SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
Prevention of Thromboembolism After Spinal Cord Injury DAVID GREEN, M.D., Ph.D.
From the Atherosclerosis Program, Rehabilitation Institute, and the Section of Hematology/ Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois. Reprint requests: Dr. Green, Rehabilitation Institute of Chicago, 345 E. Superior Street—Room 1407, Chicago, IL 60611.
Prophylaxis Against Thromboembolism Calf Compression Boots Calf compression boots are leggings containing an air-filled bladder that rhythmically compress the calf musculature, usually in 1-minute cycles with 15-second compressions at a pressure of 40 to 45 mmHg. In a study of 27 patients with complete motor paralysis, we observed that 6 of 15 (40%) treated with calf compression boots alone developed evidence of deep vein thrombosis as detected by the very sensitive radiofibrinogen method.2 This compares favorably with the 78% incidence in untreated patients. We also noted that the increased platelet affinity for collagen and elevated Factor VHI/von Willebrand activities were less marked in the treated patients. Finally, use of the compression boots delayed the onset of thrombosis and shifted the site of thrombi from more proximal to more distal veins.
Anti-platelet Agents Coagulant activities associated with platelets play an important role in the pathogenesis of DVT in patients undergoing hip surgery,5 and inhibitors of platelet function have significantly decreased the incidence of DVT in patients undergoing hip arthroplasty6,7 or total knee replacement.8 Because platelet hyperactivity was noted in our patients with spinal cord injury,4 we added aspirin, 325 mg twice daily, and dipyridamole, 75 mg thrice daily, to the calf compression boot regimen.2 This resulted in a further decrease in DVT to 25% (3 of 12 patients), but one aspirin-treated patient had serious bleeding during a surgical procedure to stabilize his spine.
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
347
Downloaded by: Universite Laval. Copyrighted material.
Thromboembolism is a major cause of morbidity and mortality in patients with spinal cord injury and complete motor paralysis. In a recent study by Myllynen et al.1 all 23 patients with this condition had evidence of deep vein thrombosis (DVT) as measured by the 125I fibrinogen test and confirmed by contrast venography. Two (9%) had pulmonary emboli (PE). Using the same methodology, we identified thrombosis in 29 of 37 patients (78%).2 Fatal PE is a major cause of mortality in this condition. The factors responsible for the thrombotic tendency undoubtedly include the triad of vessel wall, blood flow, and plasma constituents, as originally proposed by Virchow3 more than a century ago. In spinal cord-injured patients alterations in the blood vessel wall may be due to trauma, either direct or indirect in the form of external pressure on immobile limbs; disturbed blood flow is due to lack of muscular pumping and hyperviscosity secondary to stress-raised fibrinogen levels and dehydration, and several abnormalities of clotting elements have been described. There are significant increases in Factor VIII:C activity, von Willebrand factor antigen, and ristocetin cofactor activity beginning shortly after spinal cord injury and persisting for at least 2 to 3 weeks.4 In addition, increased platelet aggregation and responsiveness to collagen are noted during the same time intervals and correspond to the period when thrombi are detected. It is likely that studies of fibrinogen and fibrinolysis would also be abnormal, but these components have not yet been analyzed.
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
Anticoagulant Prophylaxis Warfarin Oral anticoagulation has been found to provide effective prophylaxis in patients undergoing elective hip surgery and in patients with a fractured hip (recently summarized by Hull and Raskob).9 In a trial of patients with spinal cord injury, Silver10 noted that the regimen was effective, but bleeding was a problem. More recent studies have suggested that lower doses of warfarin, to prolong the prothrombin time to only 1.3 to 1.5 times control values, provide effective anticoagulation in patients at risk for DVT. 11,12 Whether such regimens would be effective for the spinal cord injured is unknown.
