Perioperative fibronolytic activity in cholecystectomized patients The postoperative fibrinolytic shutdown is only a temporary event

mnno/ys~s 8 Proreo/yM(1999) 13 (3). 118-123 ~~~Harcour( Brace 8 Co Lld 1999

Perioperative fibrinolytic activity in cholecystectomised patients The postoperative fibrinolytic shutdown is only a temporary event M. Szczepariski,’ ‘Laboratory *Department

W. Kucharski,*

J. Ratajczak,*

of Hemostasis. Medical Center of Postgraduate Education of Surgery, Institute of Hematology and Transfusiology. Warsaw.

A. J. Meissner*

Poland

Summary Objective: to estimate the influence of successive steps of abdominal surgery and of postoperative course on the components of fibrinolytic system. Design: a prospective open study. Setting: the patients were treated in medical research institute and the laboratory tests were done in postgraduate teaching hospital. Interventions: open cholecystectomy, performed in general anesthesia. Main outcome measures: the plasminogen concentration in plasma was determined by amidolytic method. The concentrations of t-PA antigen, PAI- antigen, and PAP complex antigen were measured by enzyme-linked immunosorbent assays [ELISA]. Results: the induction of anaesthesia was followed by the decline in plasminogen concentration and this decline was observed until the beginning of intraperitoneal part of operation. The decrease of PAI- concentration was encountered also at this period of time but was significant only during surgical opening of abdominal wall. Both variables increased then gradually till the end of investigations, i.e. 7th postoperative day. t-PA and PAP complex increased during the intraperitoneal part of cholecystectomy but their concentrations differed postoperatively. t-PA level declined but the concentration of PAP complex increased until the end of investigations, except of the slight, transient decline on the 1st postoperative day. Conclusion: the early drop of plasminogen concentration cannot be explained by its conversion to plasmin. It is hypothesized that the binding of this zymogen to proteins, endothelial cells, and to subendothelial matrix may be regarded as a cause of its early decline in plasma. We suppose that the surgical maneuvers inside the peritoneal cavity during cholecystectomy resulted in the release of t-PA from endothelial cells of systemic circulation and it is speculated that this release is mediated by cytokines. t-PA level decreased gradually after the end of operation, while PAP complex rose till the end of the 1 st postoperative week after a slight, transient decrease on the 1st postoperative day. These latter findings can be explained by the local activation of fibrinolysis in the surgical wound: t-PA remains bound to fibrin inside this wound while plasmin, generated on the fibrin matrix, is released into the circulation as PAP complex. The gradual increase of PAI- together with an enhanced production of plasminogen, observed after cholecystectomy up to the 7th postoperative day, can be explained by a delayed systemic response to surgery.

INTRODUCTION ReC8iv8d Accepted

7 October 1998 a/ter revision 17 February

1999

Correspondence to: Maciej Szczepariski MD, Laboratory of Hemostasis. Postgraduate Teaching Hospital, ui.Czerniakowska 231,00-416 Warsaw, Poland. Tel.: +46 22 622 76 16; fax: +46 22 634 01 65

The intraoperative increase and postoperative reduction of fibrinolytic activity in patients undergoing abdominal surgery has been reported by several authors.‘-’ This activity was usually estimated by one of its global assays: dilute plasma clot lysis, euglobulin clot lysis or the 118

Perioperative fibrinolytic activity in cholecystectomized

assessment of euglobulin activity on the fibrin plates. The postoperative reduction of fibrinolytic activity, commonly found in these assays, has been referred to as fibrinolytic shut-down8 The estimations of fibrinolytic activity were performed in most studies before and after the surgery, and the more frequent assessments were seldom performed.‘,‘,“’ The aim of our studies was to estimate the intra- and postoperative changes of main components of fibrinolytic system: plasminogen, tissue activator of plasminogen and its inhibitor. The complex: plasmin-crz-antiplasmin was simultaneously determined. The plasminogen level was measured by amidolytic method and other variables were assessed by immunoenzymatic methods. The baseline values were estimated before surgery; the next three determinations were performed during the operation and the postoperative ones up to the 7th day after surgery. Such the frequent estimations made possible the assessment of the influence of the sequential steps of abdominal surgery and of postoperative course on the fibrinolytic system. PATIENTS

