Stagnation within the veins is the most important factor in initiating venous thrombosis. Calf muscles act as a venous pump returning blood to the heart. Failure of the calf pump due to enforced immobility (e.g. postoperative bed rest, plaster cast, paralysed limb) leads to venous stasis. This is a particular problem in the elderly, the obese and those with varicose veins: in these patients even 3 or 4 days of immobility can be critical.

Thrombosis is triggered by the activation of clotting mechanisms that occurs when there is damage to the vein wall – indeed, this is the normal mechanism for preventing bleeding at the sites of trauma. Typical situations that lead to vein damage are pressure injuries to the calf from the operating theatre table and the deterioration that occurs in the veins as a result of recurrent venous thrombosis.

There are several inherited and acquired abnormalities of the clotting mechanisms that increase the risk of venous thromboembolic disease (→Box 7.1). The most common acquired abnormalities are those associated with the oral contraceptive pill, hormone replacement therapy, pregnancy and the presence of malignant disease.

Inherited clotting abnormalities (‘thrombophilias’) are increasingly recognised as underlying the cause of recurrent DVTs, particularly in younger patients and in those with a positive family history. The most important of several inherited coagulation abnormalities, known as Factor V Leiden, is present in 5% of the population and increases the risk of thrombosis by ten times the normal rate. One in five patients with their first DVT are Factor V Leiden positive. Recent estimates suggest up to half of all patients who present with a venous thromboembolic episode, either DVT or pulmonary embolus, may have a single or multiple inherited abnormalities of their clotting. In these individuals, each episode can be triggered by trivial external events such as minor surgery or immobility. In the future, increasing attention will be paid to identifying these inherited risk factors.

In most situations in which the chances of a venous thrombosis are high there are multiple risk factors. Thus in major orthopaedic procedures to the leg there is vein damage and immobility; in pregnancy there is abnormal clotting and stagnation of blood due to intraabdominal mechanical effects; and in prolonged air travel there is immobility, often associated with a degree of dehydration. The combination of the oral contraceptive pill and the presence of Factor V Leiden increases the risk of a DVT 30-fold.

In a patient with suspicious symptoms, the presence of major risk factors (those that increase the risk by between 5 and 20 times normal) makes the diagnosis of a pulmonary embolism much more likely.

Confirmatory tests are chosen according to the clinical likelihood of a PE and the presence or absence of major risk factors (page 254). If the clinical picture is consistent with a PE, and the patient has no other obvious alternative diagnosis such as pneumonia or COPD, the presence of a major risk factor makes the probability of a PE high. If the clinical picture is consistent with a PE but the patient has either no obvious alternative diagnosis or a major risk factor, the probability of a PE is intermediate. If the clinical picture would fit a PE but there is an obvious alternative diagnosis and no major risk factor, the probability of a PE is low. High probability patients should start heparin immediately and need a definitive test (CTPA or isotope lung scan) – patients where the probability of a PE is intermediate or low should have the screening blood test (D-dimer) which, if it is normal, rules out a PE. A normal D-dimer test can give false reassurance in cases where the clinical suspicion is scored high – in this situation the test should not be done.

A number of tests are available to identify venous thromboembolic disease (→Table 7.1). They are described in more detail below.

The investigation of possible pulmonary emboli has been revolutionised by the introduction of the CTPA. It is superior to both the isotope lung scan and the conventional angiogram. A negative CTPA rules out a significant pulmonary embolus and often gives additional information on alternative causes of the patient’s symptoms.

Lung scans are easy to perform and, when used in conjunction with the clinical details, are useful in the diagnosis of pulmonary emboli. Although positive scans are also seen in other conditions and have to be interpreted with care, a normal scan result is very helpful, as it rules out the possibility of a pulmonary embolus.

D-dimers are fragments of dissolving blood clots that can be identified from a blood sample whenever a thromboembolic process is under way. A positive test is also seen after surgery, in infections, after myocardial infarction and in malignant disease: a positive D-dimer test is not therefore in itself diagnostic. D-dimer tests are most useful for ruling out thromboembolism when the initial clinical assessment suggests a low or intermediate suspicion of the diagnosis. For example a patient who is breathless may have a major risk factor such as recent hip surgery, but has other possible causes of breathlessness such as COPD: in this situation, a negative D-dimer means there is another cause for the breathlessness. When the clinical suspicion is high, D-dimers are not helpful, because a negative result under these circumstances is not reliable enough to rule out the diagnosis (an example would be a patient who is breathless, with no alternative explanation, plus a major risk factor for pulmonary embolus).