Heparin The American College of Chest Physicians and the National Heart, Lung, and Blood Institute National Conference on Antithrombotic Therapy have recommended that heparin in doses of 5000 U twice daily by the subcutaneous route be given to patients at moderate risk of DVT and that those at higher risk, such as patients undergoing elective hip surgery, receive adjusted dose heparin to prolong the activated partial thromboplastin time (APTT) to the upper half of the normal range. 13,14 This latter recommendation stems from the study of Leyvraz et al, 15 who showed that such adjusted dose heparin therapy reduced the frequency of DVT in patients having total hip replacement from 39% in those receiving 3500 U every 8 hours to 13% (p < 0.003) in those on the adjusted dose. We conducted a similar study in 58 patients with acute spinal cord injury and complete motor paralysis, comparing heparin in doses of 5000 U every 12 hours with doses adjusted to keep the APTT at 1.5 times control values. l6 DVT frequency was reduced from 31 to 7% (p < 0.05). However, bleeding interrupted therapy in 24% of those on the adjusted dose regimen, but in none on the fixed dose treatment. We concluded that while the adjusted dose regimen is effective, patients receiving this treatment are at high risk of bleeding, especially if they have trauma to other tissues in addition to their spinal cord injury. Merli et al17 evaluated fixed doses of heparin of 5000 U every 8 hours and screened for DVT with the radiofibrinogen test. They found thrombi in 8 of 16 patients, but whether these were proximal or distal thrombi was not indicated. When they augmented the heparin prophylaxis with electrical stimulation of the calf muscles continuously for a 28-day period, there was a dramatic decrease in the incidence of DVT (1 in 15 patients). The feasibility of this approach in terms of need for experienced personnel, cost, and patient tolerability, were not discussed.
Low Molecular Weight Heparin Conventional heparin is a mixture of polysaccharide molecules with molecular weights ranging from 2000 to 40,000 daltons. The lower molecular weight molecules appear to be more effective in binding antithrombin and potentiating its antithrombotic activity. Several low molecular weight heparin preparations have been shown to provide effective thromboprophylaxis for stroke patients18 and persons undergoing orthopedic surgery.19 We evaluated Logiparin, a heparin prepared by Novo Laboratories with a mean molecular weight of 4500 d, in our spinal cord-injured patients.20 Logiparin was given in a dose of 3500 anti-Xa U daily subcutaneously and compared with 5000 U of standard heparin given every 8 hours. Twenty-one patients were randomized to receive standard heparin; five of these patients had thrombotic events, including fatal PE in two. Two other patients experienced bleeding sufficiently severe as to require cessation of the heparin therapy. None of the 20 patients treated with Logiparin had an untoward event; the difference in event rate between the two groups was significant at p < 0.03. We concluded that Logiparin low molecular weight heparin is safe and effective in the prevention of thromboembolism in selected patients with spinal cord injury and complete motor paralysis and should probably replace standard heparin in the management of these patients. In Table 1 are summarized our experiences with the various methods of thromboprophylaxis described in this report. It can be seen that the frequency of thrombotic events is reduced from 78% with no treatment to 40% with calf compression boots. When antithrombotic drugs such as aspirin, dipyridamole, or standard heparin are introduced, the number of thrombotic events decreases but bleeding becomes a problem and the overall event rate is about 30%. Low molecular weight heparin has been studied in only a small number of patients, but appears to have a very favorable effect on this overall rate.
SUMMARY Thromboembolism is a major cause of morbidity and mortality in patients with spinal cord injury. The prevalence of DVT approaches 100%, and 1 to 2% will die of PE. Following injury, there is hypercoagulability as reflected by an increase in von Willebrand factor activity and antigen, and increased platelet reactivity to collagen. Thrombosis usually occurs 1 to 3 weeks after injury, with a peak between days 7 and 9. Intermittent calf compression boots reduce the frequency of throm-
Downloaded by: Universite Laval. Copyrighted material.