AND

METHODS

Twenty patients (18 females and 2 males) with a mean age of 46f16 years (range: 16-65 years) suffering from chronic calculous cholecystitis and subjected to cholecystectomy were included in this prospective open study. Cholecystectomy was performed in each patient by laparotomy and splenectomy was done additionally in two of these patients because of accompanying spherocytosis. The postoperative course was uneventful in all patients. The exclusion criteria were as follows: an acute inflammation of gallbladder or other abdominal organ, the presence of malignant neoplasm, diabetes or an age over 70. Ingestion of corticosteroids, oral anticoagulants or the presence of any hemostatic disturbances were also regarded as the causes of exclusion from this study. Each patient was injected i.m. with 15-20 mg of diazepam 45-60 min before anesthesia as a premedication. The induction of anesthesia consisted of the iv. infusion of fentanyl 0.1 mg, dihydrobenzoperidol2.5 mg, pavulon 1 mg, penthotal sodium 3-5 mg/kg b.w., and chlorsuccilin 100 mg. The general anesthesia was then continued with iv. infusion of divided doses of fentanyl and pavulon and breathing was mantained with the mixture of oxygen and nitrogen monoxide. The duration of operation was approximately l-l.5 h. The blood was collected in the 0.13 M trisodium citrate (9:1, v:v), centrifuged at 2500 g for 15 min at 4°C and the separated plasma samples were kept at -70°C until determinations; specimens for PAI- antigen assay were obtained from the uppermost layer of plasma samples. The following blood samples were obtained in each @ HarCOuti

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patient: (1) 24 h before surgery; (2) immediately after anesthetizing the patient, but before any surgical procedure; (3) after opening the peritoneal cavity but before any intraperitoneal surgical activity; (4) immediately after closure of the surgical wound; (5) on the 1st postoperative day (6) on the 3rd postoperative day; and (7) on the 7th postoperative day. All patients were injected with enoxaparin 20 mg q.d. S.C.for thromboembolic prophylaxis, 2 h before surgery and then up to the 7th day; none of them displayed postoperative venous thrombosis. The following tests were performed in each plasma sample: the concentration of plasminogen by amidolytic method (Plasminogen calorimetric test, Boehringer Marmheim) the total tissue plasminogen activator antigen by enzyme-linked immunosorbent assay (Thrombonostika t-PA, Organon Teknika) the total plasrninogen activator inhibitor-I antigen by enzyme-linked immunosorbent assay (Thrombonostika PAI- 1, Organon Teknika) the plasrnin~-antiplasmin complex antigen by enzyme immunoassay (Enzygnost PAP micro, Behring). The hypothesis of normal distribution of analyzed variables was verified and confirmed by Kolmogorov-Smimov test. The differences between the mean values of these variables, obtained on consecutive days of blood sampling were tested by Student’s t-test for paired samples and regarded as significant on the probability level of PSO.05 RESULTS

The concentration of plasminogen (Pig. 1) decreased early and it was apparent after induction of anesthesia, before beginning of surgery. This decline of plasminogen level progressed throughout the opening of the abdominal wall until the initiation of the intraperitoneal part of operation. The slight, but statistically significant, drop of PAP antigen concentration was also noted after the induction of anesthesia (Pig. 2). t-PA antigen did not si@cantly change up to the opening of the peritoneal cavity (Fig. 3), but the concentration of its inhibitor, PA&l, decreased and this decline was significant during the incision of abdominal wall (Pig. 4). The main part of the operation, connected with manual and instrumental maneuvers inside the peritoneal cavity during the dissection and extraction of the gallbladder, and the closure of the surgical wound, resulted in the sharp increases of t-PA and PAP antigens. The plasminogen concentration and PAIantigen level did not change during this part of the operation. Plasminogen concentration rose postoperatively and this rise was significant from the 1st postoperative Fibrinolysis

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nR/ml 25-

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Flg. 1 Plasminogen. Ordinate: plasminogen concentration in percent of reference value. Abscissa: (A) blood sample drawn 24 h before operation, (B) blood sample obtained after induction of anesthesia, (C) blood sample taken after opening of peritoneal cavity, (D) blood sample taken after closure of surgical wound, (E) blood drawn on the 1st (F) blood taken on the 3rd, (G) blood sampled on the 7th postoperative day. + difference significant on the probability level of PI 0.05.

