Pathogenesis and Prophylaxis of Postoperative Thromboembolic Disease in Urological Pelvic Surgery

0022-5347/95/1536-1763$03.00/0 THE JOURNAL OF UROL~CY Copyright 0 1995 by AMERICAN UROlioClCAL ASSWIATION, INC.

Vol. 153. 1763-1774, June 1995 Printed in I I S A

Review Article PATHOGENESIS AND PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLIC DISEASE IN UROLOGIC& PELVIC SURGERY ADAM S. KIBEL

AND

KEVIN R. LOUGHLIN

From the Division of Urology, Department of Surgery, Brigham and Women's Hospital, Haruard Medical School, Boston, Massachusetts

KEY WORDS:thromboembolism,thrombolytic therapy Thromboembolic disease is a serious, potentially lethal complication of urological and, in particular, pelvic surgery. In patients undergoing pelvic surgery without thromboembolic prophylaxis, studies have demonstrated deep vein thrombosis rates as high as 51%,122 pulmonary embolism rates as high as 22%3and fatal pulmonary embolism rates as high as 2.6%.4These high rates have spurred urologists to use various methods of prophylaxis to prevent thromboembolic complications. We review the pathogenesis of postoperative thromboembolic disease in pelvic surgery, its predisposing factors and methods of prophylaxis. In addition, we examine the effect that a changing economic climate may have on thromboembolic complications.

tive.6.12 Wheeler found that in 1,464 patients screened for suspected deep vein thrombosis or pulmonary embolism there was a marked correlation between number of risk factors and radiological confirmation of a thromboembolic event.18Risk factors evaluated were patient age greater than 40 years, obesity, malignancy, recent surgery and history of pulmonary embolism or deep vein thrombosis. Patients with no risk factors had an 11%deep vein thrombosis rate and a 1%pulmonary embolism rate. The deep vein thrombosis and pulmonary embolism rates increased to 24%and 4%,respectively, with 1 risk factor, 36% and 5%, respectively, with 2 risk factors, 50% and 8%, respectively, with 3 risk factors, and 100% and 67%, respectively, with 4 risk factors. All patients undergoing radical prostatectomy and cystectomy SCOPE OF THE PROBLEM have at least 3 of the risk factors examined in this study, as It is estimated that there are approximately 5 million cases well as others that were not evaluated. Thus, it is not surof deep vein thrombosis per year, 500,000 to 630,000 cases of prising that they have an increased risk of deep vein thrompulmonary embolism and as many as 200,000 cases of fatal pul- bosis compared to the general surgical population. In an monary embolism.5.6 Of the 630,000 cases of pulmonary embo- untreated population of pelvic surgery patients, the risk of lism 63% are not diagnosed and 30% are lethal. Of the esti- calf vein thrombosis was estimated a t 40 to 80%, thigh vein mated 200,000 cases of fatal pulmonary embolism 67% are thrombosis a t 10 to 20%and fatal pulmonary embolism a t 1 never diagnosed and 34%occur rapidly, within 1 hour, when to 5%.'3 Open prostatic surgery has long been associated with deep no intervention can be instituted.5 These data suggest that vein thrombosis. In 1948 Colby demonstrated a 6.26%thromspecial emphasis should be placed on preventing the initial boembolic complication rate and a 2.64% fatal pulmonary complication. Surgery is strongly associated with thromboembolic com- embolism rate in an open prostate surgery population.4 If one plications. In a general surgical population, deep vein throm- examines only the data for suprapubic prostatectomy, the bosis rates of 30%7and pulmonary embolism rates of 14.1%3 deep vein thrombosis rate increases to 17.39%and the fatal have been reported using radiological imaging. Thromboem- pulmonary embolism rate to 8.69%.More contemporary sebolic events have also been strongly associated with postop- ries are much lower. Walsh reported a 1.1%thromboembolic erative mortality. Autopsy data reviewed by Morrell demon- complication rate in a series of radical retropubic prostastrated a 62.8% pulmonary embolism rate in postoperative tectomy patients.19 Others have reported deep vein thrombodeaths and only a 45.6%rate in medical deaths. These find- sis rates of 1.2 to 3.0%,pulmonary embolism rates of 0.4 to Comings strongly implicate surgery in the genesis of the throm- 2.7%and a fatal pulmonary embolism rate of 0.6%.2°-23 boembolism.8 More recent studies demonstrate a 31%pulmo- parable thromboembolic complication rates have been found nary embolism rate among postoperative surgical a u t o p ~ i e s . ~in contemporary cystectomy series with overall thromboemIn 8 to 10%of the cases pulmonary embolism was believed to bolic complication rates as high as 8.1%,24 pulmonary emboand a fatal pulmonary embolism lism rates of 1.8 to 4.1%25.26 be the primary cause of death.Vx10 Risk factors predisposing patients to thromboembolic com- rate as high as 2.0%.24Radiological diagnosis of thrombosis plications may be classified as patient factors (patient age in pelvic surgery patients has been much more frequent and greater than 40 years, previous thromboembolic event, obe- with deep vein thrombosis rates of 21 to 51%,1,2.27-29 The difference sity, varicose veins, use of oral contraceptives, estrogen ther- pulmonary embolism rates of 11 to 22%.3.30 apy, pregnancy and immobility), disease states (malignancy, between clinical and radiological diagnostic rates is caused congestive heart failure, the nephrotic syndrome, recent by the greater sensitivity of radiological tests over clinical myocardial infarction and inflammatory bowel disease), sur- diagnoses.6.18.31.32 scanning of the lower extremity was used in '2510dine (1251) gical factors (procedure time longer than 30 minutes, or pelvic, hip or knee surgery), and hematological disorders the majority of the radiological studies and it has some major (protein C and S deficiencies, antithrombin I11 deficiency, shortcomings. While good a t diagnosing distal (calf vein) lupus anticoagulant, polycythemia Vera, paroxysmal noctur- thrombosis, Iz5I is inaccurate at diagnosing proximal (poplinal hemoglobinuria and dysfibrinogenemia).11-17 The risk teal and femoral vein) thrombosis. Moreover, distal deep vein factors found in all patients undergoing radical pelvic sur- thrombosis is of questionable clinical significance, and has gery include patient age greater than 40 years, malignancy, been demonstrated in 26.5%of the patients postoperatively but 84% of these cases resolved without treatment before Procedure time longer than 30 minutes and pelvic surgery. It is important to recognize that risk factors are addi- hospital discharge.33 These patients have a negligible risk of 1763

