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Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery
THROMBOSIS 0049-3848/93 Copyright(c)
RESEARCH 70; 451-458,1993 $6.00 + .OO Printed in the USA. 1993 Pergamon Press Ltd. All rights reserved,
SEQUENTIAL INTRAPULMONARY AND SYSTEMIC ACTIVATION OF COAGULATION AND FIBRINOLYSIS DURING AND AFTER TOTAL HIP REPLACEMENT SURGERY Ola E. DahllA, Trude Pedersenl, Peter Kierul@, &e-B&t Westvik2, Per Lund3, Harald Arnesenl, Ingebjorg Seljeflotl, Michael Abdelnoorl and Torstein Lybergl Research Forum1 and Dept. of Clinical Chemistry2, Ullevaal University Hospital, and Ftirst Laboratory33 Oslo, Norway. Former adress4: The Norwegian Lutheran Hospital (Diakonhjemmets sykehus), Oslo, Norway (Received
23.11.1992;
accepted
in revised form 10.3.1993
by Editor N.O. Solum)
Abstract Hip joint replacement surgery, using acrylic cement for prosthesis fixation, is associated with intraoperative cardiorespiratory dysfunction, and a high frequency of postoperative proximal deep vein thrombosis (DVT). Levels of prothrombin fragments 1+2 (F1+2), tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor 1 activity (PAI-l), D-dimer and interleukin 6 (IL-6) were measured in arterial (AB) and mixed venous blood (MVB) in five patients during and after total hip replacement operation with acrylic cement prosthesis fixation. Sequential peaks of F1+2, t-PA, PAI- and IL-6 appeared, starting with activation of coagulation during preparation of bone, closely followed by activation of fibrinolysis. Later, this was counteracted by an antifibrinolytic response and increase of IL-6. After a fibrinolytic shutdown on the third postoperative day as evidenced by a drop in t-PA and D-dimer concentrations, a second wave of coagulation was seen at the end of the first week. The present model, with frequent sampling of blood entering and leaving the lungs, confirms our earlier findings of the lung as a key organ in promoting coagulation following traumatic activation. Total hip replacement (THR) is highly traumatic surgery associated with both peroperative cardiorespiratory depression (1,2) and a high incidence of postoperative deep vein thrombosis (DVT) (3,4). The use of self-curing acrylic resin (polymer of methylmethacrylate monomer (MMA)) for fixation of prosthesis apparently adds to the morbidity (5). In an earlier communi -cation we have focused on a substantial intrapulmonary thrombin generation, probably in response to sequestrated blood-borne procoagulant debris from the operation field. Furthermore, we demonstrated the rapid appearence of acrylic monomer in mixed venous blood during cement polymerization, and its almost immediate extraction upon passage of the pulmonary capillary bed (6,7). Methylmethacrylate monomer, an organic solvent, has been shown in experimental studies to be cytotoxic @-lo), and its effect on pulmonary endothelium may act to potentiate the effect of procoagulant factors already present due to trapping of debris (6,ll). In this setting the lung seems to be an organ with a marked potential for activation of coagulation, which may relate to the immediate cardiorespiratory depression occuring in a small percentage of cases (2) and contribute to the hypercoagulable state which eventually may result in the development of deep vein thromKey words: THR, coagulation, fibrinolysis, antifibrinolysis, acute phase response, DVT. Corresponding author: Dr. Ola E. Dahl, Research Forum, Department of Surgery, Ullevaal Hospital, Kirkevn. 166, 0407 Oslo, Norway. 451
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bosis. In this paper we have complemented our earlier studies on activation of coagulation in response to a defined surgical trauma (2,6,7). We have also extended the observations to include studies of the fibrinolytic and preinflammatory responses to contribute to our understanding of the thrombopathogenetic mechanisms and its linkage to acute phase reaction, involved in major orthopaedic surgery.
MATERIALS AND METHODS Patients. Five patients undergoing elective total hip replacement for osteoarthrosis with cemented prosthesis components were monitored for activation of coagulation and fibrinolysis during and after the operation. Three were females and two were males, age ranging from 64 to 84 years. All patients were interviewed on the day before operation and gave informed consent. The study had been approved by the Regional Ethics Committee. Perioperutive procedures. Dextran-70 was given as thromboprophylaxis, 500 ml during induction of analgesia and on the first, third and fifth postoperative day. Epidural analgesia was performed (18-20 ml bupivacain 7.5mgAnl). A catheter (Pulmoball, Vygon, Ecouen, France) was introduced via the internal jugular vein into the pulmonary artery, and another polyethylene catheter into the radial artery, for blood sampling. Both catheters were continuously flushed with heparin (lo-15 IU/hour). The catheters were removed on the fust postoperative day. Surgery was performed through an anterolateral incision. Reaming of the acetabular cavity, broaching and lavage with saline of the femoral shaft were done before the implantation procedure was initiated. The acrylic cement (Palaces, Schering, Kenilworth, NJ, USA) and installation of the prosthesis (Landanger, Landos, Chaumont, France) started with the acetabular socket whereafter the femoral component was introduced. The patients were breathing air during the surgical procedure. No blood transfusion was given before the intraoperative blood samplings were done. Blood transfusion (SAGMAN) was given to replace the amount in the suction drains which were removed on the second postoperative day. Protocol of blood sampling. During the operation and the first postoperative day almost parallel and frequent blood samples were withdrawn from the pulmonary artery (mixed venous blood, MVB) and the radial artery (arterial blood, AB) during the different phases of surgery and the fust postoperative week (Table I). The catheters were removed on the first postoperative day after withdrawal of the blood samples. On the third and sixth postoperative day puncture of the femoral artery was performed for arterial blood aspiration. For practical reasons, no mixed venous blood was obtained during this period. Method of sampling. 15 ml blood were collected from the catheters into plastic syringes (Fabersanitas, Zaragoza, Spain) after discarding the first few millilitres, and transferred into 4.5 ml vacutainer tubes, containing 4.1 mmol/l K2EDTA (Becton Dickinson, Plymouth, England) placed on melting ice. The samples were centrifuged within two hours (1500 x g for 30 min at 2oOC) and plasma stored in aliquots at -135oC until assayed. Assays. Haematocritwas analysed for assessment of hemodilution. The D othrombin f-s 1+2 (Fr+2) were determined using an enzyme immunoassay (EIAR, Bedgwerke A.G., Marburg, Germany). Reference value: cl.5 nmol/l. ’ ’ analyses were performed using kits from Biopool, Umeb, Sweden; t-PA anTint Elize TM t-PA and Spectrolyse TM pL, respectively. Reference values: t-PA ag 3-10 ng/ml, PAI-I cl6 IU/ml. D-dimers were measured using an ELISA kit (Asserachrom R D-di) from Stago, Asnibres, France. Reference value: ~400 ng/ml. IL_6 was measured in blood obtained in the later phase of surgery and during the postoperative days (sampling times 4-11 of Table I) using an immunoassay based kit (EASIAR) from Medgenix Diagnostics, Brussels, Belgium. According to manufacturers pamphlet, values in 80
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normal donors were as follows: 49 not detectable levels, 29 low levels (range 3-8.5 pg/ml) and 2 >8.5 pg/ml. Diagnosis of DVT. On the seventh postoperative day ascending venography was performed on both legs using the “hand trigger system” (12).
