The Prevention of Deep Vein Thrombosis and Pulmonary Embolism L. P. Le Quesne, DM, MCH, FRCS, London, England
The development of the iodine 125 (1251)-fibrinogen technic for the diagnosis of deep vein thrombosis [1] provided a valuable tool for the investigation of this important postoperative complication. Despite some limitations, its use has enabled many basic facts concerning this condition to be established with certainty [2]. It is now clear that with allowance for variations due principally to age and the type and severity of the operation, approximately 25 to 30 per cent of patients more than forty years old undergoing an abdominal operation in a temperate climate develop isotopically detectable deep vein thrombosis. It is initially detected in the calf in the majority of patients; although the disease remains localized there in approximately 90 per cent, proximal spread occurs in the minority. Approximately 90 per cent of these thrombi are first detected within 48 hours of operation, but some may not be detected until ten days or more after operation. Furthermore, there is evidence [3] that in some patients deep vein thrombosis may develop before operation. The 1251-fibrinogen technic is also admirably suited for prospective trials of prophylactic regimes, and such trials gain in significance when assessed against the basic facts outlined above. Our concepts of the causes of intravascular thrombosis are still bound by Virchow’s triad (1856) in which he defined the three main factors responsible for the condition: (1) changes in the vessel wall; (2) changes in flow; and (3) changes in the blood. Little is known about any changes that may occur in the intima of veins during and after operation, but it is known that after operation the venous return from the lower limbs is slowed and that there are a group of changes in the blood that render it more liable to clot. In relation to these factors the many prophylactic regimes which have been tested can, at least on superficial analysis, From the Department of Surgical Studies, The Miilesex Hospital, London. England. Reprint requests should ba addressed to L. P. Le Quesne, DM, Department of Surgical Studies, The Middlesex Hospital, London WlN 8AA. England.
Volume 135. March 1970
be divided into two groups: (1) those designed to combat stasis and speed venous return (antistasis technics) and (2) those designed to mitigate the postoperative changes in the clotting mechanism (antithrombotic regimes). Prophylactic Regimes
Antistasis Technics. The main antistasis technics that have been shown to cause significant diminution in the incidence of deep vein thrombosis as detected by the fibrinogen technic are intermittent galvanic stimulation of the calf muscles [4], passive dorsiflexion of the ankle [5], and intermittent calf compression [6]. Despite the fact that the first two of these technics were applied only during the operation and the third continued only for a relatively few hours thereafter, in several of the studies the apparent benefit was greater than expected from treatment over so short a period. Recently two other antistasis technics have been shown to be effective. Sigel et al [7] in 1975 showed that graduated compression to the lower limb, the compression diminishing from the ankle proximally, speeds the rate of venous return, and recent studies [8,9] have shown that elastic stockings designed on this principle diminish the incidence of isotopically detected deep vein thrombosis. In addition, dihydroergotamine tartrate has been shown to have a specific constrictor effect on capacitance vessels and minimal effect on resistance vessels, so that it markedly speeds the rate of venous return, and Butterman et al [IO] have shown that dihydroergotamine significantly reduces the incidence of postoperative deep vein thrombosis. Both of these technics clearly require further evaluation. Antithrombotic Regimes. Many studies have shown that infusions of high molecular weight dextran significantly reduce the incidence of deep vein thrombosis [11,12]. Further, it appears that any clots formed in patients receiving dextran are of looser
421
Le Quesne
TABLE I
Main Published Results of the Use of Subcutaneous Perioperative Heparin in the Prevention of Deep Vefn Thrombosis Controls % DVT No.
Treated Patients % DVT No.
