Deep venous thrombosis (DVT) and pulmonary embolism (PE) are two major complications after gynecologic surgery that can result in significant morbidity and mortality. Each year, about 260,000 cases of clinically diagnosed DVT occur,¹ resulting in 100,000 recognized deaths attributed directly to PE.² The incidence of DVT is suspected to be higher because of undiagnosed and asymptomatic cases as well as nationally low rates of autopsy detecting fatal PE in nursing home and rehabilitation hospital settings.^1,2

The incidence of DVT in gynecologic surgery varies widely depending on the risk factors of the individual patient. About 14% of patients undergoing gynecologic surgery for benign indications develop thromboembolism.³ DVT has been observed in 38% of gynecologic oncology patients postoperatively.⁴ Pulmonary embolism accounts for 3% of all deaths after gynecologic surgery⁵ and is a leading cause of postoperative death in the highest-risk patients with uterine, ovarian, or cervical carcinoma.⁶ Strategies to lower the rate of fatal PE must be directed at preventing the occurrence of DVT in patients at risk.

In 1858, Virchow⁷ reported that the development of thromboembolism is dependent on three factors: hypercoagulability, venous stasis, and vessel wall injury. Gynecologic surgery patients are predisposed to thromboembolism because of alteration in one or more of these factors. Perioperative immobility can adversely affect the drainage of blood from the lower extremity, promoting the development of a DVT.⁸ Surgically induced hematomas or lymphocysts also can lead to postoperative venous stasis.⁹ Additionally, vessel wall injury can result from surgical dissection or malignant growth of a tumor into vascular tissues. Coagulation can result from decreased fibrinolytic activity associated with an operative procedure.¹⁰ Elevated coagulation factors (i.e., factors I, V, VIII, IX, X, and XI), activated intermediates (thrombin-antithrombin III complexes), and platelet abnormalities contribute to a hypercoagulable state in the gynecologic oncology patient.¹¹ Cancer cells also secrete procoagulants (e.g., tissue factor and cancer procoagulant) as well as factors that affect endothelial permeability (e.g., vascular endothelial growth factor) and promote fibrin deposition.¹²

Once a thrombus is formed, the risk of PE depends on the location of the clot. In a prospective study of 382 gynecologic oncology patients, 17% of subjects developed DVT. Eighty-five percent of these thrombi were located in the calf veins.¹³ Nearly one third of these calf thrombi lysed spontaneously, and 65% did not propagate during postoperative surveillance. Only 4% propagated to the proximal leg veins, and an additional 4% became symptomatic pulmonary emboli. These findings emphasize that calf vein thrombosis, although a frequent event, is of minimal clinical significance. Moreover, 40% of the gynecologic oncology patients, who developed postoperative symptomatic PE, had no evidence of DVT in the legs, emphasizing that pelvic vein thrombi pose a high risk of PE.¹³ Prevention of PE secondary to proximal vein thrombosis also may prove difficult because half of these thrombi are clinically silent.¹⁴

Identification of risk factors that predispose patients to postoperative DVT and PE is important in the detection of high-risk patients and in the appropriate use of prophylactic therapies. Three prospective studies have evaluated clinical factors associated with the postoperative occurrence of DVT in patients undergoing major gynecologic surgery.^15,16,17 Clayton and colleagues¹⁵ prospectively evaluated 124 surgical patients, none of whom received DVT prophylaxis. Using linear regression analysis, the investigators identified several risk factors for postoperative DVT: age, varicose veins, percentage overweight, euglobulin lysis time, and serum fibrin-related antigen. A prognostic index score, using these five risk factors, identified 95% of the patients who developed postoperative DVT in the study.¹⁵ Crandon and associates¹⁶ subsequently evaluated 105 patients and found that unnecessary prophylaxis could be avoided by using this prognostic index score.

A prospective investigation of 411 consecutive patients undergoing major abdominal and pelvic gynecologic surgery was undertaken at Duke University Medical Center.¹⁷ Demographic risk factors identified in this study included age, nonwhite patients, increasing stage of malignancy, past history of radiation therapy, previous DVT, lower extremity edema or venous stasis changes, varicose veins, and obesity. Intraoperative risk factors associated with postoperative DVT included increased blood loss, increased anesthesia time, and transfusion requirements in the operating room. When all of these factors were evaluated in a stepwise logistic regression model, age, type of surgical procedure, ankle edema, nonwhite race, varicose veins, past history of radiation therapy, previous DVT, and duration of surgery were found to be the most important variables associated with thromboembolic complications. Table 1 shows the frequency of DVT associated with these variables. Beginning at age 40 years, the risk increases enough that thrombosis prophylaxis should be offered to all oncology patients. This risk was increased nearly twofold in women 60 years of age compared with those who were 40 years of age.

TABLE 1. Variables Associated with Postoperative Deep Venous Thrombosis (DVT)

Hormonal therapy may increase the risk of postoperative DVT.¹⁸ A review of the Michigan Medicaid data revealed that oral contraceptive formulations containing 50 μg of estrogen were associated with an increased risk of DVT.¹⁹ The risk associated with preparations containing lower doses of estrogen used is not known. A metaanalysis by Koster and colleagues²⁰ indicated that the risk of DVT for nonoral contraceptive users was 1.1 per 10,000 and that the risk for oral contraceptive users was 3.3 per 10,000. This analysis included patients predominantly using preparations containing higher estrogen content.

