THROMBOSIS RESEARCH 68; 429-433, 1992 0049-3848192 $5.00 + .OOPrinted in the USA. Copyright (c) 1992 Pergamon Press Ltd. Ail rights reserved.
BRIEF
COMMUNICATION
DESMOPRESSIN AND POSTOPERATIVE THROMBOEMBOLISM Per Anders Flordall, Karl-Gosta Ljungstriimt and Anders Fehrm*. Departments of Surgery1 and Radiology2, Danderyd Hospital, S-182 88 Danderyd, S’weden.
(Received 25.5.1992; accepted in revised form 6.10.1992 by Editor B. Hessel)
Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is effective in a variety of congenital and acquired bleeding disorders (1) and has been shown to reduce blood loss also in hemostatically normal patients undergoing specific types of surgery (2-5). It has been proposed that the activation of coagulation that is induced by desmopressin may entail a risk for postoperative thrombosis (6), although this is contradicted by two pilot studies indicatin a benefit from desmopressin in the prophylaxis (7) and treatment (8) of deep vein thrombosis. & e aim of the present investigation was to study the possible effect of desmopressin on postoperative thromboembolism in patients undergoing total hip replacement - a patient group at very high risk of such complications (9). PATIENTS AND METHODS A randomized, prospective, placebo-controlled study was undertaken in 50 patients scheduled for total hip replacement (Table I). The patients were also studied with respect to blood loss as reported separately (5). Patients with severe vascular, hepatic or renal disease or above: the age of 80 or were excluded. No prostaglandin synthesis inhibitors were in use during the last two weeks before surgery. Surgery was performed under spinal anesthesia induced by bupivacaine 0.5% (Marcain Spinal, Astra AB, Sweden). Ephedrine was administered pre- or intraoperatively to treat any hypotension. Epidural anesthesia with bupivacaine infusion was used for postoperative pain relief in all but seven patients. Patients were in the lateral position during surgery. For thromboprop ylaxis and plasma expansion they received an intraoperative infusion of 500-1000 ml 6% !l extran 70 (Macrodex, Pharmacia, Sweden). The volume infused was depending on blood loss, A further 500 ml dextran was infused on the first postoperative day. Furosemide was administered intravenously to maintain urine production at about 1 ml/kg per hour. Blood transfusions were given as microaggregate-poor erythrocyte concentrate, in units made from 450 ml donor blood, suspended in SAGM solution (10). Each patient received a double blind infusion of placebo or desmopressin (Minirin, Ferring, Sweden) 0.3 pg/kg body weight diluted in 50 ml saline at the start of surgery. The same infusion was repeated six hours later, on both occasions at an infusion rate of 20-30 minutes.
Key words: orthopedic surgery, desmopressin, dextran, phlebography, thromboembolism. Correspondig author: Dr. Per Anders Flordal, Department of Surgery, Danderyd Hospiital, S-182 88 Danderyd, Sweden. 429
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DESMOPRESSIN AND THROMBOSIS
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TABLE I Descriptive Data on Included Patients, and Infusions and Injections during the Perioperative 24 Hour Period.
Men/women Age b-1 Body weight [kg] Body height [cm] Preoperative Hb [g/l] Primary arthrosis Secondary arthrosis Revision arthroplasty Uncemented prosthesis Operation time [min] Infusions of - crystalloid solutions [ml] - dextran [ml, 60 mg/ml] - albumin solution [ml, 0.2 g/ml] - erythrocyte concentrate [units] - ephedrine [mg] - furosemide [mg] Urine production [ml]
Control
Desmopressin
12/13 68 z!9 71+15 171 fll 134 +12 21 2 2
12/13 64 +9 75 f12 172 +9 135 fll 23 0 2 4 106 f23
104 &2: 3640 +940 760 f255 40 f130 1.5 +1.2 22 +22 8&9 2040 +600
3820 +620 760 &255 30 f80 1.2 fl.O 35 +27 12flO * 2070 f590
Values are number, or mean *SD, 25 patients in each group. * significant difference between the groups, ~~0.05. The patients were mobilized from the first postoperative day with the aid of a physiotherapist. Compressive stockings were not used. On the third and eighth postoperative days patients were clinically assessed for signs of venous thrombosis or pulmonary embolism. All but six patients underwent postoperative ascending phlebography (11) of the operated leg on postoperative day 8 +l. Two patients were excluded due to intercurrent complications, three due to technical difficulties in inserting the venous cannula in the foot and one because of patient refusal. The anterior and posterior tibial, peroneal, popliteal, femoral and external and common iliac veins were possible to assess in all 44 patients and the muscle veins of the calf in 43 patients. All phlebographies were performed and assessed by the same senior radiologist (A.F.). The study was approved by the ethics committee of Karolinska Hospital. All patients gave their consent after oral and written information. Differences between groups were tested using Mann-Whitney U test and Fisher’s exact test (12). A p value less than 0.05 was considered to denote statistical significance.
