An Overview of Venous Thromboembolism Prophylaxis Donald Silver,
MD, Columbia,
This symposium reviewed the risk factors and prohlems associated with venous thromboembolism in surgical patients, especially those patients having total hip replacement. The importance of venous thromboembolism prophylaxis was emphasized by a theoretical analysis indicating that venous thromboembolism in patients having hip replacement not only saves lives hut is also effective. A discussion of the pharmacology of low-molecular-weight heparin (LMWH) included a review of its role, clinically and experimentally, in venous thromboembolism prophylaxis. Three of the discussants presented their favorable experiences with LMWH in reducing the incidence of venous thromboembolism in patients having hip replacement. It can be concluded that LMWH does reduce the incidence of venous thromboembolism in patients having hip replacement without causing an increase in blood loss. If its effectiveness and safety remain substantiated, LMWH may soon become the preferred agent for venous thromboembolism prophylaxis.
enous thromboembolism remains a major cause of disability and death in all patient populations. It is V estimated that venous thrombosis and pulmonary embolism are associated with 300,000 to 600,000 hospital admissions in the United States each year [I] and that 50,000 to 100,000 individuals die as a result of pulmonary embolism each year [2]. Most investigators of venous thromboembolism agree that these estimates are conservative and that the frequencies of occurrences of the disorders are much higher. Some of the pulmonary emboli occur in terminally ill patients; however, pulmonary embolism contributes to, or is, the major cause of death in the majority of patients. A significant number of the patients dying of pulmonary embolism would be expected to lead normal lives after recovering from their primary disorder. From the University of Missouri-Columbia, Department of Surgery, Columbia, Missouri. Requests for reprints should be addressed to Donald Silver, MD, Department of Surgery, MS80 Health Sciences Center, Columbia, Missouri 652 12.
THE AMERICAN
WSSOW~
The frequency of deep venous thrombosis in patients has been determined by screening selected patient populations with I251fibrinogen. Deep venous thrombosis, in the absence of venous thrombosis prophylaxis, has been found to occur in 25% to 33% of patients undergoing general surgery [3,4] and 45% to 70% of patients having total hip replacement [5]. The screening studies have indicated that all patient populations are at risk for developing venous thromboembolism [6,7] and that the risks are increased in trauma patients, seriously ill patients, and patients having major surgical procedures. The frequency of fatal pulmonary embolism ranges from 0.1% to 0.8% in patients undergoing elective general surgery [8,9], from 1.O%to 3.0% in patients having elective hip surgery [I 01, and from 4% to 7% in patients having emergency hip surgery [I J] . The pathogenesis of venous thromboembolism was established in the mid-1800s when Virchow established the connection between thromboses in the extremities and thromboemboli in the pulmonary circulation. Virchow suggested that venous thromboembolism usually occurred in patients with hypercoagulability of blood, vascular injury, and/or venostasis (Virchow’s triad). If one adds diminished fibrinolytic potential, as occurs during times of vascular trauma [J 21 or congenitally [I 31, to Virchow’s triad, most cases of thromboembolism will have one or more of these “etiologic factors.” A number of clinical risk factors for venous thromboembolism have been identified. These risk factors include advanced age, obesity, malignant disease, immobility, previous venous thromboembolism, varicose veins, low cardiac output, major trauma, major surgery, and oral contraceptives. Clearly, some patients are at greater risk for venous thromboembolism than are others. Wheeler and associates [J4,15] have used plethysmography to study patients with known risk factors for the presence of deep venous thrombosis. The risk factors which they have reported [ 141 and reviewed in this symposium [J5] include patient’s age, obesity, malignancy, recent surgery, and history of deep venous thrombosis or pulmonary embolism. If no risk factors were present in the patients studied with impedance plethysmography for the possibility of deep venous thrombosis, only 11% were found to have deep venous thrombosis and 1% had pulmonary embolism. When three risk factors were present, 50% had deep venous thrombosis and 8% had pulmonary embolism. Deep venous thrombosis was present in 100% of the patients with four or more risk factors. The importance of a careful history, which is supplemented by noninvasive testing for patients with two or more risk factors, has been repeatedly emphasized by Wheeler and others.