Preoperative screening for an inherited defect in coagulation should be considered in low-risk patients who have a history of DVT while taking oral contraceptives. Activated protein C resistance results from a point mutation in factor V Leiden. Vandenbroucke and associates²¹ noted that patients with this mutation who take oral contraceptives have a 30-fold increased risk of DVT when compared with women without the mutation who do not use oral contraceptives. Other studies have confirmed an increased risk of DVT among carriers of this mutation who use oral contraceptives.^22,23

Pulmonary embolism occurs in 1.6% of patients who undergo abdominal surgery without prophylaxis, resulting in death in 0.9% of patients.²⁴ About 70% of patients with fatal PE are diagnosed at autopsy because the diagnosis of PE is not suspected clinically.^25,26 Most patients experiencing fatal PE die within 30 minutes of the onset of symptoms,²⁷ preventing timely administration of thrombolytic therapy or surgical intervention. Improved methods of DVT prevention (in contrast to surveillance or intervention) must therefore be devised to decrease the mortality associated with PE. The ideal prophylactic method should be effective, free of significant side effects, well accepted by the patient and nursing staff, applicable to most patient groups, and inexpensive.²⁸

Pharmacologic

UNFRACTIONATED LOW-DOSE HEPARIN.

Unfractionated low-dose heparin (LDH) is a polymer of glycosaminoglycan units with an approximate molecular weight of 15,000 daltons. The heparin molecule mediates anticoagulant activity by binding antithrombin III, primarily resulting in thrombin (factor IIa) and factor Xa inhibition. The half-life of heparin can vary from 60 minutes for intravenous infusion to 3 hours for subcutaneous administration.²⁹

The efficacy of LDH has been demonstrated in benign gynecologic surgery patients. A regimen of LDH, 5000 U given subcutaneously 2 hours preoperatively and then every 12 hours postoperatively, has reduced the incidence of DVT. In an evaluation of 110 patients, predominantly with benign gynecologic disease, the incidence of postoperative DVT was 29% among controls and 3.6% among the patients treated with the LDH regimen (p < 0.001).³⁰ A reduction of 22% (p < 0.05) in the rate of thromboembolism was also noted in a separate trial by Taberner et al.³¹

At Duke University Medical Center, LDH regimens also have been evaluated as prophylaxis for gynecologic oncology patients undergoing major pelvic and abdominal surgery.³² A regimen of LDH, 5000 U given subcutaneously 2 hours preoperatively and every 12 hours postoperatively, was found to be ineffective in lowering the incidence of DVT in these high-risk patients. In this randomized controlled trial of 185 patients, the overall incidence of DVT was 12.4% among controls and 14.8% among LDH patients. When the analysis was limited to the first 7 days after surgery (during the time of prophylaxis), the incidence was 12.4% for the control group and 6.8% for the LDH group. Although this trend suggests prophylactic efficacy, the difference was not statistically significant (p = 0.2).

In a subsequent controlled trial, 304 patients were randomly assigned to receive no prophylaxis (control); 5000 U administered subcutaneously 2 hours preoperatively and every 8 hours postoperatively for 7 days (regimen I); or 5000 U administered subcutaneously every 8 hours preoperatively (three to nine doses) and every 8 hours postoperatively for 7 days (regimen II). Regimen II significantly lowered the rate of postoperative thromboembolic events when compared with controls (p = 0.008), even after logistic regression analysis adjusting for confounding variables (p = 0.005). No significant complications of bleeding were associated with any of these regimens.³³

The beneficial effects of prophylactic LDH in gynecologic surgery patients are similarly seen in general surgery patients. In a metaanalysis of more than 8000 patients from 29 studies, LDH (5000 U given subcutaneously 2 hours preoperatively and every 12 hours postoperatively for 7 days) was shown to reduce the incidence of postoperative DVT from 25% to 8%.²⁴ Additional trials have demonstrated a significant prophylactic effect of LDH on decreasing postoperative PE.^34,35 A risk reduction in nonfatal and fatal pulmonary embolism of 40% and 64%, respectively, was reported by Collins and colleagues³⁶ in an analysis of more than 70 randomized trials using heparin in general, orthopedic, and urologic surgery.

In gynecologic surgery, the complications of bleeding or lymphocele that may be associated with LDH are of particular concern. In most series, excessive bleeding is associated with LDH prophylaxis, although the absolute excess in bleeding is only about 2%.³⁷ More intense LDH regimens (e.g., 5000 U given every 8 hours for three doses preoperatively and 7 days postoperatively) have been associated with an increased requirement for postoperative blood transfusion.³⁸ Thrombocytopenia also may occur as a result of heparin-induced antiplatelet antibodies, although it is more common with the therapeutic doses of heparin used to treat DVT and PE.

In oncology patients undergoing pelvic and paraaortic lymphadenectomy, LDH may increase the incidence of postoperative lymphatic fluid drainage. A prospective study of 182 oncology patients given LDH, 5000 U 2 hours preoperatively and every 12 hours for 7 days, revealed significantly increased daily retroperitoneal Hemovac drainage.³⁷ Lymphatic fluid drainage was increased nearly twofold in a subsequent prospective trial involving the use of LDH in gynecologic oncology patients.³⁸ A prospective trial in which 48 prostatic cancer patients undergoing prostatectomy were randomized to LDH or no thromboprophylaxis revealed a significantly increased incidence of postoperative lymphocele in the LDH group.³⁹

LOW-MOLECULAR-WEIGHT HEPARIN.