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Fig. 3 t-PA antigen. Ordinate: Other details as in Figure 1.

Fig. 4 PAI- antigen. Ordinate: rig/ml. Other details as in Figure Fig. 2 PAP antigen. Ordinate: PAP antigen ug/ml. Other details as in Figure 1.

concentration

DISCUSSION

We have observed in our previous studies” the postoperative drop of plasminogen concentration in plasma and the & Proteolysis

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, F

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t-PA antigen

PAI-1 1.

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day until the end of the observations. t-PA antigen declined postoperatively, but this decline was statistically signifkant only between the 1st and 3rd day after surgery. PAI-1 antigen changed postoperatively in a opposite way: its level rose steadily and this rise was significant between the end of the operation and 1st postoperative day and between 3rd and 7th day after surgery. The mean concentration of PAP antigen dropped after the end of the operation but this change was significant on the probability level of P= 0.08. The next rise of this antigen was noted between the 1st and 3rd postoperative day, and its high level was still present at the end of observations, i.e. on the 7th day.

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similar phenomenon was reported by others.‘,‘2 The early decline of plasminogen was noted in the present investigations after the induction of anesthesia and deepened throughout the incision of abdominal wall. The concentration of this zymogen reached again the preoperative values on the 3rd postoperative day and rose till the end of observations. Similar results were obtained by Ygge12 and Mellbring et al.l3 On the other hand, D’Angelo et alI4 did not find any difference in plasminogen concentration between pre- and postoperative determinations. We were prone to explain in the past the decrease of plasminogen found immediately after the operation by its intraoperative conversion into plasmin.” The present investigations did not confirm this explanation, because the actual decline of plasminogen concentration was observed before any surgical activity has been started and was not accompanied by the rise of t-PA or PAP. The molecule of plasminogen has five kringles and four of them contain regions referred to to as lysine-binding sites. These sites mediate the binding of plasminogen 0 Harcowt

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to fibronectin,15 thrombospondin,lh the surface of endothelial cells,‘7 and to subendothelial matrices.‘R We are inclined to explain the phenomenon of the early drop of plasminogen level in plasma by its enhanced binding to these proteins and structures. According to Kluft,x t-PA is released during surgery in increased amounts and its level increases gradually toward the end of surgery. Kluft’s opinion was confirmed in our investigations: the main part of operation, connected with surgical maneuvers inside the peritoneal cavity, resulted in the sharp increase of t-PA antigen in plasma, but the level of this antigen lowered gradually, beginning from the 1st postoperative day. The findings of others depended on whether the activity or antigen oftPA was estimated. Koh et al.’ have not seen any significant change in t-PA antigen during and after gynaecological surgery, while t-PA activity rose during the operation and decreased 24 h later. Quite opposite observations were made by Ivarsson et al.:ly the t-PA activity did not change during abdominal surgery while t-PA antigen rose intraoperatively. t-PA activity was low postoperatively in the studies of D’Angelo et al.” and Kluft et al.*” On the other hand, Mellbring et al.” have found a significant increase of t-PA activity during cholecystectomy and its return to the baseline values on the 1st postoperative day. Estimating the t-PA antigen level, Dabrowiecki et al.‘* encountered its sharp rise during the cholecystectomy. Mellbring et a1.13perceived this rise a few hours after the end of abdominal surgery and Dexter et al.“’ in the 6th postoperative h. Kluft et a12” found its sharp increase on the 1st postoperative day while D’Angelo et al.lJ determined this antigen on the 2nd postoperative day, and its change was not found in comparison to the preoperative values. The results of Dabrowiecki et al.,‘” Mellbring et al.,‘” and Kluft et a12” confirm our fmdings that there is a significant increase of circulating t-PA antigen during and at the end of abdominal surgery but its source is uncertain. It is known that human peritoneal mesothelium produces tPA.‘y,‘d,2sScott-Coombes et alZ6 and Holmdahl et al.” determined the t-PA activity of peritoneal serosa in patients undergoing elective abdominal operations for non-infIammatory diseases and noted a significant decrease of this activity at the end of surgery. According to the suggestion of Ivarsson et al.,lY it is possible that t-PA, released from peritoneal mesothelium and shredded into the abdominal cavity, is next absorbed by systemic circulation. The area of peritoneal serosa subjected in our patients to the operative trauma was, however, circumscribed only to the right upper abdominal quadrant. Aberg and Nilsson*” and Ljungner et al.*9 estimated the plasminogen activator activity in the superficial vein segments obtained from the hands of patients undergoing abdominal or vascular surgery and the decrease of this activity @