JOURNAL
OF SURGERY
VOLUME
161
APRIL
1991
537
A number of programs have been developed to reduce the frequency of venous thromboembolism. For the surgeon, these programs include optimizing the patient’s condition preoperatively, especially achieving adequate hydration and cardiac output, and reducing or eliminating as many of the other risk factors as possible. A variety of methods for inducing prophylaxis for lower extremity venous thromboembolism have been evaluated. These methods include anticoagulation (heparin, heparin-dihydroergotamine, low-molecular-weight heparin [LMWH], vitamin K antagonists); platelet function inhibition; dextran; and physical methods which include compressive stockings, electrical calf muscle stimulation, and intermittent pneumatic compression. Most of these methods have been found to be of value in reducing venous thromboembolism. Compressive stockings and early ambulation may suffice for prophylaxis in the low-risk (one to two risk factors) patient population, whereas low-dose heparin and mechanical calf compression are needed for prophylaxis in the high-risk (four or more risk factors) patient population. It has been noted that only about one third of patients with two or more risk factors receive venous thromboembolism prophylaxis [ 151. It is estimated that the routine use of effective prophlactic measures in patients undergoing elective general surgery could prevent 4,000 to 8,000 postoperative deaths each year in the United States [16]. Dr. Paiement and colleagues, using a “theoretical analysis,” report in this symposium that venous thromboembolism prophylaxis should be quite effective in patients undergoing total hip replacement [I 71. They noted, in patients having total hip replacement, that “. . . low-dose warfarin combined with clinical surveillance of deep vein thrombosis would reduce the incidence of fatal pulmonary embolism from 20 per 1,000 patients to 4 per 1,000 patients and simultaneously reduce the charges for venous thromboembolic disease from $550,000 to about $400,000 per 1,000 patients.” They suggested that the addition of venography or duplex sonography to this regimen “. . . would, in this theoretical analysis, reduce the incidence of fatal pulmonary embolism from 4 per 1,000 to 0.15 per 1,000 . . . .” However, the cost would be increased from $50,000 to $200,000 per life saved. The authors calculated that no prophylaxis for patients having total hip replacement is more expensive (and life-threatening to 16 patients per 1,000 operations) than a simple anticoagulation/surveillance program. In the late 196Os,reports began appearing that small doses of heparin, with minimal anticoagulant effect, were effective in reducing the frequency of venous thromboses. It was subsequently demonstrated that low-dose subcutaneous heparin (5,000 U administered every 8 or 12 hours postoperatively) was effective in reducing the incidence of postoperative venous thromboembolism. The more than 30 randomized prospective trials and 12,000 patients studied have indicated that the incidence of deep venous thrombosis was reduced from approximately 30% in the control groups to less than 7% in patients having major abdominal, pelvic, or thoracic procedures treated with low doses of heparin [18]. Collins and associates [19]
performed a meta-analysis of a low-dose heparin prophylaxis in general surgery patients and noted that the “ . typical reduction in the odds of thrombosis in the patients assigned to the heparin group as compared to the control was 67 f 4% . . . .” The authors noted similar reductions in the incidence of deep venous thrombosis in trials in patients having urologic surgery, elective orthopedic surgery, and “traumatic” surgery. Low-dose heparin use has, as would be expected, also reduced the incidence of fatal and nonfatal pulmonary embolism in surgical patients [3,20]. A potential complication of low-dose heparin prophylaxis is bleeding. Collins and associates [19] in their extensive review noted that “. . . there was clear and consistent evidence of an increased risk of bleeding after administration of subcutaneous heparin . . . .” The amount of excessive bleeding has been difficult to quantitate. Nevertheless, this potential for bleeding has inhibited the widespread