RESULTS Deep venous thrombi were found in six out of 44 phlebograms (Table II). All thrombi were short (5-30 mm) and non-occluding and none produced clinical signs or needed medical treatment.
Vol. 68, Nos. 415
DESMOPRESSIN
AND THROMBOSIS
431
TABLE II Thromboembolic complications. Control Deep venous thrombi - distal - proximal Pulmonary embolism
Desmopressin
4122 2122 2122 1125
2122 2122 O/22 l/25
Values are number of complications I number of patients. No significant differences between the groups. One patient in each group developed pulmonary embolism, confirmed by pulmonary ventilation and perfusion scintigraphy on clinical suspicion. The placebo patient had sudden dyspnloe on the 13thpostoperative day. He had not undergone phlebography because of technical difficu~lties. The desmopressin treated patient had light coughing from the fifth postoperative day. Pulmonary embolism was not confirmed until the 42nd postoperative day. On phlebography he had’a 30 mm thrombus in the peroneal vein. Both patients were treated with heparin and warfarin and recovered completely. Two patients in the placebo group had proximal thrombosis, but none in the desmopressin group. Five patients in the placebo group had thromboembolic events, compared with two in the desmopressin group. The differences were not statistically significant. DISCUSSION We found two proximal thrombi in the placebo group, but none in the desmopressin group. The frequencies of other kinds of thromboembolic events were equal between the groups. Ope cannot conclude that desmopressin decreases the risk of thromboembolic events, but on the other hand no evidence was found of an increase, as speculated by some authors (6). It has been argued that an increase of coagulation factor VIII (FVIII) complex induces a risk for venous thrombosis (13-15). However, the FVIII increase after desmopressin observed in identically treated patients (16) may be balanced by the simultaneous stimulation of fibrinolysis achieved (6, 16). Pilot studies have shown positive effects of desmopressin in the prophylaxis (7) and treatment (8) of venous thrombosis. Also, desmopressin prevents the pronounced antithrombin III decrease otherwise seen in identically treated patients (16), thus having the same effect as very expensive antithrombin II1 infusion, which has been shown to prevent venous thromboembolism (17). We find it questionable that FVIII decrease is a major cause of the thromboprophylactic effect of dextran (18), since we found that an increased FVIII, known to be present in the group ‘receiving both dextran and desmopressin (16), did not result in a higher incidence of venous throrribosis. The frequency of phlebography-proven venous thrombosis was 6/44, i.e. 14%. We performed phlebography only on the operated leg, but isolated thrombosis in the contralateral limb is uncommon. In six studies compiled by Haake et al. (9) including a total of 180 total hip replacement patients with thromboembolic events, 170 (94%) had deep vein thrombosis in the
432
DESMOPRESSIN AND THROMBOSIS
Vol. 68, Nos. 415
operated leg. Assuming the same distribution of thrombi in our study we would have overlooked at most one patient with a thromboembolic event. It is doubtful to make comparisons with other studies, but using dextran, epidural anesthesia, surgery in the lateral position and early mobilization seems to be a competitive regimen, resulting in a low frequency of thromboembolic complications. To conclude, desmopressin administration and FVIII increase do not seem to increase the risk of postoperative deep vein thrombosis. Acknowledgements Financial support was obtained from Berth von Kantzow’s foundation, the Stockholm county health service, the Department of Clinical Chemistry of Karolinska Institute at Danderyd Hospital and the research funds of the Karolinska Institutet. Ferring AB supplied desmopressin free of charge. REFERENCES 1. SCHULMAN,S. DDAVP - the multipotent drug in patients with coagulopathies. Transfusion Medicine Reviews. V, 132-144, 1991. 