Venous thrombosis is common in elective hip surgery, and prophylaxis is recommended. Clinical trials suggest that the drug dose and timing of initiating prophylaxis significantly influence antithrombotic effectiveness and safety. We studied the time course and gradient of plasma coagulation and fibrinolysis during total hip arthroplasty (THA) in twenty patients that were randomly assigned to have the first dose of 5000？IU dalteparin subcutaneously (sc) injected 12 hours before or 6 hours after surgery. Baseline characteristics were similar in both groups. Specific biomarkers on coagulation (prothrombin fragment 1+2 (F1+2)) and fibrinolytic activity (plasmin/α2-antiplasmin complex (PAP) and D-dimer) were collected at six events during hospitalization and analysed. There were no significant group differences in the biomarkers at any time point. The highest concentrations were measured 6 hours after surgery and before the first postoperative injection. A marked decrease followed at the first postoperative day, and then a second increase in plasma concentrations was observed 6 days after surgery. This study showed that activation of coagulation and fibrinolysis by the operative trauma was the same when the first dose of dalteparin was injected 12 hours before or 6 hours after surgery. 1. Introduction Thrombosis formation begins during joint replacement surgery [1, 2], and a few patients may develop nonfatal or fatal pulmonary embolism (PE) [3]. It has been suggested that it is easier to prevent thrombus formation than to arrest thrombus growth once it has been established. Preoperative initiation of thromboprophylaxis therefore has been recommended [4, 5]. However, most thrombi develop postoperatively [6, 7], and, because anticoagulants have the potential to increase bleeding, some surgeons and anesthesiologists prefer postoperative initiation to reduce blood loss, need for transfusion, and bleeding complications [8–10]. Low-molecular-weight heparins (LMWHs) are widely used as antithrombotic because of their favorable efficacy-to-safety profiles and the absence of accumulated postmarketing reports on severe adverse events. Trials on timing of thromboprophylaxis have been designed to detect thrombotic events, and venographically detected DVT has been the primary end point. Bleeding has been a secondary underpowered outcome, and trials have been criticized for underestimating the risk of bleeding and related complications [11]. From surgeons point of view, blood loss and bleeding complications are important and pharmaceutical prophylaxis has remained
References
[1]
N. E. Sharrock, G. Go, P. C. Harpel, C. S. Ranawat, T. P. Sculco, and E. A. Salvati, “Thrombogenesis during total hip arthroplasty,” Clinical Orthopaedics and Related Research, no. 319, pp. 16–27, 1995.
[2]
O. E. Dahl, T. Pedersen, P. Kierulf et al., “Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery,” Thrombosis Research, vol. 70, no. 6, pp. 451–458, 1993.
[3]
A. B. Pedersen, J. A. Baron, S. Overgaard, and S. P. Johnsen, “Short—and long-term mortality following primary total hip replacement for osteoarthritis: a Danish nationwide epidemiological study,” Journal of Bone and Joint Surgery B, vol. 93, no. 2, pp. 172–177, 2011.
[4]
D. Bergqvist, U. S. Burmark, P. A. Flordal et al., “Low molecular weight heparin started before surgery as prophylaxis against deep vein thrombosis: 2500 versus 5000？XaI units in 2070 patients,” British Journal of Surgery, vol. 82, no. 4, pp. 496–501, 1995.
[5]
A. Planes, N. Vochelle, M. Fagola et al., “Efficacy and safety of a perioperative enoxaparin regimen in total hip replacement under various anesthesias,” American Journal of Surgery, vol. 161, no. 4, pp. 525–531, 1991.
[6]
O. E. Dahl, T. E. Gudmundsen, and L. Haukeland, “Late occurring clinical deep vein thrombosis in joint-operated patients,” Acta Orthopaedica Scandinavica, vol. 71, no. 1, pp. 47–50, 2000.
[7]
B. T. Bj？rnar？, T. E. Gudmundsen, and O. E. Dahl, “Frequency and timming of clinical venous thromboembolism after major joint surgery,” Journal of Bone and Joint Surgery B, vol. 88, no. 3, pp. 386–391, 2006.
[8]
A. G. G. Turpie, M. N. Levine, and J. Hirsch, “A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery,” The New England Journal of Medicine, vol. 315, no. 15, pp. 925–929, 1986.
[9]
G. E. Raskob and J. Hirsh, “Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery,” Chest, vol. 124, supplement 6, pp. 379S–385S, 2003.
[10]
C. Kearon and J. Hirsh, “Starting prophylaxis for venous thromboembolism postoperatively,” Archives of Internal Medicine, vol. 155, no. 4, pp. 366–372, 1995.
[11]
O. E. Dahl, D. J. Quinlan, D. Bergqvist, and J. W. Eikelboom, “A critical appraisal of bleeding events reported in venous thromboembolism prevention trials of patients undergoing hip and knee arthroplasty,” Journal of Thrombosis and Haemostasis, vol. 8, no. 9, pp. 1966–1975, 2010.
[12]
N. Strebel, M. Prins, G. Agnelli, and H. R. Büller, “Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery?” Archives of Internal Medicine, vol. 162, no. 13, pp. 1451–1456, 2002.
[13]
E. Ginzburg and F. Dujardin, “Physicians' perceptions of the definition of major bleeding in major orthopedic surgery: results of an international survey,” Journal of Thrombosis and Thrombolysis, vol. 31, no. 2, pp. 188–195, 2011.