utilization of low-dose heparin for venous thromboembolism prophylaxis in surgical patients. This increased bleeding has been of special concern to orthopedic surgeons in their cases of total hip replacement. Heparin is an anionic mucopolysaccharide (a glycosaminoglycan) which is synthesized by the mast cell. Clinical heparin (unfractionated heparin, UH) contains glycosaminoglycan chains that range in weight from 4,000 to around 40,000. Some of the heparin chains (about 30%) contain a unique pentasacchride which is responsible for the high-affinity interactions between heparin and antithrombin III (ATIII) and thus are responsible for the anticoagulation effects of heparin. All LMWHs and UH chains with the high affinity pentasacchride units can bind to AT111 and catalyze factor Xa inhibition. If the LMWH contains less than 18 to 20 saccharides, it cannot simultaneously bind to AT111 and thrombin and therefore cannot accelerate the catalysis of thrombin. This difference in the binding of UH and LMWH to AT111 is responsible for the different activities of UH and LMWH: LMWHs have decreased ability to bind and inhibit thrombin but maintain the ability to bind and catalyze Xa. Thus, LMWHs are said to have a limited anticoagulant effect while maintaining an antithrombotic effect. LMWHs are relatively resistant to neutralization by platelet factor IV; the resistance increases as the molecular size decreases. The LMWHs produce less bleeding for an equivalent antithrombotic effect to that of UHs. Dr. Hirsh [21] provided, in the symposium, a lucid review of the biochemistry and function of LMWH and reviewed some of the animal and clinical trials of LMWH prophylaxis in deep venous thrombosis. He noted that bleeding occurred in early studies using LMWH but stated that “. . . when used in more appropriate doses, which are highly effective in preventing thrombosis, LMWHs are not associated with an increased risk of perioperative bleeding, even in patients who undergo hip surgery.” Dr. Hirsh reviewed the results of eight randomized trials comparing LMWH with UH in patients having abdomi-
538
16 1
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
APRIL
199 1
VENOUS THROMBOEMBOLISM
nal surgery. He found that “. . . LMWH’s are at least as effective and safe in general surgical patients as standard heparin when given once daily by subcutaneous injection . . . .” He also noted that LMWH is safe and effective venous thromboembolism prophylaxis in medical patients, patients with stroke, and patients having elective hip surgery. Subsequent presentations during the symposium by Dr. Planes [22], Dr. Lassen [23], and Dr. Tut-pie [24], confirmed that the LMWH enoxaparin (Lovenox, Pharmuka Laboratories, Genevilliers, France) reduced venous thrombosis in patients having total hip replacement when compared with patients receiving dextran, placebos, or oral anticoagulants. Dr. Planes noted that 40 mg of LMWH given 12 hours before surgery, 12 hours after surgery, and once daily thereafter effectively reduced deep venous thrombosis in patients having total hip replacement and did not result in excessive bleeding [22]. Dr. Planes and associates evaluated the use of LMWH in patients having total hip replacement and spinal anesthesia. They noted that 20 mg of LMWH given “1 hour after the lumbar puncture” followed by their standard 40 mg 12 hours postoperatively and daily thereafter was safe and effective in reducing deep venous thrombosis. They do not yet recommend the use of LMWH in patients with indwelling epidural catheters. Lassen and associates [23] found a marked reduction in proximal deep venous thrombosis in 108 patients treated with LMWH when they were compared with 111 matched patients treated with dextran 70 (p = 0.0013). Furthermore, there was less bleeding in the patients treated with LMWH than in those receiving dextran 70. Dr. Turpie and associates [24] noted that enoxaparin significantly reduced the incidence of deep venous thrombosis in their patients having total hip replacement when compared with patients receiving a placebo (p = 0.007). Furthermore, they also noted that there was no increase in bleeding in the patients receiving LMWH. Their patients were maintained on warfarin for at least 1 month postoperatively.