2. SALZMAN, E.W., WEINSTEIN, M.J., WEINTRAUB, R.M., WARE, J.A., THURER, R.L., ROBERTSON, L., DONOVAN, A., GAFFNEY, T., BERTELE, V., TROLL, J., SMITH, M. and CHUTE, L.E. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial. N Engl J Med. 314,1402-1406, 1986. 3. CZER, L.S.C., BATEMAN, T.M., GRAY, R.J., RAYMOND, M., STEWART, M.E., LEE, S., GOLDFINGER,D., CHAUX, A. and MATLOW, J.M. Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin. J Am Co11Cardiol. 9, 1139-l 147, 1987. 4. KOBRINSKY, N.L., LETTS, R.M., PATEL, L.R., ISRAELS, E.D., MONSON, R.C., SCHWETZ, N. and CHEANG, M.S. 1-desamino-8-D-arginine vasopressin (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery. A randomized, double-blinded, controlled trial. Ann Intern Med. 207,446-450, 1987. 5. FLORDAL, P.A.. LJUNGSTROM. K.-G.. EKMAN. B. and NEANDER. G. Effects of desmopressin on blood loss in hip arthroplasty. Controlled study in 50 patients. Acta Grthop Stand. 63, 381-385, 1992. 6. MELI&ARI, E., SCULLY, M.F., PAES, T., ELLIS, V. and KAKKAR, V.V. The influence of DDAVP infusion on the coagulation and fibrinolytic response to surgery. Thromb Haemost. 55, 54-57, 1986. 7. NILSEN, D.W.T., HAEREM, J., WESTHEIM, A., SKJENNALD, A., GRENDAHL, H. and GODAL, H.C. Venous thrombosis following diagnostic transvenous catheterization by percutaneous catheter insertion: an evaluation of desmopressin as a thromboprophylactic agent. Thromb Haemost. 52, 121-123, 1984. 8. T~RNEBOHM, E., BRATT, G., GRANQVIST, S., LOCKNER, D. and EGBERG, N. A pilot study: desmopressin (DDAVP) in the treatment of deep venous thrombosis. Thromb Res. 45, 635-643, 1987. 9. HAAKE, D.A. and BERKMAN,S.A. Venous thromboembolic disease after hip surgery. Risk factors, prophylaxis, and diagnosis. Clin Grthop. 242.212-231, 1989. 10. HOGMAN, C.F., ROSBN, I., ANDREEN, M., AKERBLOM, 0. and HELLSING, K. Haemotherapy with red-cell concentrates and a new red-cell storage medium. Lancet. i(feb 5), 269-272, 1983. 11. RABINOV, K. and PAULIN, S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 104, 134-144, 1972. 12. SIEGEL, S. and CASTELLAN, N.J.J. Nonparametric Statistics for the Behavioral Sciences. 2nd ed. McGraw-Hill, Singapore (1989).
Vol. 68, Nos. 415
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AND THROMBOSIS
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13. BONNAR, J., WALSH, J.J., HADDON, M., FAIRWEATHER, J. and DENSON, K.W.E. Coagulation system changes induced by pelvic surgery and the effect of dextran 70. Bib1 Anat. 12, 35 l-355, 1973. 14. BRJZDBACKA,S., BLOMB~~CK,M., H~~GNEVIK,K., IRESTEDT, L. and RAABE, N. Per- and
postoperative changes in coagulation and fibrinolytic variables during abdominal hysterectomy under epidural or general anaesthesia. Acta Anaesthesiol Stand. 30,204-210, 1986. 15. PET&& J., MYLLYNEN, P., ROKKANEN,P. and NOKELAINEN,M. Fibrinolysis and spinal injury. Relationship to post-traumatic deep vein thrombosis. Acta Chir Stand. 155, 241-246, 1989. 16. FLORDAL, P.A., SVENSSON, J., LJUNGSTR~M, K.-G., EKMAN, B. and NEANDER, G. Effects on coagulation and fibrinolysis of desmopressin in patients undergoing total hip replacement. Thromb Haemost. 66,562-566, 1991. 17. FRANCIS, C.W., PELLEGRINI, V.D., MARDER, V.J., HARRIS, C.M., TOTTERNIAN, S., GABRIEL, K.R., BAUGHMAN, D.J., ROEMER, S., BURKE, J., GOODMAN, T.L. and &ARTS, C.M.C. Prevention of venous thrombosis after total hip arthroplasty. Antithrombin III and lowdose heparin compared with dextran 40. J Bone Joint Surg [Am]. 71-A, 327-335,1989. 18. MESSMER,K.F.W. The use of plasma substitutes with special attention to their side effects. World J Surg. 11, 69-74, 1987.
