Post-operative blood loss after transurethral prostatectomy is dependent on in situ fibrinolysis

Transcription

1 British Journal of Urology (997), 8, Post-operative blood loss after transurethral prostatectomy is dependent on in situ fibrinolysis J.D. NIELSEN, J. GRAM, A. HOLM-NIELSEN, K. FABRIN and J. JESPERSEN Department of Surgery and Department of Clinical Biochemistry, Ribe County Hospital in Esbjerg and the Institute for Thrombosis Research, South Jutland University Centre, Esbjerg, Denmark Objective To evaluate whether post-operative blood loss Results The post-operative blood loss correlated significantly in patients with benign prostatic hyperplasia, undergoing with the per-operative loss (P=.7) and the transurethral resection of the prostate (TURP), weight of resected tissue (P=.29). There was a depends on in situ fibrinolysis in urine, and to determine highly significant correlation between the area under the relative contributions of the urokinase and the curve of FbDP in the urine and the post-operative tissue-type plasminogen activator systems. blood loss (P<.), while there was no significant Patients and methods TURP was performed in 2 men positive correlation between the PA concentration or (median age 68. years, range 2 78) and the weight activity in the urine and post-operative blood loss. of resected tissue, the operative and post-operative There was a significant correlation between the urinary blood loss determined. The concentrations of the t-pa activity and the amount of FbDP in the urokinase- (u-pa) and tissue-type plasminogen acti- urine (P=.7), and a significant correlation vator (t-pa)-related fibrinolysis in their urine was between the weight of resected tissue and the amount followed using sensitive and specific assays, and the of FbDP in the urine (P=.). changes related to post-operative blood loss. Conclusion The post-operative blood loss after TURP is Measurements of the urinary concentrations of free significantly related to an increase of the urinary t-pa activity, t-pa antigen, free u-pa activity, u-pa fibrinolytic activity and the enhanced fibrinolytic antigen and fibrin degradation products (FbDP) were activity is probably caused by t-pa. determined and the area under the curve for each of Keywords In situ fibrinolysis, blood loss, transurethral these quantities correlated with the post-operative prostatic resection blood loss. antifibrinolytic drugs on post-operative blood loss [6 9]. Introduction However, these results are conflicting, because some Bleeding is one of the most important problems associated authors have reported a significant reduction in blood with TURP; although haemostasis is usually loss [6,7], while others have shown no significant ecect subcient during surgery, re-bleeding may continue for of anti-fibrinolytic agents [8,9]. several days, requiring blood transfusions and sometimes We and others have recently [,] shown that re-operation []. The risk of post-operative haemorrhage systemic (i.e. blood) fibrinolysis does not influence the has been related to both the per-operative blood loss and persistent delayed haemorrhage after TURP. In the present the weight of resected tissue [2], aspirin ingestion [3] study we assessed whether in situ fibrinolysis deterthe and to activation of the fibrinolytic system [,]. mined bleeding after TURP, using sensitive and specific The constant flow of urine containing urokinase over methods to determine plasminogen activators, both urokthe resected prostatic cavity, in combination with the inase (u-pa) and tissue-type (t-pa) and the end-products high concentration of plasminogen activators in the of plasmin degradation of fibrin, i.e. fibrin degradation prostate gland, is believed to play a major role in the products (FbDP), in the urine of patients undergoing activation of the fibrinolytic system and blood loss in TURP, relating the changes to post-operative blood loss. the post-operative period [,]. Several investigators have studied the role of the fibrinolytic system by estimating the ebcacy of systemic or local administration of Patients and methods Details of the patients, selection criteria, operative procedures Accepted for publication 9 August 997 and the estimation of blood loss were described 997 British Journal of Urology 889