CONCLUSION This symposium, chaired by Drs. Hirsh and Wheeler, has nicely reviewed the problems of venous thromboembolism in surgical patients, especially the thromboembolic problems encountered in orthopedic patients having total hip replacement. The participants have provided data which confirm that LMWH is an effective prophylaxis against in uivo thrombosis when given early and in adequate doses in orthopedic patients having total hip replacement. The symposium provided hope to those who attended that a relatively simple method for protecting orthopedic patients having total hip replacement (and, it is hoped, for all patients having surgical procedures) from deep venous thromboses and fatal pulmonary embolism may be available. Three of the symposium speakers reviewed their favorable experiences with enoxaparin. Other investigators have had equal successes in preventing deep venous thrombosis and fatal pulmonary embolism in surgical
PROPHYLAXIS
patients when using other forms of LMWH (at least four LMWHs are being evaluated). Small daily injections of LMWH appear to provide adequate prophylaxis for deep venous thromboembolism. If the efficacy and safety of LMWH remains substantiated, one anticipates that LMWH will be widely used in all appropriate patient populations to reduce the incidence of venous thromboembolism. The amount of LMWH needed, the rate at which it should be administered, and the possible occurrence of allergic and/or sensitive reactions from longterm exposure remain to be determined. One member of the audience asked, “Why not give LMWH to patients having knee, ankle, and other forms of surgery?” The answer to this question is that venous thromboembolism prophylaxis should be given to all patients at risk. Currently, in the United States, unfractionated heparin and some form of venous compression remain the most popular methods for providing deep venous thromboembolism prophylaxis. It appears that LMWH may soon become the preferred agent for venous thrombosis prophylaxis. Dr. Silver attended the symposium as a representative of The American Journal of Surgery. His review provides further insight into a complex clinical problem.
REFERENCES 1. National Institutes of Health Consensus Development Conference Statement. Prevention of venous thrombosis and pulmonary embolism. JAMA 1986: 256: 744-9. 2. Dalen JE, Alpert JS’Natural history of pulmonary embolism. Proa Cardiovasc Dis 1975: 17: 259-70. 3. Kakkar VV. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. One International Trial. Lancet 1975; 2: 45-51. 4. Doouss TW. The clinical significance of venous thrombosis of the calf. Br J Surg 1976; 63: 377-8. 5. Hull RD, Raskob GE. Prophylaxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg [Am] 1986; 68: 146-50. 6. Eskeland G, Solheim K, Skjorten F. Anticoagulant prophylaxis, thromboembolism and mortality in elderly patients with hip fractures. Acta Chir Stand 1966; 131: 16-29. 7. Kakkar VV, Stamartakis JD, Bentley PG, Lawrence D, deHaas HA, Ward VP. Prophylaxis for postoperative deep-vein thrombosis: synergistic effect of heparin and dihydroergotamine. JAMA 1979; 241: 39-42. 8. Skinner DB, Salzman EW. Anticoagulant prophylaxis in surgical patients. Surg Gynecol Obstet 1967; 125: 741-6. 9. Shepard RM Jr, White HA, Shirkey AI. Anticoagulant prophylaxis of thromboembolism in postsurgical patients. Am J Surg 1966; 112: 698-702. 10. Leyvraz PF, Richard J, Bachmann F, et al. Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 1983: 309: 954-8. 11. Gallus AS, Hirsh J. Prevention of venous thromboembolism. Semin Thromb Hemost 1976; 2: 232-90. 12. Silver D. Vascular injury: its effect on thrombolysis. J Trauma 1969; 9: 668-74. 13. Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen: a hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61: 1186-95.
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14. Wheeler HB. Diagnosis of deep vein thrombosis. Am J Surg Ott 1985 [Suppl], 150: 7-13. 15. Wheeler HB, Anderson FA Jr. Prophylaxis against venous thromboembolism in surgical patients. Am J Surg 1991; 161: 50711. 16. Frantantoni J, Wessler S. Prophylactic therapy of deep vein thrombosis and pulmonary embolism. Dept of Health, Education and Welfare Publication (NIH) 76-866. Washington: Unites States Government Printing Office, 1975. 17. Paiement GD, Wessinger SJ, Harris WH. Cost-effectiveness of prophylaxis in total hip replacement. Am J Surg 199 1; 16 1: 5 19-24. 18. Turpie AGG, Leclerc JR. Prophylaxis of venous thromboembolism. In: Leclerc JR, ed. Venous thromboembolic disorders. Philadelphia: Lea and Febiger, 1991: 303-45. 19. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative ad-
540
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ministration of subcutaneous heparin. N Engl J Med 1988; 318: 1162-73. 20. Report by the Coordinating Centre. Reappraisal of results of International Multicentre Trial. Lancet 1977; 1: 567-9. 21. Hirsh J. Rationale for development of low-molecular-weight heparins and their clinical potential in the prevention of postoperative venous thrombosis. Am J Surg 1991; 161: 512-8. 22. Planes A, Vochelle M, Fagola M, et al. Efficacy and safety of a perioperative enoxaparin regimen in total hip replacement under various anesthesias. Am J Surg 1991; 161: 525-31. 23. Lassen MR. A comparison of the efficacy of enoxaparin with dextran in THR. Presented at the Rhone-Poulenc Symposium, Montreal, Quebec, Canada, September 10, 1990. 24. Turpie AGG. Efficacy of a postoperative regimen of enoxaparin in deep vein thrombosis prophylaxis. Am J Surg 1991; 161: 532-6.