This looks at compressibility of the vein with an ultrasound probe and also examines venous blood flow using colour Doppler. Compression ultrasound is accurate for thigh vein thrombosis, but not for thrombosis in the pelvis or calf. It is also unreliable at picking up recurrent thrombotic episodes. In spite of these drawbacks, ultrasound is a simple, rapid and very effective diagnostic tool, particularly when combined with clinical assessment and initial screening by the measurement of D-dimers. If a DVT is thought likely (based on clinical assessment in the form of a scoring system – page 265 and an elevated D-dimers) but a compression scan is negative, the scan should be repeated in seven days in case a calf vein thrombosis (not dangerous) has extended above the knee to involve the thigh veins (dangerous).

The venogram examines the veins of the legs and pelvis and the inferior vena cava and is considered to be the ‘gold standard’ for the identification of venous thrombosis. An invasive test and unpleasant for the patient, its use is confined to difficult cases, particularly those in which active intervention with a vena cava filter is under consideration. The pulmonary angiogram was the ‘gold standard’ investigation for diagnosing pulmonary emboli, but it has been replaced by the CT pulmonary angiogram.

In this test, the flow of blood out of the calf is impeded by inflating a thigh cuff. The cuff is then suddenly let down and the flow of blood out of the calf is measured to assess the degree of venous obstruction. The term ‘impedance’ refers to the technique of deriving a measure of blood flow from sensors placed over the calf.

Ultrasound and plethysmography are reliable for proximal deep vein thrombosis, but are poor at identifying calf vein thrombosis. However, in practical terms (i.e. the risk of pulmonary embolus) thrombosis in the calf only becomes important if it spreads to the thigh – so if the initial clinical suspicion is high it is prudent to repeat either test after a few days, in case a missed calf vein thrombosis has extended proximally to the thigh.

If the patient has collapsed with a cardiac arrest, cardiopulmonary resuscitation is started without delay. A massive embolus can present with a cardiac arrest, typically in the form of electromechanical dissociation (an ECG rhythm trace, but no palpable pulse or blood pressure).

A major embolus cuts off the circulation to the lung, so the patient becomes acutely cyanosed. Immediate high-flow oxygen with a tight-fitting mask and a non-rebreathing bag is indicated to correct this. Intubation and ventilation may be needed in extreme cases.

There is an immediate decrease in cardiac output, due to interruption of the circulation by the clot. The blood pressure falls dramatically even though the heart may continue to beat strongly. To help the heart by maximising venous return, the patient must be kept flat with the legs raised. A persistently low blood pressure is an indication for i.v. fluids. However, it is unwise to give, say, more than 500ml of isotonic saline, as the right side of the heart is already under strain and may not cope with a large volume load.

If these measures do not restore the blood pressure, then inotropic support is needed: the options are noradrenaline (norepinephrine), dopamine, dobutamine and adrenaline (epinephrine). Drugs such as GTN or frusemide are contraindicated, as they will reduce an already dangerously low blood pressure.

While resuscitation continues, the pulse, blood pressure and oxygen saturation need to be measured every few minutes. Persistent hypotension and tachycardia, in spite of efforts to restore the circulation, suggest that the clot has not shifted and that it continues to obstruct the circulation to the lung. Repeated urgent blood gas measurements will be needed during the initial phase.

If the initial management is successful and the patient’s condition stabilises, heparin is used to prevent further, and possibly fatal, emboli. The choice lies between i.v. heparin as an initial bolus, then infusion, and subcutaneous lowmolecular-weight heparin. Heparin prevents further clotting and allows the body’s natural enzymes to disperse existing clots. In the patient who remains hypotensive and ill, the thrombolytic, rt-PA, can be used to help break up the emboli more rapidly. The recommended treatment is a 50-mg bolus of i.v. alteplase.

Further tests may be needed to confirm the diagnosis, usually a CTPA or an isotope lung scan in medical physics or, less commonly, a pulmonary angiogram. A pulmonary angiogram is primarily diagnostic, but it can help the patient directly if the catheter is used to dislodge the clot or to put thrombolytic drugs such as rt-PA directly into the pulmonary vessels where the embolus is lodged.

