Prevention of Venous Thromboembolism in the Gynecologic Surgery Patient
Daniel L. Clarke-Pearson, MD, FACS, FACOG
James M. Ingram Professor of Gynecologic Oncology
Duke University Medical Center
Durham, NC 27710 clark011@mc.duke.edu
Deep venous thrombosis and pulmonary embolism, although largely preventable, are significant complications in postoperative patients. The magnitude of this problem is relevant to the gynecologist, because 40% of all deaths following gynecologic surgery are directly attributed to pulmonary emboli (98). Pulmonary embolism is also the second leading cause of death in women who undergo a legally induced abortion (99) and the most frequent cause of postoperative death in patients with uterine (100) or cervical carcinoma (101).

Risk Factors
The causal factors of venous thrombosis were first proposed by Virchow in 1858 and include the following: a hypercoagulable state, venous stasis, and vessel intima injury. Two prospective studies have evaluated risk factors associated with the postoperative occurrence of deep venous thrombosis in patients undergoing gynecology surgery. In one study, the risk factors of 124 patients undergoing vaginal and abdominal surgery for benign gynecologic disease were studied (102). Five factors were identified to be associated with postoperative deep venous thrombosis included increasing age, presence of varicose veins, being overweight, prolonged euglobulin lysis time, and presence of serum fibrin-related antigen. In another prospective study, the risk factors associated with venous thromboembolic complications were also assessed in 411 patients undergoing major abdominal and pelvic surgery (103). Preoperative risk factors identified in this study include advanced age; nonwhite race; increasing stage of malignancy; history of deep venous thrombosis, lower extremity edema or venous stasis changes; presence of varicose veins; being overweight; and a history of radiation therapy.
Intraoperative factors associated with postoperative deep venous thrombosis included increased anesthesia time, increased blood loss, and the need for transfusion in the operating room. Other recognized risk factors include patients with thrombophilias, the use of estrogen, oral contraceptives, tamoxifen, pregnancy, obesity and prologned air travel. It is important to recognize these risk factors in order to provided the appropriate level of venous thrombosis prophylaxis.
Prophylactic Methods

During the past two decades, a number of prophylactic methods have undergone clinical trials showing significant reduction in the incidence of deep venous thrombosis, and a few studies have been completed that have demonstrated a reduction in fatal pulmonary emboli. The ideal prophylactic method would be effective, free of significant side effects, well accepted by the patient and nursing staff, widely applicable to most patient groups, and inexpensive.
Low-Dose Heparin

The use of small doses of subcutaneously administered heparin for the prevention of deep venous thrombosis and pulmonary embolism is the most widely studied of all prophylactic methods. More than 25 controlled trials have demonstrated that heparin given subcutaneously 2 hours preoperatively and every 8–12 hours postoperatively is effective in reducing the incidence of deep venous thrombosis. The value of low-dose heparin in preventing fatal pulmonary emboli was established by a randomized, controlled, multicenter international trial, which demonstrated a significant reduction in fatal postoperative pulmonary emboli in general surgery patients receiving low-dose heparin every 8 hours postoperatively (104). Trials of low-dose heparin in gynecologic surgery patients are limited, and a clear consensus regarding the value of low-dose heparin in all groups of patients has not been established, because of differences in patient selection and length of follow-up. Three randomized controlled studies used the same regimen of low-dose heparin administration: 5000 units subcutaneously 2 hours preoperatively and every 12 hours for 7 days postoperatively. Two trials were conducted in patients with benign gynecologic conditions (98%); all patients were older than 40 years of age, and follow-up was discontinued at the time of discharge from hospital (105,
106). One trial showed a 23% incidence of deep venous thrombosis in the control group, as compared with a 6% incidence of deep venous thrombosis in the patients treated with low-dose heparin (106). This difference was statistically significant (P,0.05). Although this was a randomized trial, the control group contained a larger number of patients with malignancy and, when the cancer patients were excluded from the trial analysis, there was no significant value to the use of low-dose heparin in patients with benign conditions. In the other study, the nontreated control group had a 29% incidence of deep

venous thrombosis compared with a 3.6% incidence in the group treated with low-dose heparin (P,0.001) (105). A third trial evaluated a larger group of patients receiving treatment in gynecologic oncology unit, only 16% of whom had benign gynecologic conditions; follow-up included the first 6 weeks postoperatively (107). In this trial, there was no difference in the incidence of thromboembolic complications between the control group (12.4%) and the group treated with low-dose heparin (14.8%) (107).
In a subsequent trial (108), two more intense heparin regimens were evaluated in high-risk gynecologic oncology patients. Heparin was given either in a regimen of 5000 units subcutaneously 2 hours preoperatively and every 8 hours postoperatively or 5000 units subcutaneously every 8 hours preoperatively (a minimum of three preoperative doses) and every 8 hours postoperatively. Both of these prophylaxis regimens were effective in significantly reducing the incidence of postoperative deep venous thrombosis in patients with gynecologic cancers.