Low molecular-weight heparin (LMWH) is fragmented, unfractionated heparin that varies in size from 4500 to 6500 daltons. When compared with unfractionated heparin, LMWH has more anti-factor Xa and less antithrombin activity, leading to less effect on activated partial thromboplastin time (aPTT). Decreased platelet inhibition and microvascular bleeding has been noted with LMWH, which also may lead to fewer complications with bleeding.⁴⁰ An increased half-life of 4 hours (in both intravenous and subcutaneous administrations) leads to increased bioavailability when compared with unfractionated heparin; this may allow once- or twice-daily dosing. Several LMWH preparations are available internationally, but only two (enoxaparin and dalteparin) have been approved by the US Food and Drug Administration for DVT prophylaxis.^29,40

The investigation of perioperative LMWH prophylaxis is limited in gynecologic surgery. Four randomized controlled trials have compared LMWH to unfractionated LDH, revealing similar rates of bleeding complications.^41,42,43,44 The rate of thromboembolism was about 2% in this collective group of 521 operative patients, with DVT diagnosed in 7 patients receiving LDH and in 3 patients receiving LMWH prophylaxis. A metaanalysis of general and gynecologic surgery patients from 32 trials likewise indicated that daily LMWH administration is as effective as unfractionated LDH in DVT prophylaxis without any difference in hemorrhagic complications.⁴⁵ Caution should be maintained in interpretation of assimilated data involving LMWH because different anti-factor Xa activities are associated with the different preparations.⁴⁶ In a comparison of prophylactic methods of DVT treatment, LMWH has been suggested by some investigators to be more cost-effective than LDH in general and orthopedic surgery patients, owing to the convenience of once-daily dosing.^47,48

Mechanical

GRADED COMPRESSION STOCKINGS.

The grade compression stockings (GCS) are designed so that the gradient of pressure is highest at the ankle and diminishes toward the thigh. The use of GCS can increase the lower extremity blood flow velocity by about 20% over baseline,⁴⁹ which can have a beneficial effect on the stasis associated with the postoperative patient at risk of developing DVT.

The use of GCS in benign gynecologic surgery patients has not been studied extensively. The single study performed included 196 benign gynecology surgery patients; 4 of 92 control patients and none of the 104 GCS patients developed postoperative DVT (p = 0.048).⁵⁰

Ensuring proper fit of the GCS is important, and clinicians should understand that variations in body habitus prohibit the safe use of stockings in 15% to 20% of cases.²⁴ In a retrospective study of 281 gynecologic oncology patients at Duke University Medical Center,⁶ a fourfold increased risk of postoperative DVT or PE was noted in patients who weighed more than 90 kg and who wore GCS postoperatively. Tourniquet-like leg compression by poorly fitting GCS in these obese patients may have led to increased venous stasis.

In general surgery, the use of GCS has been demonstrated in metaanalysis to reduce the risk of postoperative DVT by 64%.²⁴ Another metaanalysis evaluating 1752 patients involving moderate-risk surgery (i.e., abdominal, gynecologic, and neurosurgical) revealed a similar risk reduction of 68%.⁵¹ In high-risk patients undergoing total hip replacement, GCS results in a risk reduction of only 25%²⁴; therefore, in gynecologic oncology patients with several risk factors, the use of GCS alone may not be adequate prophylaxis against postoperative DVT.

INTERMITTENT PNEUMATIC COMPRESSION.

Cyclic compression of the lower extremity venous system by pneumatically inflated sleeves (intermittent pneumatic compression [IPC]) has been used in an attempt to improve the venous stasis that often occurs perioperatively. IPC stockings can augment lower extremity blood flow 180% to 240% over baseline.⁵² Application of IPC should be performed before surgery because venous stasis begins with the induction of anesthesia.⁸ Prostaglandin-mediated stimulation of the endogenous fibrinolytic system has been suggested as an additional mechanism by which IPC decreases the incidence of thromboembolism.⁵³ Knight and Dawson's⁵⁴ findings of decreased DVT among patients receiving intermittent compression of the arm support this theory.

Different methods of IPC have been evaluated in an effort to optimize prophylactic effects. Salzman and associates,⁵⁵ in a randomized trial involving 136 patients, demonstrated that the incidence of postoperative DVT does not appear to be influenced by whether uniform or sequential methods of calf compression are used. The use of sequential thigh and calf IPC when compared with uniform calf IPC leads to a significantly higher rate of blood velocity and a lower incidence of proximal postoperative DVT.⁵² It is possible that the use of IPC that includes both the thigh and calf may improve postoperative rates of DVT when compared with devices that include only the calf. No studies are available that compare sequential and uniform IPC devices. The surgical nursing staff should be instructed in the proper use of the particular IPC device; improper functioning of the device has been observed in 52% of patients on routine nursing U and in 22% of patients in the intensive care setting.⁵⁶

IPC has not been evaluated in benign gynecologic surgery patients. In a metaanalysis of general surgery patients, however, Clagett and colleagues²⁴ found a risk reduction of 60% with the use of IPC in moderate- and high-risk patients. In gynecologic oncology patients, the use of IPC has been shown to decrease the incidence of postoperative DVT from 34.6% to 12.7% (p < 0.005).⁵⁷ In this prospective trial, calf compression was applied intraoperatively and for the first 5 days after surgery. The maximal effect was noted during the 5 days of compression and diminished after IPC was stopped. A subsequent trial evaluated whether IPC would have similar a prophylactic effect if used only intraoperatively and for the first 24 hours after surgery; no reduction of DVT was seen.⁵⁸ It appears that patients with gynecologic malignancies may constitute a high-risk group of patients who require at least 5 days of IPC to demonstrate reduction in the risk of DVT.

Subsequent trials involving gynecologic surgery patients have compared IPC to various LDH regimens in DVT prophylaxis. In a prospective trial, 107 patients received LDH, 5000 U given subcutaneously every 8 hours for three doses preoperatively and for 7 days postoperatively, and 101 patients received calf IPC for 5 days postoperatively. The incidence of postoperative DVT was similar in both groups; however, the frequency of transfusion requirements and the volume of retroperitoneal lymphatic drainage were significantly increased in patients receiving LDH.³⁸ Borow and Goldson⁵⁹ also revealed no difference in postoperative DVT among gynecologic surgery patients receiving LDH or IPC.