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was found in the early postoperative period in most patients. The endothelial cells are believed to be the main source of plasminogen activator activity30.31and the intraoperative rise of t-PA antigen seems to be mainly a result of its release from the endothelial cells of blood vessels. Most of the authors measuring the intra- and postoperative activity of PAL1 observed a rise of this activity on the 1st day after surgery;s.“.20.32D’Angelo et aliJ noted the increase of fast-acting t-PA inhibitor, corresponding to PAI-1, on the 2nd day after surgery. Except Juhan-Vague et al.,3Zwho still noted the increase of fast-acting t-PA inhibitor level on the 3rd postoperative day, other authorss.6.‘” found the return of this level to the baseline values on that day. Koh et al9 did not detect any change of PAI- activity until 24 h after gynaecological surgery and, in addition, there were no changes in this activity among the patients of Dabrowiecki et alz2 until the 3rd postcholecystectomy day. We have also estimated PAIactivity in cholecystectomized patients receiving placebo in our previous study33 and we did not find any changes of this activity up to the 7th postoperative day. Estimating PAI- antigen level, Koh et al9 did not encounter any change during 24 h after gynaecological surgery. Dexter et al.‘” found a significant drop of PAIantigen during cholecystectomy, followed by its rise 6 h after the conclusion of the operation; 18 hours later the PAI- antigen returned to the preoperative values in this study. Neither of these two groups of investigators followed PAI- 1 antigen for a longer period of time. We have found the early drop of PAI- 1 antigen level just at the opening of peritoneal cavity and this may correspond with the intraoperative finding of Dexter et allo noted at the initial gallbladder mobilization. The rise of PAI- antigen was observed on the 1st postoperative day which is similar to the increment of PAI- activity seen by others. The main discrepancy between our results of PAI1 antigen, and the results of PAI- activity obtained by others, is a gradual but steady increase of PAI- antigen observed up to the 7th postoperative day in our study. We are prone to explain this discrepancy by the fact that the immunoassay estimates the total PAI- antigen in plasma, while the tests of PAI- activity disclose the free, noncomplexed and non-latent form of this inhibitor only. Plasmin cannot be detected in plasma because of a very short half-life, 0.1 s34 and the conclusions on its level in plasma are drawn from the presence of its complex with a,-antiplasmin. The concentration of plasminaz-antiplasmin (PAP) antigen can be regarded as an outcome of ongoing or recent activity of fibrinolytic system. We have observed its sharp increase, almost parallel with t-PA antigen, during the intraperitoneal part of cholecystectomy. This rise was followed by the transient fall of PAP antigen level on the 1st postoperative day, but this finding has a weak statistical significance: Z%l.OS. Fibrinolysis

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The intraoperative increase of PAP antigen concentration followed by its subsequent decline on the 1st postoperative day was noted also by other authors.21~22,35 Mellbring et al.13 and Lopez et al.36 found also a postoperative decrease of PAP antigen but without preceding intraoperative rise. All these authors noted the significant increase of PAP antigen level after surgery: it was observed up to 3rd postoperative day by Dabrowiecki et al?* and up to 6th or 7th day by other authors. A similar increase of this antigen between 1st and 7th postoperative day was observed in our present study. Looking for the explanation of this delayed activation of fibrinolytic system, we are inclined to agree with Tsuji et al.’ who suggested that the late postoperative activation of fibrinolytic system in their patients could have resulted from the local fibrinolysis in the healing wound. The lack of the simultaneously increased level of t-PA antigen in plasma of our patients can be explained by the high-affinity binding of t-PA to fibrin in the surgical wound. The plasmin generated locally and complexed with ~antiplasmin was then detected in systemic circulation. Nevertheless, there is no reason to interpret the transient decline of PAP antigen level on the 1st day after surgery, followed by its steady ascent up to the end of 1st postoperative week, as a definite shut-down of fibrinolytic activity. In conclusion: The early drop of plasminogen concentration, occuring before the frost surgical incision, cannot be explained by the conversion of this zymogen into plaSlTliIl. t-PA antigen rose during the intraperitoneal part of cholecystectomy and then its level declined gradually until the 7th postoperative day. PAI- antigen decreased till the beginning of the intraperitoneal part of the operation and its level rose then from the end of surgery up to the end of observations. The PAP complex antigen, corresponding to the activity of fibrinolytic system, increased simultaneously with t-PA antigen during the operation. There was then a slight temporary reduction of PAP antigen on the 1st postoperative day, followed thereafter by its steady rise until the end of 1st postoperative week.

