Thromboembolic disease: The case for routine prophylaxis
Preventive strategies can reduce fatal pulmonary embolism as much as 75% in gynecologic surgery patients. This article explains the evidence on how to assess risk and choose mechanical and drug therapies for these women, including gravidas.
- Prophylaxis must start before surgery for maximal benefit, since at least 50% of postoperative thromboembolic disease begins intraoperatively.
- A consensus conference found that prophylaxis reduced fatal pulmonary emboli by 75% in 7,000 gynecologic surgery patients.
- Low-dose unfractionated heparin and low molecular weight heparin appear similarly effective in reducing thromboembolic disease in perioperative patients, but it is unclear which form has fewer bleeding complications.
The case is strong for routine prophylaxis against venous thrombosis and pulmonary embolism. The primary reasons: efficacy, ease of use, and safety.
This article reviews the evidence on routine prophylaxis, pros and cons of mechanical and drug therapies (including a comparison of 2 heparins), patient risk factors, and cost-effectiveness. A table (page 32) lists patient characteristics for low, moderate, high, and very high levels of risk, with corresponding appropriate preventive measures.
Routine prophylaxis is a wiser strategy than postevent treatment or surveillance because:
- Thromboembolism is a stealthy adversary, particularly pulmonary embolism. Between 10% and 20% of patients with pulmonary emboli die, often within 30 minutes of the sentinel complaint.
- Even when pulmonary embolus is documented during autopsy, as many as 80% of patients have no antecedent clinical evidence of deep venous thrombosis (DVT)—and no chance of life-saving therapy.2
- Surveillance is the least desirable preventive option due to lack of sensitivity of noninvasive tests for thromboembolic disease.
Scope of thromboembolic disease
Thromboembolism is the leading potentially preventable cause of hospital fatality.1
In postoperative gynecologic surgery patients, pulmonary embolism occurs in 0.1% to 5% of cases, depending on risk.2 Venous thrombosis occurs on average in 15% of postoperative gynecologic surgery patients, with a range of 5% to 29%, depending on patient risk factors and the surgical procedures performed.3 Almost 50% of gynecologic patients undergoing surgery for cancer develop a lower-extremity venous thrombosis if left untreated.4
Overall, thromboembolic disease is linked with some 500,000 hospital admissions every year. Pulmonary embolism, the most serious complication, causes 60,000 to 200,000 deaths annually.
High risk of recurrence. Postthrombotic syndrome is characterized by pain, swelling, and leg ulceration. At least 50% of patients successfully treated for proximal venous thrombosis (thigh) and about 33% treated for distal venous thrombosis (calf) develop postthrombotic syndrome.1 The risk for recurrent thrombosis is high.
Risk factors are listed in TABLE 1. The risk of fatal pulmonary embolism is directly related to age; persons over 60 are at greatest risk. When the patient is obese—particularly when she exceeds 120% of ideal body weight—the risk is even greater due to venous stasis.
Risk factors for thromboembolism
Extended pelvic surgery
Indwelling central venous catheter(s)
Chronic pulmonary disease
Congestive heart failure
Inflammatory bowel disease
Prior thromboembolic disease
Common hypercoagulable states
Prothrombin gene mutation G20210A, the next most common thrombophilia, occurs in 2% of Caucasians.7
Antiphospholipid antibody syndromes are acquired thrombophilias that may be associated with arterial and venous thrombosis, thrombocytopenia, and complications of pregnancy.8
Hyperhomocystinemia may be congenital or acquired. It is associated with venous thromboembolism and early atherosclerosis with arterial thrombosis.
Thrombosis is more likely with multiple predisposing factors. Most patients with one of the thrombophilia syndromes do not have sentinel thrombotic events unless they are further challenged by environmental risks such as oral contraceptives (OCs), pregnancy, prolonged immobilization, or surgery.9
Risk is markedly enhanced if multiple predisposing factors are present. For example, when factor V Leiden mutation and hyperhomocystinemia coexist, the risk for thrombosis increases 10 to 20 times over that of patients with neither abnormality.10 This combined risk far exceeds the sum of risks for each abnormality alone.