2 89 J.D. NIELSEN et al. previously []. Urine samples were initially collected was 68 (22 89) ml. The median (range) weight of into a ml plastic container from which aliquots were resected tissue was 22. ( 9) g. The post-operative drawn into ml siliconized evacuated glass tubes with bleeding was dependent on time (Fig. ) and in the sodium citrate (. ml urine,. ml.3 mol/l sodium present study, most patients had clinically clear urine citrate; Vacutainer A 326 SBW-E, Becton Dickinson, by 8 h. The calculation of the AUC of the fibrinolytic Heidelberg, Germany) and with tripotassium EDTA (3 ml variables was only possible in 2 of the 2 patients, urine,.6 ml.7 mol/l EDTA; Venoject VT-3TK, because three patients had values missing in period. Terumo Europe, Leuven, Belgium). To the samples collected The urinary t-pa activity (Fig. 2a) decreased signifi- for the determination of FbDP was added ml of cantly at the end of surgery (period 2) and remained mmol/l D-Phe-Pro-Arg-CH Cl, a potent inhibitor of significantly depressed in the first h after surgery 2 serine proteases, e.g. thrombin, t-pa and plasmin, (period 3) compared with the pre-operative value (period thereby preventing any in vitro activation. In addition, ). This was followed by an increase in the concentration samples were collected in Stabilyte tubes (. ml urine, of t-pa activity in period and period, but these values. ml acidified citrate, Biopool, Umeå, Sweden) for the were not significantly dicerent from the pre-operative determination of t-pa activity. The samples were centri- value. The concentration of t-pa antigen (Fig. 2b) started fuged at 2 g for 2 min at C and stored at 6 C to increase slowly h after surgery, but only the value until analysis. The urine samples were collected from at 8 h post-operatively (period ) was significantly the patients on five occasions; period, pre-operatively dicerent from the pre-operative value. between 7.3 and 8. hours on the day of the The urinary concentration of both u-pa activity and operation; period 2, at the end of the operation when antigen showed a similar U-shaped curve (Fig. 2c and d) the patient had arrived in the recovery room; period 3, with a significant decrease from the pre-operative level h after the end of surgery; period, the first postoperative (period ) to period 2 and period 3, followed by a gradual day between 7.3 and 8. hours; and recovery of the activity in period and period. The period, on the second post-operative day between urinary concentration of FbDP increased significantly at 7.3 and 8. hours []. the end of surgery and remained significantly higher The urinary concentrations of free t-pa and t-pa throughout the study period (Fig. 2e). antigen were assessed as described previously []. There was a significant correlation between postoperative Concentrations of u-pa activity and antigen were determined blood loss and per-operative blood loss, and with a combined bio-immunoassay and an ELISA the weight of resected tissue, and a significant correlation (Actibind u-pa; Technoclone, Vienna, Austria). The urinary between the weight of resected tissue and the AUC of concentrations of crossed-linked and non-crossed- linked FbDP were assessed as reported previously []. The concentrations of t-pa activity and u-pa activity were expressed in IU/mL, while the concentrations of t-pa and u-pa antigen, and FbDP were expressed as ng/ml. 9 8 The statistical methods applied were those described previously []. The area under the curve (AUC) of the variables of the fibrinolytic system, the weight of removed tissue and the operative blood loss were correlated with the post-operative blood loss using Spearman s rank 7 6 order correlation test. The area was estimated from sampling period 2 to period. Spearman s rank order correlation test was also used to test any relation between the variables and the amount of FbDP (AUC) in the urine. Multiple linear regression (parametric) was used 3 2 to estimate which variable had the highest probability of predicting post-operative blood loss. A P value <. was considered to indicate statistical significance. Results Post-operative blood loss (ml) (h) The median (range) operative blood loss in the 2 Fig.. Changes in post-operative blood loss with time. Data points patients was 287 (9 2) ml and post-operatively are median values and quartiles. 997 British Journal of Urology 8,

