44.4 years) treated by repeated haemodialysis due to end-stage renal failure. Patients were dialysed three times a week for four hours, over a period from 3 to 108 months (mean 41.7 months). In 4 patients the cause of renal failure was chronic glomerulonephritis, in 4 others polycystic kidney disease, in 1 chronic interstitial nephritis and in 1 renal cirrhosis. The patients studied constituted per se the control group. Patients with arrhythmias, coronary disease, tuberculosis, diabetes mellitus and haemostatic defect diagnosed prior to haemodialysis were excluded from the study. All patients showed normal platelet count, normal plasma prothrombin level, and only minor alterations in the K, Na and Ca blood concentrations in the period between consecutive haemodialyses. Two weeks before investigations the patients received no drugs altering the blood coagulation system such as aspirin, indomethacin or dipyridamol. Examinations of the coagulation system were performed after an overnight fast. The study included two successive haemodialyses performed at one week interval. The first haemodialysis was carried out using heparin alone (Polfa, Warsaw) as the antithrombotic agent. The initial heparin dose was 2500 units and subsequently heparin was infused using a peristaltic pump to the arterial section of the drain supplying blood to the dialyzer at a rate of 11300units per hour. During the second haemodialysis, heparin was administered in the same doses but with addition of prostacyclin (Wellcome Research Laboratories, Beckenham, England) in a dose of 5 ng/kg/min. Prostacyclin sodium salt was dissolved immediately before use in glycine buffer, pH 10.5 (Wellcome Foundation Ltd.) and infused intravenously International Urology and Nephrology 23, 1991
K u 2 n i e w s k i et aL : B l o o d coagulation
91
using a Razel A-99H pump, starting 10 rain before haemodialysis. Administration of both drugs was terminated after 240 rain of dialysis. Initial assessment of blood haemostatic indices was performed using blood samples obtained directly from a needle inserted into the fistula before the administration of heparin or prostacyclin. Since the assessment was performed in the same patients, the initial conditions of dialysis using heparin or heparin with addition of prostacyclin (prostacyclin-heparin) were comparable. In all patients haemodialysis was carried out with a capillary dialyzer (Travenol Model 15.11) and acetate dialysis fluid. The flow rate and pressure in the dialyzer capillaries were the same in all patients. Throughout the dialysis, arterial pressure and heart rate were controlled every 10 min. The possible effect of prostacyclin solvent glycine buffer on the studied parameters was excluded by infusion of that buffer during the first dialysis using heparin only. The following haemostatic parameters were determined: bleeding time, who/e-blood coagulation time, one-stage prothrombin time, thrombin time of plasma, activated partial thromboplastin time (APTT) [29], fibrinogen level [20] and euglobulin lysis time [36]. Bleeding time and fibrinogen level were determined before and after dialysis, whereas the other parameters were assessed before dialysis, at 1.5 hours and at the end of dialysis.
Results
The results are summarized in Table 1. Bleeding time. The mean values of bleeding time before dialysis, at 1.5 hours and at the end of dialysis did not significantly differ if patients treated solely with heparin and those treated with prostacyclin-heparin were compared. Whole-blood coagulation time. The mean values of blood coagulation time were significantly higher at 1.5 hours and at the end of dialysis if compared with that before dialysis both in patients treated solely with heparin and in those treated with prostacyclin-heparin. The longest blood coagulation time was noted at the end of dialysis, however, the difference between the two groups of patients was insignificant. Patients treated with prostacyclin-heparin showed longer blood coagulation time than those treated solely with heparin; however, the difference was again insignificant. One-stage prothrombin time. The mean values of plasma prothrombin time at 1.5 hours and at the end of dialysis both in patients treated solely with heparin and in those treated with prostacyclin-heparin did not significantly differ from that before dialysis. The differences between values of plasma prothrombin time measured in various periods in both groups of patients are also insignificant. Thrombin time of plasma. The mean values of plasma thrombin time were significantly higher at 1.5 hours and at the end of dialysis than before dialysis both in the heparin- and the prostacyclin-heparin-treated groups. The plasma thrombin time values at the end of dialysis in both groups of dialysed patients differed insignificantly from that found at 1.5 hours of dialysis. No differences International Urology and Nephrology 23, 1991
92
Ku$niewski et al.: Blood coagulation
Table l Selected blood coagulation parameters in dialysed patients treated Before dialysis H
P
4.8 2.6 11.11,2 3.9
4.3 2.2 13.4aa 5.0
SD
17.7 4.7 16.4 2.8
17.5 2.5 16.27'8 2.3
Activated partial thromboplastin time (normal value 35--55 s)
83.89 78.1
60.010'11
SD
Fibrinogen level (normal value 2.5--5.0 g/l)
SD
Euglobulin lysis time (normal value 6 0 - 8 0 min)
SD
3.6lz 1.0 172.0 62.7
4.0 0.9 160.514'18 52.2
Bleeding time (normal value 1--4 min)
SD
Whole-blood coagulation time (normal value 6--12 min)
SD
One-stage prothrombin time (normal value 14--16 s)
SD
Thrombin time of plasma (normal value 12--15 s)
24.0
- mean; S D - standard deviation 1-- 17 -- statistically significant differences (1 : 1, 2 : 2, etc.)
