Thrombosis

23 Thrombosis

P.A. Routledge, H.G.M. Shetty

Venous thromboembolism (VTE)

• VTE has an incidence of 2–5%.

• Combinations of sluggish blood flow and hypercoagulability are the commonest causes of VTE. Vascular injury is also a recognised causative factor.

• Treatment of VTE involves the use of anticoagulants and, in severe cases, thrombolytic drugs.

• Anticoagulant therapy usually involves an immediate-acting agent such as heparin followed by maintenance treatment with warfarin.

• Unfractionated heparins increase the rate of interaction of thrombin with antithrombin III 1000-fold and prevent the production of fibrin from fibrinogen.

• Low molecular weight heparins inactivate factor Xa, have a longer half-life and produce a more predictable response than unfractionated heparins.

• Warfarin is the most widely used coumarin because of potency, reliable bioavailability and an intermediate half-life of elimination (36 h).

• Warfarin consists of an equal mixture of two enantiomers, (R)- and (S)-warfarins, that have different anticoagulant potencies and routes of metabolism.

Thrombosis is the development of a ‘thrombus’ consisting of platelets, fibrin, red cells and white cells in the arterial or venous circulation. If part of this thrombus in the venous circulation breaks off and enters the right heart, it may be lodged in the pulmonary arterial circulation, causing pulmonary embolism (PE). In the left-sided circulation, an embolus may result in peripheral arterial occlusion, either in the lower limbs or in the cerebral circulation (where it may cause thromboembolic stroke). Since the pathophysiology of each of these conditions differs, they will be discussed separately under the headings ‘Venous thromboembolism’ (VTE) and ‘Arterial thromboembolism’.

Venous thromboembolism

Epidemiology

VTE is common, with an incidence of 2–5%. PE is now the commonest cause of maternal death, and deep vein thrombosis may result in not only PE but also subsequent morbidity as a result of the post-phlebitic limb. Thromboembolism appears to increase in prevalence over the age of 50 years, and the diagnosis is more often missed in this age group.

Aetiology

VTE occurs primarily due to a combination of stagnation of blood flow and hypercoagulability. Vascular injury is also a recognised causative factor but is not necessary for the development of venous thrombosis. In VTE, the structure of the thrombus is different from that in arterial thromboembolism. In the former, platelets seem to be uniformly distributed through a mesh of fibrin and other blood cell components, whereas in arterial thromboembolism the white platelet ‘head’ is more prominent and it appears to play a much more important initiatory role in thrombus.

Sluggishness of blood flow may be related to bed rest, surgery or reduced cardiac output, for example in heart failure. Factors increasing the risk of hypercoagulability include surgery, pregnancy, oestrogen administration, malignancy, myocardial infarction and several acquired or inherited disorders of coagulation (for further detail of genetic factors, see Rosendaal and Reitsma, 2009).

Protein C deficiency

Protein C deficiency is inherited by an autosomal dominant transmission. Such patients are at increased risk not only of VTE but also of warfarin skin necrosis. This occurs because protein C (and its closely related co-factor, protein S) is a vitamin K-dependent antithrombotic factor that can be further suppressed by the administration of warfarin. Thrombosis in the small vessels of the skin may occur if large loading (induction) doses of warfarin are given to such patients when the suppression of the antithrombotic effects of these factors occurs before the antithrombotic effects of blockade of vitamin K-dependent clotting factor (II, VII, IX and X) production has occurred. Although the prevalence of protein C deficiency is 0.2%, only one subject in 70 (i.e. 0.0003%) will be symptomatic, and the condition accounts for around 4% of patients presenting with thromboembolic disease before the age of 45 years.

Protein S deficiency

Protein S deficiency is probably even rarer than protein C deficiency, but the familial form, inherited in an autosomal dominant fashion, is a high-risk state, accounting for possibly 5–8% of cases of thromboembolism in patients less than 45 years old.

Factor V Leiden

The presence of factor V Leiden, a point mutation in the factor V gene, causes the activated factor V molecule to be resistant to deactivation by activated protein C (APC). This defect may have a prevalence of 5% in Caucasian populations, and higher in patients with thromboembolic disease, and may in itself be of little consequence until there is another risk factor, such as immobility and use of the contraceptive pill. In these circumstances, the combination of risks may be responsible for the increased predisposition to thromboembolism in a high proportion of affected individuals.

Antithrombin III deficiency

Antithrombin III deficiency is a rare autosomal dominantly inherited abnormality associated with a reduced plasma concentration of this protein. The defect may not result in clinical problems until pregnancy or until patients enter their fourth decade, when venous and (to a lesser extent) arterial thrombosis becomes more common. Nevertheless, it has been estimated to be responsible for between 2% and 5% of thromboembolism occurring before age 45.