TABLE I. Blood Sampling Schedule iample no.
Statisticalanalyses. As we were in an observational situation of repeated measurements, we estimated the mean biological variation as the mean per cent between two sampling times as e.g. 1 and 8 (Table I), : (The mean 8 - The mean l)lOO/Tbemean 1. Statistical difference between MVB and AB measurements, were estimated by calculating The Area Under The Curve (AUC) for each patient, by adding the areas under the graphs between each pair of consecutive observations. We compared the areas in the two groups (AB and MVB), using Wilcoxon signed rank sum test (13). P I 0.05 was chosen as level of statistical significance. Based on our earlier knowledge about intrapulmonary thrombin generation (10,l l), we used a one-tailed test on Ft+2, and two-tailed tests for the other parameters. In variation, all results are expressed as mean * SEM.
ZO-
O-
453
Surgical procedure After induction of epidural analgesia After femoral osteotomy
1 2 3 4
After bone preparation
5 6
Ten minutes later
7
Ten minutes later
8
One hour after surgery
9
1. postoperative day
10
3. postoperative day
11
6. postoperative day
Acetabular implantation
Femoral implantation
order to pinpoint the huge biological
16-
1
1
,
2
E 3
1 4
I 5
Sample
FIG.
1
1 6
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AB
-
MVB
1 7 no.
I’il 8’9
r 1 1011
z-
, 1
I 2
1 , 3
A , , , , ,‘I, 4 5 6 7 8”9 Sample no.
, , 10 11
FIG. 2
Intraoperative and postoperative values of F1+2 (Fig. 1) and t-PA ag (Fig. 2) in mixed venous (MVB) and arterial blood (AB) during and after operation (mean f SEM).
464
THR, COAGULATION AND FIBRINOLYSIS
600
t
1
Sample no. FIG. 3
I
2
I
3
Vol. 70, No. 6
I
I
I
4 5 6 Sanple
I
l”,
7 8"9 no.
I
1011
1
FIG. 4
Intraoperative and postoperative values of PAI-I activity (Fig. 3) and D-dimer concentration (Fig. 4) in mixed venous (MVB) and arterial blood (AB) during and after operation (mean + SEM)
RESULTS The mean huematocrit values were similar in arterial and mixed venous blood and changed with a fraction less than 0.05 during the sampling times l-l 1 (data not shown), Thus, no correction for haemodilution was necessary. Prothrombin fragments 1+2 (F1+2) concentrations increased 188%, in arterial blood during and after bone preparation and reached maximal mean values following the acetabular implantation (maximum level sampling time 5) whereafter it decreased until the third postoperative day when a second rise occured (Fig. 1). In mixed venous blood, only a slight rise of 34% was found between start of surgery and the time of femoral implantation (maximum level sampling time 7). This marked biological difference in prothrombin fragments levels between arterial and mixed venous blood during surgery, showed statistical significance (p = 0.05, AUC). Tissue plusminogen activator antigen (t-PA ag) fell markedly (58% reduction, minimum level sampling time 4), in arterial blood during bone preparation and socket impaction, whereafter a rapid increase was found, reaching a higher level than preoperatively, followed by a fall between the first and third postoperative day (Fig. 2). Contrary, in mixed venous blood the mean t-PA values increased (53%, maximum level sampling time 4). During surgery, difference of borderline statistical significance was found (p = 0.07, AUC) between mixed venous and arterial blood, with higher t-PA values in blood entering than leaving the lung. Plusminogen activator inhibitor (PAI- 1) activity in arterial blood was mainly unchanged until ten minutes after shaft implantation, whereafter it rose 250% from the initial mean value, peaking 24 hours postoperatively (maximum level sampling time 9). From the first to the third day an equally marked drop was seen followed by a slight increase on day six. The same pattern and equal concentrations were found in MVB (Fig. 3)
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D-dimer
2501 __e~-_-
AB
(D-d) concentration increased slowly and almost equally in mixed venous (54%, maximum level sampling time 9) and arterial blood (72% maximum level sampling time 8) ) during operation, whereafter lower values were found on the third and sixth postoperative day (Fig. 4).
zoo-
Interleukin-6
(IL-6) rose dramatically in mixed venous and arterial blood from one hour after the operation, with maximal levels the first postoperative day (Fig. 5). The mean values found in mixed venous blood were slightly higher than the corresponding values of arterial blood, however, the difference was not statistically significant.
" \E
150.