Combination Therapy (Pharmacologic and Mechanical)

Combination therapy using heparin and a compression device has been used in an attempt to diminish both the hypercoaguability and venous stasis that can be found in many postoperative patients. The prophylactic use of LDH has been compared with LDH combined with GCS for DVT prophylaxis among general surgery patients. Willie-Jorgensen and associates,⁶⁰ 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 GSC and LDH (5000 U given subcutaneously 1 hour preoperatively and every 12 hours postoperatively) when compared with 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.⁶¹ A metaanalysis of six studies involving 898 general surgery patients subsequently revealed that combination therapy with LDH and GCS provides significantly better DVT prophylaxis postoperatively than either single modality (odds ratio, 0.40; 95% confidence interval, 0.27 to 0.59).⁶² Although the prophylactic efficacy of combination therapy has not been specifically evaluated in gynecologic surgery, this method often is recommended for the high-risk gynecologic surgery patient.

Clinical Signs and Symptoms

The classic signs and symptoms of DVT include the acute onset of lower extremity edema, pain, and erythema. About 70% of patients with DVT who develop PE do not have symptoms.^25,26 Additionally, only half of patients who have signs and symptoms of DVT have proven thrombosis on venography.⁶³ Because of the low sensitivity and specificity associated with the clinical diagnosis, all clinical events suggestive of DVT should undergo more accurate diagnostic testing.

Venography

The most accurate diagnostic test for detecting DVT is ascending contrast venography, and other, less invasive methods must be assessed against this diagnostic gold standard. The invasive nature of the procedure and the requirements for significant radiographic technical support can make venography less appealing as a diagnostic test. The procedure can result in discomfort in 18% to 44% of patients and may lead to postvenography thrombosis in 8% to 9% of patients.⁶⁴ Venography should be performed to confirm the clinical suspicion of DVT; it should not be used as a method of surveillance for DVT in the asymptomatic patient. Patients with signs and symptoms suggestive of DVT who have a negative venogram do not need anticoagulant therapy. Hull and co-workers⁶⁵ followed 160 patients who had negative venograms and found that 2 (1.3%) subsequently developed DVT and none developed a pulmonary embolism. Recent economic analysis indicates that venography, even when performed on an outpatient basis, is less cost-effective than serial noninvasive methods (e.g., Doppler ultrasonography and impedance plethysmography) in the diagnosis of postoperative DVT.⁶⁶

Impedance Plethysmography

Impedance plethysmography is a noninvasive diagnostic test that measures venous capacitance and outflow as reflected in changes of electrical impedance within the calf. In gynecologic surgery patients with clinical symptoms of DVT, impedance plethysmography testing has a positive predictive value of 96%, sensitivity of 88%, and specificity of 94% in the detection of proximal DVT.⁶⁷ Impedance plethysmography is less accurate in detecting thrombi confined to the calf veins because venous flow is not significantly altered by calf vein thrombi. False-positive results may be encountered in patients with vascular disease and cardiac failure, as may abnormal venous drainage secondary to extrinsic compression by a pelvic mass or lymphocyst. If a patient who maintains persistent symptoms of DVT has negative test results initially, the test should be repeated serially or a venogram obtained to rule out nonocclusive or proximally extending thrombi. Impedance plethysmography is neither sensitive nor specific enough to be used for surveillance of high-risk patients who do not have symptoms.

Ultrasound

B-mode ultrasonography provides a two-dimensional image of the lower extremity vessels and, using compression techniques, results in a sensitivity of 88% to 89% and specificity of 96% to 100% in the detection of DVT.^68,69 Duplex ultrasonography combines B-mode with Doppler flow, which provides information regarding flow velocity. Color Doppler flow has been used with compression B-mode ultrasonography (color duplex ultrasonography) to provide information regarding flow direction in addition to velocity. Color flow may be helpful when compression B-mode ultrasonography results are indeterminate or in situations in which a patient's body habitus or clinical status prevents an optimal ultrasonographic study.⁷⁰ Patients suspected of having DVT should undergo serial noninvasive testing (ultrasonography or impedance plethysmography), and anticoagulant therapy should not be administered if test results are normal.

Magnetic Resonance Venography

Magnetic resonance venography (MRV) is an imaging technique that uses magnetic resonance imaging to provide venograms without the use of intravenous contrast. Additionally, MRV provides an infinite number of views reconstructed from a single imaging session. The predictive value, sensitivity, and specificity of MRV are similar to those of duplex scanning, but the cost can be 2.5 times more in some institutions.⁷¹ The more costly nature and the lack of improvement in detection over ultrasonographic methods may hinder the widespread application of MRV in the diagnosis of DVT.

Scintigraphy

The use of radiopharmaceuticals followed by scintigraphy has been investigated in the diagnosis of DVT. Labeled substances that bind directly to the clot are more specific than contrast venography because they exclude vascular obstruction secondary to extrinsic sources. Radiopharmaceuticals have been designed to bind to mature thrombi in patients with symptoms and to bind to thrombi as they form in high-risk patients as part of postoperative screening. Fibrin-directed radiopharmaceuticals, such as labeled fibrin fragment E1, tissue plasminogen activator, or antifibrin monoclonal antibodies, bind to fibrin monomers or cross-linked fibrin within the thrombus.⁷² Antiplatelet monoclonal antibodies and indium-111-labeled platelets alternatively bind platelets as they organize to form the DVT.^72,73 Data regarding the clinical efficacy of various scintigraphic methods is limited and has not yet demonstrated improvements over standard methods.