348
THROMBOEMBOLISM PREVENTION—GREEN
349
TABLE 1. Thromboprophylaxis in Spinal Cord Injury: The Northwestern Experience Method of Prophylaxis
Thrombosis
Bleeding
Percent with Event
None
29/37
0/37
78
6/15
0/15
40
3/12
1/12
33
5000 every 12 hours
9/29
0/29
31
5000 every 8 hours
5/21
2/21
33
Adjusted† Low molecular weight (Logiparin)
2/29
7/29
31
0/20
0/20
0
Calf compression With ASA/Dip* Heparin
bosis to 40%, and the addition of aspirin, 300 mg twice daily, and dipyridamole, 75 mg thrice daily, decrease this further to 25%. In an attempt to provide more effective prophylaxis, a further trial was conducted using heparin. Twenty-nine patients were randomized to re ceive 5000 U subcutaneously every 12 hours and com pared with an equal number of patients treated with doses of heparin adjusted to prolong the APTT to 1.5 times control values; the mean dose was 13,200 U every 12 hours. Thromboembolism occurred in 9 (31%) of those on the fixed dose (6 DVT and 3 PE) and only 2 (7%) on the adjusted dose (p < 0.05); however, 7 (24%) of the patients receiving the higher doses of heparin had bleed ing compared with none of those on the fixed dose (p < 0.02). Most recently, we have compared the safety and effectiveness of a low molecular weight heparin (Logiparin, Novo) with standard heparin. The former was given once daily in a dose of 3500 anti-Xa units, and the latter was 5000 U every 8 hours, both given subcutaneously. No thrombosis or bleeding occurred in 20 Logiparin-treated patients, whereas 5 of 21 receiving standard heparin had thrombosis, including two with fatal PE, and two additional patients had bleeding. This difference in event rate between the two treatments was statistically significant (p < 0.02). We conclude that thromboprophylaxis with a low molecular weight heparin (Logiparin) offers great promise in the management of patients with spinal cord injury. Acknowledgment. These studies would not have been possible without the assistance and cooperation of the staff of the Northwestern Spinal Cord Injury Unit (directed by Paul R. Meyer, Jr, M.D.) and the Spinal Cord Injury Center of the Rehabilitation Institute of Chicago (directed by Gary Yarkony, M.D.). These investigations were supported by grants G008535129 and H133B80007 from the National Institute of Disability and Rehabilitation Research, Department of Educa tion, to the Midwest Regional Spinal Cord Injury Care System.
REFERENCES 1. Myllynen P, M Kammonen, P Rokkanen, O Bostman, M Lalla, E Laasonen: Deep venous thrombosis and pulmonary embolism in patients with acute spinal cord injury: A comparison with nonparalyzed patients immobilized due to spinal fractures. J Trauma 25:541-543, 1986. 2. Green D, EC Rossi, JST Yao, WR Flinn, SM Spies: Deep vein thrombosis in spinal cord injury: Effect of prophylaxis with calf compression, aspirin, and dipyridamole. Paraplegia 20:227-234, 1982. 3. Virchow R. Phlogose und thrombose in gefaβsystem. In Virchow R (Ed): Gesammelte Abhandlungen zur Wissenschaftlicgen Medizin, Von Meidinger Sohn, Frankfurt, 1856, p 458. 4. Rossi EC, D Green, JS Rosen, SM Spies, JST Yao: Sequential changes in factor VIII and platelets preceding deep vein thrombo sis in patients with spinal cord injury. Br J Haematol 45:143-151, 1980. 5. Walsh PN, PH Rogers, VJ Marder, G Cagnatelli, ES Escovitz, S Sherry. The relationship of platelet coagulant activities to venous thrombosis following hip surgery. Br J Haematol 32:421-37, 1976. 6. Salzman EW, WH Harris, RW DeSanctis. Reduction in venous thromboembolism by agents affecting platelet function. N Engl J Med 284:1287-1292, 1971. 7. Harris WH, EW Salzman, CA Athanasoulis, AC Waltman, RW DeSanctis: Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 297:1246-1249, 1977. 8. McKenna R, J Galonte, F Bachmann, DL Wallace, SP Kaushal, P Meredith: Prevention of venous thromboembolism after total knee replacement by high-dose aspirin or intermittent calf and thigh compression. Br Med J 1:514-517, 1980. 9. Hull RD, GE Raskob: Prophylaxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg 68A: 146-150, 1986. 10. Silver JR: The prophylactic use of anticoagulant therapy in the prevention of pulmonary embolism in 100 consecutive spinal injury patients. Paraplegia 12:188-196, 1974. 11. Hull R, J Hirsh, R Jay, C Carter, C England, M Gent, AGG Turpie, D McLoughlin, P Dodd, M Thomas, G Raskob, P Ockelford: Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 307:16761681, 1982.
Downloaded by: Universite Laval. Copyrighted material.
* Aspirin, 325 mg twice daily, dipyridamole, 75 mg three times daily. † Adjusted to a partial thromboplastin time of 40 to 50 seconds.