VOLUME 161 APRIL 1991
MD, Columbia,
This symposium reviewed the risk factors and prohlems associated with venous thromboembolism in surgical patients, especially those patients having total hip replacement. The importance of venous thromboembolism prophylaxis was emphasized by a theoretical analysis indicating that venous thromboembolism in patients having hip replacement not only saves lives hut is also effective. A discussion of the pharmacology of low-molecular-weight heparin (LMWH) included a review of its role, clinically and experimentally, in venous thromboembolism prophylaxis. Three of the discussants presented their favorable experiences with LMWH in reducing the incidence of venous thromboembolism in patients having hip replacement. It can be concluded that LMWH does reduce the incidence of venous thromboembolism in patients having hip replacement without causing an increase in blood loss. If its effectiveness and safety remain substantiated, LMWH may soon become the preferred agent for venous thromboembolism prophylaxis.
enous thromboembolism remains a major cause of disability and death in all patient populations. It is V estimated that venous thrombosis and pulmonary embolism are associated with 300,000 to 600,000 hospital admissions in the United States each year [I] and that 50,000 to 100,000 individuals die as a result of pulmonary embolism each year [2]. Most investigators of venous thromboembolism agree that these estimates are conservative and that the frequencies of occurrences of the disorders are much higher. Some of the pulmonary emboli occur in terminally ill patients; however, pulmonary embolism contributes to, or is, the major cause of death in the majority of patients. A significant number of the patients dying of pulmonary embolism would be expected to lead normal lives after recovering from their primary disorder. From the University of Missouri-Columbia, Department of Surgery, Columbia, Missouri. Requests for reprints should be addressed to Donald Silver, MD, Department of Surgery, MS80 Health Sciences Center, Columbia, Missouri 652 12.
THE AMERICAN
WSSOW~
The frequency of deep venous thrombosis in patients has been determined by screening selected patient populations with I251fibrinogen. Deep venous thrombosis, in the absence of venous thrombosis prophylaxis, has been found to occur in 25% to 33% of patients undergoing general surgery [3,4] and 45% to 70% of patients having total hip replacement [5]. The screening studies have indicated that all patient populations are at risk for developing venous thromboembolism [6,7] and that the risks are increased in trauma patients, seriously ill patients, and patients having major surgical procedures. The frequency of fatal pulmonary embolism ranges from 0.1% to 0.8% in patients undergoing elective general surgery [8,9], from 1.O%to 3.0% in patients having elective hip surgery [I 01, and from 4% to 7% in patients having emergency hip surgery [I J] . The pathogenesis of venous thromboembolism was established in the mid-1800s when Virchow established the connection between thromboses in the extremities and thromboemboli in the pulmonary circulation. Virchow suggested that venous thromboembolism usually occurred in patients with hypercoagulability of blood, vascular injury, and/or venostasis (Virchow’s triad). If one adds diminished fibrinolytic potential, as occurs during times of vascular trauma [J 21 or congenitally [I 31, to Virchow’s triad, most cases of thromboembolism will have one or more of these “etiologic factors.” A number of clinical risk factors for venous thromboembolism have been identified. These risk factors include advanced age, obesity, malignant disease, immobility, previous venous thromboembolism, varicose veins, low cardiac output, major trauma, major surgery, and oral contraceptives. Clearly, some patients are at greater risk for venous thromboembolism than are others. Wheeler and associates [J4,15] have used plethysmography to study patients with known risk factors for the presence of deep venous thrombosis. The risk factors which they have reported [ 141 and reviewed in this symposium [J5] include patient’s age, obesity, malignancy, recent surgery, and history of deep venous thrombosis or pulmonary embolism. If no risk factors were present in the patients studied with impedance plethysmography for the possibility of deep venous thrombosis, only 11% were found to have deep venous thrombosis and 1% had pulmonary embolism. When three risk factors were present, 50% had deep venous thrombosis and 8% had pulmonary embolism. Deep venous thrombosis was present in 100% of the patients with four or more risk factors. The importance of a careful history, which is supplemented by noninvasive testing for patients with two or more risk factors, has been repeatedly emphasized by Wheeler and others.