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embolization without propagation to the thigh,31,34 which 1lysis through synthesis and secretion of tissue plasminogen occurs in approximately 20% of patients without treatment.34 activator.57 When the endothelium is damaged, these mediProximal vein thrombosis has a much worse prognosis, with ators are no longer present to retard thrombus formation. In 50% of the patients having pulmonary emboli by ventilation addition, endothelial damage exposes underlying collagen, quantitation scan.31 These shortcomings and the concern which activates the coagulation cascade directly58and through about unnecessarily injecting blood products into patients platelet adhesion.59 Surgery has been implicated in creating the initial endohave prompted many centers to switch to other methods of diagnosis. Impedance plethysmography has been found to thelial injury. Coleridge-Smith et a1 documented lower exvenous dilation of 22 to 28% intraoperatively.60 The compare favorably with venography and 1251~ c a n n i n g ? ~ .tremity ~~ and real-time ultrasound has also proved to be e f f e ~ t i v e . ~ ~dilatation increased to 57% with infusion of only 11. extra of Clinical diagnosis of deep vein thrombosis is notoriously intravenous fluid. Comerota et a1 found a positive correlation as 75%of the patients with pulmonary between the deep vein thrombosis rate and the amount of i n a c ~ u r a t eAs . ~many ~ embolism will be asymptomatic.31 Flanc et a1 screened post- lower extremity venous dilation, that is 100% of the patients operative patients with 1251and venography, and found that with dilatation of more than 20% had a deep vein thromboonly 50% with thrombus had symptoms.39 Homans' sign is sis.61These investigators believed that venous dilatation was found in only 10% of patients with deep vein thrombosis,18 cracking the endothelial lining and exposing the underlying and the classical triad of pain, swelling and erythema is subendothelial tissue to the blood stream.60s61 found in patients with and without deep vein t h r o m b o ~ i s . ~ ~ Hypercoagulable state. Blood coagulation and fibrinolysis Finally, the decrease in the incidence of clinical thrombo- are normally in a constant state of homeostasis with low embolic complicationsfrom that reported by Colby in 19484is levels of coagulation and fibrinolysis present.62 This balance probably due partly to the use of routine prophylaxis in tips in favor of coagulation by a number of factors, such as , ~ patients ~ response to the high prevalence of thromboembolic events in patient age greater than 4563 and m a l i g n a n ~ yin pelvic surgery. While there has been concern regarding undergoing radial pelvic surgery. While the hypercoagulable whether surgeons are administering adequate prophylaxis t o state has oRen been associated with metastatic prostate canthere is also evidence high risk patients20 recent epidemiological data indicate cer and treatment with e~trogens,65.6~ that current management schemes are being effectively im- that coagulation properties are altered in local disease as plemented in nonurological high risk populations.41 The in- well.67 Variables from platelet adhesione8 to mucin secrecreased risk in pelvic surgery patients, the difficulty in diag- tion69 to cytokine production70 have been implicated in the nosis of thromboembolic events and the high mortality rate procoagulant properties of prostate cancer. Surgery alters the homeostatic balance on a molecular associated with a missed diagnosis all indicate that all pelvic level. Cytokines, tumor necrosis factor and interleukin-1 surgery patients should continue routine prophylaxis. have all been implicated in increasing the procoagulant properties of endothelium,71-74 possibly through changes in the PATHOPHYSIOLOGY expression of cell surface adhesion molecules, such as selecVenous thrombi form in response to Virchow's triad (stasis, tins and integrins. These molecules promote platelet and endothelial injury and a hypercoagulable state).42Evidence neutrophil adherence to the endothelium.75 Specifically, has accumulated during the years that all 3 of these mecha- changes in cytokines have been implicated in increasing the nisms have a role in increasing the risk of deep vein throm- thrombogenic properties of endothelium postoperatively.76 bosis in the postoperative period. Although studies tend to The serum coagulation factors are also altered in the postexamine them individually, they do not act in isolation but in operative period. Studies have found an increase in fibrinoconcert to form thrombi.43 gen, platelets and platelet adhesiveness, and a decrease in Stasis. Prolonged immobilization has long been associated fibrinolysis lasting for 3 days to 3 weeks postoperatively.77-79 with thromboembolic disease. Deep vein thrombosis rates of Mansfield found that patients with radiographically docu15 to 35% are found in patients immobilized for 1week and mented deep vein thrombosis have a decrease in fibrinolysis this rate increases to 80%if immobilization lasts longer than that starts sooner, lasts longer postoperatively and is greater 1 week.a.45 It is particularly striking that stroke patients than that in patients without evidence of deep vein thromwith hemiparesis have higher deep vein thrombosis rates in b o s i ~However, .~~ not all of the laboratory changes observed the paralyzed limb than in the nonparalyzed limb.46 Immo- are important in the pathogenesis of thrombotic events. For bilization increases the deep vein thrombosis rates by caus- example, while increased platelets have been found 14 to 21 ing venous stasis. Activated coagulation factors cannot be days postoperatively in pelvic surgery, this increase is not cleared from the site of activation and trigger the coagulation associated with thromboembolic complications.80 cascade.47 In postoperative patients high deep vein thrombosis rates are caused partly by prolonged immobilization and METHODS OF PROPHYLAXIS the secondary venous stasis. To prove that immobilization causes stasis, Clark and Cotton measured venous blood flow Numerous methods of decreasing deep vein thrombosis by thermodilution and found that blood velocity decreased by rates, and thereby decreasing pulmonary embolism rates and 50% upon induction of anesthesia.48 Makin,49 and Tripolitis overall mortality from surgery, have been explored. The speet a150 found similar results. The soleal sinuses are a site of cific means by which the various methods of prophylaxis venous stasis in immobile patientssl and have been impli- provide protection against deep vein thrombosis are outlined cated as the nidus of thrombus formation.39.52.53 However, in the figure. Comparison of different methods of prophylaxis any venous site of prolonged stasis can form a nidus of requires large cohorts. It is estimated that to achieve a 90% thrombus. Stasis simply allows coagulation factors t o come power of detection, a change in the deep vein thrombosis rate into contact with a stimulus for a prolonged period, thereby from 20 t o 10%requires 500 patients. Even larger cohorts are increasing thrombus formation. needed to detect changes in other significant end points. A Endothelial injury. Damage to the endothelium of lower change in the pulmonary embolism rate from 3 to 1.5% reextremity vessels can create the surface irregularity needed quires 5,000 patients, the fatal pulmonary embolism rate to form a thrombus. Normal vascular endothelium is non- from 0.8 to 0.4% requires 20,000 patients and the total morthrombogenic."4 Cell surface factors, such as thrombomodu- tality rate from 4.0 to 3.6% requires 100,000 patients.8' NO lin and heparin sulfate, are present on endothelial cells and studies of sufficient size exist in the urological literature even serve to inhibit the binding of coagulation factors, particu- to detect changes in the deep vein thrombosis rate. While larly thrombin.55.56 The endothelium also promotes fibrino- such studies are needed, presently the general surgery and