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
12. Hirsh J: Is the dose of warfarin prescribed by American Physicians unnecessarily high? Arch Intern Med 147:769-771, 1987. 13. Dalen JE, J Hirsh. Antithrombotic therapy. Arch Intern Med 146:462-472, 1986. 14. Hyers TM, RD Hull, JG Weg. Antithrombotic therapy for venous thromboembolic disease. Chest 95:37S-51S, 1989. 15. Leyvraz PF, J Righard, F Bachmann, G Van Melle, J-M Treyvaud, J-J Livio, G Candardjis: Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 309:854-858, 1983. 16. Green D, MY Lee, VY Ito, T Cohn, J Press, PR Filbrandt, WC VandenBerg, GM Yarkony, PR Meyer Jr. Fixed- vs adjusted-dose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA 260:1255-1258, 1988. 17. Merli GJ, GJ Herbison, JF Ditunno, HH Weitz, JH Henzes, CH Park, MM Jaweed, J Heltzel. Deep vein thrombosis: Prophylaxis
in acute spinal cord injured patients. Arch Phys Med Rehabil 69:661-664, 1988. 18. Turpie AGG, J Hirsh, RM Jay, M Andrew, RD Hull, MN Levine, CJ Carter, PJ Powers, HN Magnani, M Gent: Double-blind randomized trial of ORG 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1:523-526, 1987. 19. Turpie AGG, MN Levine, J Hirsh, CJ Carter, RM Jay, PJ Powers, M Andrew, RD Hull, M Gent: A randomized controlled trial of a low-molecular-weight heparin (Enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 315:925-929, 1986. 20. Green D, MY Lee, AC Lim, JS Chmiel, M Vetter, T Pang, D Chen, L Fenton, GM Yarkony, PR Meyer Jr: Prevention of thromboembolism after spinal cord injury using low-molecularweight heparin. Ann Intern Med 113:571-574, 1990.
Downloaded by: Universite Laval. Copyrighted material.
350
Prevention of Thromboembolism After Spinal Cord Injury DAVID GREEN, M.D., Ph.D.
From the Atherosclerosis Program, Rehabilitation Institute, and the Section of Hematology/ Oncology, Department of Medicine, Northwestern University Medical School, Chicago, Illinois. Reprint requests: Dr. Green, Rehabilitation Institute of Chicago, 345 E. Superior Street—Room 1407, Chicago, IL 60611.
Prophylaxis Against Thromboembolism Calf Compression Boots Calf compression boots are leggings containing an air-filled bladder that rhythmically compress the calf musculature, usually in 1-minute cycles with 15-second compressions at a pressure of 40 to 45 mmHg. In a study of 27 patients with complete motor paralysis, we observed that 6 of 15 (40%) treated with calf compression boots alone developed evidence of deep vein thrombosis as detected by the very sensitive radiofibrinogen method.2 This compares favorably with the 78% incidence in untreated patients. We also noted that the increased platelet affinity for collagen and elevated Factor VHI/von Willebrand activities were less marked in the treated patients. Finally, use of the compression boots delayed the onset of thrombosis and shifted the site of thrombi from more proximal to more distal veins.
Anti-platelet Agents Coagulant activities associated with platelets play an important role in the pathogenesis of DVT in patients undergoing hip surgery,5 and inhibitors of platelet function have significantly decreased the incidence of DVT in patients undergoing hip arthroplasty6,7 or total knee replacement.8 Because platelet hyperactivity was noted in our patients with spinal cord injury,4 we added aspirin, 325 mg twice daily, and dipyridamole, 75 mg thrice daily, to the calf compression boot regimen.2 This resulted in a further decrease in DVT to 25% (3 of 12 patients), but one aspirin-treated patient had serious bleeding during a surgical procedure to stabilize his spine.
Copyright © 1991 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, NY 10016. All rights reserved.
347
Downloaded by: Universite Laval. Copyrighted material.
