Prevention of deep leg vein thrombosis

Introduction
Deep vein thrombosis causes pain, swelling and tenderness of the leg. It may lead to acute or subacute and sometimes fatal pulmonary embolism. Long-term post-phlebitic venous insufficiency ranges from trivial to severe and disabling.

Thrombosis is usually triggered by one or more short-term predisposing risk factors, but there is no apparent cause in a sizeable minority. Sometimes, and especially when there is a strong family history, laboratory tests can detect an underlying inherited or acquired hypercoagulable state.

Just waiting for leg vein thrombosis to develop in the presence of predisposing risk factors is a lost opportunity for prevention. With the ready availability of safe and effective prophylaxis, prevention must be discussed before surgery.

Pathophysiology
Conceptually, the risk factors for thrombosis can almost all be fitted into Virchow's classic prothrombotic `triad'. This consists of changes in the blood vessel wall, in blood flow, and/or in blood composition. After hip replacement, the ultra-high thrombosis risk and predominance of proximal vein thrombosis are due to a combination of direct femoral vein injury with venous stasis and postoperative changes in the blood e.g. increased platelets and fibrinogen.

No laboratory test can measure the degree of 'hypercoagulability' supposedly provoked by acute injury, but testing is essential for detecting inherited disorders. These include antithrombin III, protein C or protein S deficiency, Factor V Leiden (the clotting factor V mutation responsible for activated protein C resistance) and homocysteinaemia. Routine investigation in sporadic thrombosis for these and other abnormalities like antiphospholipid antibodies often yields only confusing information. Laboratory testing is most likely to help:

– in people with a strong family history of venous thromboembolism (in one or more first degree blood relatives)

– after an apparently idiopathic first or recurrent thrombosis

– when thrombosis is associated with other clinical markers of the antiphospholipid syndrome (thrombocytopenia
and/or repeated miscarriage).

Prevention
Most clinical trials have focused on elective general, hip or knee surgery. There is often a need to extrapolate the results when considering other situations such as emergency surgery, vascular surgery, major trauma and acutely ill medical patients. Our research experience is much greater with standard heparin, low molecular weight heparins and oral anticoagulants than it is with physical methods of preventing venous stasis.

Indications for prevention
Prophylaxis is required in patients aged over 40 years having a major operation that is expected to last more than 30 minutes. The pointers to above-average risk include age over 60 years, cancer and the likelihood of slow mobilisation or postoperative complications. Joint replacement poses special problems. It has a very high risk and a relative resistance to many otherwise effective preventive methods. There is also a potential conflict between the need for prophylactic anticoagulants and a preference for regional anaesthesia.

The indications for prevention in medical patients are less clear. There have been few studies of risk in medical patients except after myocardial infarction, where the best predictor is heart failure, and in stroke, where thrombosis usually involves the paralysed leg. However, hospitals find that more medical than surgical patients develop thrombosis and embolism. Other risk factors include old age, debility and immobility.

Both pregnancy and oral contraceptives predispose to thrombosis, but the absolute risk is so small that thrombosis prophylaxis for these reasons should be contemplated only in people with previous thrombosis or inherited thrombophilia.

Preventing venous stasis
Low cost and relative safety ensure there is wide use of graded pressure elastic stockings, intermittent pneumatic leg compression, and per-operative electrical calf muscle stimulation. However, these methods have been studied less thoroughly than anticoagulants, in fewer patients and across a narrower clinical spectrum. As a result, even though they have been shown to prevent sub-clinical thrombosis in low- to medium-risk patients, their performance in high-risk patients remains uncertain. It is difficult to judge, even after meta-analysis, whether physical methods can prevent pulmonary embolism.

There is limited evidence that anticoagulants are better than calf muscle stimulation or stockings in cancer surgery and in major orthopaedic surgery. There is also limited evidence that a combination of stockings with anticoagulant prophylaxis works better than the anticoagulant alone.

Like other preventive methods, stockings and intermittent leg compression must be applied throughout the period of excess risk. For instance, when intermittent leg compression is applied for only 5 days after neurosurgery, it merely delays the onset of thrombosis in patients with ongoing paralysis.

Elastic stockings may endanger blood flow in people with peripheral vascular disease. The cumbersome design of some intermittent leg compression devices invites poor compliance from patients or ward staff.

Nevertheless, physical methods remain a cost-efficient alternative to anticoagulants in people at low to medium risk of developing venous thrombosis (general surgery and some medical conditions).

Anticoagulants
The mainstays of preventive therapy are standard (unfractionated) heparin and the low molecular weight heparins.¹

The low molecular weight heparins have less antithrombin and more anti-factor Xa activity than standard heparin.
They have a much more predictable anticoagulant effect, a longer circulating half-life of 3-4 hours (compared with
40-60 minutes for heparin) and a near 100% bioavailability after subcutaneous injection. Despite small variations in pharmacological properties, low molecular weight heparins all tend to give similar results in clinical trials.

Elective general surgery
There is little difference in efficacy and safety between 8-hourly injections of 5000 IU standard heparin and once-daily low molecular weight heparin. The choice can therefore be left to patient preference, nursing convenience and cost.

Prophylactic doses of standard heparin and of low molecular weight heparins have increased surgical bleeding to a very small extent in some randomised trials, but this is not clinically important. In one very large comparison², a low molecular weight heparin caused marginally less major bleeding after general surgery than standard heparin prophylaxis.

Standard heparin is started 1-2 hours before the operation. Some low molecular weight heparins cause less bleeding when the first dose is given on the night before surgery. No more is given until after the operation. Many surgeons begin prophylaxis postoperatively, but this approach is almost untested in general surgery and cannot, therefore, be recommended.

Major elective orthopaedic surgery
In hip or knee replacement, low molecular weight heparins are clearly superior to standard heparin. There is, however, ongoing controversy about how they should best be used.

In North America, low molecular weight heparins are routinely started 12-24 hours after orthopaedic surgery. This practice is supported by acceptable comparisons with warfarin or standard heparin. There is also one small randomised trial that found little gain from retaining the pre-operative dose.³ In contrast, the recommendation in Australia is to give a pre-operative dose.

There have been anecdotal reports of spinal compression caused by local bleeding following spinal or epidural anaesthesia in patients having prophylactic anticoagulants. Many anaesthetists avoid this combination. The published evidence does not exclude a small excess of spinal bleeding, and the Food and Drug Administration in the U.S.A. has recently issued an alert prompted by more than 30 reports, received by November 1997, of patients who developed bleeding within the spinal column, some of which resulted in prolonged or permanent paralysis, where a low molecular weight heparin was used in conjunction with spinal or epidural anaesthesia or spinal puncture. Delaying low molecular weight heparin prophylaxis until 12-24 hours after a hip operation would avoid some but not all of this concern, given that epidural catheters are often left in place for 36-48 hours or longer to give pain relief. One widely used compromise is to start prophylaxis after surgery if epidural catheter placement was uncomplicated. The catheter is later withdrawn just before an injection is due, when the anticoagulant effect is minimal.

Many surgeons suspect that prophylaxis after joint replacement should continue after the patient goes home, especially now that patients often leave hospital before regaining mobility. Recent trials suggest these surgeons may be correct as asymptomatic thrombosis is not uncommon during follow-up. This can be prevented by self-injected low molecular weight heparin at home. There are, however, few clinically important events during follow-up.

When considering prophylaxis, it is important to remember that its effectiveness is incomplete. Even the best regimens achieve no better than a 60-80% risk reduction, and prophylaxis is no guarantee that thrombosis will not happen.