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In pelvic surgery the complications of bleeding and lymphWarfarin Dextran Heparin ocele formation associated with heparin are of particular concern. Large studies in the general surgery literature have demonstrated increased rates of minor bleeding complications from 3.8 to 5.9% with heparin,s' and smaller studies have found the rate of minor bleeding associated with hepaAspirin rin use to be as high as 27%.89 However, these studies failed to demonstrate increases in major bleeding complicat i 0 n s ~ ~ ~ and ~ 4 ~in9 fatal 0 bleeding.91 Clagett and Reisch found identical 0.33% major bleeding complication rates in controls and heparin treated patients, and an increase in minor bleedGCS ing complications from 4.1 to 6.3%.86 In the urological literature, Halverstadt et al found an increase in blood loss and transfusion requirements among a general urological population receiving heparin prophylaxis,gZ and Bigg and Catalona found that intraoperative blood loss increased from 1,886 to 2,152 cc in radical retropubic prostatectomy patients.30 In a larger but retrospective study, Jasper found no increase in bleeding after open prostatectomy.93 Another complication associated with heparin prophylaxis Deep Vein Thrombosis is lymphocele formation. Catalona et a1 found that with heparin prophylaxis, lymphocele formation increased from 3 to Pulmonary Embolus 38% and persistent drainage from pelvic drains increased Overview of mechanisms of thromboembolic complications and from 3 to 12%.94Koonce et a1 found a similar increase in effect of prophylactic methods (bold face) on prevention. Arrows lymphocele formation from 2.5 to 38%.95 indicate stimulation. Flat ended lines indicate inhibition. IPCS, inStill another potential complication of heparin is thrombotermittent pneumatic compression stockings. GCS, graduated com- cytopenia, which occurs when the platelets are destroyed by pression stockings. heparin stimulated antibodies. Thrombocytopenia itself has not been associated with significant morbidity and mortality orthopedic literature provide the best available data to de- but it can precipitate arterial thrombosis, which is associated termine effective prophylaxis. Hopefully, prospective ran- with significant morbidity and mortality rates.96 While artedomized trials of sufficient size will be performed to assess rial thrombosis has never been reported in a prospective the benefits in a urological population adequately. We will heparin prophylaxis trial,97 Silver et a1 did report 24 cases of explore the different methods of prophylaxis, the rationale arterial thrombus caused by heparin prophylaxis.98 Therebehind the effectiveness of each method and the possible fore, it appears prudent to follow platelet counts of patients with heparin prophylaxis and to change to another form of complications associated with each method. Heparin. Heparin is the best studied method of prophy- prophylaxis if platelet counts are found to decrease. Other laxis. It has been proved to decrease the deep vein thrombosis potential complications include urticaria1 lesions at the site rate, pulmonary embolism rate and overall mortality rate of of injection, osteoporosis (which is unlikely with short-term patients treated. Heparin is a glycosaminoglycan that mim- heparin use) and skin necrosis secondary to thrombosis of ics naturally occurring heparin sulfate by stimulating anti- dermal vessels.99 Several different strategies have been developed to provide thrombin 111. Antithrombin 111then inhibits thrombin, factor Xa and factor XIa,76 thereby retarding thrombus formation. heparin prophylaxis with decreased complication rates, the In several studies of general surgical patients deep vein best of which is low molecular weight heparin. Heparin is not thrombosis rates were decreased from 25% (range 22.4 to a uniform molecule but simply a repeating sequence of idu42%) to 10% (range 7.7 to 15%) as measured by lZ5Iscan- ronic acid-glucosamine of varying lengths.100 Low molecular ning.a1-S6 In addition to demonstrating decreased deep vein weight heparin contains only the shorter repeating sethrombosis rates, the large multicenter studies and meta- quences, which inhibit factor Xa more and inhibit platelet analyses also demonstrated a significant decrease in pulmo- function less than the longer sequences in unfractionated nary embolism, fatal pulmonary embolism and overall mor- heparin.101.1°2 In addition, since inhibition of factor IIa retality rate~.S1~S4,s6 Kakkar et al studied 4,121 postoperative quires a heparin molecule greater than 18 saccharides, there patients in a randomized prospective trial of heparin and is a decrease in factor IIa inhibition.99 It was hoped that demonstrated a decrease in the deep vein thrombosis rate these changes would decrease the bleeding complication from 24.6 to 7.7%, a decrease in the fatal pulmonary embo- rates without decreasing the prophylactic effect. In metalism rate from 0.8 to 0.01% and even a decrease in the overall analysis and multicenter studies, the antithrombotic effects patient mortality rate from 4.8 to 3.9%.84 Meta-analysis by of low molecular weight heparin compared favorably with Collins et a1,81 and Clagett and Reisch86 demonstrated sim- unfractionated heparinlOS"J5 and provided superior prophyilar findings, with a decrease in the fatal pulmonary embo- laxis in 1 report.106 However, these studies failed to demonlism rate from 0.7 to 0.8% t o a range of 0.21 to 0.26%, and a strate a decrease in the bleeding complication rates when decrease in the overall mortality rate from 4.2 to 3.3.81 Claggett compared to unfractionated heparin.103.106 The multicenter and Reisch also analyzed the incidence of proximal deep vein study by Kakkar et a1 offers the sole exception, and they thrombosis, which is much more likely to embolize, and found could demonstrate a statistically significant difference in a decrease from 6.4 to 1.4% in the treated groups.86 In the only minor, and not in major, bleeding complication^.^^^ A urological literature, heparin has been found to decrease the more recent tactic has been to use other proteoglycans. deep vein thrombosis rate from 36 to 58% to a range of 9 to Prandoni et a1 demonstrated similar efficacy of heparin 12%.29.87In open prostatectomy patients heparin has been and dermatan sulfate, with a decrease in hemorrhage from found to decrease the deep vein thrombosis rate from 39.4 to 17.6 to 5.7%.107 To our knowledge low molecular weight heparin has not been studied in a urological population. 9.7%'OS8and the pulmonary embolism rate from 11 to O%.30 Another approach to decrease complication rates has been The major flaw in all of these urological studies was that the patient populations were too small to draw definite conclu- to combine heparin with dihydroergotamine, a venous vasoconstrictor. Constricting the veins leads to increased blood sions.