Common hypercoagulable conditions
Factor V Leiden mutation
Prothrombin gene mutation G20210A
Protein C deficiency
Protein S deficiency
Antithrombin III deficiency (Heparin cofactor II)
When to test for thrombophilias
Although women with thrombophilias are at high risk for thromboembolic disease, it is unclear whether identifying the thrombophilia is more beneficial than universal prophylaxis. If a patient has a personal or family history of thromboembolic disease—especially a patient with Caucasian ancestry—testing is probably warranted. While documentation of the thrombophilia may not help with perioperative management, it may be useful for long-term care.
Testing for factor V Leiden mutation is recommended due to its prevalence. If the results are negative in a patient at risk, test for prothrombin gene mutation G20210A, as well as deficiencies in the naturally occurring inhibitors protein C, protein S, and antithrombin III.
Assess antiphospholipid antibodies in women who have experienced recurrent fetal loss or early pregnancy-induced hypertension.
Continue OCs or hormone therapy
OCs and menopausal hormone replacement therapy produce measurable prothrombotic changes in the clotting system that appear to be directly related to the estrogen content. In theory, discontinuing the OC or hormone replacement therapy preoperatively would allow these changes to return to baseline and help prevent thromboembolic disease.
Although the risk of thromboembolic disease is 0.96% if patients are current users of OCs and 0.5% if they are not, studies have failed to confirm a clinical benefit of discontinuation.11 Further, the patient does not return to baseline for 4 to 6 weeks after ceasing therapy.
The potential risk of thromboembolic events also should be weighed against the risk of conception prior to surgery. We usually do not recommend discontinuation of OCs and hormone therapy before surgery, but give prophylaxis based on risk assessment.
Virchow’s triad: How intraoperative factors lead to clot formation
Venous stasis, vessel-wall trauma, and increased blood coagulability—the major contributors to perioperative DVT, known as Virchow’s triad—were identified more than 125 years ago.
Venous stasis. Intraoperatively, venous blood return from the lower extremities is reduced to less than half its normal rate,34 secondary to muscle relaxation during anesthesia, which causes venous dilation and reduced blood-flow velocity. Packing the abdominal contents may further impede blood return from the legs.
Resultant venous stasis causes platelet adhesion to the vein wall, followed by release of a thromboplastin-like substance that may trigger thrombus formation.
Blood flow increases in the immediate postoperative period with return of muscle tone, but remains significantly diminished for 21 days because of immobilization—specifically, lack of the usual pumping action of the leg muscles.
Vessel-wall trauma. Veins are highly likely to be damaged as vessels are skeletonized during major pelvic surgery, especially when malignancy is involved. Tissue injury activates the coagulation cascade by exposing blood to tissue thromboplastin (extrinsic path) and subendothelial collagen in the vessel wall, which activates factor XII (intrinsic path). Both pathways lead to conversion of factor X to its active form, factor Xa. Acting in concert with factor V, calcium, and phospholipids from platelet factor III, factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin regulates the conversion of fibrinogen to fibrin, the basic building block of a thrombus.
Increased blood coagulability. Clotting factors XI, IX, and VII increase following surgery, as do circulating platelets and platelet aggregation. This enhances coagulability, which persists from 72 to 96 hours after surgery but is usually balanced by the fibrinolytic system. Fibrinolysis is mediated primarily by plasmin, which digests fibrin and fibrinogen and activates factors V and VIII. If the fibrinolytic system is overwhelmed, the clotting system is unimpeded and thrombus formation may accelerate.
Pregnancy increases the risk of thrombosis, in part due to the progressive increase in resistance to activated protein C in the second and third trimesters. Risk is increased eightfold in women with inherited deficiency in any of the naturally occurring anticoagulants—antithrombin III, protein C, or protein S—compared with those with no deficiency.12
Two approaches to thromboembolic prophylaxis have been proposed, with prevention of fatal postoperative pulmonary emboli as a clear endpoint:
- Stratify a targeted group into levels of risk; then treat those at higher risk. Unfortunately, efforts to define risk have met with only partial success, due to limited availability of noninvasive screening, screening logistics, and expense. Further, specificity and positive predictive value of screening asymptomatic patients is low.
