Section ofPathology
11 Sabri S, Roberts V C & Cotton L T (1971a) British Medical Journal iii, 82 (1971b) British Medical Journal iv, 394 Spiro M, Roberb V C & Richards J B (1970) British Medical Journal i, 719-723
Mr V V Kakkar (King's College Hospital Medical School, Denmark Hill, London SE5 8RX)
Prophylaxis of Venous Thromboembolism Fatal pulmonary embolism has become an increasingly important cause of death during the last fifty years. The deaths recorded in the Registrar General's Report for England and Wales (Department of Health and Social Security 1970) indicate that there has been nearly a sixfold increase in mortality due to pulmonary embolism during the period 1943-71. The true magnitude of the problem has been revealed by several studies. The cause of almost all deaths has been determined by post-mortem examination. These autopsy studies have clearly shown that if the mortality due to pulmonary embolism is to be significantly reduced the prophylaxis must be directed towards patients who are confined to bed at home with various illnesses, those in medical wards, those with fractures of the lower limbs, those undergoing various orthopedic procedures, high risk patients having general abdominal surgery and obstetric patients, especially those with complicated pregnancy.
Many attempts have now been made to prevent thrombosis by simple means such as the use of chemical agents. Following surgery or childbirth there is increased platelet adhesiveness and some workers believe that this increased adhesiveness makes the platelets more likely to form a platelet nidus; for example at the site of endothelial damage or in the area of maximal stasis. It is argued that if this increased platelet adhesiveness could be prevented the likelihood ofthrombus formation would be reduced. It is with this background that various drugs have been investigated which decrease platelet adhesiveness. These include dextran (usually dextran 70), dipyridamole, aspirin and other compounds. The second chemical approach has been the use of drugs which interfere with the coagulation mechanism. A vital step in the sequence of coagulation is the conversion of prothrombin to thrombin following the activation of factor X. The thrombin so formed converts fibrinogen into fibrin, which in turn forms the essential network of a venous thrombus. Two different types of drugs have been investigated - oral anticoagulants, which act by reducing the synthesis in the liver of clotting factors II, VII, DX and X - and heparin, which also interferes with the coagulation mechanism. The third group of drugs increases naturally occurring fibrinolytic activity in the body, presutnably by acting on the venous endothelium, so that small thrombi which are formed frequently are rapidly dissolved. Many papers have recently been published, claiming success or otherwise, with various types of drugs and their results are summarized in Table 1. The evidence that drugs such as aspirin and dipyridamole, known to interfere with platelet
Table 1 Prophylaxis: drugs which affect platelet function and the incidence of postoperative deep vein thrombosis
Incidence of DVT Source Salzman et al. (1971) Medical Research Council (1972) Johnsson et al. Dextran (1967) Sawyer (1968) Brisman et al. (1971) Kakkar (1975) Bonnar & Walsh (1972) Dipyridamole Browse & Hall (1969) Fossard et al. Phenformin (1974) and
Drug Aspirin
ethylmastrenol
Diagnostic technique Clinical
Control group Treated group No. % No. % 9 4 23 34
"'I-fibrinogen
32
22
20
27.5
Clinical
13
52
1
4
Clinical
5 14
9.4 15.5
3 11
6 12.4
23
35
16
27
15
10.7
Clinical/ autopsy
"III-fibrinogen test
1'I-fibrinogen
1
0.8
test
Clinical
"I'-fibrinogen test
7
10
2.1
20
263
12 10
3.8 20
264
Proc. roy. Soc. Med. Volume 68 April 1975
12
Table 2 Prophylaxis: effect of low doses of heparin on the incidence of postoperative DVT as assessel in controlled clinical trials Control group Source Kakkaretal.(I971) Williams (1971)
GordonSmithetal.@ (1972) X.akkar et al. (1972)
No. studied 27 29 50 39
Nicolaides etal. (1972) 122
Gallusetal.(1973)
118
Treated group
No. with No. D VT studied 7(26%) 26 12 (4i %) 27 21(42%) 52 48 17(42%) 39 133 50 29(24%) 122 19(16%) 108
No. with D VT 1 (4%) 4 (15 Y.) 7(13.5%) 4(8.3%) 3 (8%) 13 (9.7%) 20(40%) 1 (0.8%)
2(2%)
Statistical significance 0.05 >P>0.025 0.02 >P > 0.01 P>0.003 P > 0.001 P > 0.001 P >0.000003 P>0.003
* A trial comparing 2 different regimes * Double-blind randomly allocated trial have now entered the trial, approximately equally distributed in 2 groups. Sixteen patients in the control group and 2 in the heparin group died of acute, massive, pulmonary embolism. The difference is statistically significant (P < 0.01)
14 200 patients