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flow, thereby decreasing stasis and deep vein thrombosis increase in intraoperative blood loss from 1,807 to 2,541 cc while possibly decreasing blood loss. Meta-analysis and mul- associated with the use of intermittent pneumatic compresticenter trials have demonstrated significant decreases in sion stockings in radical retropubic prostatectomy and cysthrombus and hemorrhage formation when compared to hep- tectomy patients.124 This finding could be caused by the arin alone.86.108 In a n uncontrolled study Hansberry et a1 increased blood flow from the lower extremities or systemic found that the deep vein thrombosis rate decreased to 8% in activation of the fibrinolytic system. Intermittent pneumatic compression stockings have a population of 25 patients undergoing general urological procedures.109 Unfortunately, dihydroergotamine has been proved to be effective in decreasing the rate of deep vein found to cause significant arterial vasoconstriction leading thrombosis in the general surgical and urological populato tissue and limb ischemia, and even to death in some tions. Decreasing the rate of deep vein thrombosis should patients. Therefore, it is no longer available in the United decrease the rate of other thromboembolic complications, although this has not been proved. States.102.108 Graduated compression stockings. Elastic stockings retard Intermittent pneumatic compression stockings. Intermittent pneumatic compression stockings were developed to pro- thrombus formation by increasing the velocity of venous blood vide pulsatile venous blood flow from the lower extremities flow up to 2O%125 and by preventing over distension of the during periods of immobility and thereby decrease the effect veins, which leads to endothelial damage. Meta-analysis in of stasis on thrombus formation. While blood flow has been the general surgical population demonstrated a decrease in the shown to increase between 180 and 240% over base line with deep vein thrombosis rate from 25.1 to 9.3%, but could not intermittent pneumatic compression stockings,llo it rapidly demonstrate decreased pulmonary embolism ratess6 A 68% became apparent that increased blood flow was not the sole risk reduction of thromboembolic complications was demonmechanism. Knight and Dawson demonstrated a decrease in strated by meta-analysis in general surgery patients,l26 and the deep vein thrombosis rate from 31.6 to 13.6%by applying recent meta-analysis of orthopedic patients revealed that while the boot to a n arm instead of a leg. Fibrinolysis parameters graduated compression stockings only prevented deep vein were higher in the intermittent pneumatic compression thrombosis marginally, they did a better job at preventing pulstockings cohort and it was hypothesized that the device monary embolism than any other method. 127 Several studies have demonstrated improved efficacy when stimulated fibrinolysis.111 Since then, other studies have strongly implicated increased fibrinolysis as the mechanism graduated compression stockings are used as a n adjunct to by which intermittent pneumatic compression stockings pro- other methods of prophylaxis. In the general surgery population, Scum et a1 demonstrated a decrease in the deep vein tect patients.112-114 Studies on intermittent pneumatic compression stockings thrombosis rate from 9 t o 1%by adding elastic stockings to a have demonstrated a decrease in the deep vein thrombosis rate, regimen of compression stockings.117Nicolaides et a1 demonwhich compares favorably with heparin controls.86.110,11>117 strated a similar decrease to 4% when compared t o electrical The meta-analysis by Clagett and Reisch showed a decrease calf stimulation and subcutaneous heparin alone.115 The urological literature has not clearly supported the use from 20.3 to 9.9% compared with untreated patients and a statistically insignificant decrease from 13.3 to 6.9%compared of elastic stockings. A small study by Van Arsdalen et a1 with heparin86 In patients undergoing total hip replacement found that intermittent pneumatic compression stockings (a high risk population) Hull et a1 demonstrated a decrease and elastic stockings were equally effective at preventing from 49 to 24% with intermittent pneumatic compression thromboembolic complications in post-prostatectomy pastockings.118 Studies have not been able to demonstrate a tients.122 However, in a study of general urological patients, statistically significant decrease in the pulmonary embolism, Hansberry et a1 found a deep vein thrombosis rate of 20%in fatal pulmonary embolism or overall mortality rate second- the elastic stocking cohort compared with 8% and 12.5%in ary to insufficient cohorts.86.102 No significant benefit has the hepariddihydroergotamine and intermittent pneumatic been found from sequential compared to uniform intermit- compression stockings cohorts, respectively. 109 Neither study tent pneumatic compression stockings. 119 contained sufficient numbers of patients to draw definite Intermittent pneumatic compression stockings were f i s t conclusions. studied in a general urological population by Coe et al, who No complications have been attributed to elastic stockings found a decrease in the deep vein thrombosis rate from 25 to if they fit properly. It is important to remember that poorly 7%.120 The study was flawed by its small population and by fitting elastic stockings compress the thigh and may promote the high deep vein thrombosis rate (21%) in the heparin instead of inhibit thrombosis.125 Elastic stockings have not cohort. Since then, several studies have confirmed that in- been conclusively proved to decrease deep vein thrombosis or termittent pneumatic compression stockings are useful to pulmonary embolism in high risk patients and, therefore, prevent deep vein thrombosis in general urological and pros- they cannot be recommended as the sole source of prophytatectomy patients.109.121-122A recent retrospective analysis laxis after pelvic surgery. However, they may prove to be a of deep vein thrombosis rates in post-radical retropubic pros- useful adjunctive measure. tatectomy patients concluded that intermittent pneumatic Warfarin. Oral anticoagulants have been used for deep compression stockings did not prevent thromboembolic com- vein thrombosis prophylaxis since the 1950s and signifiplications. A total of 784 patients undergoing surgery before cantly decreased thromboembolic events and mortality,128 the routine use of intermittent pneumatic compression stock- but their use was curtailed secondary to concerns about ings was compared with 516 undergoing surgery after their bleeding.lo2 The current oral anticoagulant of choice is waruse became routine.123 While not statistically significant, farin, which is particularly useful in high risk patients. In hip there was an increase in the thromboembolic complication and knee surgery patients it has decreased the deep vein rate from 1.1 to 2.3%, the deep vein thrombosis rate from 0.3 thrombosis rate by 66%and the pulmonary embolism rate by to 0.6%and the pulmonary embolism rate from 0.9 to 1.7%. 80%.129Warfarin works by inhibiting vitamin K oxide reducWhile this study was correctly criticized for its retrospective tase and vitamin K reductase, both of which are necessary for nature and the lack of radiological screening for thromboem- carboxylation of factors 11,VII, M and X by the liver. Since it bolic complications, it does lead one to question whether inhibits production of the factors, not the enzymatic activity, intermittent pneumatic compression stockings are adequate and the coagulation factors have a serum half-life of 36 to 42 prophylaxis in all patients. hours, there is an approximately 2-day lag time until the The lack of bleeding complications makes intermittent patient is anti~oagulated.l30,~3~ Its use for prophylaxis has pneumatic compression stockings attractive to urologists. been best studied in the orthopedic population. In a meta However, in a recent article Strup et a1 demonstrated an analysis by Imperiale and Speroff, analyzing multiple meth,