Lupus anticoagulant

Lupus anticoagulant, an antibody against phospholipid, is so named because it increases the clotting time in blood when measured by some standard coagulation tests. Patients affected are more prone to thromboembolism. This factor is found in 10% of patients with systemic lupus erythematosus (SLE) where it is associated with a threefold increase in thromboembolic risk; it is also found in the primary antiphospholipid syndrome (PAPS), where it may signify an increased risk of venous and arterial thrombosis and of recurrent miscarriage.

Prothrombin 20210 mutation

A mutation in part of the prothrombin gene (prothrombin 20210A) results in increased prothrombin concentrations and an increased risk of venous thrombosis. Carriers have a two- to threefold increased risk of venous thrombosis, and the variant is found with similar frequency as factor V Leiden in Caucasian populations.

Fibrinogen gamma 10034T

Approximately 6% of individuals carry this variant gene, which increases thrombotic risk approximately twofold.

Oestrogens

Oestrogens increase the circulating concentrations of clotting factors I, II, VII, VIII, IX and X and reduce fibrinolytic activity. They also depress the concentrations of antithrombin III, which is protective against thrombosis. This effect is dose-related, and venous thrombosis was more often seen with the high (50 μcg) oestrogen-containing contraceptive pill than with the present lower dose preparations. Hormonal replacement therapy, pregnancy and the puerperium (up to 6 weeks after delivery) are also recognised risk factors for VTE.

Malignancy

VTE is also commoner in malignancy (the risk may be up to fivefold greater). Although first described in association with carcinoma of the pancreas, all solid tumours seem to be associated with this problem. This may be related to the expression of tissue factor or factor X activators, but several other mechanisms may also be responsible. Cancer treatment also appears to be a risk factor.

Surgery

The increased risk of VTE in surgery is related in part to stagnation of venous blood in the calves during the operation and also to tissue trauma, since it appears to be more common in operations that involve marked tissue damage, such as orthopaedic surgery. This may in turn be related to release of tissue thromboplastin and to reduced fibrinolytic activity. The most important risk factors associated with clinical thromboembolism after surgery are age, varicose veins with associated phlebitis and obesity (body mass index > 30 kg/m²), prolonged immobility or continuous travel of greater than 3 h approximately 4 weeks before or after surgery.

Other risk factors

There are several other patient-related risk factors for VTE. Age over 60 years is an important factor. Critical care admission, dehydration, and one or more significant medical comorbidities such as heart disease, metabolic, endocrine or respiratory pathologies, acute infectious diseases and inflammatory conditions are all important risk factors for VTE. A full list can be found in the relevant National Institute for Health and Clinical Excellence (2010) guideline.

Clinical manifestations

In 90% of patients, deep vein thrombosis occurs in the veins of the lower limbs and pelvis. In up to half of cases, this may not result in local symptoms or signs, and the onset of PE may be the first evidence of the presence of VTE. In other cases, patients classically present with pain involving the calf or thigh associated with swelling, redness of the overlying skin and increased warmth. In a large deep venous thrombosis that prevents venous return, the leg may become discolored and oedematous. Massive venous thrombus can occasionally result in gangrene, although this occurs very rarely now that effective drug therapies are available.

PE may occur in the absence of clinical signs of venous thrombosis. It may be very difficult to diagnose because of the non-specificity of symptoms and signs. Clinical diagnosis is often made because of the presence of associated risk factors. Obstruction with a large embolus of a major pulmonary artery may result in acute massive PE, presenting with sudden shortness of breath and dull central chest pain, together with marked haemodynamic disturbance, for example severe hypotension and right ventricular failure, sometimes resulting in death due to acute circulatory failure unless rapidly treated.

Acute submassive pulmonary embolus occurs when less than 50% of the pulmonary circulation is occluded by embolus, and the embolus normally lodges in a more distal branch of the pulmonary artery. It may result in some shortness of breath but if the lung normally supplied by that branch of the pulmonary artery becomes necrotic, pulmonary infarction results with pleuritic pain and haemoptysis (coughing up blood), and there may be a pleural ‘rub’ (a sound like Velcro® being torn apart when the patient breathes in) as a result of inflammation of the lung. Patients may, rarely, develop recurrent thromboembolism. This may not result in immediate symptoms or signs but the patient may present with increasing breathlessness and signs of pulmonary hypertension (right ventricular hypertrophy) and, if untreated, progressive respiratory failure.