2. 3. 4. 5.

6. z 8. 9.

IO. 11. 12. 13. 14.

15. 16 17. 18. 19.

ACKNOWLEDGEMENT

This study was supported by the Medical Center of Postgraduate Education grant no. 50 1-2-l -0 l-04197. REFERENCES

21.

1. Chakrabarti R, Hocking ED, Feamley GR. Reaction pattern to three stresses - electroplexy, surgery, and myocardial infarction Fibrinolysis

& Proteolysis

20.

(1999)

13(3),

118-123

- of fibrinolysis and plasma fibrinogen. J Clin Path01 1969; 22: 659-662. Mansfield AO. Alteration in fibrinolysis associated with surgery and venous thrombosis. Brit J Surg 1972; 59: 754-757 MacIntyre IMC, Webber RG, Crispin JR et al. Plasma fibrinolysis and postoperative deep vein thrombosis. Brit J Surg 1976; 63: 694-697. Knight MTN. Dawson R, Melrose DC. Fibrinolytic response to surgery. Lancet 1977; 2: 370-373. Paramo JA, AIfaro MJ, Rocha E. Postoperative changes in the plasmatic levels of tissue-type plasminogen activator and its fast-acting inhibitor - relationship to deep vein thrombosis and influence of prophylaxis. Thromb Haemostas 1985; 54: 713-716. Aranda A, Paramo JA, Rocha E. Fibrinolytic activity in plasma after gynecological and urological surgery. Haemostasis 1988; 18: 129-134. Tsuji K, Eguchi Y, Kodama M. Postoperative hypercoagulable state followed by hyperfibrinolysis related to wound healing after hepatic resection. J Amer COB Surg 1996; 183: 230-238. KIuft C. Fibrinolytic shut-down after surgery. In: Sawaya R (ed.) Fibrinolysis and the central nervous system, Philadelphia: Haley and Belfus, 1990; 127- 140. Koh SCL, Pua HL, Tay DHB et al. The effects of gynaecological surgery on fibrinolysis, fibrinolytic inhibitor and the haemostatic status as assessed by thromboelastography. Thromb Haemostas 1995; 73: 1138 (abstr 9 12) Dexter SPL, Griffith JP, Grant PJ, McMahon MJ. Activation of coagulation and hbrinolysis in open and laparoscopic cholecystectomy. Surg Endosc 1996; 10: 1069-1074. Szczepafrski M, Duchmski T, Kretowicz P. Single dose of nandrolone does not prevent postoperative Bbrinolytic shutdown. Fibrinolysis 1995; 9: 350-355. Ygge J. Changes in blood coagulation and fibrinolysis during the postoperative period. Amer J Surg 1970; 119: 225-232. Mellbring G, Dahlgren S, Reiz S, Wiman B. Fibrinolytic activity in plasma and deep vein thrombosis after major abdominal surgery. Thromb Res 1983; 32: 575-584. D’Angelo D, KIuft C, Verheijen JH et al. Fibrinolytic shut-down after surgery: impairment of the balance between tissue-type plasminogen activator and its specific inhibitor. Eur J Clin Invest 1985; 15: 308-3 12. Salonen E, Saksela T, Vat-do T et al. Plasminogen and tissue-type plasminogen activator bind to immobilized hbronectin. J Biol Chem 1985; 260: 12302-12307 Silverstein R, HarpeI PC, Nachman RL. Tissue plasminogen activator and urokinase enhance the binding of plasminogen to thrombospondin. J Biol Chem 1986; 26 1: 9959-9965. Hajjar KA, Harpel PC, Jaffe EA, Nachman RL. Binding of plasminogen to cultured human endothelial cells. J Biol Chem 1986; 261: 11656-l 1662. Knudsen B, Silverstein R, Leung L et al. Binding of plasminogen to extracellular matrix. J Biol Chem 1986; 26 1: 10765- 10771. Ivarsson M-L, Holmdahl L, Eriksson E, Soderberg R, Risberg B. Expression and kinetics of fibrinolytic components in plasma and peritoneum during abdominal surgery. Fibrinolys Proteolys 1998; 12: 61-67 Khtft C, Verheijen JH, Jie AFH, Rijken DC et al. The postoperative Bbrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Stand J Clin Lab Invest 1985; 45: 605-610. Mellbring G, Dahlgren S, Wiman B. Plasma frbrinolytic activity in patients undergoing major abdominal surgery. Acta Chir Stand 1985; 151: 109-I 14. 0 HarcouH