Kakkar et al [ 181 (1971) Williams [ 191 (1971)
27 29
26 41
26 27
Ni$$s et al [ ZO] Kakkar et al [27] (1972) Ballard et al [22] (1973) Gallus et al [23] (1973) M. H. series’ Totals
122 39 55 141 123 536
24 43 29 21 37 30
122 172 55 131 80 613
4 15 1 9.3 3.6 3.8 12.4 6.5
Note: In all series the dose was oiven initially 1 hour prior to operation and thereafter at 12 hour intervals for 5 to 7 days postoberatively. In all series the heparin administration resulted in a significant reduction in the incidence of deep vein thrombosis (DVT). Patients studied at The Middlesex Hospital (including [ 241). l
texture [13] and are more readily lysed than those in controls, which may account for the effectiveness of dextran in preventing pulmonary embolus [ 141. Recently the administration of dipyridamole and aspirin together, both drugs affecting platelet aggregation, has been shown to be effective in reducing the incidence of isotopically detected deep vein thrombosis [15]. Previous studies of each of these drugs separately had shown them to have little or no benefit in this respect, and their synergistic effect is of importance in suggesting that other combinations of prophylactic measures might also be effective. The greatest interest has centered around the use of low dose heparin; that is, doses of approximately 5,000 units given subcutaneously usually at 12 hour intervals. Originally introduced by Sharnoff, Kass, and Mistica [16] and Sharnoff and De Blasio [17], who claimed that it reduced the incidence of fatal pulmonary embolism, a number of trials (Table I) have shown clearly that heparin given in this dosage, with the initial dose shortly before operation and continued thereafter every 12 hours for five days or more, reduces the incidence of isotopically detected deep vein thrombosis. In this dosage the heparin causes little or no detectable change in whole blood clotting, with the result that blood loss during and after operation is not significantly increased. However, the heparin levels in blood vary the occurrence of excessive blood loss, especially if the drug is given every 8 hours.
Problems
in Prevention
Three general considerations of the prophylactic regimes discussed herein demand attention.
422
TABLE II
Prevention of Postoperative Deep Vein Thrombosis by Various Regimes of Subcutaneous Heparln
tieparin Regime
Total Patients Per Cent Positive*
Controls 5,000 IU with premeditation only
80 54
27 21
5,000 IU every 12 hr for 36 5 hr days
82 33
18 9
l
Deep vein thrombosis diagnosed by 1251-fibrinogentechnic.
First, while there is no doubt that all these methods of treatment are in general effective in diminishing the incidence of isotopically detected deep vein thrombosis, their relative efficacy, both absolutely and in terms of cost-effectiveness, requires ‘further study. This is particularly the case in certain specific situations, as with patients undergoing operations for malignant disease when it is more difficult to prevent deep vein thrombosis and those undergoing reconstructive operations on the hip. In both these groups of patients there is a conflict as to the efficacy of the various regimes, and it may well be that in the latter group the condition differs in important respects from that of patients undergoing abdominal operations. Secondly, it is becoming apparent that the division of the prophylactic regimes into two clear-cut categories, those aimed at combatting stasis and those aimed at mitigating the hypercoagulable state, is unduly simplistic. There is evidence suggesting that intermittent limb compression not only influences the rate of venous return, but also enhances fibrinolysis [25]. In addition, although it is generally accepted that the efficacy of low dose heparin is due to the fact that in small concentrations it is a potent inhibitol’ of activated factor X, there is also recent evidence that it diminishes blood viscosity [26], and hence presumably increases flow. This suggests that the mode of action of these various prophylactic measures is more complex than initialIy thought. Thirdly, although in general the so-called antistasis technics appear to be less effective than heparin, there is an interesting contrast between the two. Table II shows the results of a study testing the efficacy of low dose heparin given in three courses, all with the same individual dosage but with a different length of time over which the dosage was given. Even though the majority of thrombi form in the first 48 hours after operation, it is clear that the shorter the course of heparin administration the lesser the benefit. It is of interest that heparin given only during
The American Journal of Surgery
Deep Vein Thrombosis and Pulmonary Embolism
Figure 1. Left, phiebogram showingasmaiittsvn&s inacaWveiq typical of the majority of clots detected by the 125Cfibrlnogen technic. Right, phiebogram showing a iarge thrombus in the proximal femoral vein extending up into the iiiac vein. 771istype of thrombus can give rise to a dangerous puimonary embolus.