:: tD loo1 SO-
Venogruphy performed bilaterally on the lower limbs
the seventh postoperative day visualized one proximal DVT in one patient and a distal one in the fibular vein in another patient, both on their operated side.
o-
DISCUSSION FIG.5
Acrylic hip joint replacement surgery is associated with peroperative cardiorespiratory depression (1,2) Intraoperative and postoperand a high frequency of postoperative deep vein ative values of IL-6 in mixed thrombosis (3,4). In our earlier reports we have venous (MVB) and arterial focused on the substantial intrapulmonary thrombii blood (AB) during and after generation which was detected before high levels of operation (mean +SEM). monomethylmethacrylate was observed, and a possible connection between these findings and peroperative clinical events (6,7). In this report we show that systemic activation of coagulation, as evidenced by the appearance of prothrombin fragments Fl+2 mostly occurs during bone preparation and especially as blood passes the pulmonary capillary bed. The Fl+2 appearance presented here closely corresponds to the fibrinopeptide A (FPA) (7) and the thrombin-antithrombin (TAT) complex generation (6) as previously demonstrated, all markers of ongoing proteolytic activity in the late sequence of the coagulation cascade. Analyses of mixed venous and arterial blood, revealed substantial intrapulmonary proteolytic enzyme activities with great individual variations, but of weak statistical significance. However, as biological power is not synonymous with statistical power, the fact that only a few patients were included in this study, might be the reason why stronger statistical significance was not obtained, although tremendous enzyme activities appeared. Marked peaks of plasma thromboplastin activity have been found during bone preparation in total hip replacement (14) indicating release of thromboplastin-rich material to the systemic circulation from the traumatized tissues. In animal experiments bolus injections of purified human tissue thromboplastin have been shown to cause immediate platelet aggregation and fibrin deposition in the lungs (15). This is in line with our in vivo observations of activation of coagulation mainly during bone preparation, leading to generation of thrombin in the pulmonary capillary bed. Thus, the lung seems to have an outstanding position in the activation of coagulation in this setting, which in turn probably contributes to local fibrin deposition and formation of microthrombi in the pulmonary microcirculation (7, 14, 15). This may be explained on the basis of trapping of procoagulant material released into the venous circulation (1 l), particularly during bone preparation (7,16).
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Earlier studies have shown that THR surgery is associated with increased thromboplastin activity of circulating blood monocytes (17,18). The thromboplastin activity of stimulated monocytes is mainly confined to the cell surface (19) allowing pericellular fibrin formation to occur, which may contribute to the hypercoagulable state that is induced when blood passes the lung. Adherence of monocytes to vessel walls due to pericellular fibrin deposition may promote thrombus formation in a blood stream containing high levels of activated coagulation factors. This especially holds true if the endothelial surface also is perturbated due to local mechanical, biochemical and chemical (bone cement) factors. Activated monocytes may also be envisioned to increase their surface expression of adhesion molcules (e.g. Mac-l, LFA-1, selectins). This might further add to their entrapment in the fibrin primed lung capillary bed. The hypercoagulable state of the blood leaving the pulmonary circulation may also contribute to the high frequency of DVT observed in patients receiving cemented hip prostheses (3,4). Conflicting observations on the role of the lungs in modulating systemic fibrinolytic activity during major surgery have been reported (20-22). The present study, with frequent blood sampling from mixed venous and arterial blood during acrylic hip substitute surgery, disclosed a rapid fibrinolytic response measured as a marked increase of t-PA in mixed venous blood in the early phases of the operative procedures, almost paralleling the activation of coagulation. This finding of a close connection between coagulation and fibrinolysis has also been demonstrated in earlier studies in man (23) and animals (15) giving clearance of aggregates of fibrin minutes after deposition. The increased fibrinolytic activity could be due to release of t-PA from damaged endothelium and other tissue sources, especially at the operating field. A note of special interest is that t-PA seems to be effectively cleared by the blood passage through the lung microcirculation. This indicates preferential fibrinolytic clearance in the lungs before fibrin dissolution starts in peripheral microcapillaries. The most reasonable explanation might be that t-PA binds directly to deposited fibrin and exerts its homeostatic clot-dissolving function by giving rise to clot-localized plasmin. However, the t-PA clearance capacity of the lung is rapidly saturated, and is followed by a phase of sustained high systemic profibrinolytic activity which is maintained during at least the first day postoperatively before a sudden drop is noted both in t-PA and D-dimer concentration. This fibrinolytic shutdown seems to be a common reaction pattern following soft tissue and bone surgery, and coincides with a marked rise in plasma PAI- activity (21,24,25) which in this study was maximal 24 hours postoperatively. This PAI- 1 increase corresponds in time intimately to an almost identical rise in IL-6 which precedes increase in the acute phase proteins after surgery (26) reflecting the role of IL-6 and other cytokines (TNF, IL-l) in the regulation of acute phase protein genes in hepatocytes (27). PAI-1 behaves like an acute phase protein in vivo (24). It has been proposed that this acute phase behaviour is also due to the effect of cytokines on endothelial cells (28). The increased fibrinolytic inhibition is followed by a decline in PAI- activity (24,29,30) possibly in large part due to complexation with plasminogen activators and subsequent clearence of the complexes. The risk of developing DVT a few days after surgery largely seems to depend on the amount of peroperative systemic activation of coagulation which is markedly higher in orthopaedic surgery compared to major soft tissue surgery (7,20,31), and the subsequent antifibrinolytic reaction. A slight reactivation of both coagulation and antifibrinolysis was noted at the end of the first postoperative week at a time when elevated levels of fibrinogen and platelets also have been demonstrated (2,32). This late hypemoagulability may have a bearing on the development of late deep vein thrombosis. The high frequency of deep vein thrombosis in spite of thromboprophylaxis noted in this as well as in several other studies (3,4), requires further investigations bot to clearify the role of the surgical traumager se and not least to elucidate the specific effects of acrylic cement in the thrombotic processes. In conclusion, during and after acrylic hip replacement surgery a sequential activation of coagulation, fibrinolysis, and antifibrlnolysis occured. In sum these three processes seemed unbalanced with a preponderance of procoagulant and antifibrinolytic activity during surgery and
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towards the end of the first postoperative week. This may favor the development of thrombosis, and is also intimately linked to inflammatory activation. The study also confirms our earlier observations of the lung as a key organ in promoting proteolytic enzyme activation, with a substantial intrapuhnonary thrombii generation and tissue plasminogen activator clearance.
Acknowledgements The practical work with these patients were performed at the end of the principal investigators engagement at the Norwegian Lutheran Hospital. Thanks are due to Dr. Johs. Rp, for his never failing support and helpfulness, and the staff of the Department of Anaesthesiology for the help with vascular catheterization and withdrawal of intraoperative blood samples.
