Prevention Of Perioperative Deep Venous
Thrombosis And Pulmonary Embolism

B. Todd Sitzman, M.D., M.P.H.
B. Todd Sitzman, M.D., M.P.H. is with the Department of
Anesthesiology and Pain Management, Mayo Clinic Jacksonville

Introduction

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are major causes of morbidity and mortality in the perioperative period (Figure 1). Despite the availability of effective prophylactic agents, most patients who are at significant risk for postoperative DVT do not receive appropriate preventive care. This article will review the etiology of perioperative DVT and PE, the pharmacology of common anticoagulant therapies, and the risks and benefits of various prophylactic regimens. This article will also review the safe and effective use of anticoagulant and mechanical therapies in the perioperative periods with regard to type of surgery: general, gynecologic, urologic, neurosurgical and orthopedic.

Figure 1. Autopsy photograph of a postoperative right pulmonary artery embolus from a 75 year old gentleman status-post an open cholecystectomy with common bile duct exploration (Photograph courtesy of Stephen F. Hogan, M.D).

Etiology

Virchow's triad of reduced blood flow, abnormal clot formation and loss of vascular integrity describes the conditions that promote thrombus formation. Likewise, similar conditions common and unavoidable in the postoperative state include venous stasis, hypercoagulability and the presence of vessel injury. Risk factors for postoperative DVT are listed in Table 1. Estimates of the incidence of perioperative DVT and PE are quite high, although they vary from study to study depending on the study population and diagnostic criteria utilized. Estimates of the incidence of postoperative DVT in various surgical settings are listed in Table 2. Age, comorbidities, duration and type of surgery, type of anesthesia (general versus regional) and delayed ambulation all contribute to the incidence rates and should all be considered when assessing a patient's risk for postoperative DVT.

Types Of Prophylaxis

A variety of DVT and PE prophylactic agents are available. Table 3 list the types of prophylactic agents available. In addition to medications that prevent clot formation, several mechanical devices are available. These devices either augment blood flow (e.g., elastic compression stockings, intermittent pneumatic compression boots) or interrupt blood flow to prevent embolization (vena cava filters).

Pharmacology Of Anticoagulant Therapy

Management of the postoperative patient requires knowledge of not only the risks and incidences of postoperative thromboembolism, but also the pharmacology of common anticoagulants.

Warfarin is a vitamin-K antagonist which interferes with the carboxylation of coagulation factors II, VII, IX, X, and proteins C and S. These coagulation factors are hepatically synthesized and are inactive unless their glutamate residues are carboxylated. The half-life of these coagulation factors varies widely, from approximately 6 hours for factor VII to 50 hours for factor II, which accounts for the time required for return of normal coagulation following discontinuation of warfarin. Warfarin is 99% plasma protein bound.

Warfarin therapy has a decreased effect in patients with low-protein states (nephrotic syndrome), high dietary intake of vitamin-K and in states of hepatic enzyme induction (e.g., chronic use of barbiturates, phenytoin, rifampin, and alcohol). Increased warfarin effect may be seen in patients with severe hepatic or renal insufficiency, as well as with acute alcohol use, decreased dietary intake of vitamin-K, and decreased metabolic clearance or protein binding of warfarin (e.g., use of cimetidine, metronidazole, acetaminophen, allopurinol).

Prothrombin time (PT) is used to monitor coumadin therapy. The International Normalized Ratio (INR) is currently utilized in the United States to standardize anticoagulation therapy with coumadin. The surgical procedure and the risk of thromboembolism guide the INR target range.

Heparin is a human glycoprotein synthesized in the liver, which increases the activity of antithrombin III one thousand-fold. This activity suppresses the production of thrombin and formation of fibrin. It is a naturally occurring circulating anticoagulant that inhibits activated coagulation factors IXa, Xa, XIa, XIIa, thrombin and kallikrein. Heparin has an immediate onset and its half-life is dependent upon the dose administered. While the anticoagulation effects of intravenous heparin usually disappear within three hours, it can be rapidly reversed with protamine. Full anticoagulation with heparin requires a continuous intravenous infusion directed toward prolonging the activated partial thromboplastin time (aPTT) to 1.5 to 2.0 times the normal. Subcutaneous heparin (e.g., 5000 units every 12 hours) should not significantly effect the aPTT.

Low-molecular weight heparins/heparinoids (LMWH) consist of smaller heparin fragments which have more specific activated factor Xa inhibitory effects. LMWH weigh approximately one-third that of unfractionated heparin and, like that of unfractionated heparin, increase the activity of antithrombin III. Major differences from unfractionated heparin include a higher bioavailability (100%), longer biologic half-life (4-7 hours versus 1-3 hours), and minimal effects on platelets. LMWH can be used in a fixed dosage regimen and without monitoring. There are currently four LMWH available and approved by the Food and Drug Administration: enoxaparin, dalte-parin, ardeparin and danaparoid.

General, Gynecologic And Urologic Surgery

Patients undergoing general, gynecologic and urologic surgical procedures have comparable risks for postoperative DVT. Low-dose unfractionated heparin (5000 units subcutaneously every 12 hours) is generally effective and has been shown to decrease the incidence of postoperative DVT by greater than 50%. Patients undergoing major cancer surgery often require more aggressive prophylaxis, with target aPTT values in the high normal range. LMWH may be advantageous in these high-risk patients by reducing postoperative bleeding complications and as replacing the need for monitoring aPTT values.

