Refer to: Olcott C IV: Heparin prophylaxis for deep vein thrombosis and pulmonary embolism. West J Med 125:187190, Sep 1976

Heparin Prophylaxis for Deep Vein Thrombosis and Pulmonary Embolism CORNELIUS OLCOTT, IV, MD, San Francisco

Thromboembolic prophylaxis remains a significant problem and is obviously incompletely understood. It would appear, however, that at present the information available implies several points. First, administration of low-dose heparin is efficacious in preventing deep vein thrombosis and pulmonary emboli in most general surgical patients who are at risk for thromboembolic complications. Second, low-dose heparin probably works by augmenting the effect of the naturally occurring inhibitor to Factor Xa. Third, patients in whom surgical operations are done and extensive tissue dissection or postoperative immobilization (such as hip arthroplasties) is required are probably not protected by low-dose heparin administration; full anticoagulation with warfarin or treatment with one of the platelet antiaggregating agents should be carried out. Fourth, any form of anticoagulation carries some risk of bleeding complications, but it appears that the incidence of major bleeding complications is not significantly greater in the treatment groups.

DEEP VEIN THROMBOSIS and thrombophlebitis are responsible for a significant degree of morbidity in hospital. The complications, particularly chronic venous insufficiency and pulmonary emboli, are also important medical problems; the former contributing heavily to chronic disability and the latter a leading cause of death. It is estimated that in the United States there are 182,000 new cases of thrombophlebitis and 106,000 cases of pulmonary emboli annually.' Therefore, thromboemFrom the Department of Surgery, University of California, San Francisco. Submitted, revised, May 13, 1976 Reprint requests to: Cornelius Olcott, IV, MD, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143.

bolic complications occur in a little over a quarter of a million patients each year, many of these complications occurring while the patients are in the hospital. Hume and co-workers estimated that 5 of every 1,000 adults in whom major surgical procedures are carried out will die from a massive pulmonary embolus.1 Because of the magnitude of this problem, a number of investigators have explored the possibility of using low-dose heparin or other forms of anticoagulation as prophylaxis against deep vein thrombosis and pulmonary emboli. A great deal has been learned about the incidence of deep vein thrombosis since the developTHE WESTERN JOURNAL OF MEDICINE

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ment of accurate diagnostic techniques. The most widely used at this time is the 125I-fibrinogen scan which utilizes radioactively labeled fibrinogen to detect venous thrombosis. Early work by Kakkar has shown that the actual incidence of deep vein thrombosis as detected by the 1251-fibrinogen scan, is between 30 and 35 percent in patients in whom major surgical procedures are done.2 3 In only about half of these will the classical physical findings of thrombophlebitis be seen. This work also showed that about half of all cases of deep vein thrombosis occur in the perioperative period. Many investigators have utilized the 1251-fibrinogen scan, and it has subsequently been accepted as an accurate technique for the detection of deep vein thrombosis. Work by Harris and his colleagues showed that the results of fibrinogen scan correlated with those on phlebograms in 83 percent of the cases in which they were attempting to document fresh thrombi.4 It is recognized that certain patients are more prone to thromboembolic complications than

others. Work by Kakkar and associates has defined this high risk group.3 He studied 203 patients over the age of 40 who were admitted for elective surgical operations. In all patients studies were made utilizing the 125I-fibrinogen scan. Certain patients were found to have an inordinately high incidence of deep vein thrombosis-such as patients with previous pulmonary emboli (100 percent), previous history of deep vein thrombosis (68.4 percent), varicose veins (56.5 percent), obesity (47.9 percent), malignancy (40.7 percent) and increased age (45.7 percent in patients over 60 years of age and 24.4 percent in patients under 60 years of age). This study therefore defined those patients in whom thromboembolic complications are most likely to occur and who would therefore be candidates for some form of prophylactic therapy. The possible use of low-dose heparin was suggested 25 years ago by DeTakats when he noted that it took less heparin to prevent clotting than to stop it.5 Kakkar and co-workers were the first

TABLE 1.-Efficacy of Low-Dose Heparin Administration Incidence of Deep Number of

Date Patients

Author

Regimen

Vein Thrombosis Low-Dose Control Heparin

(percent) (percent)