[14]
Y. Falck-Ytter, C. W. Francis, N. A. Johanson et al., “Prevention of VTE in orthopedic surgery patients. antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines,” Chest, vol. 141, no. 2, pp. e278–e325, 2012.
[15]
P. O. Borgen, O. E. Dahl, and O. Reikeras, “Preoperative versus postoperative initiation of dalteparin thromboprophylaxis in THA,” HIP International, vol. 20, no. 3, pp. 301–307, 2010.
[16]
P. O. Borgen, O. E. Dahl, and O. Reiker？s, “Blood loss in cemented THA is not reduced with postoperative versus preoperative start of thromboprophylaxis,” Clinical Orthopaedics and Related Research, vol. 470, no. 9, pp. 2591–2598, 2012.
[17]
J. V. Llau, E. Gil-Garay, and E. Castellet, “Thromboprophylaxis with enoxaparin for total knee replacement: an observational, retrospective and multicentre study comparing starting the treatment before and after the operation,” Revista Espanola De Anestesiologia Y Reanimacion, vol. 59, no. 6, pp. 306–314, 2012.
[18]
H. Arnesen, O. E. Dahl, T. Aspelin, I. Seljeflot, P. Kierulf, and T. Lyberg, “Sustained prothrombotic profile after hip replacement surgery: the influence influence of prolonged prophylaxis with dalteparin,” Journal of Thrombosis and Haemostasis, vol. 1, no. 5, pp. 971–975, 2003.
[19]
N. E. Sharrock, G. Go, T. P. Sculco, E. A. Salvati, G. H. Westrich, and P. C. Harpel, “Dose response of intravenous heparin on markers of thrombosis during primary total hip replacement,” Anesthesiology, vol. 90, no. 4, pp. 981–987, 1999.
[20]
J. V. Sorensen, L. C. Borris, M. R. Lassen et al., “Association between plasma levels of tissue plasminogen activator and postoperative deep vein thrombosis—Influence of prophylaxis with a low molecular weight heparin,” Thrombosis Research, vol. 59, no. 1, pp. 131–138, 1990.
[21]
B. I. Eriksson, E. Eriksson, and B. Risberg, “Impaired fibrinolysis and postoperative thromboembolism in orthopedic patients,” Thrombosis Research, vol. 62, no. 1-2, pp. 55–64, 1991.
[22]
H. K. Lau, J. S. Rosenberg, D. L. Beeler, and R. D. Rosenberg, “The isolation and characterization of a specific antibody population directed against the prothrombin activation fragments F2 and F1+2,” Journal of Biological Chemistry, vol. 254, no. 18, pp. 8751–8761, 1979.
[23]
S. Gando, I. Tedo, and M. Kubota, “Posttrauma coagulation and fibrinolysis,” Critical Care Medicine, vol. 20, no. 5, pp. 594–600, 1992.
[24]
O. Reikeras and T. Clementsen, “Thrombosis markers in hip versus knee arthroplasty: a pilot study,” Journal of Orthopaedic Surgery, vol. 17, no. 3, pp. 291–295, 2009.
[25]
O. E. Dahl, I. Molnar, A. Vinje et al., “Studies on coagulation, fibrinolysis, kallikrein-kinin and complement activation in systemic and pulmonary circulation during hip arthroplasty with acrylic cement,” Thrombosis Research, vol. 50, no. 6, pp. 875–884, 1988.
[26]
J. Fareed, Q. Ma, M. Florian et al., “Differentiation of low-molecular-weight heparins: impact on the future of the management of thrombosis,” Seminars in Thrombosis and Hemostasis, vol. 30, no. 1, pp. 89–104, 2004.
[27]
J. Hirsh and M. N. Levine, “Low molecular weight heparin,” Blood, vol. 79, no. 1, pp. 1–17, 1992.
[28]
C. Kluft, J. H. Verheijen, and A. F. H. Jie, “The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 45, no. 7, pp. 605–610, 1985.
[29]
W. M. Feinberg, E. Macy, E. S. Cornell et al., “Plasmin-alpha2-antiplasmin complex in patients with atrial fibrillation. stroke prevention in atrial fibrillation investigators,” Thrombosis and Haemostasis, vol. 82, no. 1, pp. 100–103, 1999.
[30]
O. E. Dahl, T. Aspelin, H. Arnesen et al., “Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery,” Thrombosis Research, vol. 80, no. 4, pp. 299–306, 1995.
[31]
E. Cofrancesco, M. Cortellaro, A. Corradi, F. Ravasi, and F. Bertocchi, “Clinical utility of prothrombin fragment 1+2, thrombin antithrombin III complexes and D-dimer measurements in the diagnosis of deep vein thrombosis following total hip replacement,” Thrombosis and Haemostasis, vol. 79, no. 3, pp. 509–510, 1998.
[32]
B. Boneu, G. Bes, H. Pelzer, P. Sie, and H. Boccalon, “D-dimers, thrombin antithrombin III complexes and prothrombin fragments 1 + 2: diagnostic value in clinically suspected deep vein thrombosis,” Thrombosis and Haemostasis, vol. 65, no. 1, pp. 28–32, 1991.
[33]
R. D. Hull, G. F. Pineo, P. D. Stein et al., “Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review,” Archives of Internal Medicine, vol. 161, no. 21, pp. 1952–1960, 2001.