Deep Venous Thrombosis and Pulmonary Embolism

STANDARD REGIMENS.

Patients with documented DVT or PE should undergo anticoagulation to prevent propagation of the thrombus and to allow physiologic thrombolytic pathways to dissolve the clot. A bolus of intravenous heparin followed by continuous infusion is administered with a goal of maintaining the aPTT at 1.5 to 2.5 times control. Patients should be managed aggressively to achieve prompt anticoagulation. Wheeler and colleagues,⁷⁴ in a report on physician practices in three university-affiliated hospitals, revealed that 60% of patients failed to achieve an adequate anticoagulant response (i.e., threshold of aPTT more than 1.5) during the first 24 hours of heparin infusion. Over the next 3 to 4 days, more than 30% of patients maintained suboptimal aPTT values.⁷⁴

Traditionally, heparin has been given for 10 days, with the initiation of anticoagulant therapy on the 5th day of heparin administration. Alternatively, Hull and co-workers⁷⁵ demonstrated that the risks of DVT recurrence and bleeding complications were similar when anticoagulants were initiated with heparin on the first day of a 5-day treatment regimen. To shorten the duration of hospitalization, most clinicians use the 5-day regimen. The change in the international normalized ratio (INR) resulting from warfarin administration often precedes the anticoagulant effects by about 2 days, during which time low protein C levels are associated with a transient hypercoagulable state.⁷⁶ Therefore, heparin should administered until the INR has been maintained in a therapeutic range for at least 2 days, confirming proper warfarin dose.⁷⁷ Patients who experience a thromboembolic event for the first time should take warfarin for about 3 to 6 months to prevent recurrence of thrombus.⁷⁸ Longer periods of anticoagulation should be considered in patients who experience a second recurrence. Indefinite anticoagulation has not been proved to decrease the risk of DVT recurrence, and the risk of bleeding is increased in patients who maintain prolonged therapy.⁷⁹

LOW-MOLECULAR-WEIGHT HEPARIN.

The efficacy and safety of treatment with LMWH have been compared with those of unfractionated heparin in numerous studies. A metaanalysis concluded that weight-adjusted LMWH was more effective and safer than weight-adjusted unfractionated heparin in the treatment of patients with DVT.⁸⁰ Because the different LMWH preparations are not interchangeable in terms of anti-factor Xa activity, the conclusions of the study should be interpreted with caution. For the individual LMWH preparations, however, relative risk reduction was significant for Fraxiparine (p < 0.04) in this analysis.⁸⁰

In an effort to improve the cost-effectiveness of DVT treatment, the use of LMWH on an outpatient basis has been compared with that of standard inpatient regimens using intravenous unfractionated heparin. Because patients who take LMWH do not have an associated change in aPTT, laboratory monitoring is not required, and daily or twice-daily administration is convenient in the home setting. Two prospective randomized trials collectively involving 900 patients have both concluded that home administration of LMWH is a safe and effective alternative to inpatient heparin infusion.^81,82 These regimens have not yet been evaluated in postoperative patients, but findings in the surgical population would be expected to be similar.

INFERIOR VENA CAVA INTERRUPTION.

Inferior vena cava interruption is considered to be an alternative method of PE prophylaxis in patients with DVT and an absolute contraindication to heparin use (e.g., recent hemorrhagic cerebrovascular accident, neurosurgery, ocular or spinal surgery), embolization despite adequate anticoagulation, or severe complications resulting from heparin use (e.g., thrombocytopenia, bleeding requiring ongoing transfusions).⁸³ Methods of interruption have included clipping, suture ligation, and intravascular filters. Heaps and Lagasse⁸⁴ reported the successful clipping of the vena cavae of 16 patients during laparotomy for gynecologic cancer. All patients had a history of DVT at the time of surgery; none developed PE postoperatively.

Intravenous insertion of vena caval filters avoids the use of general anesthesia and is associated with a lower mortality rate (0.7%) than is surgical ligation (15%).⁸⁵ No controlled trials have evaluated the efficacy and safety of vena caval filters in the treatment or prophylaxis of DVT or PE. Numerous case series have reported on the risk of complications and DVT recurrence associated with intravascular filters.

Cohen and colleagues⁸⁵ have advocated the use of the Greenfield filter instead of heparin as primary treatment for DVT or PE in patients. In this series of 41 patients, 1 patient was noted to have chronic prong penetration of the vena cava, and another was diagnosed with PE recurrence. The investigators concluded that filter insertion was safe and effective and eliminated the patient's burden of heparin administration.⁸⁵ Anticoagulants may be used after filter placement to prevent insertion-site DVT, inferior vena cava thrombosis, and cephalad propagation from an occluded filter. Anticoagulation after filter insertion would eliminate the advantages associated with this procedure as primary treatment in patients with no contraindications to anticoagulant therapy.