REFERENCES 1. DUNCAN, J.A.T. Irma-operative collapse and death related to the use of acrylic cement in hip surgery. Anaesthesia 44, 149-153, 1989. 2. DAHL, O.E., MOLNAR, I., R0, J.S. and VINJE, A. Global tests on coagulation and fibrinolysis in systemic and pulmonary circulation accompanying hip arthroplasty with acrylic cement. Thromb Res 5,865-873 1988. 3. NILLIUS, A.S. and NYLANDER, G. Deep vein thrombosis after total hip replacement: A clinical and phlebographic study. Br. J. Surg. 66,324-326, 1979. 4. STAMATAKIS, J.D., KAKKAR, V.V., SAGAR, S., LAWRENCE, D., NAIRN, D. and BENTLEY, P.G. Femoral vein thrombosis and total hip replacement. Brit Med J 2, 223-225, 1977. 5. RITTER, M.A., GIOE, T.J. and SIEBER, J.M. Systemic effects of polymethylmethacrylate. Acta Orthop Stand 55,411-413, 1984. 6. DAHL, O.E., JOHNSEN, H., KIERULF, P., MOLNAR, I., R0, J.S., VINJE, A. and MOWINCKEL, P. Intrapulmonary thrombin generation and its relation to monomethylmethacrylate plasma levels during hip arthroplasty. Acta Anaesthesiol Scand. 36,331-335, 1992. 7. DAHL, O.E., MOLNAR, I., VINJE, A., R0, J.S., KIERULF, P., ANDERSEN, A-B., DALAKER, K. and PRYDZ, H. Studies on coagulation, fibrinolysis, kallikrein-kinin and complement activation in systemic and pulmonary circulation during hip arthroplasty with acrylic cement. Thromb Res j&875-884,1988. 8. WONG, K.C., MARTIN, W.E., KENNEDY, W.F., AKAMATSU, T.J., CONVERY, R.F. and SHAW, C.L. Cardiovascular effects of total hip replacement in man. With observations on the effects of methylmethacrylate on the isolated rabbit heart. Clin Pharmacol Therap 21, 709-7 14, 1977. 9. OHNSORGE, J. and KUTZNER, F. Pharmakologishe Auswirkungen des Monomers. Akt Traumatol4,257-260, 1974. 10. LINDER, L. Bone cement monomer. Experimental in vitro and in vivo studies on the monomer leakage from polymerizing bone cement and its effect on soft tissue and bone. Doctoral Thesis, University of Gothenburg, Gothenburg, Sweden, 1976. ll.MODIG, J., BUSH, C., OLERUD, S., SALDEEN, T. and WAERNBAUM, G. Arterial hypotension and hypoxaemia during total hip replacement; The importance of thromboplastic products, fat embolism and acrylic monomers. Acta Anaesthesiol Stand 19,28-43, 1975. 12. DAHL, O.E., LEISTAD, E., NYHUS, S. and HAVIG, 0. 99mTc-plasmin uptake test is unreliable for diagnosing asymptomatic deep vein thrombosis after hip replacement surgery. Thromb Res 62,781-784, 1991. 13. MATTHEWS, J.N.S., ALTMAN, D. G., CAMPBELL, M. J. and ROYSTON, P. Analysis of serial measurements in medical research. Br Med J 300,230-235,199O. 14. GIERCKSKY, K.E., BJ0RKLID, E., PRYDZ, H. and RENCK, H. Circulating tissue thromboplastin during surgery. Eur Surg Resl I, 296-3OO,l979. 15. GIERCKSKY, K.E., BJldRKLID, E. and PRYDZ, H. The effect of intravenous injection of purified human tissue thromboplastin in rats. Stand J HaematolI6,300-310,1976. 16 MODIG, J., BUSCH, C.,OLERUD, S., SALDEEN, T. and WAERNBAUM, G. Pulmonary microembolism during intramedullary orthopaedic trauma. Acta Anaesthesiol Stand I8,133-143, 1974.
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17. HPIGEVOLD, H.E., LYBERG, T., KIERULF, P. and REIKERAS, 0. Generation of procoagulant (thromboplastin) and plasminogen activator activities in peripheral blood monocytes after total hip replacement surgery. Effects of high doses of corticosteroids. Thromb Res 62,449457, 1991. 18 NYGAARD, 0.P., UNNEBERG, K., REIKERAS, 0. and QISTERUD, B. Thromboplastin activity of blood monocytes after total hip replacement. Stand J Clin Lab Invest 50, 183-186, 1990. 19. LYBERG, T. Clinical significance of increased thromboplastin activity on the monocyte surface. A brief review. Haemostasis 14,430-439, 1984. 20. McLOUGHLIN, G.A., GRINDLINGER, G.A., MANNY, J., VALERI, C.R., LIPINSKI, B., MANNICK, J.A. and HECHTMAN, H.B. Intrapulmonary clotting and fibrinolysis during abdominal aortic aneurysm surgery. Ann Surg 5,623- 630,1979. 21. ERIKSSON, E. and RISBERG, B. Tissue plasminogen activator and its inhibitor following major surgery in relation to ventilator-y pattern. Acta Chir Stand 154,57-60,1988. 22. KAMBAYASHI, J., SAKON, M., YKOTA, M., SHIBA, E., KAWASAKI, T. and MORI, T. Activation of coagulation and fibrinolysis during surgery, analyzed by molecular markers. Thromb Res 60, 157-167, 1990. 23. MODIG, J., BUSH, C., OLERUD, S. and SALDEEN, T. Pulmonary microembolism during intramedullary orthopaedic trauma. Acta Anaestesiol Stand I&133-143,1974. 24. KLUFT, C., VERHEIJEN, J.H., JIE, A.F.H., RIJKEN, D.C, PRESTON, F.E., SUELING, H.M., JESPERSEN, J. and AASEN, A.O. The postoperative fibrinolytic shutdown: a rapid reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Stand J Clin Lab Invest 45,605610,1985. 25. ERIKSSON, B.I., ERIKSSON, E. and RISBERG, B. Impaired fibrinolysis and postoperative thromboembolism in orthopaedic patients. Thromb Res 62,55-64,199l. 26. HPK;EVOLD, H.E., KIERULF, P., 0VSTEB0, R and REIKERAS, 0. Acute phase reactants and interleukin 6 after total hip replacement. Effects of high-dose corticosteroids in a standardized musculo-skeletal trauma. Eur J Surg 158,339-345,1992. 27. LE. J. and VILCEK, J. Interleukin 6: A multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 61,588-602, 1989. 