function, effectively reduce the incidence of deep vein thrombosis is unconvincing. However, the role of dextran is still uncertain and its efficacy in reducing the incidence of fatal pulmonary embolism remains to be determined. There is no doubt that drugs which are known to enhance naturally occurring fibrinolytic activity, such as phenformin and ethyleestrenol, are totally ineffective in preventing deep vein thrombosis in surgical patients. Oral anticoagulant therapy, properly employed (starting before operation or immediately after admission to hospital) is the most effective and proved method of preventing venous thrombosis. However, in spite of strict laboratory control, the risk of hbemorrhage is real and may even be greater than the dangers of thromboembolism if such therapy was accepted for general use. Of all the chemical agents which are being investigated at present, low-dose heparin (5000 units subcutaneously begun 2 hours before surgery and 8 hours thereafter for 7 to 10 days) seems to be the most promising drug for preventing deep vein thrombosis (Table 2). The efficacy of this method has been assessed in a number of controlled clinical trials and these studies have sAhownrctarly that this -form of prophylaxis- is well tolerated by patients, is devoid of sideeffects, requires no special monitoring, except that the patients receive the drug, and does not seem to result in excessive bleeding during or after surgery. Furthermore, it can be used on an extensive scale without straining hospital resources. However, final judgment on the value of this form of prophylaxis can only be established by unequivocal demonstration of a significant reduction in postoperative deaths from pulmonary embolism. This requires large-scale studies involving thousands of patients and such a multicentre trial is already under way in the United- Kingdom and abroad. Thirty-one centres in 11 countries are taking part in this study and a uniform protocol is being followed. Patients
over the age of 40 having major operations are being randomly allocated to control or treatment groups. The incidence of fatal pulmonary embolism, confirmed at autopsy, is being recorded in both groups. The results are being analysed by computer. In the first nine months of the trial 2055 patients have been entered - 1020 in the control group and. 1035 in the heparin group. Computer analysis of these patients has shown that the two groups are well matched for age, sex, presence of malignancy, type of operation performed and other factors likely to influence the incidence of thromboembolism. Seven patients in the control group and one in the heparin group died due to acute, massive, isolated pulmonary embolism. In another two patients in each group pulmonary emboli were confined to the lobar or segmental branches and, though not thought to be the primary cause, were contributory factors. If these findings are confirmed in larger numbers of patients, then low-dose heparin will provide an effective prophylactic method. REFERENCES Bonnar S & Walsh J (1972) Lancet i, 614 Brisman R, Parks L C & Haller J A (1971) Annals of Surgery 174, 137 Browse N L & Hall J H (1969) Lancet ii, 718 Fosard D P, Friend J R, Field E S, Corrigan R P, Kakkar V V & Flute P T (1974) Lancet i, 9 Gallus A S, Hirsh J, Tuttle R J, Trebilcock R, O'Brien S E, Carroll J J, Minden J H & Hudecki S M (1973) New England Journal of Medicine 288, 545-551 Gordon-Smith J C. Grundig D J, Le Quesne L P, Newcombe J F & Bramble F J (1972) Lancet i, 1133 Johnsson S R, Bygdeman S & Eliason R (1967) Acta chirurgica Scandinavica Suppl. 337, 80 Kakkar V V (1975) Platelets, drugs and Thrombosis. Karger, Basel; p 292 Kakkar V V, Corrigan R P, Spindler J, Fossard D P, Flute P T & Crellin R Q (1972) Lancet ii, 101 Kakkar V V, Field W S, Nicolaides A N, Flute P T, Wessier S & Yin E T (1971) Lancet ii, 699 Nicolaides A N, Dupont D A, Desai S, Lewis J D, Douglas J N, Dodsworth H, Fourides G, Luck R J & Jamieson C W (1972) Lancet ii, 890 Salzman E W, William H H & De Sanctis R W (1971) New England Journal ofMedicine284, 1287 Sawyer R (1968) Acta chirurgica Scandinavica Suppl. 387, 58 Williams H T(1971) Lancet ii, 950
11 Sabri S, Roberts V C & Cotton L T (1971a) British Medical Journal iii, 82 (1971b) British Medical Journal iv, 394 Spiro M, Roberb V C & Richards J B (1970) British Medical Journal i, 719-723
Mr V V Kakkar (King's College Hospital Medical School, Denmark Hill, London SE5 8RX)
Prophylaxis of Venous Thromboembolism Fatal pulmonary embolism has become an increasingly important cause of death during the last fifty years. The deaths recorded in the Registrar General's Report for England and Wales (Department of Health and Social Security 1970) indicate that there has been nearly a sixfold increase in mortality due to pulmonary embolism during the period 1943-71. The true magnitude of the problem has been revealed by several studies. The cause of almost all deaths has been determined by post-mortem examination. These autopsy studies have clearly shown that if the mortality due to pulmonary embolism is to be significantly reduced the prophylaxis must be directed towards patients who are confined to bed at home with various illnesses, those in medical wards, those with fractures of the lower limbs, those undergoing various orthopedic procedures, high risk patients having general abdominal surgery and obstetric patients, especially those with complicated pregnancy.