In addition to heparin therapy, elastic compression stockings and intermittent pneumatic compression boots (IPCBs) are effective DVT prophylaxis devices in low to moderate risk patient populations. Elastic compression stockings and IPCBs achieve their effect through compression of calf veins, the initial site of most postoperative DVT. They should be applied prior to surgery and continued until full ambulation. However, because of the potential for poor calf fit, elastic compression stockings should be reserved for patients at low risk for DVT. In higher-risk patient populations and in those where possible heparin-induced bleeding is a concern, IPCBs have been shown to be as effective as low dose unfractionated heparin. Patients at very high risk for DVT, such as an elderly patient with a past history of postoperative DVT undergoing abdominal, gynecologic or urologic surgery for malignancy, may benefit from concurrent pharmacological and mechanical device prophylactic therapies.

Neurosurgery

Patients undergoing intracranial procedures as well as patients with acute spinal cord injuries are at high risk for DVT. After spinal cord injury, the greatest risk for DVT and clinical PE is in the first few weeks. These risks decrease significantly after three months; therefore, prophylaxis should be continued for at least three months.

In the untreated spinal cord injured patient the risk of DVT is consistently above 50%, whereas in patients treated with adjusted-dose unfractionated heparin or LMWH, the risk of DVT is below 10%. Combination therapy utilizing elastic compression stockings or IPCBs and low dose unfractionated heparin also appear effective.

In patients undergoing intracranial procedures, IPCBs with or without elastic compression stockings appear effective in preventing DVT. The combination of IPCBs and low dose unfractionated heparin may reduce the incidence of DVT even further without increasing the risk of intracranial bleeding.

Orthopedic Surgery

Patients undergoing major orthopedic procedures of the hip or knee represent a population at great risk for DVT and PE. In addition to the high incidences of DVT as outlined in Table 2, the risk of PE in those patients who do not receive DVT prophylaxis is approximately 5% with a 20% mortality. While early ambulation is effective in lowering the risk of a thromboembolic event, prophylactic anticoagulant therapy is also necessary in patients with hip fractures and in those undergoing hip and knee arthroplasty.

While subcutaneously administered low dose unfractionated heparin will reduce the incidence of postoperative DVT in this patient population, there are more effective anticoagulation regimens. Adjusted low-dose unfractionated heparin works but requires close monitoring of the aPTT with dose adjustments. LMWH is approximately twice as effective as low-dose unfractionated heparin, decreasing the incidence by greater than 50% following hip and knee arthroplasty.

Low-dose warfarin therapy is also effective in reducing the incidence of DVT in the postoperative orthopedic patient. Unlike LMWH, warfarin therapy requires close monitoring and dose adjustment. The goal of low-dose warfarin therapy is to prolong the prothrombin time such that the INR is approximately 2.0 to 3.0. Nevertheless, clinically significant bleeding after orthopedic surgery occurs as often with warfarin therapy as with LMWH, in approximately 5% of patients.

The use of elastic stockings and IPCBs reduces the incidence of DVT following major orthopedic surgery by increasing lower extremity venous blood flow. Elastic stockings have been shown to reduce the risk of DVT by about 25% and IPCBs have been shown to further decrease this risk by 50%.

Does the type of anesthesia make a difference in the incidence of DVT in the orthopedic patient? Yes, regional anesthesia (spinal or epidural) compared with general anesthesia has been shown to reduce the risk of DVT in patients undergoing total hip and knee replacement surgery. However, regional anesthesia alone is not considered effective prophylaxis, and low_dose warfarin or LMWH should also be used.

The use of regional anesthesia may also pose a risk to the anticoagulated patient. Untreated spinal or epidural hematoma formation following regional anesthesia may have catastrophic consequences, including permanent paralysis. It is widely accepted that spinal or epidural anesthesia should be avoided in patients with elevated PT or PTT times. But how safe is the use of LMWH which does not require laboratory level monitoring? After receiving reports of more than 30 cases of spinal or epidural hematomas in patients receiving concurrent LMWH, the United States Food and Drug Administration issued a Public Health Advisory in December 1997 calling this risk to the attention of all healthcare practitioners. Although it is impossible to completely eliminate the risk of spinal or epidural hematoma in patients receiving LMWH and regional anesthesia, several steps can be taken to reduce this risk. Table 4 lists several recommendations for patients receiving LMWH concurrently with spinal or epidural anesthesia.

Conclusions

The prophylactic use of pharmacologic agents and/or mechanical devices for the prevention of deep venous thrombosis and pulmonary emboli has become standard care for the perioperative patient. It is hoped that this article provides a general understanding of the etiology and incidence of perioperative DVT, as well as the pharmacology, indications and risks of various prophylactic regimens. The information and recommendations contained in this article are not intended to dictate clinical practice, but rather to stimulate further reading on this topic.

References

Clagett GP, Anderson FA, Heit J, et al. Prevention of venous thromboembolism. Fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy. Chest. 1995; 4:312S-334S.

Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic and urologic surgery. N Engl J Med. 1988; 318:1162-1173.

Flinn WR, Sandager GP, Silva MB, et al. Prospective surveillance for perioperative venous thrombosis. Arch Surg. 1996; 131:472-480.

Horlocker TT, Heit JA. Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management. Anesth Analg. 1997; 85:874-885.

Lassen MR, Borris LC. Managing the risk of thrombosis in the perioperative period in patients undergoing orthopedic and trauma surgery with low-molecular-weight-heparin: enoxaparin.Orthopedics. 1997; 20(S):14-17.

Lumpkin MM. FDA Public Health Advisory: Reports of epidural or spinal hematomas with the concurrent use of low moleculary weight heparin and spinal/epidural anesthesia or spinal puncture. Reprinted in Anesth Analg. 1998; 86:1156.

Jacksonville Medicine / December, 1998

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