Introduction
Venous thromboembolism (VTE) is a major public health issue. VTE is thus one of the main causes of mortality. It is also associated with considerable morbidity because nonfatal pulmonary embolism (PE) and deep vein thrombosis (DVT) induce short- and long-term complications. In addition, anticoagulant treatment, although effective, may be a potential source of iatrogenic complications.
Nevertheless, the benefit–risk ratio of widespread postoperative prophylaxis is highly positive, at least in patients at moderate or high risk of DVT. Furthermore, the global VTE rate has been continuously decreasing since the early 1970s, as a result of prophylaxis, the development of day surgery, fast-track procedures and related improvements in the rehabilitation processes, and major progress in surgical and anesthetic techniques. Currently, less than 1.5% of patients undergoing major orthopedic surgery will develop a symptomatic VTE event. The PE rate is well below 0.5%, and the fatal PE rate is much lower than 0.1% in this setting.
Although the likelihood of a fatal PE episode in a patient with a hip fracture is now very low, this is not the case in other surgical settings such as thoracic or bariatric surgery. In addition, an increasing number of elderly patients with severe risk factors are undergoing major surgical procedures. Therefore many questions still need to be answered. New controversial data have recently been published on mechanical prophylaxis and are causing much debate. The new oral anticoagulants (OACs) are also an issue of interest in that their high efficacy rate may be offset by an increase in bleeding risk.
Pathophysiology and Risk
Postoperative thromboembolic risk comprises both patient-related risk and surgical risk.
Patient-related risk increases linearly with age, becoming more marked after 40 years of age and even more so after 60 years. Obesity is responsible for an increased risk of thrombosis as a result of longer immobilization and decreased fibrinolytic activity. Cancer, especially lung, pancreas, colon, or pelvic cancer, increases thromboembolic risk, although surprisingly metastases do not. Cancer-related risk is independent of age. Several other important factors increasing perioperative VTE risk have been reported ( Box 35-1 ).
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Age older than 40 years
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Obesity (body mass index >30)
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Cancer and cancer treatment (hormones, chemotherapy, radiotherapy)
and
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History of venous thromboembolism
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Idiopathic or acquired thrombophilia
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Acute medical illness
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Active heart or respiratory failure
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Severe infection
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Estrogen-containing contraception or hormone replacement therapy
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Selective estrogen response modifiers
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Inflammatory bowel disease
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Immobilization, bed rest, limb paralysis
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Nephrotic syndrome
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Myeloproliferative syndrome
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Paroxysmal nocturnal hemoglobinuria
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Smoking
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Varicose veins
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Central venous catheter
The surgical risk is usually well-established and ranges from low or absent (e.g., hand surgery or osteosynthesis device removal) to high (e.g., surgery for hip fracture or pelvic surgery for cancer) ( Table 35-1 ). However, the risk may also be uncertain in instances such as laparoscopy. Although the minimally invasive nature of laparoscopy might be thought to reduce risk, other aspects—the reverse Trendelenburg position, gas insufflation (vena cava compression with impaired venous return), and a longer operative time—might increase the risk.
| Examples of Surgical Procedures | Risk Category |
|---|---|
| Varicose vein | Low |
| Minor abdominal surgery | Low |
| Knee arthroscopy | Low |
| Trauma to knee without fracture | Low |
| Endoscopic prostate surgery | Low |
| Percutaneous kidney surgery | Low |
| Diagnostic laparoscopy (<30 mm) | Low |
| Minor abdominal surgery with extensive and/or bloody dissection, very long operative time or emergency | Moderate |
| Fracture of lower extremity | Moderate |
| Laminectomy | Moderate |
| Vaginal hysterectomy | Moderate |
| Breast cancer surgery | Moderate |
| Major abdominal surgery (even in the absence of cancer) | High |
| Bariatric surgery | High |
| Total hip or knee replacement | High |
| Hip fracture | High |
| Open kidney surgery | High |
| Open prostate surgery | High |
| Prolapse surgery | High |
| Uterine and ovarian surgery for cancer | High |
| Lung resection by thoracotomy | High |
| Intracranial neurosurgery | High |
The overall risk, which combines patient-related risk and surgical risk, can be classified into three broad categories: low, moderate, and high; however, these categories have not been precisely quantified. The level of risk should be a consideration in the choice of prophylaxis, but if three moderate risks are summed (e.g., prolonged immobilization, obesity, and age older than 60 years), the crucial question is whether the overall risk is significantly increased.
Prevention not only stops the formation of a thrombus but also controls its extension. The new generation of antithrombotic agents, which interact with both free and clot-bound thrombin, should prove to be particularly useful in prevention.
The bleeding risk should also be considered. The clinical development of new antithrombotic agents during the last 10 years has focused on several intrinsic and extrinsic criteria that could increase the perioperative bleeding risk in anticoagulant-treated patients. Renal insufficiency, age older than 75 years, and a low body weight (<50 kg) represent the three major bleeding risk factors that can be summarized by the use of the Cockroft-Gault formula for the calculation of creatinine clearance. A patient with a clearance less than 30 mL/min has a definite increased risk of bleeding. Other bleeding factors are shown in Box 35-2 .