JOURNAL
OF SURGERY
VOLUME
161
APRIL
1991
537
A number of programs have been developed to reduce the frequency of venous thromboembolism. For the surgeon, these programs include optimizing the patient’s condition preoperatively, especially achieving adequate hydration and cardiac output, and reducing or eliminating as many of the other risk factors as possible. A variety of methods for inducing prophylaxis for lower extremity venous thromboembolism have been evaluated. These methods include anticoagulation (heparin, heparin-dihydroergotamine, low-molecular-weight heparin [LMWH], vitamin K antagonists); platelet function inhibition; dextran; and physical methods which include compressive stockings, electrical calf muscle stimulation, and intermittent pneumatic compression. Most of these methods have been found to be of value in reducing venous thromboembolism. Compressive stockings and early ambulation may suffice for prophylaxis in the low-risk (one to two risk factors) patient population, whereas low-dose heparin and mechanical calf compression are needed for prophylaxis in the high-risk (four or more risk factors) patient population. It has been noted that only about one third of patients with two or more risk factors receive venous thromboembolism prophylaxis [ 151. It is estimated that the routine use of effective prophlactic measures in patients undergoing elective general surgery could prevent 4,000 to 8,000 postoperative deaths each year in the United States [16]. Dr. Paiement and colleagues, using a “theoretical analysis,” report in this symposium that venous thromboembolism prophylaxis should be quite effective in patients undergoing total hip replacement [I 71. They noted, in patients having total hip replacement, that “. . . low-dose warfarin combined with clinical surveillance of deep vein thrombosis would reduce the incidence of fatal pulmonary embolism from 20 per 1,000 patients to 4 per 1,000 patients and simultaneously reduce the charges for venous thromboembolic disease from $550,000 to about $400,000 per 1,000 patients.” They suggested that the addition of venography or duplex sonography to this regimen “. . . would, in this theoretical analysis, reduce the incidence of fatal pulmonary embolism from 4 per 1,000 to 0.15 per 1,000 . . . .” However, the cost would be increased from $50,000 to $200,000 per life saved. The authors calculated that no prophylaxis for patients having total hip replacement is more expensive (and life-threatening to 16 patients per 1,000 operations) than a simple anticoagulation/surveillance program. In the late 196Os,reports began appearing that small doses of heparin, with minimal anticoagulant effect, were effective in reducing the frequency of venous thromboses. It was subsequently demonstrated that low-dose subcutaneous heparin (5,000 U administered every 8 or 12 hours postoperatively) was effective in reducing the incidence of postoperative venous thromboembolism. The more than 30 randomized prospective trials and 12,000 patients studied have indicated that the incidence of deep venous thrombosis was reduced from approximately 30% in the control groups to less than 7% in patients having major abdominal, pelvic, or thoracic procedures treated with low doses of heparin [18]. Collins and associates [19]
performed a meta-analysis of a low-dose heparin prophylaxis in general surgery patients and noted that the “ . typical reduction in the odds of thrombosis in the patients assigned to the heparin group as compared to the control was 67 f 4% . . . .” The authors noted similar reductions in the incidence of deep venous thrombosis in trials in patients having urologic surgery, elective orthopedic surgery, and “traumatic” surgery. Low-dose heparin use has, as would be expected, also reduced the incidence of fatal and nonfatal pulmonary embolism in surgical patients [3,20]. A potential complication of low-dose heparin prophylaxis is bleeding. Collins and associates [19] in their extensive review noted that “. . . there was clear and consistent evidence of an increased risk of bleeding after administration of subcutaneous heparin . . . .” The amount of excessive bleeding has been difficult to quantitate. Nevertheless, this potential for bleeding has inhibited the