were f o u n d between patients treated with heparin alone and those treated with prostacyclin-heparin if values o f plasma t h r o m b i n time obtained before, at 1.5 hours and at the end o f dialysis were compared. A c t i v a t e d partial thrornboplastin time. The mean values of A P T T time during dialysis in the heparin- and the prostacyclin-heparin-treated patients were higher than before dialysis. The differences were significant at 1.5 hours o f dialysis with heparin, and at 1.5 hours and at the end o f dialysis accompanied by prostacyclin-heparin infusion. The differences in A P T T value before, at 1.5 hours and at the end of dialysis were insignificant when c o m p a r i n g heparin- and prostacyclin-heparin-treated groups. Fibrinogen level. The fibrinogen level in plasma after dialysis was significantly lower in the heparin-treated group and insignificantly lower in the prostaInternational Urology and Nephrology 23, 1991
Ku~nfewski et al.." Blood coagulation
93
with heparin (H) or prostacyclin-heparin (P) infusion A t 1.5 h o u r s
A t end Statistical significance
o f dialysis H
P
H
P
--
--
3.4
3.2
--
--
1.3
95.71 47.5
132.03 56.2
137.92 81.1
150.04 76.3
19.2 2.6
19.6 3.5
17.9 4.4
18.9 4.0
286.7 '~ 40.0
288.07 37.9
261.8 n 87,2
263.58 82.4
200.29 92.5
215.41~ 110.3
168.7 104.9
196.511 111.6
__
__
2.312.13
--
--
1.0
130.016 40.1
87.514'16 25.7
134.517 28.9
1.6
3.713 0.9 96.01sat 23.7
1. 2. 3. 4.
p p p p
< < <
Effect of Heparin and Prostacyclin-heparin Infusion on Blood Coagulation in Haemodialysed Patients M . KU:~NIFWSKI,* W. SULOWICZ,* J. LISIEWICZ** Departments of *Nephrology an d ** Haematology, Institute of Internal Medicine, Copernicus Medical Academy, Cracow, Poland (Received January 11, 1990) In 10 patients (8 men and 2 women) aged 28 to 58 years (mean 44.4 years) treated by repeated haemodialysis due to end-stage renal failure, the bleeding time, whole-blood coagulation time, one-stage prothrombin time, thrombin time of plasma, activated partial thromboplastin time (APTT), fibrinogen level and euglobulin lysis time have been determined (1) during a 4-hour haemodialysis using heparin as an antithrombotic agent, and (2) one week later in the course of another haemodialysis using prostacyclin-heparin. The values for any of the above parameters with both anticoagulant treatment types did not differ. Plasma fibrinogen level after haemodialysis was significantly lower after administration of heparin alone as compared with the group treated by prostacyclin-heparin infusion. During haemodialysis performed with prostacyclin-heparin infusion, activation of the blood fibrinolytic system was manifested by a significant shortening of euglobulin lysis time, observed after 1.5 hours and after the end of haemodialysis. The above phenomenon did not occur when haemodialysis was performed with heparin alone.