28. MEDINA, R., SOCHER, S.H., HAN, J.H. and FRIEDMAN, P.A. Interleukin 1, endotoxin or tumor necrosis factor/cache&n enhance the level of plasminogen activator inhibitor messenger RNA in bovine aortic endothelial cells. Thromb Res 54,41-52, 1989. 29. JIZIRGENSEN, L.N., LIND, B., HAUCH, O., LEFFERS, A., ALBRECH-BESTE, B. and KONRADSEN, L.A.G. Thrombin-antithrombin III-complex & fibrin degradation products in plasma: surgery and postoperative deep venous thrombosis. Thromb Res 59,69-76,199O. 30. BORRIS, L.C., SPIRENSEN, J.V., LASSEN, M.R., WALENGA, J.M., FAREED, J., JPIRGENSEN, L.N., HAUCH, 0. and WILLE-JPIRGENSEN, P. Components of coagulation and fibrinolysis during thrombosis prophylaxis with low molecular weight heparin (Enoxaparin) versus dextran 70 in hip arthroplasty. Thromb Res 63,21-28, 1991. 3 1. GITEL, S.N., SALVATI, E.A., WESSLER, S., ROBINSON, H.J. and WORTH, M.H. The effect of total hip replacement and general surgery on antithrombin III in relation to venous thrombosis. J Bone Joint Surg 6I,653-656, 1979. 32. SPIRENSEN, J.V., LASSEN, M.R., BORRIS, L.C., RAHR, H.B., JENSEN, H.P., HOPPENSTEADT, D., WALENGA, J.A. and FAREED, J. Reduction of plasma levels of prothrombin fragments 1 and 2 during thromboprophylaxis with a low-molecular-weight heparin. Blood Coag Fibrinol3,55-59, 1992.
RESEARCH 70; 451-458,1993 $6.00 + .OO Printed in the USA. 1993 Pergamon Press Ltd. All rights reserved,
SEQUENTIAL INTRAPULMONARY AND SYSTEMIC ACTIVATION OF COAGULATION AND FIBRINOLYSIS DURING AND AFTER TOTAL HIP REPLACEMENT SURGERY Ola E. DahllA, Trude Pedersenl, Peter Kierul@, &e-B&t Westvik2, Per Lund3, Harald Arnesenl, Ingebjorg Seljeflotl, Michael Abdelnoorl and Torstein Lybergl Research Forum1 and Dept. of Clinical Chemistry2, Ullevaal University Hospital, and Ftirst Laboratory33 Oslo, Norway. Former adress4: The Norwegian Lutheran Hospital (Diakonhjemmets sykehus), Oslo, Norway (Received
23.11.1992;
accepted
in revised form 10.3.1993
by Editor N.O. Solum)
Abstract Hip joint replacement surgery, using acrylic cement for prosthesis fixation, is associated with intraoperative cardiorespiratory dysfunction, and a high frequency of postoperative proximal deep vein thrombosis (DVT). Levels of prothrombin fragments 1+2 (F1+2), tissue plasminogen activator antigen (t-PA), plasminogen activator inhibitor 1 activity (PAI-l), D-dimer and interleukin 6 (IL-6) were measured in arterial (AB) and mixed venous blood (MVB) in five patients during and after total hip replacement operation with acrylic cement prosthesis fixation. Sequential peaks of F1+2, t-PA, PAI- and IL-6 appeared, starting with activation of coagulation during preparation of bone, closely followed by activation of fibrinolysis. Later, this was counteracted by an antifibrinolytic response and increase of IL-6. After a fibrinolytic shutdown on the third postoperative day as evidenced by a drop in t-PA and D-dimer concentrations, a second wave of coagulation was seen at the end of the first week. The present model, with frequent sampling of blood entering and leaving the lungs, confirms our earlier findings of the lung as a key organ in promoting coagulation following traumatic activation. Total hip replacement (THR) is highly traumatic surgery associated with both peroperative cardiorespiratory depression (1,2) and a high incidence of postoperative deep vein thrombosis (DVT) (3,4). The use of self-curing acrylic resin (polymer of methylmethacrylate monomer (MMA)) for fixation of prosthesis apparently adds to the morbidity (5). In an earlier communi -cation we have focused on a substantial intrapulmonary thrombin generation, probably in response to sequestrated blood-borne procoagulant debris from the operation field. Furthermore, we demonstrated the rapid appearence of acrylic monomer in mixed venous blood during cement polymerization, and its almost immediate extraction upon passage of the pulmonary capillary bed (6,7). Methylmethacrylate monomer, an organic solvent, has been shown in experimental studies to be cytotoxic @-lo), and its effect on pulmonary endothelium may act to potentiate the effect of procoagulant factors already present due to trapping of debris (6,ll). In this setting the lung seems to be an organ with a marked potential for activation of coagulation, which may relate to the immediate cardiorespiratory depression occuring in a small percentage of cases (2) and contribute to the hypercoagulable state which eventually may result in the development of deep vein thromKey words: THR, coagulation, fibrinolysis, antifibrinolysis, acute phase response, DVT. Corresponding author: Dr. Ola E. Dahl, Research Forum, Department of Surgery, Ullevaal Hospital, Kirkevn. 166, 0407 Oslo, Norway. 451
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bosis. In this paper we have complemented our earlier studies on activation of coagulation in response to a defined surgical trauma (2,6,7). We have also extended the observations to include studies of the fibrinolytic and preinflammatory responses to contribute to our understanding of the thrombopathogenetic mechanisms and its linkage to acute phase reaction, involved in major orthopaedic surgery.