If, despite adequate anticoagulation, there are recurrent emboli arising from residual clots in the deep veins, filter devices can be placed in the inferior vena cava. These are effective in preventing further emboli and are usually well tolerated.

The major risk factors are:

Lower limb immobility. After a stroke, a paralysed lower limb often develops chronic ankle oedema, so the diagnosis of a DVT can be difficult, particularly if there is a problem with communication. The risks are similar if a limb is immobilised in a plaster cast.

Surgery within previous 4 weeks. Venous thrombosis is especially common after hip and knee replacements and can occur 4–6 weeks after surgery. Diagnosis can be difficult because of swelling and discomfort due to the surgery itself, but investigations need to be pursued, because 20% of patients undergoing a major lower limb joint replacement will develop a DVT despite prophylactic subcutaneous heparin in the immediate postoperative period.

Cancer. Active malignant disease within the previous 6 months increases the risk of DVT. Malignancy, particularly in the lung, prostate and pancreas, can also present as unexplained, often recurrent, venous thrombosis.

Positive family history. There is increasing recognition of the importance of a positive history of venous thromboembolic disease in first-degree relatives. The inherited thrombophilias are passed on to half of the offspring, as they are all inherited as autosomal dominant characteristics.

Previous DVT/PE. A previous thromboembolic episode is a major risk factor. The recurrence rate at 5 years is 25%; it is particularly high if there are residual associated risk factors such as malignant disease or immobility.

Obesity. Obesity is an important risk factor for both DVT and cellulitis. Commonly, obese middle-aged and elderly medical patients have chronically swollen and oedematous ankles, with areas of pigmentation, old healed varicose ulceration and discrete cellulitic looking areas. These legs can be difficult to assess, in particular to differentiate between acute and long-standing changes.

There are three important signs of venous thrombosis in the legs (→Fig. 7.2):

Three additional signs may be present:

There is increasing interest in using procedures that combine the results of clinical assessment in the form of a scoring system with the result of a screening test procedure such as the D-dimer tests to determine the next step: immediate discharge, immediate anticoagulation, or further investigation with lung scan, venogram or ultrasound (→Box 7.3, Fig. 7.3).

A modified Well’s Score (Box 7.3) is used to score the patient’s DVT as likely or unlikely. If it is unlikely and the D-dimer is negative a DVT can be ruled out – if the D-dimer is positive a compression ultrasound is done to exclude a DVT. If a DVT is likely the definitive test, compression ultrasound, is done. Only if this negative is a D-dimer done which, if elevated (suggesting a calf vein clot, undetectable by ultrasound) leads to a follow up scan in seven days to exclude extension of the clot into the thigh.

Mechanical pain from the knee is suggested by a sudden onset during twisting, turning or crouching. The joint may be swollen, stiff and tender. The history is particularly important in rupture of a Baker’s cyst, as the signs in the leg can be identical to those found in a DVT.

The history is all important. Torn muscle fibres usually occur during exertion and may be associated with local bruising around the heel and side of the foot. Patients on long-term oral steroids are prone to rupture of the Achilles’ tendon, which may occur with surprisingly little effort – even using the stairs.

There is a clear relationship in the history of lifting or sudden straining, with the pain commonly radiating from the spine down the back of the leg. With the patient lying on his back, the pain can be triggered by lifting the affected leg straight up in the air.

The following case studies illustrate possible diagnoses for acutely swollen red legs (→Case Study 7.5, Case Study 7.6 and Case Study 7.7).

Major risk factors for cellulitis are:

NB: If the pain from a ‘cellulitic’ leg is extreme, worsening and seemingly out of proportion to the changes in the leg, it is important to consider the possibility of necrotising fasciitis, a deep, rapidly spreading soft tissue infection.

The main features of necrotising fasciitis are:

Cellulitis can be confused with varicose eczema:

Heparin increases the effect of the naturally occurring anticoagulant called antithrombin. There is a wide variation in the response to i.v. heparin, so that the treatment needs careful monitoring, using the APPT in order to individualise the dose. Inadequate initial therapy is associated with a much worse outcome. The aim is to anticoagulate to 1.5–2.5 times the control APPT. Intravenous heparin is continued for at least 4 days and should overlap with warfarin treatment until the INR is in the therapeutic range of 2.0–3.0 for at least 2 days.