BRIEF
COMMUNICATION
DESMOPRESSIN AND POSTOPERATIVE THROMBOEMBOLISM Per Anders Flordall, Karl-Gosta Ljungstriimt and Anders Fehrm*. Departments of Surgery1 and Radiology2, Danderyd Hospital, S-182 88 Danderyd, S’weden.
(Received 25.5.1992; accepted in revised form 6.10.1992 by Editor B. Hessel)
Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is effective in a variety of congenital and acquired bleeding disorders (1) and has been shown to reduce blood loss also in hemostatically normal patients undergoing specific types of surgery (2-5). It has been proposed that the activation of coagulation that is induced by desmopressin may entail a risk for postoperative thrombosis (6), although this is contradicted by two pilot studies indicatin a benefit from desmopressin in the prophylaxis (7) and treatment (8) of deep vein thrombosis. & e aim of the present investigation was to study the possible effect of desmopressin on postoperative thromboembolism in patients undergoing total hip replacement - a patient group at very high risk of such complications (9). PATIENTS AND METHODS A randomized, prospective, placebo-controlled study was undertaken in 50 patients scheduled for total hip replacement (Table I). The patients were also studied with respect to blood loss as reported separately (5). Patients with severe vascular, hepatic or renal disease or above: the age of 80 or were excluded. No prostaglandin synthesis inhibitors were in use during the last two weeks before surgery. Surgery was performed under spinal anesthesia induced by bupivacaine 0.5% (Marcain Spinal, Astra AB, Sweden). Ephedrine was administered pre- or intraoperatively to treat any hypotension. Epidural anesthesia with bupivacaine infusion was used for postoperative pain relief in all but seven patients. Patients were in the lateral position during surgery. For thromboprop ylaxis and plasma expansion they received an intraoperative infusion of 500-1000 ml 6% !l extran 70 (Macrodex, Pharmacia, Sweden). The volume infused was depending on blood loss, A further 500 ml dextran was infused on the first postoperative day. Furosemide was administered intravenously to maintain urine production at about 1 ml/kg per hour. Blood transfusions were given as microaggregate-poor erythrocyte concentrate, in units made from 450 ml donor blood, suspended in SAGM solution (10). Each patient received a double blind infusion of placebo or desmopressin (Minirin, Ferring, Sweden) 0.3 pg/kg body weight diluted in 50 ml saline at the start of surgery. The same infusion was repeated six hours later, on both occasions at an infusion rate of 20-30 minutes.
Key words: orthopedic surgery, desmopressin, dextran, phlebography, thromboembolism. Correspondig author: Dr. Per Anders Flordal, Department of Surgery, Danderyd Hospiital, S-182 88 Danderyd, Sweden. 429
430
DESMOPRESSIN AND THROMBOSIS
Vol. 68, Nos. 45
TABLE I Descriptive Data on Included Patients, and Infusions and Injections during the Perioperative 24 Hour Period.
Men/women Age b-1 Body weight [kg] Body height [cm] Preoperative Hb [g/l] Primary arthrosis Secondary arthrosis Revision arthroplasty Uncemented prosthesis Operation time [min] Infusions of - crystalloid solutions [ml] - dextran [ml, 60 mg/ml] - albumin solution [ml, 0.2 g/ml] - erythrocyte concentrate [units] - ephedrine [mg] - furosemide [mg] Urine production [ml]
Control
Desmopressin
12/13 68 z!9 71+15 171 fll 134 +12 21 2 2
12/13 64 +9 75 f12 172 +9 135 fll 23 0 2 4 106 f23
104 &2: 3640 +940 760 f255 40 f130 1.5 +1.2 22 +22 8&9 2040 +600
3820 +620 760 &255 30 f80 1.2 fl.O 35 +27 12flO * 2070 f590
Values are number, or mean *SD, 25 patients in each group. * significant difference between the groups, ~~0.05. The patients were mobilized from the first postoperative day with the aid of a physiotherapist. Compressive stockings were not used. On the third and eighth postoperative days patients were clinically assessed for signs of venous thrombosis or pulmonary embolism. All but six patients underwent postoperative ascending phlebography (11) of the operated leg on postoperative day 8 +l. Two patients were excluded due to intercurrent complications, three due to technical difficulties in inserting the venous cannula in the foot and one because of patient refusal. The anterior and posterior tibial, peroneal, popliteal, femoral and external and common iliac veins were possible to assess in all 44 patients and the muscle veins of the calf in 43 patients. All phlebographies were performed and assessed by the same senior radiologist (A.F.). The study was approved by the ethics committee of Karolinska Hospital. All patients gave their consent after oral and written information. Differences between groups were tested using Mann-Whitney U test and Fisher’s exact test (12). A p value less than 0.05 was considered to denote statistical significance.