widespread utilization of low-dose heparin for venous thromboembolism prophylaxis in surgical patients. This increased bleeding has been of special concern to orthopedic surgeons in their cases of total hip replacement. Heparin is an anionic mucopolysaccharide (a glycosaminoglycan) which is synthesized by the mast cell. Clinical heparin (unfractionated heparin, UH) contains glycosaminoglycan chains that range in weight from 4,000 to around 40,000. Some of the heparin chains (about 30%) contain a unique pentasacchride which is responsible for the high-affinity interactions between heparin and antithrombin III (ATIII) and thus are responsible for the anticoagulation effects of heparin. All LMWHs and UH chains with the high affinity pentasacchride units can bind to AT111 and catalyze factor Xa inhibition. If the LMWH contains less than 18 to 20 saccharides, it cannot simultaneously bind to AT111 and thrombin and therefore cannot accelerate the catalysis of thrombin. This difference in the binding of UH and LMWH to AT111 is responsible for the different activities of UH and LMWH: LMWHs have decreased ability to bind and inhibit thrombin but maintain the ability to bind and catalyze Xa. Thus, LMWHs are said to have a limited anticoagulant effect while maintaining an antithrombotic effect. LMWHs are relatively resistant to neutralization by platelet factor IV; the resistance increases as the molecular size decreases. The LMWHs produce less bleeding for an equivalent antithrombotic effect to that of UHs. Dr. Hirsh [21] provided, in the symposium, a lucid review of the biochemistry and function of LMWH and reviewed some of the animal and clinical trials of LMWH prophylaxis in deep venous thrombosis. He noted that bleeding occurred in early studies using LMWH but stated that “. . . when used in more appropriate doses, which are highly effective in preventing thrombosis, LMWHs are not associated with an increased risk of perioperative bleeding, even in patients who undergo hip surgery.” Dr. Hirsh reviewed the results of eight randomized trials comparing LMWH with UH in patients having abdomi-
538
16 1
THE AMERICAN
JOURNAL
OF SURGERY
VOLUME
APRIL
199 1
VENOUS THROMBOEMBOLISM
nal surgery. He found that “. . . LMWH’s are at least as effective and safe in general surgical patients as standard heparin when given once daily by subcutaneous injection . . . .” He also noted that LMWH is safe and effective venous thromboembolism prophylaxis in medical patients, patients with stroke, and patients having elective hip surgery. Subsequent presentations during the symposium by Dr. Planes [22], Dr. Lassen [23], and Dr. Tut-pie [24], confirmed that the LMWH enoxaparin (Lovenox, Pharmuka Laboratories, Genevilliers, France) reduced venous thrombosis in patients having total hip replacement when compared with patients receiving dextran, placebos, or oral anticoagulants. Dr. Planes noted that 40 mg of LMWH given 12 hours before surgery, 12 hours after surgery, and once daily thereafter effectively reduced deep venous thrombosis in patients having total hip replacement and did not result in excessive bleeding [22]. Dr. Planes and associates evaluated the use of LMWH in patients having total hip replacement and spinal anesthesia. They noted that 20 mg of LMWH given “1 hour after the lumbar puncture” followed by their standard 40 mg 12 hours postoperatively and daily thereafter was safe and effective in reducing deep venous thrombosis. They do not yet recommend the use of LMWH in patients with indwelling epidural catheters. Lassen and associates [23] found a marked reduction in proximal deep venous thrombosis in 108 patients treated with LMWH when they were compared with 111 matched patients treated with dextran 70 (p = 0.0013). Furthermore, there was less bleeding in the patients treated with LMWH than in those receiving dextran 70. Dr. Turpie and associates [24] noted that enoxaparin significantly reduced the incidence of deep venous thrombosis in their patients having total hip replacement when compared with patients receiving a placebo (p = 0.007). Furthermore, they also noted that there was no increase in bleeding in the patients receiving LMWH. Their patients were maintained on warfarin for at least 1 month postoperatively.