the perioperative period has less effect than the antistatis technics, many of which are applied only in this period. This suggests that the antistasis technics may interfere with the process of thrombus formation at an early stage, perhaps in the initial deposition of platelets. Although thrombus formation can take place several days after operation, so that it may be desirable to use prophylactic technics with continuing effects throughout this period, this contrast draws attention to the vital importance of the changes taking place during the operation itself. Do These Regimes Prevent Pulmonary Embolism? All the studies referred to herein are based on the incidence of isotopically detected deep vein thrombosis-mostly small thrombi confined to the calf. (Figure 1, left.) These small clots are in themselves of no importance, and the cardinal question is their relationship to the large clots in the proximal veins
Vokmu 135, March 1979
(Figure 1, right) which are responsible for the majority of major pulmonary emboli. According to the orthodox, or classic, view of the spread of thrombosis, the thrombus starts in the calf, and spread occurs as a continuous, centripetal process, resulting in the formation of a long thrombus anchored mainly or solely at its site of origin. If this is the manner in which large thrombi form, then the prevention of calf vein thrombosis should indeed diminish the incidence of pulmonary embolus. There is, however, an alternative view, according to which large proximal thrombi form separate from and not necessarily in any way related to distal calf thrombi. If this is true, then the prevention of calf vein thrombosis would not influence the incidence of pulmonary embolus, save in so far as the methods used also prevented the formation of the proximal thrombi. These two theories are apparently irreconcilable; yet, a single chance observation raises the
423
Le Quesne
suggestion that the conflict may be more apparent than real, and that it is possible that some of the isolated thrombi seen in the femoral vein did not form there ab initio, but formed in the calf, at some time broke loose, and rather than passing into the lungs stuck proximally in the femoral vein. There are many postmortem studies of the distribution of thrombi in the leg and also of the origin of pulmonary emboli. With regard to the latter, there is general agreement that although some major pulmonary emboli may arise from pelvic veins, the majority come from the femoroiliac venous segment. But there is more disagreement with regard to the former problem. Leaving aside the question of platelet deposition, which is often seen in the valve cusps of the femoral vein, in some studies all the proximal thrombi were associated with and often in continuity with distal calf vein thrombosis [27], whereas in other studies there was a definite incidence of separate, proximal thrombi [28]. However, considering all the evidence, most proximal thrombi are associated with distal thrombosis. In assessing the meaning of these autopsy studies it is important to bear in mind that frequently death is not an instantaneous event and that some of the thrombi seen at autopsy may in fact represent agonal events, in contrast to isotopic and venographic studies which reflect changes in life. Bauer [29], in his often overlooked study of forty postoperative patients with repeated phlebography, observed “no single case in which a failure of filling of the femoral vein was found in conjunction with normally filled veins of the lower leg.” Based on a much larger phlebographic study, Fossard et al [30] concluded that more than 90 per cent of thrombi form in the calf veins and propagate proximally. This evidence suggests that the orthodox theory of the spread of thrombus in the lower limb is correct in the majority of instances, and hence, prevention of calf vein thrombosis should materially diminish the incidence of pulmonary embolism. To obtain direct evidence in support of this proposition is difficult for a number of reasons, especially that of establishing the diagnosis of pulmonary embolism not only in life but also after death. A number of studies like that of Lahnborg et al [31] have shown that the incidence of pulmonary embolism as diagnosed by lung scans is significantly higher in patients with isotopic evidence of deep vein thrombosis than in those without such evidence, but this does not necessarily mean that the incidence of major embolism in the former group is less, for as pointed out earlier, small emboli arising distally may be unrelated to the large dangerous thrombus arising in the proximal veins.