Introduction
In patients with uraemia several disturbances of haemostasis occur, among which decreased platelet adhesion and aggregation, lowered availability of platelet factor 3 and prolonged bleeding time may be mentioned [3, 8, 10]. Mechanisms of these disturbances are not known in detail, however, there is a general opinion that they result from an inhibition of platelet function due to increased concentrations of such metabolites as guanidine succinic and phenolic acids [9, 22], parathormone [24], or defect of factor VIII platelets and platelet vascular endothelium binding, mediated by the factor VIII complex [15]. Moreover, mechanisms involving disturbed interaction between platelets and ~essel wall caused by anaemia [13 ], diminished platelet pool [33 ], defect of fibrinogen-platelet binding [5], increased prostacyclin synthesis in vessel walls [26, 33] or abnormal metabolism of arachidonic acid in platelets [25] are discussed in this regard. The treatment with haemodialysis may result in elimination of certain metabolites disturbing the haemostatic balance from the blood on the one hand, and in additional damage to platelets Changed by the uraemic process, on the other [23, 26]. The Contact of blood with the haemodialyzer membrane results in an VSP, Utrecht Akaddrniai Kiad6, Budapest
90
K u 2 n i e w s k i e t al. : B l o o d c o a g u l a t i o n
instant activation of the blood coagulation system including platelets [12, 41]. Moreover, adsorption of several plasma proteins, first of all of fibrinogen, to the artificial surface devoid of endothelium takes place [11, 21 ]. The artificial surface induces adhesion of platelets with subsequent release of the platelet coagulation factors [12, 16]. The role of activation of factor XII by artificial surface is also emphasized [17, 37] and heparin used during haemodialysis does not prevent that activation [28]. Antithrombotic activity of heparin is, among others, associated with binding and activation of natural coagulation inhibitor, antithrombin III [1, 27]. Furthermore, heparin inhibits the aggregating effect of thrombin on blood platelets, changing no other platelet functions [31]. It does not prevent the activation of platelets and their adhesion to artificial surfaces [12, 16]. There are data indicating that a continuous infusion of exogenous prostacyclin during haemodialysis could prevent some disturbances of the blood coagulation system accompanying that treatment [32, 34, 42]. The aim of this study was to compare the effects of haemodialysis-associated heparin and prostacyclin-heparin infusions on selected plasma blood coagulation indices in patients with end-stage renal failure.
Material and methods
The study comprised 10 patients (8 men and 2 women) aged 28 to 58 years (mean 44.4 years) treated by repeated haemodialysis due to end-stage renal failure. Patients were dialysed three times a week for four hours, over a period from 3 to 108 months (mean 41.7 months). In 4 patients the cause of renal failure was chronic glomerulonephritis, in 4 others polycystic kidney disease, in 1 chronic interstitial nephritis and in 1 renal cirrhosis. The patients studied constituted per se the control group. Patients with arrhythmias, coronary disease, tuberculosis, diabetes mellitus and haemostatic defect diagnosed prior to haemodialysis were excluded from the study. All patients showed normal platelet count, normal plasma prothrombin level, and only minor alterations in the K, Na and Ca blood concentrations in the period between consecutive haemodialyses. Two weeks before investigations the patients received no drugs altering the blood coagulation system such as aspirin, indomethacin or dipyridamol. Examinations of the coagulation system were performed after an overnight fast. The study included two successive haemodialyses performed at one week interval. The first haemodialysis was carried out using heparin alone (Polfa, Warsaw) as the antithrombotic agent. The initial heparin dose was 2500 units and subsequently heparin was infused using a peristaltic pump to the arterial section of the drain supplying blood to the dialyzer at a rate of 11300units per hour. During the second haemodialysis, heparin was administered in the same doses but with addition of prostacyclin (Wellcome Research Laboratories, Beckenham, England) in a dose of 5 ng/kg/min. Prostacyclin sodium salt was dissolved immediately before use in glycine buffer, pH 10.5 (Wellcome Foundation Ltd.) and infused intravenously International Urology and Nephrology 23, 1991
K u 2 n i e w s k i et aL : B l o o d coagulation
91
using a Razel A-99H pump, starting 10 rain before haemodialysis. Administration of both drugs was terminated after 240 rain of dialysis. Initial assessment of blood haemostatic indices was performed using blood samples obtained directly from a needle inserted into the fistula before the administration of heparin or prostacyclin. Since the assessment was performed in the same patients, the initial conditions of dialysis using heparin or heparin with addition of prostacyclin (prostacyclin-heparin) were comparable. In all patients haemodialysis was carried out with a capillary dialyzer (Travenol Model 15.11) and acetate dialysis fluid. The flow rate and pressure in the dialyzer capillaries were the same in all patients. Throughout the dialysis, arterial pressure and heart rate were controlled every 10 min. The possible effect of prostacyclin solvent glycine buffer on the studied parameters was excluded by infusion of that buffer during the first dialysis using heparin only. The following haemostatic parameters were determined: bleeding time, who/e-blood coagulation time, one-stage prothrombin time, thrombin time of plasma, activated partial thromboplastin time (APTT) [29], fibrinogen level [20] and euglobulin lysis time [36]. Bleeding time and fibrinogen level were determined before and after dialysis, whereas the other parameters were assessed before dialysis, at 1.5 hours and at the end of dialysis.