Brace

8 Co. Ltd 1999

Perioperative fibrinolytic activity in cholecystectomized

22.

23.

24.

Dabrowiecki S, Rose D, Jurkowski P. The influence of laparoscopic cholecystectomy on perioperative blood clotting and fibrinolysis. Blood Coag Fibrinolys 1997; 8: 1-5. Mellbring G, Nilsson T, Bergsdorf N, Wallen P. Tissue plasminogen activator concentration in major abdominal surgery. Thromb Res 1984; 36: 33 l-334. Merlo G, Fansone G, Barber0 C, Castagna B. Fibrinolytic activity of the human peritoneum. Eur Surg Res 1980; 12: 433-438.

25.

26.

27

28. 29.

van Hinsbergh VWM, Kooistra T, Scheffer MA et al. Characterization and fibrinolytic properties of human omental tissue mesothelial cells. Comparison with endothelial cells. Blood 1990; 75: 1490-1497 Scott-Coombes DM, Whawell SA, Thompson JN. The operative peritoneal fibrinolytic response to abdominal operation. Eur J Surg 1995; 161: 395-399. Holmdahl L, Eriksson E, AI-Jabreen M, Risberg B. Fibrinolysis in human peritoneum during operation. Surgery 1996; 1 19: 701-705. Aberg M, Nilsson IM. Fibrinolytic activity of the vein wall after surgery. Brit J Surg 1978; 65: 259-262. Ljungner H, Bergqvist D, von Hebel J, lsacson S. Influence of major surgery on plasminogen activator activity in superficial hand veins. Eur Surg Res 1983; 15: 16 l- 167

0 Harcouti Brace& Co. Lfd

1999

patients

123

30.

Noordhoek Hegt V. Distribution and variation of fibrinolytic activity in the walls of human arteries and veins. Haemostasis 1976; 5: 355-372. 3 1. Lijnen HR. Collen D. Endothelium in hemostasis and thrombosis. Prog Cardiovasc Dis 1997; 39: 343-350. 32. Juhan-Vague J, Ailland MF, DeCock F. et al. The fast-acting inhibitor of tissue-type plasminogen activator is an acute phase reactant protein. Davidson JF, Donati MB, Cocheri S (eds.) Progress in fibrinolysis, vol. Z Edinburgh: Churchill Livingstone, 1985; 146-149. 33. Szczepahski M, Kubiak J, Lembas L. Postoperative injection of phenylbutazone does not influence frbrinolytic shutdown. Curr Med Res Opinion 1998; 14: 105-l 10. 34. Francis WC, Marder VJ. Physiologic regulation and pathologic disorders of fibrinolysis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, (eds.) Hemostasis and thrombosis. Basic principles and clinical practice, 3rd edn. Philadelphia: JB Lippincot, 1994. 35. Psuja P, Zozulihska M, Tokarz A, Zawilska. Fibrinolytic suppresion in patients after minor abdominal surgery. Brit J Haemat 1994; 87 (suppl 1): 185 (abstr 72 1). 36. Lopez Y, Paramo JA, Valenti JR et al. Hemostatic markers in surgery: a different Bbrinolytic activity may be of pathophysiological significance in orthopedic versus abdominal surgery. Int J Clin Lab Res 1997; 27: 233-237

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