424
Bearing in mind that the predominant danger of deep vein thrombosis is death from pulmonary embolism, the crucial evidence required is the effect of the various prophylactic measures on the incidence of such deaths. The great difficulty in the search for such evidence is the large number of patients that need to be studied to obtain significant results. Two studies involving comparatively modest numbers of patients, one using low dose heparin [32] and the other dextran infusion [14], showed an apparently significant diminution in the deaths from pulmonary embolism. However, the most important study has been the International Multicenter Trial organized by Kakkar [33] in 1975. In this trial the death rate from pulmonary embolism in a series of 2,045 patients receiving 5,060 units of heparin subcutaneously every 8 hours for seven days after operation was compared with that in 2,076 control subjects. The two groups were well matched with respect to age (all >40 years), weight, type of operation, and incidence of malignancy. In all, eighty heparin-treated patients died, fifty-three (66 per cent) of whom underwent autopsy, and 100 control subjects died, seventy-two of whom underwent autopsy. The death rate from pulmonary embolism was significantly less in the treated group (2 of 80) than in the control group (16 of 100) (p
The development of the iodine 125 (1251)-fibrinogen technic for the diagnosis of deep vein thrombosis [1] provided a valuable tool for the investigation of this important postoperative complication. Despite some limitations, its use has enabled many basic facts concerning this condition to be established with certainty [2]. It is now clear that with allowance for variations due principally to age and the type and severity of the operation, approximately 25 to 30 per cent of patients more than forty years old undergoing an abdominal operation in a temperate climate develop isotopically detectable deep vein thrombosis. It is initially detected in the calf in the majority of patients; although the disease remains localized there in approximately 90 per cent, proximal spread occurs in the minority. Approximately 90 per cent of these thrombi are first detected within 48 hours of operation, but some may not be detected until ten days or more after operation. Furthermore, there is evidence [3] that in some patients deep vein thrombosis may develop before operation. The 1251-fibrinogen technic is also admirably suited for prospective trials of prophylactic regimes, and such trials gain in significance when assessed against the basic facts outlined above. Our concepts of the causes of intravascular thrombosis are still bound by Virchow’s triad (1856) in which he defined the three main factors responsible for the condition: (1) changes in the vessel wall; (2) changes in flow; and (3) changes in the blood. Little is known about any changes that may occur in the intima of veins during and after operation, but it is known that after operation the venous return from the lower limbs is slowed and that there are a group of changes in the blood that render it more liable to clot. In relation to these factors the many prophylactic regimes which have been tested can, at least on superficial analysis, From the Department of Surgical Studies, The Miilesex Hospital, London. England. Reprint requests should ba addressed to L. P. Le Quesne, DM, Department of Surgical Studies, The Middlesex Hospital, London WlN 8AA. England.
Volume 135. March 1970
be divided into two groups: (1) those designed to combat stasis and speed venous return (antistasis technics) and (2) those designed to mitigate the postoperative changes in the clotting mechanism (antithrombotic regimes). Prophylactic Regimes
Antistasis Technics. The main antistasis technics that have been shown to cause significant diminution in the incidence of deep vein thrombosis as detected by the fibrinogen technic are intermittent galvanic stimulation of the calf muscles [4], passive dorsiflexion of the ankle [5], and intermittent calf compression [6]. Despite the fact that the first two of these technics were applied only during the operation and the third continued only for a relatively few hours thereafter, in several of the studies the apparent benefit was greater than expected from treatment over so short a period. Recently two other antistasis technics have been shown to be effective. Sigel et al [7] in 1975 showed that graduated compression to the lower limb, the compression diminishing from the ankle proximally, speeds the rate of venous return, and recent studies [8,9] have shown that elastic stockings designed on this principle diminish the incidence of isotopically detected deep vein thrombosis. In addition, dihydroergotamine tartrate has been shown to have a specific constrictor effect on capacitance vessels and minimal effect on resistance vessels, so that it markedly speeds the rate of venous return, and Butterman et al [IO] have shown that dihydroergotamine significantly reduces the incidence of postoperative deep vein thrombosis. Both of these technics clearly require further evaluation. Antithrombotic Regimes. Many studies have shown that infusions of high molecular weight dextran significantly reduce the incidence of deep vein thrombosis [11,12]. Further, it appears that any clots formed in patients receiving dextran are of looser
421
Le Quesne
TABLE I
Main Published Results of the Use of Subcutaneous Perioperative Heparin in the Prevention of Deep Vefn Thrombosis Controls % DVT No.
Treated Patients % DVT No.