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Active bleeding
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Acquired bleeding disorders (such as acute liver failure)
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Concurrent use of anticoagulants known to increase the risk of bleeding (such as warfarin with international normalized ratio higher than 2)
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Lumbar puncture/epidural/spinal anesthesia expected within the next 12 hr
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Lumbar puncture/epidural/spinal anesthesia within the previous 4 hr
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Acute stroke
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Thrombocytopenia (platelets less than 75 × giga/L)
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Uncontrolled systolic hypertension (230/120 mm Hg or higher)
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Untreated inherited bleeding disorders (such as hemophilia and von Willebrand disease)
Options
The first method of VTE prevention should be early mobilization and ambulation. However, this is not always possible, and other techniques are needed. Mechanical and pharmacologic prevention can be proposed either separately or concomitantly, even if chemical prophylaxis appears to be more effective than mechanical prophylaxis, which is usually the first-line approach.
Evidence
Mechanical Prophylaxis
There are two main techniques for mechanical prophylaxis: (1) graduated elastic compression and (2) intermittent pneumatic compression of the leg or a venous foot pump. Their aim is to increase venous flux and reduce stasis. Both techniques have proven efficacy, neither increases the risk of bleeding, and contraindications are few, mainly peripheral arterial occlusive disease and skin lesions. In both cases, the longer the compression is kept in place throughout a 24-hour period, the greater the efficacy.
In graduated elastic compression, the stocking exerts graded circumferential pressure on the lower limb (18 mm Hg at the ankle, 14 mm halfway up the calf, 8 mm at the knee, and, if the stocking goes to the thigh, 10 mm at the lower half of the thigh and 8 mm at the top of the thigh). Venous flux velocity is increased by 75% ( Table 35-2 ). The 2010 guidelines published by the National Institute for Health and Clinical Excellence (NICE) recommend the systematic use of compression in all patients who have undergone surgery.
| Study, Year | Number of Trials | Number of Subjects (Intervention/No Intervention) | Total DVTs | ||
|---|---|---|---|---|---|
| Intervention | Control | Odds Ratio (Confidence Interval) | |||
| Cochrane database 2010 | 8 10 | 1279 (662/617) 1248 (621/627) | GCS alone | Control | 0.35 |
| 86 (13%) | 161 (26%) | (0.26-0.47) | |||
| GCS + AAM | AAM | 0.25 | |||
| 26 (4%) | 99 (16%) | (0.17-0.36) | |||
In intermittent pneumatic compression, bags wrapped around the calf, thigh, or both are intermittently inflated and deflated for acceleration of venous return. The reduction in risk was found to be 56% for all thromboses and 44% for proximal thromboses. However, the studies were not powerful enough to establish an effect on PE. The results for venous foot compression vary and depend on the indication. It seems to be more effective in surgery for hip replacements than for total knee prostheses but is recommended in hip replacement surgery only if anticoagulants are contraindicated. An effect on proximal thromboses and PE has not been demonstrated.
Pharmacologic Prophylaxis
Three types of anticoagulants—vitamin K antagonists, heparins (unfractionated heparin [UFH] and low-molecular-weight heparin [LMWH], and fondaparinux—and new oral antithrombotic agents (anti-IIa and anti-Xa) are currently being used or are under clinical development for VTE prophylaxis. Hirudins, danaparoid, and dextran are excluded here as they have been the subject of few studies, their efficacy is a matter of debate, and the benefit–risk ratio is lower than for the aforementioned agents.
Vitamin K Antagonists
The most frequently used vitamin K antagonist is warfarin, even though acenocoumarol and fluindione are still prescribed in Europe and Africa. Vitamin K antagonists inhibit a carboxylation step in the synthesis of factors II, VII, IX, and X by the liver and thus, by decreasing the levels of these factors, exert powerful anticoagulant activity. They are still used postoperatively in North America but are gradually being replaced by injectable anticoagulants such as LMWH and fondaparinux ; they will probably finally disappear when the new oral antithrombotic agents become fully available in the near future. In the 2007 NICE review, an analysis of 11 pooled studies (1320 patients) found a reduction in risk of 51% for all thromboses, 58% for proximal thromboses, and 82% for PE as compared with no prophylaxis. The efficacy of OACs is somewhat counterbalanced by interactions with other drugs and food and by an increased risk of bleeding: OACs increased the risk of major bleeding by 58%.
Heparins: Fondaparinux
UFH is extracted from pig intestine. It is a mixture of medium-molecular-weight polysaccharides (15,000 daltons) with equivalent anti-thrombin (IIa) and anti-Xa activity. UFH interacts with antithrombin via a pentasaccharide moiety present in one third of its molecules. It is eliminated by the reticuloendothelial system. Two or three daily subcutaneous injections are usually given to prevent postoperative thromboembolic disease.
Even though UFH has uncontested efficacy, it is being replaced by one or two daily subcutaneous injections of LMWHs. LMWHs have been marketed in Europe since 1985 and in the United States since 1993. Their anti-Xa activity is two to six times higher than their antithrombin activity, and they are eliminated by the kidneys. They are more effective than UFH in terms of the overall risk of thrombosis and proximal thrombosis and better at preventing PE without increasing the risk of bleeding ( Table 35-3 ). In addition, the risk of heparin-induced thrombocytopenia is 5 to 10 times lower than with UFH. LMWHs have become the gold standard for the prevention of perioperative VTE, and they are used as the comparator for all new anticoagulants in clinical trials of superiority or noninferiority. However, because LMWHs and UFH are extracted from pig intestine (one pig for one syringe!), it is important to remember that these molecules are not synthetic and adverse events can occur. For example, an outbreak of adverse reactions associated with contaminated heparin occurred in 2008. The contaminant was identified as oversulfated chondroitin sulfate, and the issue was resolved after a very impressive industrial reaction by Baxter, Pfizer, and Sanofi.
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