- Use prophylaxis in all patients in the targeted group, regardless of risk (TABLES 3 AND 4). This strategy seems effective. For example, in 2001, the Sixth American College of Chest Physicians Consensus Conference—the most recent of the consensus conferences—evaluated the risks of pulmonary embolus in 7,000 gynecologic surgery patients enrolled in prospective studies. Routine prophylaxis reduced fatal pulmonary emboli by 75%.13
The difficulty of defining patients at highest risk makes the concept of universal prophylaxis for a targeted group an attractive option unless a specific contraindication is identified.
Risk stratification and prophylactic regimens
LEVEL OF RISK
Less than 40 years of age
No specific recommendation for therapy
Undergoing uncomplicated minor surgery
Requires less than 30 minutes of anesthesia
Aggressive early ambulation
No additional risk factors
Undergoing minor surgery with additional risk factors
Graduated compression stockings or SPCDs or
40 to 60 years of age, undergoing minor surgery, and no additional risk factors
LDUH 5,000 U every 12 hours or
Less than 40 years of age, undergoing major surgery, and no additional risk factors
LMWH (20 mg) or 2,500 U antifactor Xa once daily
More than 60 years of age, undergoing minor surgery or with additional risk factors
LDUH 5,000 U every 8–12 hours or LMWH (40 mg) or 5,000 U antifactor Xa once daily
More than 40 years of age undergoing major surgery or with additional risk factors
SPCDs may be added
More than 60 years of age, undergoing major surgery, with other risk factors such as cancer, prior venous thromboembolism, molecular hypercoagulable state, major trauma, spinal cord injury, or lower-extremity paralysis
Graduated compression stockings or SPCDs and LDUH 5,000 U every 8 hours or
Other risk factors such as cancer, prior venous thromboembolism, molecular hypercoagulable state, major trauma, spinal cord injury, or lower-extremity paralysis
LMWH (40 mg) or 5,000 U antifactor Xa once daily
LDUH = low-dose unfractionated heparin; LMWH = low molecular weight heparin; SPCD = sequential pneumatic compression device
Note: Because perioperative prophylaxis is still evolving, these suggestions should not be considered inviolable.
Source: Modified from Geerts WH, et al.13
Incidence of thromboembolic events based on level of risk
SITE OF THROMBOSIS
RISK LEVEL (%)
Calf veins (distal)
Iliofemoral veins (proximal)
Fatal pulmonary emboli
Source: Modified from Geerts WH, et al.13
Drug and mechanical therapies
Strategies for preventing thromboembolic disease attempt to mitigate the impact of venous stasis, endothelial injury, and hypercoagulable states. Traditionally, early ambulation, adequate hydration, and elevation of the lower extremities have been used, because they are simple and inexpensive interventions.
More recently, pharmacologic and mechanical therapies have proven effective in reducing the incidence of DVT and fatal pulmonary emboli. Prophylactic measures commonly used today are:
- graduated compression stockings
- external pneumatic leg or foot compression devices
- low-dose unfractionated heparin
- low molecular weight heparin
MECHANICAL THERAPIESGraduated compression stockings
Compression stockings are one of the earliest methods of preventing perioperative thrombosis. Compression is greatest at the toe and gradually diminishes toward the thigh. When Belcaro14 studied the risk of recurrent venous thrombosis in nonsurgical hospitalized patients, thrombosis recurred in 40% of patients with no therapy, but only 9.4% of patients wearing graduated compression stockings (GCS). Adding oral antiplatelet therapy lowered the risk to 2%. However, GCS were not superior to any other method of preventing recurrent DVT.
As for surgical patients, a single study15 demonstrated protection against DVT when compared with no GCS in elective gynecologic surgery patients.
Today, GCS are usually a perioperative adjunct to other preventive methods, to provide added protection.
Proper fitting by trained personnel is vital; otherwise, a tourniquet effect may cause venous stasis and reduce benefit.
Sequential pneumatic compression devices
Like GCS, these devices decrease the caliber of veins by simple compression. They also increase blood flow velocity and stimulate the endogenous fibrinolytic system.
Enhanced fibrinolytic activity due to intermittent compression occurs even if the device is used on only 1 lower extremity, or on an upper extremity. Patient and nursing-staff compliance may affect efficacy. Sequential pneumatic compression devices (SPCDs) may be thought inconvenient, impeding nursing functions. Some patients may find the repetitive inflation-deflation cycles annoying.