3 POST-OPERATIVE BLOOD LOSS AFTER TURP IS DEPENDENT ON IN SITU FIBRINOLYSIS 89 Urine t-pa activity (IU/mL) a Urine t-pa antigen (ng/ml) b 2. c 2 d Urine U-PA activity (IU/mL) Urine u-pa antigen (µg/ml) e Urine FbDP (ng/ml) Fig. 2. The median urinary concentrations and quartiles of the measured plasminogen activators (a d) and FbDP (e) at the various sampling periods; P<. compared with the pre-operative value. FbDP in the urine (Table ). There was no correlation between the urinary activators of fibrinolysis and postoperative blood loss, but there was a significant negative correlation between the AUC of u-pa activity and postoperative blood loss (Table ). The AUC of t-pa activity and that of FbDP in the urine were correlated but the 997 British Journal of Urology 8,

4 892 J.D. NIELSEN et al. Table The Spearman rank order correlation coebcients (r) prolonged degradation of fibrin. In addition, there was a between the operative blood loss, the weight of resected tissue, the highly significant correlation between the AUC of urinary AUC of the variables of the fibrinolytic system, the post-operative FbDP post-operatively and the post-operative blood loss blood loss and the AUC of the urinary FbDP (Fig. 3; Table ). Furthermore, multiple linear regression Post-operative showed that the degradation of fibrin was the single blood loss Urinary FbDP most important factor for post-operative blood loss. These observations strongly suggest that bleeding after TURP Variables r P r P is a result of an ecective fibrinolysis at the site of tissue damage, which per se may cause the generation of Operative blood loss..7 plasmin in situ and subsequently the degradation of Resected weight fibrin. t-pa activity t-pa antigen Previously it has been claimed that the flow of urokin- u-pa activity ase over the denuded prostatic cavity, in conjunction u-pa antigen with the high concentrations of PAs in the tissue, is FbDP.78 <. responsible for the fibrinolysis-related post-operative haemorrhage [,,7 9]. In the present study, there was a negative correlation between u-pa activity and postoperative urokinase system and the AUC of FbDP in the urine blood loss, and no correlation between u-pa were not (Table ). There was a highly significant correobservations activity and the amount of FbDP in the urine. These lation between the AUC of the FbDP in urine and postis indicate that the urinary urokinase system operative blood loss (Fig. 3; Table ). Multiple linear of less importance than hitherto believed in the postoperative regression analysis showed that the AUC of FbDP in operative blood loss after TURP. urine had the highest predictive value for post-operative There was no correlation between t-pa activity, t-pa blood loss (data not shown). antigen and post-operative blood loss; however, there was a positive correlation between the AUC of active Discussion urinary t-pa and the AUC of urinary FbDP, suggesting that it is the t-pa which is mainly responsible for It was reported recently that blood fibrinolysis is of no activating the fibrinolytic system. A similar increase in importance for blood loss after TURP [,]; thus, the local fibrinolysis caused by the release of t-pa at the site main purpose of the present study was to determine of injury is a characteristic of other types of surgery whether the local fibrinolytic activity in urine determines [2 ]. In line with this conclusion, the weight of the post-operative blood loss, and to assess the importance resected tissue influenced blood loss and correlated of t-pa and u-pa in the local activation of the fibrinolytic closely with the AUC of urinary FbDP. Taken together, system. There was a marked increase in the urinary these observations suggest that the activation of concentration of FbDP throughout the study period, fibrinolysis in TURP is a local surface-related phenom- indicating a continuous activation of fibrinolysis and a enon and is primarily dependent on t-pa, a so-called fibrin-specific plasminogen activator [ 7]. The present findings may support reports which indicate that the post-operative blood loss after TURP can be significantly reduced after the administration of