Investigations

Deep vein thrombosis

Although several conditions may mimic deep vein thrombus, such as a Baker’s cyst, which involves rupture of the posterior aspect of the synovial capsule of the knee, deep vein thrombosis is the commonest cause of pain, swelling and tenderness of the leg. The clinical diagnosis of venous thrombosis is relatively unreliable, and venography is the most specific diagnostic test.

Venography

Venography involves injection of radio-opaque contrast medium, normally into a vein on the top of the foot, and subsequent radiography of the venous system.

Ultrasound

Ultrasound is a non-invasive alternative to venography that does not involve exposure to ionizing radiation or potentially allergenic contrast media. It is now the initial investigation of choice in clinically suspected deep vein thrombosis, although it is less sensitive for below-knee and isolated pelvic deep vein thrombosis.

Magnetic resonance imaging (MRI)

MRI is also non-invasive and avoids radiation exposure. When used with direct thrombus imaging (DTI), which detects methaemoglobin in the clot, MRI DTI is sensitive and specific, even with below-knee and isolated pelvic deep vein thrombosis. However, it is not widely clinically available and ultrasound remains the primary initial investigation.

Pulmonary embolism

Pulmonary arteriography

The diagnosis of PE is most often made using one of two techniques: pulmonary arteriography or ventilation–perfusion scanning. Pulmonary arteriography is the most specific test. This requires catheterisation of the right side of the heart and an injection of contrast medium into the pulmonary artery. Adequate facilities and experienced personnel are, therefore, required and it is now generally reserved for those situations where massive or submassive PE is suspected but non-invasive tests have given indeterminate results.

Ventilation–perfusion scanning

Ventilation–perfusion scanning involves the injection of a radiolabelled substance into the vein and measurement of perfusion via the pulmonary circulation, using a scintillation counter. This is often combined with a ventilation scan in which radiolabelled gas, normally xenon, is inhaled by the patient. PE classically results in an area of under- or non-perfusion of a part of the lung that, nevertheless, because the airways are patent, ventilates normally. This pattern is called ventilation–perfusion mismatch and is a specific sign of PE.

Spiral computed tomography

Computed tomography angiography (CT angiography) using helical or spiral CT (sCT) is now being increasingly used in some centres and has a high accuracy rate. Although subsegmental emboli can be missed, visualisation of smaller arterial branches, and therefore detection of small emboli, may improve with the availability of multidetector scanners. Not only does sCT enable direct visualisation of emboli, but also visualisation of the lung parenchyma and mediastinum may help in the differential diagnosis in non-embolic cases. MRI is also being developed for the diagnosis of PE and early results are promising.

Other findings

Other findings occur in PE, such as changes in the chest radiograph, for example a raised right hemidiaphragm as a result of loss of lung volume (PE more commonly affects the right than the left lung). Hypoxia is also seen, and the larger the pulmonary embolus the worse this is. The electrocardiogram may show signs of right ventricular strain. The echocardiogram may show right ventricular overload and dysfunction in massive PE. However, all these changes are relatively non-specific and do not obviate the need for the specific tests mentioned above.

Treatment

The aim of treatment of venous thrombosis is to allow normal circulation in the limbs and, wherever possible, to prevent damage to the valves of the veins, thus reducing the risk of the swollen post-phlebitic limb. Second, it is important to try to prevent associated PE and also recurrence of either venous thrombosis or PE in the risk period after the initial episode.

In acute massive PE, the initial priority is to correct the circulatory defect that has caused the haemodynamic upset, and in these circumstances, rapid removal of the obstruction using thrombolytic drugs or surgical removal of the embolus may be necessary. In acute submassive PE, the goal of treatment is to prevent further episodes, particularly of the more serious acute massive PE. In both deep vein thrombosis and PE, a search must be made for underlying risk factors, such as carcinoma, which may occur in up to 10% of patients, and particularly in those with repeated episodes of VTE.

The treatment of VTE consists of the use of anticoagulants and, in severe cases, thrombolytic drugs. Anticoagulant therapy involves the use of immediate-acting agents (particularly heparin) and oral anticoagulants, the commonest of which is warfarin. Not only do these treat the acute event, but they also prevent recurrence and may be necessary for some time after the initial event, depending on the persistence of risk factors for recurrent thromboembolism.

Prophylaxis

Prevention of initial episodes of VTE in those at risk is clearly of great importance. It was estimated that around 25,000 people in the UK die from preventable hospital-acquired VTE annually, including patients admitted to hospital for medical care as well as surgery. There is also widespread evidence of inconsistent use of prophylactic measures for VTE in hospital patients, including mechanical as well as pharmacological means of VTE prophylaxis. Some of the medicines described below contribute to those pharmacological measures. Guidelines on this are available (National Institute for Health and Clinical Excellence, 2010).