MATERIALS AND METHODS Patients. Five patients undergoing elective total hip replacement for osteoarthrosis with cemented prosthesis components were monitored for activation of coagulation and fibrinolysis during and after the operation. Three were females and two were males, age ranging from 64 to 84 years. All patients were interviewed on the day before operation and gave informed consent. The study had been approved by the Regional Ethics Committee. Perioperutive procedures. Dextran-70 was given as thromboprophylaxis, 500 ml during induction of analgesia and on the first, third and fifth postoperative day. Epidural analgesia was performed (18-20 ml bupivacain 7.5mgAnl). A catheter (Pulmoball, Vygon, Ecouen, France) was introduced via the internal jugular vein into the pulmonary artery, and another polyethylene catheter into the radial artery, for blood sampling. Both catheters were continuously flushed with heparin (lo-15 IU/hour). The catheters were removed on the fust postoperative day. Surgery was performed through an anterolateral incision. Reaming of the acetabular cavity, broaching and lavage with saline of the femoral shaft were done before the implantation procedure was initiated. The acrylic cement (Palaces, Schering, Kenilworth, NJ, USA) and installation of the prosthesis (Landanger, Landos, Chaumont, France) started with the acetabular socket whereafter the femoral component was introduced. The patients were breathing air during the surgical procedure. No blood transfusion was given before the intraoperative blood samplings were done. Blood transfusion (SAGMAN) was given to replace the amount in the suction drains which were removed on the second postoperative day. Protocol of blood sampling. During the operation and the first postoperative day almost parallel and frequent blood samples were withdrawn from the pulmonary artery (mixed venous blood, MVB) and the radial artery (arterial blood, AB) during the different phases of surgery and the fust postoperative week (Table I). The catheters were removed on the first postoperative day after withdrawal of the blood samples. On the third and sixth postoperative day puncture of the femoral artery was performed for arterial blood aspiration. For practical reasons, no mixed venous blood was obtained during this period. Method of sampling. 15 ml blood were collected from the catheters into plastic syringes (Fabersanitas, Zaragoza, Spain) after discarding the first few millilitres, and transferred into 4.5 ml vacutainer tubes, containing 4.1 mmol/l K2EDTA (Becton Dickinson, Plymouth, England) placed on melting ice. The samples were centrifuged within two hours (1500 x g for 30 min at 2oOC) and plasma stored in aliquots at -135oC until assayed. Assays. Haematocritwas analysed for assessment of hemodilution. The D othrombin f-s 1+2 (Fr+2) were determined using an enzyme immunoassay (EIAR, Bedgwerke A.G., Marburg, Germany). Reference value: cl.5 nmol/l. ’ ’ analyses were performed using kits from Biopool, Umeb, Sweden; t-PA anTint Elize TM t-PA and Spectrolyse TM pL, respectively. Reference values: t-PA ag 3-10 ng/ml, PAI-I cl6 IU/ml. D-dimers were measured using an ELISA kit (Asserachrom R D-di) from Stago, Asnibres, France. Reference value: ~400 ng/ml. IL_6 was measured in blood obtained in the later phase of surgery and during the postoperative days (sampling times 4-11 of Table I) using an immunoassay based kit (EASIAR) from Medgenix Diagnostics, Brussels, Belgium. According to manufacturers pamphlet, values in 80
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normal donors were as follows: 49 not detectable levels, 29 low levels (range 3-8.5 pg/ml) and 2 >8.5 pg/ml. Diagnosis of DVT. On the seventh postoperative day ascending venography was performed on both legs using the “hand trigger system” (12).
TABLE I. Blood Sampling Schedule iample no.
Statisticalanalyses. As we were in an observational situation of repeated measurements, we estimated the mean biological variation as the mean per cent between two sampling times as e.g. 1 and 8 (Table I), : (The mean 8 - The mean l)lOO/Tbemean 1. Statistical difference between MVB and AB measurements, were estimated by calculating The Area Under The Curve (AUC) for each patient, by adding the areas under the graphs between each pair of consecutive observations. We compared the areas in the two groups (AB and MVB), using Wilcoxon signed rank sum test (13). P I 0.05 was chosen as level of statistical significance. Based on our earlier knowledge about intrapulmonary thrombin generation (10,l l), we used a one-tailed test on Ft+2, and two-tailed tests for the other parameters. In variation, all results are expressed as mean * SEM.
ZO-
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453
Surgical procedure After induction of epidural analgesia After femoral osteotomy
1 2 3 4
After bone preparation
5 6
Ten minutes later
7
Ten minutes later
8
One hour after surgery
9
1. postoperative day
10
3. postoperative day
11
6. postoperative day
Acetabular implantation
Femoral implantation
order to pinpoint the huge biological
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1
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FIG.
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-
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r 1 1011
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, 1
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, , 10 11
FIG. 2
Intraoperative and postoperative values of F1+2 (Fig. 1) and t-PA ag (Fig. 2) in mixed venous (MVB) and arterial blood (AB) during and after operation (mean f SEM).
464
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600
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I
I
I
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FIG. 4
Intraoperative and postoperative values of PAI-I activity (Fig. 3) and D-dimer concentration (Fig. 4) in mixed venous (MVB) and arterial blood (AB) during and after operation (mean + SEM)
RESULTS The mean huematocrit values were similar in arterial and mixed venous blood and changed with a fraction less than 0.05 during the sampling times l-l 1 (data not shown), Thus, no correction for haemodilution was necessary. Prothrombin fragments 1+2 (F1+2) concentrations increased 188%, in arterial blood during and after bone preparation and reached maximal mean values following the acetabular implantation (maximum level sampling time 5) whereafter it decreased until the third postoperative day when a second rise occured (Fig. 1). In mixed venous blood, only a slight rise of 34% was found between start of surgery and the time of femoral implantation (maximum level sampling time 7). This marked biological difference in prothrombin fragments levels between arterial and mixed venous blood during surgery, showed statistical significance (p = 0.05, AUC). Tissue plusminogen activator antigen (t-PA ag) fell markedly (58% reduction, minimum level sampling time 4), in arterial blood during bone preparation and socket impaction, whereafter a rapid increase was found, reaching a higher level than preoperatively, followed by a fall between the first and third postoperative day (Fig. 2). Contrary, in mixed venous blood the mean t-PA values increased (53%, maximum level sampling time 4). During surgery, difference of borderline statistical significance was found (p = 0.07, AUC) between mixed venous and arterial blood, with higher t-PA values in blood entering than leaving the lung. Plusminogen activator inhibitor (PAI- 1) activity in arterial blood was mainly unchanged until ten minutes after shaft implantation, whereafter it rose 250% from the initial mean value, peaking 24 hours postoperatively (maximum level sampling time 9). From the first to the third day an equally marked drop was seen followed by a slight increase on day six. The same pattern and equal concentrations were found in MVB (Fig. 3)
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D-dimer
2501 __e~-_-
AB
(D-d) concentration increased slowly and almost equally in mixed venous (54%, maximum level sampling time 9) and arterial blood (72% maximum level sampling time 8) ) during operation, whereafter lower values were found on the third and sixth postoperative day (Fig. 4).