Thromboembolism is a major cause of morbidity and mortality in patients with spinal cord injury and complete motor paralysis. In a recent study by Myllynen et al.1 all 23 patients with this condition had evidence of deep vein thrombosis (DVT) as measured by the 125I fibrinogen test and confirmed by contrast venography. Two (9%) had pulmonary emboli (PE). Using the same methodology, we identified thrombosis in 29 of 37 patients (78%).2 Fatal PE is a major cause of mortality in this condition. The factors responsible for the thrombotic tendency undoubtedly include the triad of vessel wall, blood flow, and plasma constituents, as originally proposed by Virchow3 more than a century ago. In spinal cord-injured patients alterations in the blood vessel wall may be due to trauma, either direct or indirect in the form of external pressure on immobile limbs; disturbed blood flow is due to lack of muscular pumping and hyperviscosity secondary to stress-raised fibrinogen levels and dehydration, and several abnormalities of clotting elements have been described. There are significant increases in Factor VIII:C activity, von Willebrand factor antigen, and ristocetin cofactor activity beginning shortly after spinal cord injury and persisting for at least 2 to 3 weeks.4 In addition, increased platelet aggregation and responsiveness to collagen are noted during the same time intervals and correspond to the period when thrombi are detected. It is likely that studies of fibrinogen and fibrinolysis would also be abnormal, but these components have not yet been analyzed.
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
Anticoagulant Prophylaxis Warfarin Oral anticoagulation has been found to provide effective prophylaxis in patients undergoing elective hip surgery and in patients with a fractured hip (recently summarized by Hull and Raskob).9 In a trial of patients with spinal cord injury, Silver10 noted that the regimen was effective, but bleeding was a problem. More recent studies have suggested that lower doses of warfarin, to prolong the prothrombin time to only 1.3 to 1.5 times control values, provide effective anticoagulation in patients at risk for DVT. 11,12 Whether such regimens would be effective for the spinal cord injured is unknown.
Heparin The American College of Chest Physicians and the National Heart, Lung, and Blood Institute National Conference on Antithrombotic Therapy have recommended that heparin in doses of 5000 U twice daily by the subcutaneous route be given to patients at moderate risk of DVT and that those at higher risk, such as patients undergoing elective hip surgery, receive adjusted dose heparin to prolong the activated partial thromboplastin time (APTT) to the upper half of the normal range. 13,14 This latter recommendation stems from the study of Leyvraz et al, 15 who showed that such adjusted dose heparin therapy reduced the frequency of DVT in patients having total hip replacement from 39% in those receiving 3500 U every 8 hours to 13% (p < 0.003) in those on the adjusted dose. We conducted a similar study in 58 patients with acute spinal cord injury and complete motor paralysis, comparing heparin in doses of 5000 U every 12 hours with doses adjusted to keep the APTT at 1.5 times control values. l6 DVT frequency was reduced from 31 to 7% (p < 0.05). However, bleeding interrupted therapy in 24% of those on the adjusted dose regimen, but in none on the fixed dose treatment. We concluded that while the adjusted dose regimen is effective, patients receiving this treatment are at high risk of bleeding, especially if they have trauma to other tissues in addition to their spinal cord injury. Merli et al17 evaluated fixed doses of heparin of 5000 U every 8 hours and screened for DVT with the radiofibrinogen test. They found thrombi in 8 of 16 patients, but whether these were proximal or distal thrombi was not indicated. When they augmented the heparin prophylaxis with electrical stimulation of the calf muscles continuously for a 28-day period, there was a dramatic decrease in the incidence of DVT (1 in 15 patients). The feasibility of this approach in terms of need for experienced personnel, cost, and patient tolerability, were not discussed.
Low Molecular Weight Heparin Conventional heparin is a mixture of polysaccharide molecules with molecular weights ranging from 2000 to 40,000 daltons. The lower molecular weight molecules appear to be more effective in binding antithrombin and potentiating its antithrombotic activity. Several low molecular weight heparin preparations have been shown to provide effective thromboprophylaxis for stroke patients18 and persons undergoing orthopedic surgery.19 We evaluated Logiparin, a heparin prepared by Novo Laboratories with a mean molecular weight of 4500 d, in our spinal cord-injured patients.20 Logiparin was given in a dose of 3500 anti-Xa U daily subcutaneously and compared with 5000 U of standard heparin given every 8 hours. Twenty-one patients were randomized to receive standard heparin; five of these patients had thrombotic events, including fatal PE in two. Two other patients experienced bleeding sufficiently severe as to require cessation of the heparin therapy. None of the 20 patients treated with Logiparin had an untoward event; the difference in event rate between the two groups was significant at p < 0.03. We concluded that Logiparin low molecular weight heparin is safe and effective in the prevention of thromboembolism in selected patients with spinal cord injury and complete motor paralysis and should probably replace standard heparin in the management of these patients. In Table 1 are summarized our experiences with the various methods of thromboprophylaxis described in this report. It can be seen that the frequency of thrombotic events is reduced from 78% with no treatment to 40% with calf compression boots. When antithrombotic drugs such as aspirin, dipyridamole, or standard heparin are introduced, the number of thrombotic events decreases but bleeding becomes a problem and the overall event rate is about 30%. Low molecular weight heparin has been studied in only a small number of patients, but appears to have a very favorable effect on this overall rate.