Kakkar et al [ 181 (1971) Williams [ 191 (1971)
27 29
26 41
26 27
Ni$$s et al [ ZO] Kakkar et al [27] (1972) Ballard et al [22] (1973) Gallus et al [23] (1973) M. H. series’ Totals
122 39 55 141 123 536
24 43 29 21 37 30
122 172 55 131 80 613
4 15 1 9.3 3.6 3.8 12.4 6.5
Note: In all series the dose was oiven initially 1 hour prior to operation and thereafter at 12 hour intervals for 5 to 7 days postoberatively. In all series the heparin administration resulted in a significant reduction in the incidence of deep vein thrombosis (DVT). Patients studied at The Middlesex Hospital (including [ 241). l
texture [13] and are more readily lysed than those in controls, which may account for the effectiveness of dextran in preventing pulmonary embolus [ 141. Recently the administration of dipyridamole and aspirin together, both drugs affecting platelet aggregation, has been shown to be effective in reducing the incidence of isotopically detected deep vein thrombosis [15]. Previous studies of each of these drugs separately had shown them to have little or no benefit in this respect, and their synergistic effect is of importance in suggesting that other combinations of prophylactic measures might also be effective. The greatest interest has centered around the use of low dose heparin; that is, doses of approximately 5,000 units given subcutaneously usually at 12 hour intervals. Originally introduced by Sharnoff, Kass, and Mistica [16] and Sharnoff and De Blasio [17], who claimed that it reduced the incidence of fatal pulmonary embolism, a number of trials (Table I) have shown clearly that heparin given in this dosage, with the initial dose shortly before operation and continued thereafter every 12 hours for five days or more, reduces the incidence of isotopically detected deep vein thrombosis. In this dosage the heparin causes little or no detectable change in whole blood clotting, with the result that blood loss during and after operation is not significantly increased. However, the heparin levels in blood vary the occurrence of excessive blood loss, especially if the drug is given every 8 hours.
Problems
in Prevention
Three general considerations of the prophylactic regimes discussed herein demand attention.
422
TABLE II
Prevention of Postoperative Deep Vein Thrombosis by Various Regimes of Subcutaneous Heparln
tieparin Regime
Total Patients Per Cent Positive*
Controls 5,000 IU with premeditation only
80 54
27 21
5,000 IU every 12 hr for 36 5 hr days
82 33
18 9
l
Deep vein thrombosis diagnosed by 1251-fibrinogentechnic.
First, while there is no doubt that all these methods of treatment are in general effective in diminishing the incidence of isotopically detected deep vein thrombosis, their relative efficacy, both absolutely and in terms of cost-effectiveness, requires ‘further study. This is particularly the case in certain specific situations, as with patients undergoing operations for malignant disease when it is more difficult to prevent deep vein thrombosis and those undergoing reconstructive operations on the hip. In both these groups of patients there is a conflict as to the efficacy of the various regimes, and it may well be that in the latter group the condition differs in important respects from that of patients undergoing abdominal operations. Secondly, it is becoming apparent that the division of the prophylactic regimes into two clear-cut categories, those aimed at combatting stasis and those aimed at mitigating the hypercoagulable state, is unduly simplistic. There is evidence suggesting that intermittent limb compression not only influences the rate of venous return, but also enhances fibrinolysis [25]. In addition, although it is generally accepted that the efficacy of low dose heparin is due to the fact that in small concentrations it is a potent inhibitol’ of activated factor X, there is also recent evidence that it diminishes blood viscosity [26], and hence presumably increases flow. This suggests that the mode of action of these various prophylactic measures is more complex than initialIy thought. Thirdly, although in general the so-called antistasis technics appear to be less effective than heparin, there is an interesting contrast between the two. Table II shows the results of a study testing the efficacy of low dose heparin given in three courses, all with the same individual dosage but with a different length of time over which the dosage was given. Even though the majority of thrombi form in the first 48 hours after operation, it is clear that the shorter the course of heparin administration the lesser the benefit. It is of interest that heparin given only during
The American Journal of Surgery
Deep Vein Thrombosis and Pulmonary Embolism
Figure 1. Left, phiebogram showingasmaiittsvn&s inacaWveiq typical of the majority of clots detected by the 125Cfibrlnogen technic. Right, phiebogram showing a iarge thrombus in the proximal femoral vein extending up into the iiiac vein. 771istype of thrombus can give rise to a dangerous puimonary embolus.