PATHOGENESIS AND PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLIC DISEASE

ods of thromboembolic prophylaxis, warfarin was more effective in preventing proximal deep vein thrombosis than any other method.Iz7 Interestingly, although warfarin did decrease the pulmonary embolism rate, other methods (which provided less deep vein thrombosis prophylaxis), provided more pulmonary embolism prophylaxis.127 In a urologkal population, oral anticoagulation was found to be effective before radiological screening.132 Later studies questioned its effectiveness and determined that bleeding complication rates were too high to justify its use.133 In a recent study from the University of California at San Francisco, a population of patients undergoing general urological procedures (although almost all were pelvic) exhibited a 0% thromboembolic complication rate in the warfarin cohort compared with a 4% deep vein thrombosis rate and a 2% pulmonary embolism rate in the intermittent pneumatic compression stockings control cohort. No bleeding complications were reported in either group.134 The main complication of warfarin is bleeding. It has been associated with severe hemorrhage in 2 to 7% of patients129 and the risk of fatal bleeding is 0.3%.'35 Bleeding is particularly associated with coadministration of aspirin136.137 and with underlying gastrointestinal or renal pathology.138 For this reason few surgeons will start the drug preoperatively, when it would do the most to prevent thromboembolic complications. Three approaches have been taken to decrease bleeding complications. One approach was 2-step warfarin therapy. In an orthopedic population warfarin was begun preoperatively and the prothrombin time increased by 1.5 to 3.0 seconds over control. Postoperatively, the patient was fully anticoagulated. Dextran was used as a control. This prophylaxis resulted in a decrease from 51 to 21% in the deep vein thrombosis rate and from 16 to 2% in the proximal deep vein thrombosis rate.139 Another approach was low dose warfarin. In a population of gynecological pelvic surgery patients l mg. warfarin was administered preoperatively and continued until hospital discharge. This method was compared with both untreated controls and full dose warfarin anticoagulation started preoperatively. Deep vein thrombosis rates were decreased from 30% in controls to 3% in patients receiving full dose warfarin and 9% in those receiving minidose warfarin. Hemorrhage rates were not increased in the minidose arm of the study.140 Surprisingly, the decrease in thromboembolic complications was attributed to increased fibrinolysis.141 The final approach t o decrease bleeding complications to delay warfarin administration until the postoperative period. Coventry et a1 studied late warfarin administration in total hip replacement patients, and found that when prophylaxis was started 5 days postoperatively and continued for 15 days the deep vein thrombosis rate did not decrease significantly, (from 3.4 to 2.4%) but the pulmonary embolism rate did (from 3.4 to 0.05%).142 They concluded that the late warfarin was treating the complication of the deep vein thrombosis, that is pulmonary embolism, before it was diagnosed. Similar benefits were found when warfarin was begun on postoperative day 1 in total hip replacement surgery.143 Another complication of warfarin is its potential prothrombogenic properties. Proteins C and S are fibrinolytic vitamin K dependent proteins with a half-life of 6 to 7 hours. As a result, there is a hypercoagulable period that can cause skin necrosis.131 Skin necrosis is due to thrombosis of subcutaneous capillaries and venules, and it may or may not be associated with underlying protein C or S deficien~ies.'~~, 145 Drug interactions can substantially alter the level of anticoagulation achieved with a given dose of warfarin. Drugs can alter absorption, distribution, excretion and enzymatic activity.131.146 Of particular concern to urologists is the effect of antibiotics. Quinolones and sulfonamides, particularly trimethoprim-sulfamethoxazole, increase the effect of warfarin by enzymatic inhibition of its metabolism.146 While second