zoo-
Interleukin-6
(IL-6) rose dramatically in mixed venous and arterial blood from one hour after the operation, with maximal levels the first postoperative day (Fig. 5). The mean values found in mixed venous blood were slightly higher than the corresponding values of arterial blood, however, the difference was not statistically significant.
" \E
150.
:: tD loo1 SO-
Venogruphy performed bilaterally on the lower limbs
the seventh postoperative day visualized one proximal DVT in one patient and a distal one in the fibular vein in another patient, both on their operated side.
o-
DISCUSSION FIG.5
Acrylic hip joint replacement surgery is associated with peroperative cardiorespiratory depression (1,2) Intraoperative and postoperand a high frequency of postoperative deep vein ative values of IL-6 in mixed thrombosis (3,4). In our earlier reports we have venous (MVB) and arterial focused on the substantial intrapulmonary thrombii blood (AB) during and after generation which was detected before high levels of operation (mean +SEM). monomethylmethacrylate was observed, and a possible connection between these findings and peroperative clinical events (6,7). In this report we show that systemic activation of coagulation, as evidenced by the appearance of prothrombin fragments Fl+2 mostly occurs during bone preparation and especially as blood passes the pulmonary capillary bed. The Fl+2 appearance presented here closely corresponds to the fibrinopeptide A (FPA) (7) and the thrombin-antithrombin (TAT) complex generation (6) as previously demonstrated, all markers of ongoing proteolytic activity in the late sequence of the coagulation cascade. Analyses of mixed venous and arterial blood, revealed substantial intrapulmonary proteolytic enzyme activities with great individual variations, but of weak statistical significance. However, as biological power is not synonymous with statistical power, the fact that only a few patients were included in this study, might be the reason why stronger statistical significance was not obtained, although tremendous enzyme activities appeared. Marked peaks of plasma thromboplastin activity have been found during bone preparation in total hip replacement (14) indicating release of thromboplastin-rich material to the systemic circulation from the traumatized tissues. In animal experiments bolus injections of purified human tissue thromboplastin have been shown to cause immediate platelet aggregation and fibrin deposition in the lungs (15). This is in line with our in vivo observations of activation of coagulation mainly during bone preparation, leading to generation of thrombin in the pulmonary capillary bed. Thus, the lung seems to have an outstanding position in the activation of coagulation in this setting, which in turn probably contributes to local fibrin deposition and formation of microthrombi in the pulmonary microcirculation (7, 14, 15). This may be explained on the basis of trapping of procoagulant material released into the venous circulation (1 l), particularly during bone preparation (7,16).
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Earlier studies have shown that THR surgery is associated with increased thromboplastin activity of circulating blood monocytes (17,18). The thromboplastin activity of stimulated monocytes is mainly confined to the cell surface (19) allowing pericellular fibrin formation to occur, which may contribute to the hypercoagulable state that is induced when blood passes the lung. Adherence of monocytes to vessel walls due to pericellular fibrin deposition may promote thrombus formation in a blood stream containing high levels of activated coagulation factors. This especially holds true if the endothelial surface also is perturbated due to local mechanical, biochemical and chemical (bone cement) factors. Activated monocytes may also be envisioned to increase their surface expression of adhesion molcules (e.g. Mac-l, LFA-1, selectins). This might further add to their entrapment in the fibrin primed lung capillary bed. The hypercoagulable state of the blood leaving the pulmonary circulation may also contribute to the high frequency of DVT observed in patients receiving cemented hip prostheses (3,4). Conflicting observations on the role of the lungs in modulating systemic fibrinolytic activity during major surgery have been reported (20-22). The present study, with frequent blood sampling from mixed venous and arterial blood during acrylic hip substitute surgery, disclosed a rapid fibrinolytic response measured as a marked increase of t-PA in mixed venous blood in the early phases of the operative procedures, almost paralleling the activation of coagulation. This finding of a close connection between coagulation and fibrinolysis has also been demonstrated in earlier studies in man (23) and animals (15) giving clearance of aggregates of fibrin minutes after deposition. The increased fibrinolytic activity could be due to release of t-PA from damaged endothelium and other tissue sources, especially at the operating field. A note of special interest is that t-PA seems to be effectively cleared by the blood passage through the lung microcirculation. This indicates preferential fibrinolytic clearance in the lungs before fibrin dissolution starts in peripheral microcapillaries. The most reasonable explanation might be that t-PA binds directly to deposited fibrin and exerts its homeostatic clot-dissolving function by giving rise to clot-localized plasmin. However, the t-PA clearance capacity of the lung is rapidly saturated, and is followed by a phase of sustained high systemic profibrinolytic activity which is maintained during at least the first day postoperatively before a sudden drop is noted both in t-PA and D-dimer concentration. This fibrinolytic shutdown seems to be a common reaction pattern following soft tissue and bone surgery, and coincides with a marked rise in plasma PAI- activity (21,24,25) which in this study was maximal 24 hours postoperatively. This PAI- 1 increase corresponds in time intimately to an almost identical rise in IL-6 which precedes increase in the acute phase proteins after surgery (26) reflecting the role of IL-6 and other cytokines (TNF, IL-l) in the regulation of acute phase protein genes in hepatocytes (27). PAI-1 behaves like an acute phase protein in vivo (24). It has been proposed that this acute phase behaviour is also due to the effect of cytokines on endothelial cells (28). The increased fibrinolytic inhibition is followed by a decline in PAI- activity (24,29,30) possibly in large part due to complexation with plasminogen activators and subsequent clearence of the complexes. The risk of developing DVT a few days after surgery largely seems to depend on the amount of peroperative systemic activation of coagulation which is markedly higher in orthopaedic surgery compared to major soft tissue surgery (7,20,31), and the subsequent antifibrinolytic reaction. A slight reactivation of both coagulation and antifibrinolysis was noted at the end of the first postoperative week at a time when elevated levels of fibrinogen and platelets also have been demonstrated (2,32). This late hypemoagulability may have a bearing on the development of late deep vein thrombosis. The high frequency of deep vein thrombosis in spite of thromboprophylaxis noted in this as well as in several other studies (3,4), requires further investigations bot to clearify the role of the surgical traumager se and not least to elucidate the specific effects of acrylic cement in the thrombotic processes. In conclusion, during and after acrylic hip replacement surgery a sequential activation of coagulation, fibrinolysis, and antifibrlnolysis occured. In sum these three processes seemed unbalanced with a preponderance of procoagulant and antifibrinolytic activity during surgery and
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towards the end of the first postoperative week. This may favor the development of thrombosis, and is also intimately linked to inflammatory activation. The study also confirms our earlier observations of the lung as a key organ in promoting proteolytic enzyme activation, with a substantial intrapuhnonary thrombii generation and tissue plasminogen activator clearance.