Although low-dose heparin is considered to have no measurable effect on coagulation, most large series have noted an increase in the bleeding complication rate, especially a higher incidence of wound hematoma. Up to 10–15% of otherwise healthy patients develop a transiently prolonged activated partial thromboplastin time (APTT) after 5000 units of heparin is given subcutaneously (109). Retrospective studies have suggested that low-dose heparin contributed to an increased occurrence of lymphocysts
(110, 111), although a prospective study only demonstrated an increase in retroperitoneal lymph drainage volume in patients treated with low-dose heparin but no increase in the incidence of lymphocysts (109). Although relatively rare, thrombocytopenia is associated with low-dose heparin use and has been found in 6% of patients after gynecologic surgery (109). If patients remain on low dose heparin for greater than 4 days it would be reasonable to check a platelet count to assesss the possiblity of the occurrence of heparin induced thrombocytopenia.
Low Molecular Weight Heparins
Low molecular weight heparins (LMWH) are fragments of unfractionated heparin which vary in size from 4,500 to 6,500 daltons. When compared to unfractionated heparin, LMWH have more anti-Xa and less anti-thrombin activity, leading to less effect on partial thromboplastin time. Decreased platelet inhibition and microvascular bleeding has been noted with LMWH, which may also lead to fewer bleeding complications (112).
An increased half-life of 4 hours (in both intravenous and subcutaneous administrations) leads to increased bioavailability when compared to unfractionated heparin. The increase in half-life of LMWH’s allows the convenience of once a day dosing.

Several commercially available LMWH preparations are internationally available but only two (i.e. enoxaparin and dalteparin) have been approved by the FDA for DVT prophylaxis in the United States.
Four randomized controlled trials have compared LMWH to unfractionated heparin in patients undergoing gynecologic surgery. In all studies, there was a similar incidence of
DVT. Bleeding complications (113-115) were also similar between the unfractionated heparin and LMWH groups. In a trial evaluating LMWH (dalteparin) in a gynecologic cancer population the LMWH was associated with less bleeding complications than would have been expected. The rate of thromboembolism was approximately 2% in this collective group of 521 operative patients, with DVT diagnosed in 7 patients receiving unfractionated heparin and 3 patients receiving LMWH prophylaxis. A recent metaanalysis of general surgery and gynecological surgery patients from 32 trials likewise indicated that daily LMWH administration is as effective as unfractionated heparin in
DVT prophylaxis without any difference in hemorrhagic complications (116). Caution should be maintained in interpretation of assimilated data involving LMWH since different anti-Xa activities are associated with the different preparations (117). In a comparison of prophylactic methods of DVT treatment, LMWH has been suggested by some investigators to be more cost effective than unfractionated heparin due to the convenience of once daily dosing (118, 119).
Mechanical Methods

Stasis in the veins of the legs has been clearly demonstrated while the patient is undergoing surgery and continues postoperatively for varying lengths of time. Stasis occurring in the capacitance veins of the calf during surgery, plus the hypercoagulable state induced by surgery, are the prime factors contributing to the development of acute postoperative deep venous thrombosis. Prospective studies of the natural history of postoperative venous thrombosis have shown that the calf veins are the predominant site of thrombi and that most thrombi develop within 24 hours of surgery (120). Reduction of venous stasis in the perioperative period by various methods has been less extensively investigated than pharmacologic methods such as low-dose heparin. However, mechanical prophylactic methods may play an important role in the prevention of postoperative deep vein thrombosis.
Although probably of only modest benefit, reduction of stasis by short preoperative hospital stays and early postoperative ambulation should be encouraged for all patients. Elevation of the foot of the bed, raising the calf above heart level, allows gravity to drain the calf veins and should further reduce stasis. More active forms of mechanical prophylaxis include elastic gradient compression stockings and external pneumatic leg compression.
Elastic Stockings In a survey of general surgeons in the U.S., gradient elastic stockings were second only to low-dose heparin as the prophylactic method of choice in high-risk and moderate high-risk surgical patients (121). The simplicity of elastic stockings and the absence of significant side effects are probably the two most important reasons that they are often included in routine postoperative care. Controlled studies of graduated pressure stockings are limited but do suggest modest benefit when they are carefully fitted (122).