RESULTS Deep venous thrombi were found in six out of 44 phlebograms (Table II). All thrombi were short (5-30 mm) and non-occluding and none produced clinical signs or needed medical treatment.
Vol. 68, Nos. 415
DESMOPRESSIN
AND THROMBOSIS
431
TABLE II Thromboembolic complications. Control Deep venous thrombi - distal - proximal Pulmonary embolism
Desmopressin
4122 2122 2122 1125
2122 2122 O/22 l/25
Values are number of complications I number of patients. No significant differences between the groups. One patient in each group developed pulmonary embolism, confirmed by pulmonary ventilation and perfusion scintigraphy on clinical suspicion. The placebo patient had sudden dyspnloe on the 13thpostoperative day. He had not undergone phlebography because of technical difficu~lties. The desmopressin treated patient had light coughing from the fifth postoperative day. Pulmonary embolism was not confirmed until the 42nd postoperative day. On phlebography he had’a 30 mm thrombus in the peroneal vein. Both patients were treated with heparin and warfarin and recovered completely. Two patients in the placebo group had proximal thrombosis, but none in the desmopressin group. Five patients in the placebo group had thromboembolic events, compared with two in the desmopressin group. The differences were not statistically significant. DISCUSSION We found two proximal thrombi in the placebo group, but none in the desmopressin group. The frequencies of other kinds of thromboembolic events were equal between the groups. Ope cannot conclude that desmopressin decreases the risk of thromboembolic events, but on the other hand no evidence was found of an increase, as speculated by some authors (6). It has been argued that an increase of coagulation factor VIII (FVIII) complex induces a risk for venous thrombosis (13-15). However, the FVIII increase after desmopressin observed in identically treated patients (16) may be balanced by the simultaneous stimulation of fibrinolysis achieved (6, 16). Pilot studies have shown positive effects of desmopressin in the prophylaxis (7) and treatment (8) of venous thrombosis. Also, desmopressin prevents the pronounced antithrombin III decrease otherwise seen in identically treated patients (16), thus having the same effect as very expensive antithrombin II1 infusion, which has been shown to prevent venous thromboembolism (17). We find it questionable that FVIII decrease is a major cause of the thromboprophylactic effect of dextran (18), since we found that an increased FVIII, known to be present in the group ‘receiving both dextran and desmopressin (16), did not result in a higher incidence of venous throrribosis. The frequency of phlebography-proven venous thrombosis was 6/44, i.e. 14%. We performed phlebography only on the operated leg, but isolated thrombosis in the contralateral limb is uncommon. In six studies compiled by Haake et al. (9) including a total of 180 total hip replacement patients with thromboembolic events, 170 (94%) had deep vein thrombosis in the
432
DESMOPRESSIN AND THROMBOSIS
Vol. 68, Nos. 415
operated leg. Assuming the same distribution of thrombi in our study we would have overlooked at most one patient with a thromboembolic event. It is doubtful to make comparisons with other studies, but using dextran, epidural anesthesia, surgery in the lateral position and early mobilization seems to be a competitive regimen, resulting in a low frequency of thromboembolic complications. To conclude, desmopressin administration and FVIII increase do not seem to increase the risk of postoperative deep vein thrombosis. Acknowledgements Financial support was obtained from Berth von Kantzow’s foundation, the Stockholm county health service, the Department of Clinical Chemistry of Karolinska Institute at Danderyd Hospital and the research funds of the Karolinska Institutet. Ferring AB supplied desmopressin free of charge. REFERENCES 1. SCHULMAN,S. DDAVP - the multipotent drug in patients with coagulopathies. Transfusion Medicine Reviews. V, 132-144, 1991. 