CONCLUSION This symposium, chaired by Drs. Hirsh and Wheeler, has nicely reviewed the problems of venous thromboembolism in surgical patients, especially the thromboembolic problems encountered in orthopedic patients having total hip replacement. The participants have provided data which confirm that LMWH is an effective prophylaxis against in uivo thrombosis when given early and in adequate doses in orthopedic patients having total hip replacement. The symposium provided hope to those who attended that a relatively simple method for protecting orthopedic patients having total hip replacement (and, it is hoped, for all patients having surgical procedures) from deep venous thromboses and fatal pulmonary embolism may be available. Three of the symposium speakers reviewed their favorable experiences with enoxaparin. Other investigators have had equal successes in preventing deep venous thrombosis and fatal pulmonary embolism in surgical
PROPHYLAXIS
patients when using other forms of LMWH (at least four LMWHs are being evaluated). Small daily injections of LMWH appear to provide adequate prophylaxis for deep venous thromboembolism. If the efficacy and safety of LMWH remains substantiated, one anticipates that LMWH will be widely used in all appropriate patient populations to reduce the incidence of venous thromboembolism. The amount of LMWH needed, the rate at which it should be administered, and the possible occurrence of allergic and/or sensitive reactions from longterm exposure remain to be determined. One member of the audience asked, “Why not give LMWH to patients having knee, ankle, and other forms of surgery?” The answer to this question is that venous thromboembolism prophylaxis should be given to all patients at risk. Currently, in the United States, unfractionated heparin and some form of venous compression remain the most popular methods for providing deep venous thromboembolism prophylaxis. It appears that LMWH may soon become the preferred agent for venous thrombosis prophylaxis. Dr. Silver attended the symposium as a representative of The American Journal of Surgery. His review provides further insight into a complex clinical problem.
REFERENCES 1. National Institutes of Health Consensus Development Conference Statement. Prevention of venous thrombosis and pulmonary embolism. JAMA 1986: 256: 744-9. 2. Dalen JE, Alpert JS’Natural history of pulmonary embolism. Proa Cardiovasc Dis 1975: 17: 259-70. 3. Kakkar VV. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. One International Trial. Lancet 1975; 2: 45-51. 4. Doouss TW. The clinical significance of venous thrombosis of the calf. Br J Surg 1976; 63: 377-8. 5. Hull RD, Raskob GE. Prophylaxis of venous thromboembolic disease following hip and knee surgery. J Bone Joint Surg [Am] 1986; 68: 146-50. 6. Eskeland G, Solheim K, Skjorten F. Anticoagulant prophylaxis, thromboembolism and mortality in elderly patients with hip fractures. Acta Chir Stand 1966; 131: 16-29. 7. Kakkar VV, Stamartakis JD, Bentley PG, Lawrence D, deHaas HA, Ward VP. Prophylaxis for postoperative deep-vein thrombosis: synergistic effect of heparin and dihydroergotamine. JAMA 1979; 241: 39-42. 8. Skinner DB, Salzman EW. Anticoagulant prophylaxis in surgical patients. Surg Gynecol Obstet 1967; 125: 741-6. 9. Shepard RM Jr, White HA, Shirkey AI. Anticoagulant prophylaxis of thromboembolism in postsurgical patients. Am J Surg 1966; 112: 698-702. 10. Leyvraz PF, Richard J, Bachmann F, et al. Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 1983: 309: 954-8. 11. Gallus AS, Hirsh J. Prevention of venous thromboembolism. Semin Thromb Hemost 1976; 2: 232-90. 12. Silver D. Vascular injury: its effect on thrombolysis. J Trauma 1969; 9: 668-74. 13. Aoki N, Moroi M, Sakata Y, Yoshida N, Matsuda M. Abnormal plasminogen: a hereditary molecular abnormality found in a patient with recurrent thrombosis. J Clin Invest 1978; 61: 1186-95.
THE AMERICAN JOURNAL OF SURGERY
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