Septic Pelvic Thrombophlebitis

In a pathologic analysis of 500 consecutive hysterectomy specimens, Hayden⁸⁶ noted the presence of asymptomatic pelvic thrombophlebitis in 12 gynecologic patients. Symptomatic pelvic thrombophlebitis resulting in hectic postpartum fevers has been reported in 0.05 to 0.18 of routine obstetric patients and in about 1% to 2% of patients undergoing cesarean delivery. Pelvic surgery may predispose patients not only to postoperative pelvic thrombosis but also to infection as a result of iatrogenic inoculation of bacteria. Bacteria also may enter the pelvis through the ovarian venous plexus, which communicates with both the uterine and vaginal vasculature. The incidence of symptomatic pelvic thrombophlebitis in nonpregnant gynecologic surgery patients has not been reported and presumably occurs rarely.⁸⁷

Diagnosis of septic pelvic thrombophlebitis often is made presumptively in postpartum or postoperative patents with nonfocal fevers despite antibiotics. A thorough evaluation of possible sources of infection must be performed before initiation of anticoagulant therapy. Intravenous heparin is continued for 7 to 10 days, and defervescence usually occurs by day 5 of treatment.⁸⁸ Surgical intervention is reserved for patients who fail to respond to medical management. Ligation of the thrombosed vein is performed, but resection of the infected vessel is not required. Interruption of the inferior vena cava is performed concurrently in patients with perioperative PE or in patients in whom the thrombus extends to this large vessel.⁸⁷

DVT and subsequent PE are a significant source of morbidity and mortality in gynecologic surgery. Most patients experiencing fatal thromboembolism are diagnosed at autopsy. Prophylaxis against DVT therefore should be used in an effort to decrease the incidence of PE. Each patient should be assessed for thromboembolic risk. Women at low risk benefit from GCS. Moderate-risk patients should be treated with either LDH, LMWH, GCS, or IPC. High-risk patients (i.e., older than 60 years, history of DVT or PE, presence of neoplasm) should be treated with more intense techniques; those at very high-risk may benefit from combined prophylaxis (Table 2).

TABLE 2. Prophylactic Techniques Appropriate for the Obstetric and Gynecologic Surgery Patient

1. Clagett GP: Prevention of postoperative venous thromboembolism: An update. Am J Surg 168: 515, 1996

2. Dalen JE, Aert JS: Natural history of pulmonary embolism. Prog Cardiovasc Dis 17: 257, 1975

3. Walsh JJ, Bonnar J, Wright FW: A study of pulmonary embolism and deep leg thrombosis after major gynecologic surgery using labeled fibrinogen phlebography and lung scanning. J Obstet Gynaecol Br Commonw 81: 311, 1974

4. Crandon AJ, Knotts J: Incidence of post-operative thrombosis in gynecologic oncology. Aust NZ J Obstet Gynecol 23: 216, 1983

5. Jeffcoate TNA, Tindall VR: Venous thrombosis and embolism in obstetrics and gynaecology. Aust NZ J Obstet Gynaecol 5: 119, 1965

6. Clarke-Pearson DL, Jelovsek FR, Creasman WT: Thromboembolism complicating surgery for cervical and uterine malignancy: Incidence, risk factors and prophylaxis. Obstet Gynecol 61: 87, 1983

7. Virchow R: Die Cellularpathologie in ihrer Begrindung auf physiologische and pathologische Gewebslehre. Berlin, A Hirschwad, 1858

8. Clark C, Cotton LT: Blood-flow in deep veins of leg: Recording technique and evaluation of methods to increase flow during operation. Br J Surg 55: 211, 1969

9. Clarke-Pearson DL, Synan IS, Creasman WT: Significant venous thromboembolism caused by pelvic lymphocysts: Diagnosis and management. Gynecol Oncol 13: 136, 1982

10. Egan EL, Bowie EJW, Kazmier FJ et al: Effect of surgical operations on certain tests used to diagnose intravascular coagulation and fibrinolysis. Mayo Clin Proc 49: 658, 1974

11. Piccioli A, Prandoni P, Ewenstein BM, Goldhaber SZ: Cancer and venous thromboembolism. Am Heart J 132: 850, 1996

12. Goad KE, Gralnick HR: Coagulation disorders in cancer. Hematol Oncol Clin North Am 10: 457, 1996

13. Clarke-Pearson DL, Synan IS, Coleman RE et al: The natural history of postoperative venous thromboembolism in gynecologic oncology: A prospective study of 382 patients. Am J Obstet Gynecol 148: 1051, 1984

14. Clagett GP, Reisch JS: Prevention of venous thromboembolism in general surgical patients. Ann Surg 208: 227, 1988

15. Clayton JK, Anderson JA, McNicol GP: Preoperative prediction of postoperative deep vein thrombosis. Br Med J 2: 910, 1976

16. Crandon AJ, Peel KR, Anderson JA et al: Prophylaxis of postoperative deep vein thrombosis: Selective use of low-dose heparin in high-risk patients. Br Med J Aug 281: 345, 1980

17. Clarke-Pearson DL, DeLong ER, Synan IS et al: Variables associated with postoperative deep venous thrombosis: A prospective study of 411 gynecology patients and creation of a prognostic model. Obstet Gynecol 69: 146, 1987

18. Vessey MP: The epidemiology of venous thromboembolism. In: Poller L (ed): Recent Advances in Thrombosis, p 39. London, Churchill Livingstone, 1973

19. Gerstman BB, Piper JM, Tomita DK et al: Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease. Am J Epidemiol 133: 32, 1991

20. Koster T, Small RA, Rosendaal FR, Helmerhorst FM: Oral contraceptives and venous thromboembolism: A quantitative discussion of the uncertainties. J Intern Med 238: 31, 1995

21. Vandenbroucke JP, Koster T, Briet E et al: Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. 344: 1453, 1994

22. Rintelen C, Mannhalter C, Ireland H et al: Oral contraceptives enhance the risk of clinical manifestation of venous thrombosis at a young age in females homozygous for factor V Leiden. Br J Haematol 93; 487, 1996

23. Simioni P, Prandoni, Lensing AWA et al: The risk of recurrent venous thromboembolism in patients with an Arg⁵⁰⁶ -Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 336: 399, 1997

24. Clagett GP, Anderson FA, Heit J et al: Prevention of venous thromboembolism. Chest 108: 312S, 1995

25. Goldhaber SZ, Hennekens CH, Evans DA et al: Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med 73: 822, 1982

26. Rubenstien I, Murray D, Hoffstein V: Fatal pulmonary emboli in hospitalized patients. Arch Intern Med 148: 1425, 1988