SUMMARY Thromboembolism is a major cause of morbidity and mortality in patients with spinal cord injury. The prevalence of DVT approaches 100%, and 1 to 2% will die of PE. Following injury, there is hypercoagulability as reflected by an increase in von Willebrand factor activity and antigen, and increased platelet reactivity to collagen. Thrombosis usually occurs 1 to 3 weeks after injury, with a peak between days 7 and 9. Intermittent calf compression boots reduce the frequency of throm-
Downloaded by: Universite Laval. Copyrighted material.
348
THROMBOEMBOLISM PREVENTION—GREEN
349
TABLE 1. Thromboprophylaxis in Spinal Cord Injury: The Northwestern Experience Method of Prophylaxis
Thrombosis
Bleeding
Percent with Event
None
29/37
0/37
78
6/15
0/15
40
3/12
1/12
33
5000 every 12 hours
9/29
0/29
31
5000 every 8 hours
5/21
2/21
33
Adjusted† Low molecular weight (Logiparin)
2/29
7/29
31
0/20
0/20
0
Calf compression With ASA/Dip* Heparin
bosis to 40%, and the addition of aspirin, 300 mg twice daily, and dipyridamole, 75 mg thrice daily, decrease this further to 25%. In an attempt to provide more effective prophylaxis, a further trial was conducted using heparin. Twenty-nine patients were randomized to re ceive 5000 U subcutaneously every 12 hours and com pared with an equal number of patients treated with doses of heparin adjusted to prolong the APTT to 1.5 times control values; the mean dose was 13,200 U every 12 hours. Thromboembolism occurred in 9 (31%) of those on the fixed dose (6 DVT and 3 PE) and only 2 (7%) on the adjusted dose (p < 0.05); however, 7 (24%) of the patients receiving the higher doses of heparin had bleed ing compared with none of those on the fixed dose (p < 0.02). Most recently, we have compared the safety and effectiveness of a low molecular weight heparin (Logiparin, Novo) with standard heparin. The former was given once daily in a dose of 3500 anti-Xa units, and the latter was 5000 U every 8 hours, both given subcutaneously. No thrombosis or bleeding occurred in 20 Logiparin-treated patients, whereas 5 of 21 receiving standard heparin had thrombosis, including two with fatal PE, and two additional patients had bleeding. This difference in event rate between the two treatments was statistically significant (p < 0.02). We conclude that thromboprophylaxis with a low molecular weight heparin (Logiparin) offers great promise in the management of patients with spinal cord injury. Acknowledgment. These studies would not have been possible without the assistance and cooperation of the staff of the Northwestern Spinal Cord Injury Unit (directed by Paul R. Meyer, Jr, M.D.) and the Spinal Cord Injury Center of the Rehabilitation Institute of Chicago (directed by Gary Yarkony, M.D.). These investigations were supported by grants G008535129 and H133B80007 from the National Institute of Disability and Rehabilitation Research, Department of Educa tion, to the Midwest Regional Spinal Cord Injury Care System.