Acknowledgements The practical work with these patients were performed at the end of the principal investigators engagement at the Norwegian Lutheran Hospital. Thanks are due to Dr. Johs. Rp, for his never failing support and helpfulness, and the staff of the Department of Anaesthesiology for the help with vascular catheterization and withdrawal of intraoperative blood samples.
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17. HPIGEVOLD, H.E., LYBERG, T., KIERULF, P. and REIKERAS, 0. Generation of procoagulant (thromboplastin) and plasminogen activator activities in peripheral blood monocytes after total hip replacement surgery. Effects of high doses of corticosteroids. Thromb Res 62,449457, 1991. 18 NYGAARD, 0.P., UNNEBERG, K., REIKERAS, 0. and QISTERUD, B. Thromboplastin activity of blood monocytes after total hip replacement. Stand J Clin Lab Invest 50, 183-186, 1990. 19. LYBERG, T. Clinical significance of increased thromboplastin activity on the monocyte surface. A brief review. Haemostasis 14,430-439, 1984. 20. McLOUGHLIN, G.A., GRINDLINGER, G.A., MANNY, J., VALERI, C.R., LIPINSKI, B., MANNICK, J.A. and HECHTMAN, H.B. Intrapulmonary clotting and fibrinolysis during abdominal aortic aneurysm surgery. Ann Surg 5,623- 630,1979. 21. ERIKSSON, E. and RISBERG, B. Tissue plasminogen activator and its inhibitor following major surgery in relation to ventilator-y pattern. Acta Chir Stand 154,57-60,1988. 22. KAMBAYASHI, J., SAKON, M., YKOTA, M., SHIBA, E., KAWASAKI, T. and MORI, T. Activation of coagulation and fibrinolysis during surgery, analyzed by molecular markers. Thromb Res 60, 157-167, 1990. 23. MODIG, J., BUSH, C., OLERUD, S. and SALDEEN, T. Pulmonary microembolism during intramedullary orthopaedic trauma. Acta Anaestesiol Stand I&133-143,1974. 24. KLUFT, C., VERHEIJEN, J.H., JIE, A.F.H., RIJKEN, D.C, PRESTON, F.E., SUELING, H.M., JESPERSEN, J. and AASEN, A.O. The postoperative fibrinolytic shutdown: a rapid reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Stand J Clin Lab Invest 45,605610,1985. 25. ERIKSSON, B.I., ERIKSSON, E. and RISBERG, B. Impaired fibrinolysis and postoperative thromboembolism in orthopaedic patients. Thromb Res 62,55-64,199l. 26. HPK;EVOLD, H.E., KIERULF, P., 0VSTEB0, R and REIKERAS, 0. Acute phase reactants and interleukin 6 after total hip replacement. Effects of high-dose corticosteroids in a standardized musculo-skeletal trauma. Eur J Surg 158,339-345,1992. 27. LE. J. and VILCEK, J. Interleukin 6: A multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest 61,588-602, 1989. 28. MEDINA, R., SOCHER, S.H., HAN, J.H. and FRIEDMAN, P.A. Interleukin 1, endotoxin or tumor necrosis factor/cache&n enhance the level of plasminogen activator inhibitor messenger RNA in bovine aortic endothelial cells. Thromb Res 54,41-52, 1989. 29. JIZIRGENSEN, L.N., LIND, B., HAUCH, O., LEFFERS, A., ALBRECH-BESTE, B. and KONRADSEN, L.A.G. Thrombin-antithrombin III-complex & fibrin degradation products in plasma: surgery and postoperative deep venous thrombosis. Thromb Res 59,69-76,199O. 30. BORRIS, L.C., SPIRENSEN, J.V., LASSEN, M.R., WALENGA, J.M., FAREED, J., JPIRGENSEN, L.N., HAUCH, 0. and WILLE-JPIRGENSEN, P. Components of coagulation and fibrinolysis during thrombosis prophylaxis with low molecular weight heparin (Enoxaparin) versus dextran 70 in hip arthroplasty. Thromb Res 63,21-28, 1991. 3 1. GITEL, S.N., SALVATI, E.A., WESSLER, S., ROBINSON, H.J. and WORTH, M.H. The effect of total hip replacement and general surgery on antithrombin III in relation to venous thrombosis. J Bone Joint Surg 6I,653-656, 1979. 32. SPIRENSEN, J.V., LASSEN, M.R., BORRIS, L.C., RAHR, H.B., JENSEN, H.P., HOPPENSTEADT, D., WALENGA, J.A. and FAREED, J. Reduction of plasma levels of prothrombin fragments 1 and 2 during thromboprophylaxis with a low-molecular-weight heparin. Blood Coag Fibrinol3,55-59, 1992.