27. Donaldson GA, Williams C, Scannell JG, Shaw RS: A reappraisal of the application of the Trendelenburg operation to massive fatal embolism: Report of a successful pulmonary-artery thrombectomy using a cardiopulmonary bypass. N Engl J Med 268: 171, 1963

28. Clarke-Pearson DL: Prevention of venous thrombosis following gynecologic surgery in menopausal patients. Menopausal Med 4: 6, 1996

29. Fejgin MD, Lourwood DL: Low molecular weight heparins and their use in obstetrics and gynecology. Obstet Gynecol Surv 49: 424, 1994

30. Ballard M, Bradley-Watson PJ, Johnstome ED et al: Low doses of subcutaneous heparin in the prevention of deep venous thrombosis after gynecologic surgery. J Obstet Gynaecol Br Commonw 80: 469, 1973

31. Taberner DA, Poller L, Burslem RW, Jones JB: Oral anticoagulants controlled by British comparative thromboplastin versus low dose heparin prophylaxis of deep venous thrombosis. Br Med J 1: 272, 1978

32. Clarke-Pearson DL, Coleman RE, Synan IS et al: Venous thromboembolism prophylaxis in gynecologic oncology: A prospective controlled trial of low-dose heparin. Am J Obstet Gynecol 145: 606, 1983

33. Clarke-Pearson DL, Delong ER, Synan IS: A controlled trial of two low-dose heparin regimens for the prevention of deep vein thrombosis. Obstet Gynecol 75: 684, 1990

34. Prevention of fatal postoperative pulmonary embolism by low doses of heparin: An international multicentre trial. Lancet 2:45, 1975

35. Sagar S, Massey J, Sanderson JM: Low-dose heparin prophylaxis against fatal pulmonary embolism. Br Med J 4: 257, 1975

36. Collins R, Scrimgeour A, Yusuf S, Peto R: Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 318: 1162, 1988

37. Clarke-Pearson DL, DeLong ER, Synan IS, Creasman WT: Complications of low-dose heparin prophylaxis in gynecologic oncology surgery. Obstet Gynecol 64: 689, 1984

38. Clarke-Pearson DL, Synan IS, Dodge R et al: A randomized trial of low-dose heparin and intermittent pneumatic calf compression for the prevention of deep venous thrombosis following gynecologic oncology surgery. Am J Obstet Gynecol 168: 1146, 1993

39. Tomic R, Granfors T, Sjodin J, Ohberg L: Lymph leakage after staging pelvic lymphadenectomy for prostatic carcinoma with and without heparin prophylaxis. Scand J Urol Nephrol 28: 273, 1994

40. Tapson VF, Hull RD: Management of venous thromboembolic disease: The impact of low-molecular-weight heparin. Chest 16: 281, 1995

41. Fricker JP, Vergnes Y, Schach R et al: Low dose heparin versus low molecular weight heparin (Kabi 2165, Fragmin) in the prophylaxis of thromboembolic complications of abdominal oncological surgery. Eur J Clin Invest 18: 561, 1988

42. Borstad E, Urdal K, Handeland G, Abildgaard U: Comparison of low molecular weight heparin vs unfractionated heparin in gynecological surgery. II. Reduced dose of low molecular weight heparin. Acta Obstet Gynecol Scand 71: 471, 1992

43. Heilmann L, Kruck M, Schindler AE: Prevention of thrombosis in gynecology: Double-blind comparison of LMW heparin and unfractionated heparin. Geburtshilfe Frauenheilkd 49: 803, 1989

44. Kaaja R, Lehtovirta P, Venesmaa P et al: Comparison of enoxaparin, a low-molecular weight heparin and unfractionated heparin, with or without dihydroergotamine, in abdominal hysterectomy. Eur J Obstet Gynecol Reprod Biol 47: 141, 1992

45. Jorgensen LN, Willie-Jorgensen P, Hauch O: Prophylaxis of postoperative thromboembolism with low molecular weight heparins. Br J Surg 80: 689, 1993

46. Haas S, Haas P: Efficacy of low molecular weight heparins: An overview. Semin Thromb Hemost 19: 101, 1993

47. Bergovst D, Lindgren B, Matzsch T: Comparison of the cost of preventing postoperative deep vein thrombosis with either unfractionated or low molecular weight heparin. Br J Surg 83: 1548, 1996

48. Anderson DR, O'Brien BJ, Levine MN et al: Efficacy and cost of low-molecular weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 119: 1105, 1993

49. Meyerowitz B, Nelson R: Measurement of the velocity of blood in lower lomb veins with and without compression. Surgery 56: 481, 1964

50. Turner GM, Cole SE, Brooks JH: The efficacy of graduated compression stockings in the prevention of deep vein thrombosis after major gynaecological surgery. Br J Obstet Gynaecol 91: 588, 1984

51. Wells PS, Lensing AWA, Hirsh J: Graduated compression stockings in the prevention of postoperative venous thromboembolism. Arch Intern Med 154: 67, 1994

52. Nicolaides AN, Fernandes J, Pollock AV: Intermittent sequential pneumatic compression of the legs in the prevention of venous stasis and postoperative deep venous thrombosis. Surgery 87: 69, 1980

53. Guyton DP, Khayat A, Schreiber H: Pneumatic compression stockings and prostaglandin synthesis: A pathway of fibrinolysis? Crit Care Med 13: 266, 1985

54. Knight MT, Dawson R: Effect of intermittent compression of the arms on deep venous thrombosis in the legs. Lancet 2: 1265, 1976