Many attempts have now been made to prevent thrombosis by simple means such as the use of chemical agents. Following surgery or childbirth there is increased platelet adhesiveness and some workers believe that this increased adhesiveness makes the platelets more likely to form a platelet nidus; for example at the site of endothelial damage or in the area of maximal stasis. It is argued that if this increased platelet adhesiveness could be prevented the likelihood ofthrombus formation would be reduced. It is with this background that various drugs have been investigated which decrease platelet adhesiveness. These include dextran (usually dextran 70), dipyridamole, aspirin and other compounds. The second chemical approach has been the use of drugs which interfere with the coagulation mechanism. A vital step in the sequence of coagulation is the conversion of prothrombin to thrombin following the activation of factor X. The thrombin so formed converts fibrinogen into fibrin, which in turn forms the essential network of a venous thrombus. Two different types of drugs have been investigated - oral anticoagulants, which act by reducing the synthesis in the liver of clotting factors II, VII, DX and X - and heparin, which also interferes with the coagulation mechanism. The third group of drugs increases naturally occurring fibrinolytic activity in the body, presutnably by acting on the venous endothelium, so that small thrombi which are formed frequently are rapidly dissolved. Many papers have recently been published, claiming success or otherwise, with various types of drugs and their results are summarized in Table 1. The evidence that drugs such as aspirin and dipyridamole, known to interfere with platelet
Table 1 Prophylaxis: drugs which affect platelet function and the incidence of postoperative deep vein thrombosis
Incidence of DVT Source Salzman et al. (1971) Medical Research Council (1972) Johnsson et al. Dextran (1967) Sawyer (1968) Brisman et al. (1971) Kakkar (1975) Bonnar & Walsh (1972) Dipyridamole Browse & Hall (1969) Fossard et al. Phenformin (1974) and
Drug Aspirin
ethylmastrenol
Diagnostic technique Clinical
Control group Treated group No. % No. % 9 4 23 34
"'I-fibrinogen
32
22
20
27.5
Clinical
13
52
1
4
Clinical
5 14
9.4 15.5
3 11
6 12.4
23
35
16
27
15
10.7
Clinical/ autopsy
"III-fibrinogen test
1'I-fibrinogen
1
0.8
test
Clinical
"I'-fibrinogen test
7
10
2.1
20
263
12 10
3.8 20
264
Proc. roy. Soc. Med. Volume 68 April 1975
12
Table 2 Prophylaxis: effect of low doses of heparin on the incidence of postoperative DVT as assessel in controlled clinical trials Control group Source Kakkaretal.(I971) Williams (1971)
GordonSmithetal.@ (1972) X.akkar et al. (1972)
No. studied 27 29 50 39
Nicolaides etal. (1972) 122
Gallusetal.(1973)
118
Treated group
No. with No. D VT studied 7(26%) 26 12 (4i %) 27 21(42%) 52 48 17(42%) 39 133 50 29(24%) 122 19(16%) 108
No. with D VT 1 (4%) 4 (15 Y.) 7(13.5%) 4(8.3%) 3 (8%) 13 (9.7%) 20(40%) 1 (0.8%)
2(2%)
Statistical significance 0.05 >P>0.025 0.02 >P > 0.01 P>0.003 P > 0.001 P > 0.001 P >0.000003 P>0.003
* A trial comparing 2 different regimes * Double-blind randomly allocated trial have now entered the trial, approximately equally distributed in 2 groups. Sixteen patients in the control group and 2 in the heparin group died of acute, massive, pulmonary embolism. The difference is statistically significant (P < 0.01)
14 200 patients