Remarks

53 5,000 units 2 hours before and 24 hours 26.0 4.0 Patients over age 50 for elective hernia repair after surgical operation, then every 12 hours for 5 days .1971 56 10,000 units 10 hours preoperatively, 41.0 15.0 Patients over age 50 for Williams7 abdominal surgical pro2,500-5,000 units every 6 hours for 7 days cedures Nicolaides, et a18 . 1972 251 5,000 units 2 hours before operation and 24.0 0.8 Patients over age 40 for major surgical operation then every 12 hours for 7 days Double-blind study with 8.0 42.0 then before operation, Kakkar, Corrigan, et a19 1972 78 5,000 units 2 hours patients over age 40 5,000 units every 12 hours for 7 days Gordon-Smith, et al'0 . 1972 150 5,000 units 2 hours before operation, then 42.0 13.5* Patients over age 40 in 8.3t whom major surgical op5,000 units every 12 hours for 7 days eration was done Gallus, et all' ....... 1973 226 5,000 units 2 hours before operation and 16.0 2.0 Patients over age 40 in whom elective surgical then every 8 hours until ambulatory operation was done 46 5,000 units after admission and then 5,000 48.0 13.0 Patients admitted for emergency operation for units every 8 hours through surgical ophip fracture eration 28.0 Patients undergoing total 1973 25 5,000 units 2 hours preoperatively and Evarts and Alfidil2 hip replacement then 5,000 units every 12 hours for 7-10 days 1975 105 5,000 units preoperatively and then 5,000 9.6 7.5 Patients over age 40 unCovey, et al3 dergoing elective surgiunits every 12 hours for 8 days cal operation, doubletHeParin for 7 days *Heparin for 3 days blind

Kakkar, Field, et a16 .. 1971

.

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HEPARIN PROPHYLAXIS

to utilize low-dose heparin in a clinical trial to test its efficacy in preventing venous thrombosis in surgical patients.,; Since that time a number of other investigators have carried out clinical trials with low-dose heparin.-'1 Although the protocol has varied among investigators the results have documented the efficacy of low-dose heparin administration in preventing deep vein thrombosis in postoperative patients (see Table 1). Low-dose heparin is usually defined as 5,000 units administered subcutaneously 2 hours before surgical operation and then every 12 hours in the postoperative period for five to seven days or until the patient is fully ambulatory. However, some investigators have varied this protocol (see Table 1). The consensus from these studies is that lowdose heparin is effective in decreasing the incidence of deep vein thrombosis in patients in whom general, thoracic or gynecological surgical procedures are carried out. Patients in whom prostatectomy7 or hip reconstruction procedures'2 are done were not protected. The low incidence of deep vein thrombosis in Covey's series is difficult to explain; the authors hypothesized that it might be due to the large number of patients taking aspirin or to the type of fibrinogen used to detect deep vein thrombosis. The next obvious step was to determine whether decreasing the incidence of venous thrombosis had any effect on decreasing the occurrence of pulmonary embolism. Sagar and coworkers prospectively studied 500 patients in whom elective surgical operations were carried out and found no deaths attributable to pulmonary emboli among the 252 patients in whom low-dose heparin was administered, while eight of 236 patients (3.4 percent) of the control group died as a result of pulmonary emboli.14 Results in a recently published international multicenter trial, coordinated by Kakkar and his colleagues, have provided definitive information about the role of low-dose heparin in preventing pulmonary emboli.1' The cases of more than 4,000 patients were studied in this report. The heparin regimen was 5,000 units given subcutaneously two hours preoperatively and then every eight hours for seven days. Sixteen patients in the control group (0.77 percent) and two in the heparin-treated group (0.09 percent) died as a direct result of pulmonary emboli, a statistically significant difference. In the same study, deep vein thrombosis was detected in 24.6 percent of the control group and 7.7 percent of the heparin-treated group. In