antifibrinolytic drugs [6,7]. In particular, the present results may indicate that antifibrinolytics would probably be most beneficial when given locally, i.e. as a bladder instillation. The reported lack of a clinically significant ecect of intravesical epsilon-aminocaproic acid in the 3 study by Sharifi et al. [9] may result from the relatively small amount of tissue resected in their study. We agree that the routine administration of antifibrinolytic drugs cannot be recommended, but in cases where marked bleeding can be expected (e.g. the removal of large amounts of tissue) the administration of antifibrinolytic AUC FbDP (ng/ml) ( 3 ) drugs may be of benefit. However, a final conclusion Fig. 3. The correlation between post-operative blood loss in 2 must await the results from placebo-controlled ranpatients and the AUC of FbDP. domized studies. In conclusion, post-operative blood loss Post-operative blood loss (ml) 997 British Journal of Urology 8,

5 POST-OPERATIVE BLOOD LOSS AFTER TURP IS DEPENDENT ON IN SITU FIBRINOLYSIS 893 after TURP is significantly related to an increase in the fibrinolytic activity and the enhanced fibrinolysis is probably caused by t-pa. Acknowledgements ebcacy of intravesical aminocaproic acid for bleeding after transurethral resection of prostate. Urology 986; 27: 2 9 Nielsen JD, Gram J, Fabrin K, Holm-Nielsen A, Jespersen J. Lack of correlation between blood fibrinolysis and the immediate or post-operative blood loss in transurethral resection of the prostate. Br J Urol 997; 8: Bell CRW, Cox DJA, Murdock PJ, Sullivan ME, Pasi KJ, This study was supported by grants from Fonden for Lœgevidenskabelig Forskning mv. ved sygehusene i Morgan RJ. Thrombelastographic evaluation of coagulation Ringkøbing, Ribe og Sønderjyllands Amter and Johs. in transurethral prostatectomy. Br J Urol 996; 78: 737 M. Klein og Hustrus Mindelegat. 2 Valen G, Eriksson E, Risberg B, Vaage J. Fibrinolysis during cardiac surgery. Eur J Cardiothorac Surg 99; 8: Eriksson BI, Hultman E, Martinell S, Eriksson E, Tengborn L, Risberg B. Regional fibrinolysis following total hip replace- References ment. Thromb Res 99; 62: 7 Luke M, Kvist E, Andersen F, Hjortrup A. Reduction of Gram J, Janetzko T, Jespersen J, Bruhn HD. Enhanced post-operative bleeding after transurethral resection of the ecective fibrinolysis following the neutralization of heparin prostate by local instillation of fibrin adhesive (Beriplast). in open heart surgery increases the risk of post-surgical Br J Urol 986; 8: 672 bleeding. Thromb Haemostas 99; 63: 2 2 Lewi HJE, Hales DSM, Mahmoud S, Scott R. The character- Risberg B. Fibrinolysis and its relation to surgical pathoistics of post TUR blood loss: a preliminary study. Urol Res physiology. In Nilsson TK, Boman K, Jansson JH eds, 983; : 29 3 Clinical Aspects of Fibrinolysis. Stockholm: Almquist & 3 Watson CJE, Deane AM, Doyle PT, Bullock KN. Identifiable Wiksell International, 99: 9 79 factors in post-prostatectomy haemorrhage: the role of 6 Astrup T. Tissue activators of plasminogen. Fed Proc 966; aspirin. Br J Urol 99; 66: 8 7 2: 2 Nilsson IM. Local fibrinolysis as a mechanism for haemor- 7 Rånby M. Studies on the kinetics of plasminogen activation rhage. Thrombos Diathes Haemorrh 97; 3: by tissue plasminogen activator. Biochim Biophys Acta Kursh ED, RatnoC OD, Persky L. Current clotting concepts 982; 7: 6 9. in urology. J Urol 976; 6: Madsen PO, Strauch AE. The ecect of aminocaproic acid Authors on bleeding following transurethral prostatectomy. J Urol 966; 96: 2 6 J.D. Nielsen MD, Surgical Registrar. 7 Smart CJ, Turnbull AR, Jenkins JD. The use of frusemide J. Gram, MD, DSc, Consultant Clinical Biochemist. and epsilon-amino-caproic-acid in transurethral prostatec- A. Holm-Nielsen, MD, Consultant Urologist. tomy. Br J Urol 97; 6: 2 K. Fabrin, MD, Surgical House OBcer. 8 Smith RB, Riach P, Kaufman JJ. Epsilon aminocaproic acid J. Jespersen, MD, DSc, Consultant Clinical Biochemist, Professor. and the control of post-prostatectomy bleeding: a prospective Correspondence: Dr J.D. Nielsen, Department of Clinical double-blind study. J Urol 98; 3: 93 Biochemistry, Ribe County Hospital in Esbjerg, DK-67 9 Sharifi R, Lee M, Ray P, Millner SN, Dupont PF. Safety and Esbjerg, Denmark. 997 British Journal of Urology 8,