Results
The results are summarized in Table 1. Bleeding time. The mean values of bleeding time before dialysis, at 1.5 hours and at the end of dialysis did not significantly differ if patients treated solely with heparin and those treated with prostacyclin-heparin were compared. Whole-blood coagulation time. The mean values of blood coagulation time were significantly higher at 1.5 hours and at the end of dialysis if compared with that before dialysis both in patients treated solely with heparin and in those treated with prostacyclin-heparin. The longest blood coagulation time was noted at the end of dialysis, however, the difference between the two groups of patients was insignificant. Patients treated with prostacyclin-heparin showed longer blood coagulation time than those treated solely with heparin; however, the difference was again insignificant. One-stage prothrombin time. The mean values of plasma prothrombin time at 1.5 hours and at the end of dialysis both in patients treated solely with heparin and in those treated with prostacyclin-heparin did not significantly differ from that before dialysis. The differences between values of plasma prothrombin time measured in various periods in both groups of patients are also insignificant. Thrombin time of plasma. The mean values of plasma thrombin time were significantly higher at 1.5 hours and at the end of dialysis than before dialysis both in the heparin- and the prostacyclin-heparin-treated groups. The plasma thrombin time values at the end of dialysis in both groups of dialysed patients differed insignificantly from that found at 1.5 hours of dialysis. No differences International Urology and Nephrology 23, 1991
92
Ku$niewski et al.: Blood coagulation
Table l Selected blood coagulation parameters in dialysed patients treated Before dialysis H
P
4.8 2.6 11.11,2 3.9
4.3 2.2 13.4aa 5.0
SD
17.7 4.7 16.4 2.8
17.5 2.5 16.27'8 2.3
Activated partial thromboplastin time (normal value 35--55 s)
83.89 78.1
60.010'11
SD
Fibrinogen level (normal value 2.5--5.0 g/l)
SD
Euglobulin lysis time (normal value 6 0 - 8 0 min)
SD
3.6lz 1.0 172.0 62.7
4.0 0.9 160.514'18 52.2
Bleeding time (normal value 1--4 min)
SD
Whole-blood coagulation time (normal value 6--12 min)
SD
One-stage prothrombin time (normal value 14--16 s)
SD
Thrombin time of plasma (normal value 12--15 s)
24.0
- mean; S D - standard deviation 1-- 17 -- statistically significant differences (1 : 1, 2 : 2, etc.)
were f o u n d between patients treated with heparin alone and those treated with prostacyclin-heparin if values o f plasma t h r o m b i n time obtained before, at 1.5 hours and at the end o f dialysis were compared. A c t i v a t e d partial thrornboplastin time. The mean values of A P T T time during dialysis in the heparin- and the prostacyclin-heparin-treated patients were higher than before dialysis. The differences were significant at 1.5 hours o f dialysis with heparin, and at 1.5 hours and at the end o f dialysis accompanied by prostacyclin-heparin infusion. The differences in A P T T value before, at 1.5 hours and at the end of dialysis were insignificant when c o m p a r i n g heparin- and prostacyclin-heparin-treated groups. Fibrinogen level. The fibrinogen level in plasma after dialysis was significantly lower in the heparin-treated group and insignificantly lower in the prostaInternational Urology and Nephrology 23, 1991
Ku~nfewski et al.." Blood coagulation
93
with heparin (H) or prostacyclin-heparin (P) infusion A t 1.5 h o u r s
A t end Statistical significance
o f dialysis H
P
H
P
--
--
3.4
3.2
--
--
1.3
95.71 47.5
132.03 56.2
137.92 81.1
150.04 76.3
19.2 2.6
19.6 3.5
17.9 4.4
18.9 4.0
286.7 '~ 40.0
288.07 37.9
261.8 n 87,2
263.58 82.4
200.29 92.5
215.41~ 110.3
168.7 104.9
196.511 111.6
__
__
2.312.13
--
--
1.0
130.016 40.1
87.514'16 25.7
134.517 28.9
1.6
3.713 0.9 96.01sat 23.7
1. 2. 3. 4.
p p p p
< < <