function, effectively reduce the incidence of deep vein thrombosis is unconvincing. However, the role of dextran is still uncertain and its efficacy in reducing the incidence of fatal pulmonary embolism remains to be determined. There is no doubt that drugs which are known to enhance naturally occurring fibrinolytic activity, such as phenformin and ethyleestrenol, are totally ineffective in preventing deep vein thrombosis in surgical patients. Oral anticoagulant therapy, properly employed (starting before operation or immediately after admission to hospital) is the most effective and proved method of preventing venous thrombosis. However, in spite of strict laboratory control, the risk of hbemorrhage is real and may even be greater than the dangers of thromboembolism if such therapy was accepted for general use. Of all the chemical agents which are being investigated at present, low-dose heparin (5000 units subcutaneously begun 2 hours before surgery and 8 hours thereafter for 7 to 10 days) seems to be the most promising drug for preventing deep vein thrombosis (Table 2). The efficacy of this method has been assessed in a number of controlled clinical trials and these studies have sAhownrctarly that this -form of prophylaxis- is well tolerated by patients, is devoid of sideeffects, requires no special monitoring, except that the patients receive the drug, and does not seem to result in excessive bleeding during or after surgery. Furthermore, it can be used on an extensive scale without straining hospital resources. However, final judgment on the value of this form of prophylaxis can only be established by unequivocal demonstration of a significant reduction in postoperative deaths from pulmonary embolism. This requires large-scale studies involving thousands of patients and such a multicentre trial is already under way in the United- Kingdom and abroad. Thirty-one centres in 11 countries are taking part in this study and a uniform protocol is being followed. Patients
over the age of 40 having major operations are being randomly allocated to control or treatment groups. The incidence of fatal pulmonary embolism, confirmed at autopsy, is being recorded in both groups. The results are being analysed by computer. In the first nine months of the trial 2055 patients have been entered - 1020 in the control group and. 1035 in the heparin group. Computer analysis of these patients has shown that the two groups are well matched for age, sex, presence of malignancy, type of operation performed and other factors likely to influence the incidence of thromboembolism. Seven patients in the control group and one in the heparin group died due to acute, massive, isolated pulmonary embolism. In another two patients in each group pulmonary emboli were confined to the lobar or segmental branches and, though not thought to be the primary cause, were contributory factors. If these findings are confirmed in larger numbers of patients, then low-dose heparin will provide an effective prophylactic method. REFERENCES Bonnar S & Walsh J (1972) Lancet i, 614 Brisman R, Parks L C & Haller J A (1971) Annals of Surgery 174, 137 Browse N L & Hall J H (1969) Lancet ii, 718 Fosard D P, Friend J R, Field E S, Corrigan R P, Kakkar V V & Flute P T (1974) Lancet i, 9 Gallus A S, Hirsh J, Tuttle R J, Trebilcock R, O'Brien S E, Carroll J J, Minden J H & Hudecki S M (1973) New England Journal of Medicine 288, 545-551 Gordon-Smith J C. Grundig D J, Le Quesne L P, Newcombe J F & Bramble F J (1972) Lancet i, 1133 Johnsson S R, Bygdeman S & Eliason R (1967) Acta chirurgica Scandinavica Suppl. 337, 80 Kakkar V V (1975) Platelets, drugs and Thrombosis. Karger, Basel; p 292 Kakkar V V, Corrigan R P, Spindler J, Fossard D P, Flute P T & Crellin R Q (1972) Lancet ii, 101 Kakkar V V, Field W S, Nicolaides A N, Flute P T, Wessier S & Yin E T (1971) Lancet ii, 699 Nicolaides A N, Dupont D A, Desai S, Lewis J D, Douglas J N, Dodsworth H, Fourides G, Luck R J & Jamieson C W (1972) Lancet ii, 890 Salzman E W, William H H & De Sanctis R W (1971) New England Journal ofMedicine284, 1287 Sawyer R (1968) Acta chirurgica Scandinavica Suppl. 387, 58 Williams H T(1971) Lancet ii, 950