the perioperative period has less effect than the antistatis technics, many of which are applied only in this period. This suggests that the antistasis technics may interfere with the process of thrombus formation at an early stage, perhaps in the initial deposition of platelets. Although thrombus formation can take place several days after operation, so that it may be desirable to use prophylactic technics with continuing effects throughout this period, this contrast draws attention to the vital importance of the changes taking place during the operation itself. Do These Regimes Prevent Pulmonary Embolism? All the studies referred to herein are based on the incidence of isotopically detected deep vein thrombosis-mostly small thrombi confined to the calf. (Figure 1, left.) These small clots are in themselves of no importance, and the cardinal question is their relationship to the large clots in the proximal veins
Vokmu 135, March 1979
(Figure 1, right) which are responsible for the majority of major pulmonary emboli. According to the orthodox, or classic, view of the spread of thrombosis, the thrombus starts in the calf, and spread occurs as a continuous, centripetal process, resulting in the formation of a long thrombus anchored mainly or solely at its site of origin. If this is the manner in which large thrombi form, then the prevention of calf vein thrombosis should indeed diminish the incidence of pulmonary embolus. There is, however, an alternative view, according to which large proximal thrombi form separate from and not necessarily in any way related to distal calf thrombi. If this is true, then the prevention of calf vein thrombosis would not influence the incidence of pulmonary embolus, save in so far as the methods used also prevented the formation of the proximal thrombi. These two theories are apparently irreconcilable; yet, a single chance observation raises the
423
Le Quesne
suggestion that the conflict may be more apparent than real, and that it is possible that some of the isolated thrombi seen in the femoral vein did not form there ab initio, but formed in the calf, at some time broke loose, and rather than passing into the lungs stuck proximally in the femoral vein. There are many postmortem studies of the distribution of thrombi in the leg and also of the origin of pulmonary emboli. With regard to the latter, there is general agreement that although some major pulmonary emboli may arise from pelvic veins, the majority come from the femoroiliac venous segment. But there is more disagreement with regard to the former problem. Leaving aside the question of platelet deposition, which is often seen in the valve cusps of the femoral vein, in some studies all the proximal thrombi were associated with and often in continuity with distal calf vein thrombosis [27], whereas in other studies there was a definite incidence of separate, proximal thrombi [28]. However, considering all the evidence, most proximal thrombi are associated with distal thrombosis. In assessing the meaning of these autopsy studies it is important to bear in mind that frequently death is not an instantaneous event and that some of the thrombi seen at autopsy may in fact represent agonal events, in contrast to isotopic and venographic studies which reflect changes in life. Bauer [29], in his often overlooked study of forty postoperative patients with repeated phlebography, observed “no single case in which a failure of filling of the femoral vein was found in conjunction with normally filled veins of the lower leg.” Based on a much larger phlebographic study, Fossard et al [30] concluded that more than 90 per cent of thrombi form in the calf veins and propagate proximally. This evidence suggests that the orthodox theory of the spread of thrombus in the lower limb is correct in the majority of instances, and hence, prevention of calf vein thrombosis should materially diminish the incidence of pulmonary embolism. To obtain direct evidence in support of this proposition is difficult for a number of reasons, especially that of establishing the diagnosis of pulmonary embolism not only in life but also after death. A number of studies like that of Lahnborg et al [31] have shown that the incidence of pulmonary embolism as diagnosed by lung scans is significantly higher in patients with isotopic evidence of deep vein thrombosis than in those without such evidence, but this does not necessarily mean that the incidence of major embolism in the former group is less, for as pointed out earlier, small emboli arising distally may be unrelated to the large dangerous thrombus arising in the proximal veins.
424
Bearing in mind that the predominant danger of deep vein thrombosis is death from pulmonary embolism, the crucial evidence required is the effect of the various prophylactic measures on the incidence of such deaths. The great difficulty in the search for such evidence is the large number of patients that need to be studied to obtain significant results. Two studies involving comparatively modest numbers of patients, one using low dose heparin [32] and the other dextran infusion [14], showed an apparently significant diminution in the deaths from pulmonary embolism. However, the most important study has been the International Multicenter Trial organized by Kakkar [33] in 1975. In this trial the death rate from pulmonary embolism in a series of 2,045 patients receiving 5,060 units of heparin subcutaneously every 8 hours for seven days after operation was compared with that in 2,076 control subjects. The two groups were well matched with respect to age (all >40 years), weight, type of operation, and incidence of malignancy. In all, eighty heparin-treated patients died, fifty-three (66 per cent) of whom underwent autopsy, and 100 control subjects died, seventy-two of whom underwent autopsy. The death rate from pulmonary embolism was significantly less in the treated group (2 of 80) than in the control group (16 of 100) (p