2. SALZMAN, E.W., WEINSTEIN, M.J., WEINTRAUB, R.M., WARE, J.A., THURER, R.L., ROBERTSON, L., DONOVAN, A., GAFFNEY, T., BERTELE, V., TROLL, J., SMITH, M. and CHUTE, L.E. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial. N Engl J Med. 314,1402-1406, 1986. 3. CZER, L.S.C., BATEMAN, T.M., GRAY, R.J., RAYMOND, M., STEWART, M.E., LEE, S., GOLDFINGER,D., CHAUX, A. and MATLOW, J.M. Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin. J Am Co11Cardiol. 9, 1139-l 147, 1987. 4. KOBRINSKY, N.L., LETTS, R.M., PATEL, L.R., ISRAELS, E.D., MONSON, R.C., SCHWETZ, N. and CHEANG, M.S. 1-desamino-8-D-arginine vasopressin (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery. A randomized, double-blinded, controlled trial. Ann Intern Med. 207,446-450, 1987. 5. FLORDAL, P.A.. LJUNGSTROM. K.-G.. EKMAN. B. and NEANDER. G. Effects of desmopressin on blood loss in hip arthroplasty. Controlled study in 50 patients. Acta Grthop Stand. 63, 381-385, 1992. 6. MELI&ARI, E., SCULLY, M.F., PAES, T., ELLIS, V. and KAKKAR, V.V. The influence of DDAVP infusion on the coagulation and fibrinolytic response to surgery. Thromb Haemost. 55, 54-57, 1986. 7. NILSEN, D.W.T., HAEREM, J., WESTHEIM, A., SKJENNALD, A., GRENDAHL, H. and GODAL, H.C. Venous thrombosis following diagnostic transvenous catheterization by percutaneous catheter insertion: an evaluation of desmopressin as a thromboprophylactic agent. Thromb Haemost. 52, 121-123, 1984. 8. T~RNEBOHM, E., BRATT, G., GRANQVIST, S., LOCKNER, D. and EGBERG, N. A pilot study: desmopressin (DDAVP) in the treatment of deep venous thrombosis. Thromb Res. 45, 635-643, 1987. 9. HAAKE, D.A. and BERKMAN,S.A. Venous thromboembolic disease after hip surgery. Risk factors, prophylaxis, and diagnosis. Clin Grthop. 242.212-231, 1989. 10. HOGMAN, C.F., ROSBN, I., ANDREEN, M., AKERBLOM, 0. and HELLSING, K. Haemotherapy with red-cell concentrates and a new red-cell storage medium. Lancet. i(feb 5), 269-272, 1983. 11. RABINOV, K. and PAULIN, S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 104, 134-144, 1972. 12. SIEGEL, S. and CASTELLAN, N.J.J. Nonparametric Statistics for the Behavioral Sciences. 2nd ed. McGraw-Hill, Singapore (1989).
Vol. 68, Nos. 415
DESMOPRESSIN
AND THROMBOSIS
433
13. BONNAR, J., WALSH, J.J., HADDON, M., FAIRWEATHER, J. and DENSON, K.W.E. Coagulation system changes induced by pelvic surgery and the effect of dextran 70. Bib1 Anat. 12, 35 l-355, 1973. 14. BRJZDBACKA,S., BLOMB~~CK,M., H~~GNEVIK,K., IRESTEDT, L. and RAABE, N. Per- and
postoperative changes in coagulation and fibrinolytic variables during abdominal hysterectomy under epidural or general anaesthesia. Acta Anaesthesiol Stand. 30,204-210, 1986. 15. PET&& J., MYLLYNEN, P., ROKKANEN,P. and NOKELAINEN,M. Fibrinolysis and spinal injury. Relationship to post-traumatic deep vein thrombosis. Acta Chir Stand. 155, 241-246, 1989. 16. FLORDAL, P.A., SVENSSON, J., LJUNGSTR~M, K.-G., EKMAN, B. and NEANDER, G. Effects on coagulation and fibrinolysis of desmopressin in patients undergoing total hip replacement. Thromb Haemost. 66,562-566, 1991. 17. FRANCIS, C.W., PELLEGRINI, V.D., MARDER, V.J., HARRIS, C.M., TOTTERNIAN, S., GABRIEL, K.R., BAUGHMAN, D.J., ROEMER, S., BURKE, J., GOODMAN, T.L. and &ARTS, C.M.C. Prevention of venous thrombosis after total hip arthroplasty. Antithrombin III and lowdose heparin compared with dextran 40. J Bone Joint Surg [Am]. 71-A, 327-335,1989. 18. MESSMER,K.F.W. The use of plasma substitutes with special attention to their side effects. World J Surg. 11, 69-74, 1987.