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PATHOGENESIS AND PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLIC DISEASE

and third generation cephalosporins have a similar effect, first generation cephalosporins appear to be safe.131 Since most vitamin K is dietary, changes in gut flora secondary t o antibiotics do not alter the effect of warfarin in the majority of patients.146 Of note, opioids, histamine receptor type 2 blockers (except for cimetidine), neuroleptics and benzodiazepines appear to have insignificant pharmacological effect. Nonsteroidal anti-inflammatory drugs, except phenylbutazone, appear to have no direct effect on warfarin activity but their antiplatelet properties should be considered if they are prescribed c0ncurrently.~46 Warfarin is an effective tool to fight thromboembolic complications, particularly pulmonary embolism, and is especially useful in high risk patients in whom the risk of thromboembolic complications outweighs that of bleeding. Given the high risk of bleeding complications, great care should be taken to monitor the level of anticoagulation. Dextran. Dextran is a polysaccharide that prevents thromboembolic complications through several mechanisms. It decreases viscosity by diluting the blood, inhibits fibrin, increases fibrinolysis and inhibits platelet aggregation.102 It comes in 2 molecular weights, 40 and 70, both of which have been used to prevent deep vein thrombosis. In a general surgical population, the meta-analysis data of Clagett and Reisch demonstrated a decrease in the deep vein thrombosis rate from 24.2 to 15.6%,the pulmonary embolism rate from 2.8 to 1.2%and the fatal pulmonary embolism rate from 1.5 to 0.27%.86Data from the orthopedic literature are not as compelling. A recent meta-analysis by Imperiale and Speroff demonstrated a decrease in the deep vein thrombosis rate but an increase in the pulmonary embolism rate.127They believed that the common finding of shortness of breath secondary to pulmonary complications of the dextran was increasing the diagnosis of "asymptomatic" pulmonary embolism. Data from the urological literature are scant. A study solely evaluating fatal pulmonary embolism in a population of general surgical, orthopedic, gynecological and urological patients found no significant difference in fatal pulmonary embolism rates after use of dextran 70 versus subcutaneous heparin.147 A study of dextran 70 in pelvic gynecology patients revealed a decrease in the deep vein thrombosis rate from 10.7 to less than l%.1*8 Dextran has not been studied as much as the other anticoagulants, probably because of the large number and severity of the complications associated with its use. Major bleeding complications occur in 0.6% of the patients,l35 making bleeding more common than with any other form of prophylaxis except oral anticoagulation. lo2 Pulmonary edema and renal failure are also c0mmon.l2~The most serious complication is the high rate of anaphylaxis, oRen fatal, with the use of this drug.149 The severe nature of the complications associated with its use and the numerous other prophylaxis regimens available make dextran a much less desirable method of prophylaxis. Aspirin. Platelets are dependent on a prostaglandin, thromboxane A2,for proper adhesion. Aspirin works by irreversibly acetylating cyclooxygenase, which is responsible for synthesis of prostaglandins. Platelets, since they lack the ability to make more cyclooxygenase, can no longer effectively participate in coagulation.102 Studies on aspirin for prophylaxis have not been encouraging. In a general surgery population, small studies have failed to find a decrease in thromboembolic compli~ations15~ and meta-analysis revealed an unimpressive decrease from 25.1 to 20.3%.86One small study demonstrated a decrease in the deep vein thrombosis rate from 28 to 14%when aspirin was combined with dipyridamole.151 In an orthopedic population, there was similarly no advantage to aspirin over placeho.127 The reason that aspirin may not work is that venous thrombi, unlike arterial thrombi, have few platelets.'e If the coagulation pathway