Many audits have shown a tendency to undertreat patients with heparin, particularly in the first critical 24h: this problem can be minimised by the use of a heparin protocol.

Low-molecular-weight heparin has replaced the heparin infusion on most medical units, because it is as effective in treating both DVT and pulmonary embolus. Its simplicity raises the prospect of outpatient treatment.

In contrast to conventional heparin, low-molecular-weight heparin:

Low-molecular-weight heparin is given for at least 5 days while warfarin is introduced, until the INR is within the therapeutic range (2.5–3.0) for 2 consecutive days.

Low-risk surgery. 3500 units of tinzaparin 2h pre-op and once daily for 7 days post-op.

High-risk surgery/high-risk medical condition, e.g. severe DKA. 50 units/kg 12h pre-op and once daily for 7 days

Treatment of thromboembolic event. 175 units/kg of tinzaparin once daily.

The doses of subcutaneous low-molecular-weight heparins are presented in Table 7.2.

The most common causes for over-anticoagulation are:

Many drugs increase the effect of warfarin: those most commonly implicated are broad-spectrum antibiotics. Progressive cardiac failure, particularly in the elderly, is often associated with a sudden deterioration in anticoagulant control – INR values of 10 or more are not uncommon. Liver disease itself prolongs the prothrombin time, so clearly its development would have a major effect on the patient who is also taking warfarin.

Once the INR increases above 5.0 there is a risk of bleeding. However, provided that there is no major blood loss, INR values in the range 4–8 can be managed by discontinuing warfarin treatment until the INR falls. If the INR is greater than 8, warfarin should be stopped and if there are additional risks for bleeding (e.g. over 70 years old, previous bleeding, nose bleeds) a small dose (0.5–2.5 mg orally of the i.v. preparation) of vitamin K should be given. This will partially reverse the effects of the warfarin.

In the presence of major bleeding, the warfarin is stopped and its effect completely reversed with vitamin K 5mg by slow i.v. injection. In addition, either FFP 15ml/kg or, if it is available, prothrombin complex concentrate 50 units/kg, is administered to restore the clotting factors. FFP is the main source of serious transfusion reactions and should only be considered when there is active and serious bleeding.

Excessive bleeding on heparin usually responds to stopping the heparin and, if necessary, transfusion. Intravenous protamine sulphate will neutralise heparin at a dose of 1mg per 100 units given slowly over 10min, but it only partially reverses low-molecular-weight heparin and no more than 40mg should be given at any one injection. Treatment can be repeated hourly. FFP is not indicated for heparin overdosage.

Once investigations are under way, the patient may be off the ward for some time during the critical first few hours. The safest course of action is, in the absence of an obvious contraindication, to give the first dose of subcutaneous heparin as soon as the initial assessment is completed.

A severely swollen leg will cause intense pain. Non-steroidal anti-inflammatory drugs and aspirin are unsafe once warfarin has been started, and paracetamol may not be adequate. Oral dihydrocodeine or tramadol may be sufficient, but in extreme pain subcutaneous morphine 10mg 2–4-hourly may be needed.

Any acutely oedematous leg is at risk from ischaemia as a result of increased soft tissue pressure compromising the circulation to the legs. Persistent or increasing pain is the main warning feature, but there may simply be colour change or loss of feeling in the leg.

The heels and sides of the feet are particularly vulnerable in cases of acutely swollen legs. Inspect these areas regularly, use pressure-relieving strategies, and encourage early mobilisation. Oedematous legs are prone to superficial skin infections, particularly if pre-existing foot hygiene is poor.

The prospect of a clot breaking off and travelling to the lungs terrifies most patients. They will want to know about mobilisation (to be encouraged once any severe swelling has resolved), about what exactly happens to the clot in the leg and when the swelling will disappear.

It is important to oversee the anticoagulant therapy, particularly as the patient may be on and off the ward in the first 24h having tests, and there may be a delay, with associated uncertainty, before all the tests come back to the ward. This can lead to a delay in anticoagulation or failures in communication among the staff.

Table 7.3 details the warfarin loading schedule, depending on INR.