only five patients in the heparin group did the venous thrombosis extend above the knee, while this occurred in 49 patients of the control group. Findings in this study showed no statistically significant difference in the transfusion requirements or in postoperative hemoglobin drop between the control and the heparin-treated patients. However, the incidence of excessive intraoperative blood loss and wound hematomas was slightly greater in the heparin treated group. In only 53 of the 2,045 patients in the heparin group was discontinuation of heparin required because of bleeding complications. One question naturally arises: Why does heparin, in what would normally be considered nonanticoagulating doses, have an antithrombotic effect? While the exact mechanism still remains to be explained, many theories have been offered. The most widely accepted has been that offered by Wessler and his colleagues.',"7 They have suggested that the prevention of a hypercoagulable state is dependent upon the neutralization of activated Factor X (Xa), which is normally the result of a naturally occurring inhibitor to Xa. They have also suggested that small amounts of heparin will greatly increase the rate of Xa neutralization by its inhibitors-that is, augment severalfold the capacity of one's own naturally occurring inhibitors to block the activity of Xa and hence the conversion of prothrombin to thrombin. Wessler and his colleagues have also shown that the inhibitor to Xa is one and the same as antithrombin III and heparin cofactor.'7 Reduction in antithrombin III levels may favor the development of postoperative thrombosis, and in patients in whom there is a decreased antithrombin III level there may be no response to low-dose heparin administration if the inhibitor system is significantly compromised. In summary, it would appear that the coagulation cascade may be interrupted at the level of activated Factor X(Xa) by small amounts of heparin, providing the stimulus to coagulation is not so great that the amount of Factor X that is activated exceeds that which can be neutralized by heparin in conjunction with the naturally occurring Xa inhibitor and that Xa is neutralized before the actual formation of fibrin has begun (that is, administration of heparin is begun preoperatively). This would explain the failure of low-dose heparin administration to be effective in patients, such as those with hip fractures or hip reconstructions, in whom there is major tissue THE WESTERN JOURNAL OF MEDICINE

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dissection as part of the operative procedure. In these cases the stimulus for clotting overrides the protective effect of low-dose heparin. Other drugs, primarily warfarin and platelet antiaggregating agents, have also been studied for their usefulness in preventing thromboembolic complications. Sevitt and Gallagher were the first to investigate the efficacy of an oral anticoagulant of the warfarin type (phenindione). 18 They studied the cases of patients over the age of 55 with hip fractures and found a 28.7 percent incidence of thrombophlebitis in the control group and a 2.7 percent incidence in the phenindione series. There were 15 deaths from pulmonary emboli in the control group and only two deaths in the anticoagulated group, both of which occurred after therapy had been discontinued. Salzman and associates also studied the value of prophylactic anticoagulation with warfarin in patients with hip fractures.19 They noted a 7 percent incidence of pulmonary embolism in the control group while in none of the patients in the anticoagulated group was an embolism present. Thrombophlebitis, detected clinically, occurred in 22 percent of the control patients and 7 percent of the warfarin group. Findings in a similar study using warfarin prophylaxis in patients in whom hip arthroplasties were done at the Massachusetts General Hospital showed a 36 percent incidence of thromboembolic complications in the control group as opposed to 9 percent in the warfarin group.20 There were seven (10 percent) cases of pulmonary embolism in the control group while there were no pulmonary emboli in the treated group. In all of the above studies, full anticoagulation was the goal. Whenever full anticoagulation, as opposed to low-dose heparin administration, is utilized, a higher incidence of bleeding complications would be anticipated. In Salzman's series the incidence of major bleeding in the treated group was 7 per cent, and 5 percent in the control group.'9 Harris noted an increase in local and distant bleeding complications where warfarin was used in elective surgical procedures on the hip.20 For example, wound hematomas occurred in 23 percent of the warfarin group and 18 percent of the control group. However, their differences appear to be small and actual cessation of anticoagulation was required in only two cases because of persistent bleeding and no patient had a prolonged stay in hospital because of anticoagulation. Salzman and his group have also studied the 190