~-

Orthopedics

Wells et a1'2n

Orthopedics

Imperiale and S p e r ~ f f ' ~ ' Orthopedics

Jorgensen et al'"'

Nurmohamed et all"'

I

plethysmography, venog raphy, ultrasound

1261

lz6I, plethysmography, venography, ultrasound

'1,

126* General surgery, .. orthopedics, . general urology l zq General surgery Orthopedics Venography General surgery, gynecology lz5I, plethysmography, venography, ultrasound

Collins et ale'

1261

1251

Screening Method

General surgery

General surgery

.. Population

Claggett and Reisch"

Author

No. Pts. in Control Population No therapy 2,855

Control ,ol Population Population I

286 390 837 4,144

No therapy No therapy Heparin No therapy

310 1,383 1,436

Dextran Heparin No therapy

No theraw ._

4.1 24.8 15.0 17.1 24 24 21 16 29 32 6.2

4,425 427 313 1,427 1,745 864 391 2,065 964 511 932

Low molecular weight heparin

Heparin Warfarin Graduated compression stockings Low molecular weight heparin Dextran Amirin Griduated compression stockings

930

4,651 437

Heparin No therapy

5.3 13.8 2.8

Heparin Heparin No therapy

3,382 799 300

No therapy No therapy No therapy

3,467 672 145

9.3 20.4 9.9 11

300 372 847 4,730

9.9 4.5

557 137

8.7 15.6 9.9

6.3

142

3,265 738 313

9.6 11.1 17.6

. . . I -"I."

Rate Th%~p

% Deep Vein

3,006 532 395

No. Pts. in Prophylaxis Population Popuiation

Low molecular weight heparin Low molecular weight heparin Low molecular weight heparin

Heparin Graduated compression stockings Intermittent pneumatic compression stockings Heparidgraduated compression stockings Hepariddihydroergotamine Intermittent pneumatic compression stockingdgraduated compression stockings Heparin Dextran Intermittent pneumatic compression stockings Graduated compression stockings Aspirin Hepariddihyd roergotamine Heparin

. _ Method Prophylaxis

TABLE3. Results of meta-analysis of deep vein thrombosis prophylaxis

17.6

29.7 22.6 47

5.7 48.1

24.5 23.3 14.5 26

25.2 24.2 20.3

27.0

Thrombosis Rate

% Deep Vein

Q,

-a

0

1770

PATHOGENESIS AND PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLIC DISEASE

being inhibited by aspirin has a relatively minor role in venous thrombus formation, inhibiting it is unlikely to decrease the thromboembolic complication rate. The complications of aspirin at normal doses include prolonged bleeding, gastric erosions, gastric hemorrhage, gastric ulcers and anemia.1523153For these reasons, aspirin cannot presently be recommended as a method of prophylaxis. Tables 1 to 3 summarize the studies &sc~sed,29.Sl-88,92.103-109,111,ll5. 117,120,122,123.126,127.134.139.140,143.148.151.154