Poorly fitted stockings may be hazardous to some patients who develop a tourniquet effect at the knee or midthigh (99). Variations in human anatomy do not allow perfect fit of all patients to available stocking sizes.
External Pneumatic Compression The largest body of literature dealing with the reduction of postoperative venous stasis deals with intermittent external compression of the leg by pneumatically inflated sleeves placed around the calf or leg during intraoperative and postoperative periods. Various pneumatic compression devices and leg sleeve designs are available, and the current literature has not demonstrated superiority of one system over another. Single-chambered calf compression devices have been studied most extensively in gynecologic surgery and appear to significantly reduce the incidence of deep venous thrombosis on a level similar to that of low-dose heparin. In addition to increasing venous flow and pulsatile emptying of the calf veins, external pneumatic compression also appears to augment endogenous fibrinolysis, which may result in lysis of very early thrombi before they become clinically significant (123).
The duration of postoperative external pneumatic compression has differed in various trials. External pneumatic compression may be effective only when used in the operating room or in the operating room and for the first 24 hours postoperatively (124,
125), although they should remain in use in patients who are not ambulatory.

External pneumatic compression used in patients undergoing major surgery for gynecologic malignancy has been found to reduce the incidence of postoperative venous thromboembolic complications by nearly threefold (126). Calf compression was applied intraoperatively and for the first 5 postoperative days. In a subsequent trial of similar patients that was designed to evaluate whether external pneumatic compression might achieve similar benefits when used only intraoperatively and for the first 24 hours postoperatively, there was no reduction of deep venous thrombosis when compared with the control group (127). Patients with gynecologic malignancies may remain at risk because of stasis and hypercoagulable states for a longer period than general surgical patients and therefore appear to benefit from longer use of external pneumatic compression.
External pneumatic leg compression has no significant side effects or risks, although patient tolerance has been cited as a drawback to its use. However, we have had only five patients of nearly 900 treated with external pneumatic compression request removal because of discomfort. The equipment is easily managed by the nursing staff, and although the initial capital outlay for external pneumatic compressors may seem large, the cost per patient is slightly less than that of low-dose heparin given for 7 days postoperatively (128).
We have investigated the risk factors associated with the failure of external compression to prevent DVT in a retrospective analysis of 1862 consecutive gynecologic surgery patients who received postoperative intermittent pneumatic compression at Duke
University between 1992-1997. A history of prior DVT, diagnosis of cancer and age >60 years were factors independently associated with the development of DVT despite IPC

prophylaxis (p<0.05). Patients having two or more of these factors had a 16 fold increased risk of postoperative DVT despite prophylaxis (p<0.05) (129). In these extremely high risk- patients, combined methods of prophylaxis ought to be considered.
Combination Prophylaxis
Combination therapy using heparin and compression stockings has been utilized in other high risk surgical patients in an attempt to diminish both the hypercoaguability and venous stasis that can be found in postoperative patients at high risk for thromboembolism. The prophylactic use of LDH has been compared to LDH combined with graduated compression stockings (GCS) in DVT prophylaxis among general surgery patients. Willie-Jorgensen and associates (130), in an investigation involving 245 patients undergoing acute extensive abdominal operations, demonstrated that the rate of postoperative DVT was significantly lower among 79 patients receiving a combination regimen of GCS and LDH (i.e. 5000 units SQ 1 hour preoperatively and q12 hours postoperatively) than patients receiving only the LDH regimen (P=0.013). A statistically significant improvement (P<0.05) in postoperative DVT was similarly noted by the same investigators in the evaluation of 176 patients undergoing elective abdominal surgery
(131). A meta-analysis of 6 studies involving 898 general surgery patients has shown that combination therapy with LDH and GCS provides significantly better DVT prophylaxis postoperatively than either single modality (Odds ratio 0.40; 95% CI 0.27-
0.59) (132). Recently, a multicenter prospective randomized clinical trial demonstrated that combination prophylaxis consisting of GSC and LMWH was more effective in DVT prevention than GCS alone (Relative risk 0.52; 95 percent confidence interval, 0.17 to
0.95, p=0.04) (133). “Combination” prophylaxis might be considered in the highest risk

gynecologic oncology patients, although the efficacy, risks, and costs have not been studied.

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