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efficacy of agents which effect platelet functiondipyridamole, aspirin and dextran." They found no protection from dipyridamole, though aspirin and dextran both proved as effective as warfarin in preventing thromboembolic complications. The incidence of major bleeding complications did not differ significantly among the groups treated with warfarin, aspirin, dipyridamole and dextran. However, in the group receiving aspirin a significantly greater volume of postoperative transfusion was required and only in the warfarin group did bleeding lead to a discontinuation of therapy (four patients). However, results of a similar study, from Stinchfield's service in New York, failed to show any protective effect from administration of dextran. REFERENCES 1. Hume M, Sevitt J, Thomas DP: Venous Thrombosis and Pulmonary Embolism. Cambridge, Harvard University Press, 1970 2. Flanc C, Kakkar VV, et al: The detection of venous thrombosis of the legs using 1251-Fibrinogen. Br J Surg 55:742-747, Oct 1968 3. Kakkar VV, Howe CT, et al: Deep vein thrcmbosis of the leg: Is there a high risk group? Am J Surg 120:527-530, Oct 1970 4. Harris WH, Salzman EW, Athanasoulix C, et al: Comparison of '251-fibrinogen count scanning with phlebography for detection of venous thrombi after elective hip surgery. N Engl J Med 292: 665-667, Mar 1975 5. De Takats G: Anticoagulants in surgery. JAMA 142:527-534, Feb 1950 6. Kakkar VV, Fields ES, et al: Low dose of heparin in prevention of deep-vein thrombosis. Lancet 2:669-671, Sep 1971 7. Williams HT: Prevention of postoperative deep-vein thrombosis with perioperative subcutaneous heparin. Lancet 2:950-952, Oct 1971 8. Nicolaides AN: Small doses of subcutaneous heparin in preventing deep venous thrombosis after major surgery. Lancet 2:890-893, Oct 1972 9. Kakkar VV, Corrigan T, Spindler J, et al: Efficacy of low dose heparin in the prevention of deep-vein thrombosis after major surgery. Lancet 2:101-106, Jul 1972 10. Gordon-Smith IC, Grundy DJ, et al: Controlled trial of two regimens of subcutaneous heparin in prevention of postoperative deep-vein thrombosis. Lancet 1:1133-1135, May 1972 11. Gallus AS, Hirsh J, Tuttle RJ, et al: Small subcutaneous doses of heparin in prevention of venous thrombosis. N Engl J Med 288:545-551, Mar 1973 12. Evarts CM, Alfidi RJ: Thromboembolism after total hip reconstruction. JAMA 225:515-516, Jul 1973 13. Covey TH, Sherman L, Baue AE: Low dose heparin in postoperative patients: A prospective, coded study. Arch Surg 110:1021-1025, Aug 1975 14. Sagar S, Massey J, Sanderson JM: Low-dose heparin prophylaxis against fatal pulmonary embolism. Br Med J 4:257-259, Nov 1975 15. Kakkar VV, Corrigan TP, Fossard DP: Prevention of fatal postoperative pulmonary embolism by low dose of heparin: an international multicentre trial. Lancet 2:45-51, Jul 1975 16. Wessler S, Yin ET: Theory and practice of minidose heparin in surgical patients: A status report. Circulation 47:671-676, 1973 17. Wessler S: Small doses of heparin and a new concept of hypercoagulability. Thromb Diath Haemorrh 33:81-86, Sep 1975 18. Sevitt S, Gallagher NG: Prevention of venous thrombosis and pulmonary embolism in injured patients-A trial of anticoagulant prophylaxis with phenindione in middle-aged and elderly patients with fractured necks of the femur. Lancet 2:981-989, Dec 1959 19. Salzman EW, Harris WH, DeSanctis RW: Anticoagulation for prevention of thromboembolism following fracture of the hip. N Engl J Med 275:122-130, Jul 1966 20. Harris WH, Salzman EW, DeSanctis RW: The prevention of thromboembolic disease by prophylactic anticoagulation. J Bone Joint Surg 49:81-89, Jan 1967 21. Salzman EW, Harris WH, DeSanctis RW: Reduction in venous thromboembolisms by agents affecting platelet function. N Engl J Med 284:1287-1292, Jun 1971 22. Rothermel JE, Wessinger JJ, Stinchfield FE: Dextran 40 and thromboembolism in total hip replacement surgery. Arch Surg 106:135-141, Feb 1973

Heparin prophylaxis for deep vein thrombosis and pulmonary embolism.

Refer to: Olcott C IV: Heparin prophylaxis for deep vein thrombosis and pulmonary embolism. West J Med 125:187190, Sep 1976 Heparin Prophylaxis for D...
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