LATE THROMBOEMBOLIC COMPLICATIONS

A growing concern is that late deep vein thrombosis and pulmonary embolism may be more prevalent than initially realized. Early studies emphasized that 50 to 80%of all deep vein thromboses occurred during the first 3 days postoperativelyl. 39.155 and the deep vein thrombosis initially forms during the procedure.7 It was believed that if deep vein thrombosis could be prevented during this critical period, the unfortunate sequela of thromboembolism would be avoided. Recent studies, however, have led to a reexamination of this conclusion. Scurr et a1 examined 57 patients using lower extremity ultrasound at hospital discharge and 4 to 6 weeks later, and found a deep vein thrombosis rate of 10% during hospitalization and 21% during followup.156 In patients who received prophylaxis the deep vein thrombosis rate was 3.5% while in the hospital and 29% at followup. They concluded that this increase was secondary to immobility at home. S ~ r e n s e net a1 performed a similar study of clinical thromboembolic events in patients receiving heparin prophylaxis and found a 0% deep vein thrombosis rate in the hospital compared to 6% at 1 month.157 Both studies can be criticized for small population size. Huber et a1 evaluated retrospectively the surgical patients admitted t o the hospital and then subsequently rehospitalized within 30 days with a diagnosis of pulmonary embolism.158 Prophylaxis was not uniformly administered. Among the 19,161 postoperative patients the in hospital pulmonary embolism rate was 0.42% and fatal pulmonary embolism rate was 0.06%. The post-hospital discharge pulmonary embolism rate was 0.13% with a fatal pulmonary embolism rate of 0.01%. The late pulmonary embolism rates represent only a fraction of thromboembolic events: only 36% of pulmonary embolisms and 40% of fatal pulmonary embolisms are diagnosed,5 some of the pulmonary embolisms may have occurred more than 30 days postoperatively and some patients may have been taken to another hospital. Still, fully one-fourth of all pulmonary embolisms and one-sixth of all fatal pulmonary embolisms occurred after hospital discharge.158 WilleJ ~ r g e n s e net a1 analyzed the data from previous prophylaxis trials, and found that the post-prophylaxis pulmonary embolism and fatal pulmonary embolism rates were 1.2% and 0.2%, respectively.159 Of note, in the landmark study by Kakkar et a1 pulmonary embolism occurred an average of 14 days postoperatively, 7 days after prophylaxis had been stopped.83 Late deep vein thrombosis has also been noted in the urological population. Igel et a1 noted in a population of 692 radical retropubic prostatectomy patients that deep vein thrombosis was diagnosed an average of 12 days postoperatively.'O Hedlund and Blomback found that the beneficial effects of heparin prophylaxis disappeared once it was stopped,160and Halverstadt et a1 actually found an increase in pulmonary embolism once heparin prophylaxis was st0pped.9~More recently, Cisek and Walsh found that thromboembolic complications occurred an average of 11days postoperatively when no prophylaxis was used and 20 days postoperatively if intermittent pneumatic compression stockings were used.123 They concluded that intermittent pneumatic compression stockings may not prevent throm-

boembolism but only delay i t until after the patient is discharged from the hospital. Several factors lead to late thrombosis. Prophylaxis is designed to prevent formation of thrombus a n d o r extension of existing thrombus.lO* Once the prophylaxis is stopped a n existing nidus can propagate. The hypercoagulable state may exist for as long as 3 weeks postoperatively,77 which exceeds the length of prophylaxis of current regimens. Mansfield demonstrated t h a t while the hypercoagulable state only existed for a n average of 5 to 6 days postoperatively, in patients who subsequently had deep vein thrombosis there was a longer and more pronounced hypercoagulable peri0d.~8 The period of unprotected hypercoagulability is increasing as hospitalization is shortened for economic reasons. A recent study of cost reduction in radical retropubic prostatectomy patients decreased the average hospital stay from 5.7 to 3.6 days.161 At Brigham and Women's Hospital in 1994, patients are discharged home following radical pelvic surgery an average of 2 days earlier than they were in 1991. Moreover, it is not unusual for a radical retropubic prostatectomy patient to be discharged home on postoperative day 3. These data mirror national trends that demonstrate that the hospitalization for radical prostatectomy patients had decreased from 9.5 to 7.5 days from 1989 t o 1991.1G2This early hospital discharge means a shorter period of prophylaxis. As this trend continues, late thromboembolic complications may become more of a problem. CONCLUSIONS

Thromboembolic disease is a problem in urological patients, particularly those undergoing radical pelvic surgery. The risk of deep vein thrombosis is approximately 30%, with a risk of pulmonary embolism of approximately 10% and a risk of fatal pulmonary embolism of approximately 5%. Prophylaxis has decreased these risks to approximately lo%, 1.5% and 0.4%, respectively. For this reason prophylaxis is routinely used in radical pelvic surgery. Multiple methods have proved t o be effective in the orthopedic and general surgical literature. Unfortunately, there have been no large prospective randomized studies in the urological literature. To date several options, including subcutaneous heparin, intermittent compression stockings and warfarin, can be safely used. Serious consideration should be given to using 2 methods in patients with additional risk factors for thromboembolism. Of increasing concern is the risk of late thromboembolic complications. Estimates for pelvic surgery patients extrapolated from the general surgical literature would place the late deep vein thrombosis rate at 20%, the late pulmonary embolism rate a t 2% and the late fatal pulmonary embolism rate at 0.4%. Currently, it is often recommended that high risk patients, including those with malignancy or previous thromboembolic complications and, in particular, those undergoing orthopedic procedures, require long-term anticoag~ l a t i o n .It~may ~ ~ become , ~ ~ ~necessary in the future to perform similar post-discharge prophylaxis in pelvic surgery patients. REFERENCES

1. Mayo, M. E., Halil, T. and Browse, N. L.: The incidence of deep vein thrombosis after prostatectomy. Brit. J . Urol., 43: 738, 1971. 2. Nicolaides, A. N., Field, E. S., Kakkar, V. V., Yates-Bell, A. J., Taylor, S. and Clarke, M. B.: Prostatectomy and deep-vein thrombosis. Brit. J. Surg., 5 9 487, 1972. 3. Allgood, R. J., Cook, J . H., Weedn, R. J.,Speed, H. K., Whitcomb, W. H. and Greenfield, L. J.: Prospective analysis of pulmonary embolism in the postoperative patient. Surgery, 6 8 116,1970. 4. Colby, F. H.: The prevention of fatal oulmonarv emboli after prostatectomy. J.-Urol., 5 9 920, 1948.

PATHOGENESIS AND PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLIC DISEASE

1771

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<

1772

PATHOGENESIS AND PROPHYLAXIS OF POSTOPERATIVE THROMBOEMBOLIC DISEASE

mechanisms. J . Clin. Invest., 74: 1, 1984. 55. Busch, C. and Owen, W. G.: Identification in vitro of an endo-

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