REFERENCES 1. Myllynen P, M Kammonen, P Rokkanen, O Bostman, M Lalla, E Laasonen: Deep venous thrombosis and pulmonary embolism in patients with acute spinal cord injury: A comparison with nonparalyzed patients immobilized due to spinal fractures. J Trauma 25:541-543, 1986. 2. Green D, EC Rossi, JST Yao, WR Flinn, SM Spies: Deep vein thrombosis in spinal cord injury: Effect of prophylaxis with calf compression, aspirin, and dipyridamole. Paraplegia 20:227-234, 1982. 3. Virchow R. Phlogose und thrombose in gefaβsystem. In Virchow R (Ed): Gesammelte Abhandlungen zur Wissenschaftlicgen Medizin, Von Meidinger Sohn, Frankfurt, 1856, p 458. 4. Rossi EC, D Green, JS Rosen, SM Spies, JST Yao: Sequential changes in factor VIII and platelets preceding deep vein thrombo sis in patients with spinal cord injury. Br J Haematol 45:143-151, 1980. 5. Walsh PN, PH Rogers, VJ Marder, G Cagnatelli, ES Escovitz, S Sherry. The relationship of platelet coagulant activities to venous thrombosis following hip surgery. Br J Haematol 32:421-37, 1976. 6. Salzman EW, WH Harris, RW DeSanctis. Reduction in venous thromboembolism by agents affecting platelet function. N Engl J Med 284:1287-1292, 1971. 7. Harris WH, EW Salzman, CA Athanasoulis, AC Waltman, RW DeSanctis: Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 297:1246-1249, 1977. 8. McKenna R, J Galonte, F Bachmann, DL Wallace, SP Kaushal, P Meredith: Prevention of venous thromboembolism after total knee replacement by high-dose aspirin or intermittent calf and thigh compression. Br Med J 1:514-517, 1980. 9. Hull RD, GE Raskob: Prophylaxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg 68A: 146-150, 1986. 10. Silver JR: The prophylactic use of anticoagulant therapy in the prevention of pulmonary embolism in 100 consecutive spinal injury patients. Paraplegia 12:188-196, 1974. 11. Hull R, J Hirsh, R Jay, C Carter, C England, M Gent, AGG Turpie, D McLoughlin, P Dodd, M Thomas, G Raskob, P Ockelford: Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 307:16761681, 1982.
Downloaded by: Universite Laval. Copyrighted material.
* Aspirin, 325 mg twice daily, dipyridamole, 75 mg three times daily. † Adjusted to a partial thromboplastin time of 40 to 50 seconds.
SEMINARS IN THROMBOSIS AND HEMOSTASIS—VOLUME 17, NO. 4, 1991
12. Hirsh J: Is the dose of warfarin prescribed by American Physicians unnecessarily high? Arch Intern Med 147:769-771, 1987. 13. Dalen JE, J Hirsh. Antithrombotic therapy. Arch Intern Med 146:462-472, 1986. 14. Hyers TM, RD Hull, JG Weg. Antithrombotic therapy for venous thromboembolic disease. Chest 95:37S-51S, 1989. 15. Leyvraz PF, J Righard, F Bachmann, G Van Melle, J-M Treyvaud, J-J Livio, G Candardjis: Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 309:854-858, 1983. 16. Green D, MY Lee, VY Ito, T Cohn, J Press, PR Filbrandt, WC VandenBerg, GM Yarkony, PR Meyer Jr. Fixed- vs adjusted-dose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA 260:1255-1258, 1988. 17. Merli GJ, GJ Herbison, JF Ditunno, HH Weitz, JH Henzes, CH Park, MM Jaweed, J Heltzel. Deep vein thrombosis: Prophylaxis
in acute spinal cord injured patients. Arch Phys Med Rehabil 69:661-664, 1988. 18. Turpie AGG, J Hirsh, RM Jay, M Andrew, RD Hull, MN Levine, CJ Carter, PJ Powers, HN Magnani, M Gent: Double-blind randomized trial of ORG 10172 low-molecular-weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1:523-526, 1987. 19. Turpie AGG, MN Levine, J Hirsh, CJ Carter, RM Jay, PJ Powers, M Andrew, RD Hull, M Gent: A randomized controlled trial of a low-molecular-weight heparin (Enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 315:925-929, 1986. 20. Green D, MY Lee, AC Lim, JS Chmiel, M Vetter, T Pang, D Chen, L Fenton, GM Yarkony, PR Meyer Jr: Prevention of thromboembolism after spinal cord injury using low-molecularweight heparin. Ann Intern Med 113:571-574, 1990.
Downloaded by: Universite Laval. Copyrighted material.
350