55. Salzman EW, McManama GP, Shapiro AH et al: Effect of optimization of hemodynamics on fibrinolytic activity and antithrombotic efficacy of external pneumatic calf compression. Ann Surg 20: 636, 1987

56. Comerota AJ, Katz ML, White JV: Why does prophylaxis with external pneumatic compression for deep vein thrombosis fail? Am J Surg 164: 265, 1992

57. Clarke-Pearson DL, Synan IS, Hinshaw WM et al: Prevention of postoperative venous thromboembolism by external pneumatic calf compression in patients with gynecologic malignancy. Obstet Gynecol 63: 92, 1984

58. Clarke-Pearson DL, Creasman WT, Coleman RE et al: Perioperative external pneumatic compression as thromboembolism prophylaxis in gynecologic oncology: Report of a randomized controlled trial. Gynecol Oncol 18: 226, 1984

59. Borow M, Goldson H: Postoperative venous thrombosis: Evaluation of five methods of treatment. Am J Surg 141: 245, 1981

60. Willie-Jorgensen P, Hauch O, Dimo B et al: Prophylaxis of deep venous thrombosis after acute abdominal operation. Surgery 172: 44, 1991

61. Willie-Jorgensen P, Thorup J, Fischer A et al: Heparin with and without graded compression stockings in the prevention of thromboembolic complications of major abdominal surgery: A randomized trial. Br J Surg 72: 579, 1985

62. Willie-Jorgensen P: Prophylaxis of postoperative thromboembolism with combined modalities. Semin Thromb Hemost 17: 272, 1991

63. Salzman EW: Venous thrombosis made easy. N Engl J Med 314: 847, 1986

64. Bettmann MA, Robbins A, Braun SD et al: Contrast venography of the leg: Diagnostic efficacy, tolerance, and complication rates with ionic and nonionic contrast media. Radiology 165: 113, 1987

65. Hull RD, Hirsh J, Sackett DL et al: Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation 1981;64:622,

66. Hull RD, Feldstein W, Pineo GF, Raskob GE: Cost effectiveness of diagnosis of deep vein thrombosis in symptomatic patients. Thromb Haemost 1995;74(1):189,

67. Clarke-Pearson DL, Creasman WT: Diagnosis of deep venous thrombosis in obstetrics and gynecology by impedance phlebography. Obstet Gynecol 58: 52, 1981

68. Cronan JJ, Dorfman GS, Scola FH et al: Deep venous thrombosis: US assessment using vein compression. Radiology 162: 191, 1987

69. O'Leary DH, Kane RA, Chase BM: A prospective study of the efficacy of B-scan sonography in the detection of deep venous thrombosis in the lower extremities. J Clin Ultrasound 16: 1, 1988

70. Lewis BD, James EM, Wech TJ et al: Diagnosis of acute deep venous thrombosis of the lower extremities: Prospective evaluation of color Doppler flow imaging versus venography. Radiology 192: 651, 1994

71. Carpenter JP, Holland GA, Baum RA et al: Magnetic resonance venography for the detection of deep venous thrombosis: Comparison with contrast venography and duplex Doppler ultrasonography. J Vasc Surg 18: 734, 1993

72. Knight LC: Scintigraphic methods for detecting vascular thrombus. J Nucl Med 34: 554, 1993

73. Smyth JV, Dodd PDF, Walker MG: Indium-111 platelet scintigraphy in vascular disease. Br J Surg 82: 588, 1995

74. Wheeler AP, Jaquiss RD, Newman JH: Physician practices in the treatment of pulmonary embolism and deep-venous thrombosis. Arch Intern Med 148: 1321, 1988

75. Hull RD, Raskob GE, Rosenbloom D et al: Heparin for 5 days compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 322: 1260, 1990

76. Ginsberg JS: Management of venous thromboembolism. N Engl J Med 335: 1816, 1996

77. Pineo GF, Hull RD: Prevention and treatment of venous thromboembolism. Drugs 52: 71, 1996

78. Schulman S, Rhedin A, Lindmarker P et al: A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 332: 1661, 1995

79. Schulman S, Granqvist S, Holmstrom M et al, and the Duration of Anticoagulation Trial Study Group: The duration of oral anticoagulation therapy after a second episode of venous thromboembolism. N Engl J Med 336:393, 1997

80. Lensing AWA, Prins MH, Davidson BL, Hirsh J: Treatment of deep venous thrombosis with low-molecular-weight heparins. Arch Intern Med 155: 601, 1995

81. Koopman MMW, Prandoni P, Piovella F et al: Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 334: 682, 1996

82. Levine M, Gent, Hirsh J et al: A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 334: 677, 1996

83. Becker DM, Philbrick JT, Selby B: Inferior vena cava filters. Arch Intern Med 152: 1985, 1992

84. Heaps J, Lagasse LD: Use of the inferior vena cava clip in patients at high risk of pulmonary embolism. Gynecol Oncol 39: 227, 1990

85. Cohen JR, Grella L, Citron M: Greenfield filter instead of heparin as primary treatment for deep venous thrombosis or pulmonary embolism in patients with cancer. Cancer 70: 1993, 1992

86. Hayden GE: The incidence of unsuspected asymptomatic thrombophlebitis of pelvic veins associated with hysterectomy. Am J Obstet Gynecol 119: 396, 1974

87. Duff P, Gibbs RS: Pelvic vein thrombophlebitis: Diagnostic dilemma and therapeutic challenge. Obstet Gynecol Surv 38: 365, 1983

88. Witlin AG, Mercer BM, Sibai BM: Septic pelvic thrombophlebitis or refractory postpartum fever of undetermined etiology. J Matern Fet Med 5: 355, 1996