Heparins

Conventional or unfractionated heparin (UFH) is a heterogeneous mixture of large mucopolysaccharide molecules ranging widely in molecular weight between 3000 and 30,000, with immediate anticoagulant properties. It acts by increasing the rate of the interaction of thrombin with antithrombin III by a factor of 1000. It, thus, prevents the production of fibrin (factor I) from fibrinogen. Heparin also has effects on the inhibition of production of activated clotting factors IX, X, XI and XII, and these effects occur at concentrations lower than its effects on thrombin.

Unlike UFH, low molecular weight heparins (LMWHs) contain polysaccharide chains ranging in molecular weight between 4000 and 6000. Whereas UFH produces its anticoagulant effect by inhibiting both thrombin and factor Xa, LMWHs predominantly inactivate only factor Xa. In addition, unlike UFH, they inactivate platelet-bound factor Xa and resist inhibition by platelet factor 4 (PF4), which is released during coagulation. Bemiparin, dalteparin, enoxaparin, reviparin and tinzaparin are LMWHs with similar efficacy and adverse effects.

Because UFH and LMWHs all consist of high molecular weight molecules that are highly ionised (heparin is the strongest organic acid found naturally in the body), they are not absorbed via the gastro-intestinal tract and must be given by intravenous infusion or deep subcutaneous (never intramuscular) injection. UFH is highly protein-bound and it appears to be restricted to the intravascular space, with a consequently low volume of distribution. It does not cross the placenta and does not appear in breast milk. Its pharmacokinetics are complex, but it appears to have a dose-dependent increase in half-life. The half-life is normally about 60 min, but is shorter in patients with PE. It is removed from the body by metabolism, possibly in the reticuloendothelial cells of the liver, and by renal excretion. The latter seems to be more important after high doses of the compound.

LMWHs have a number of potentially desirable pharmacokinetic features compared with UFH. They are predominantly excreted renally and have longer and more predictable half-lives than UFH and so have a more predictable dose response than UFH. They can, therefore, be given once or, at the most, twice daily in a fixed dose, sometimes based on the patient’s body weight, without the need for laboratory monitoring, except for patients given treatment doses and at high risk of bleeding.

The major adverse effect of all heparins is haemorrhage, which is commoner in patients with severe heart or liver disease, renal disease, general debility and in women aged over 60 years. The risk of haemorrhage is increased in those with prolonged clotting times and in those given heparin by intermittent intravenous bolus rather than by continuous intravenous administration. UFH is monitored by derivatives of the activated partial thromboplastin time (APTT), for example the kaolin–cephalin clotting time (KCCT); in those patients with a KCCT three times greater than control, there is an eightfold increase in the risk of haemorrhage. The therapeutic range for the KCCT during UFH therapy, therefore, appears to be between 1.5 and 2.5 times the control values. Rapid reversal of the effect of heparin can be achieved using protamine sulphate, but this is rarely necessary because of the short duration of action of heparin. LMWHs may produce fewer haemorrhagic complications, and monitoring of effect is not routinely required. At doses normally used for treatment, they do not significantly affect coagulation tests and routine monitoring is not necessary (British Committee for Standards in Haematology, 2006a).

Heparins, particularly UFH, may also cause thrombocytopenia (low platelet count). This may occur in two forms. The first occurs 3–5 days after treatment and does not normally result in complications. The second type of thrombocytopenia occurs after about 6 days of treatment and often results in much more profound decreases in platelet count and an increased risk of thromboembolism. LMWHs are thought to be less likely to cause thrombocytopenia but this complication has been reported, including in individuals who had previously developed thrombocytopenia after UFH. For these reasons, patients should have a platelet count on the day of starting UFH and the alternate-day platelet counts should be performed from days 4 to 14 thereafter. For patients on LMWH, the platelet counts should be performed at 2–4 day intervals from day 4 to 14 (British Committee for Standards in Haematology, 2006b). If the platelet count falls by 50% and/or the patient develops new thrombosis or skin allergy during this period, heparin-induced thrombocytopenia (HIT) should be considered, and if strongly suspected or confirmed, heparin should be stopped and an alternative agent such as a heparinoid or hirudin commenced.

Heparin-induced osteoporosis is rare but may occur when the drug is used during pregnancy, and may be dose-related. The exact mechanism is unknown. Other adverse effects of heparin are alopecia, urticaria and anaphylaxis, but these are also rare.

It has been shown that there is a non-linear relationship between the dose of UFH infused and the KCCT. This means that disproportionate adjustments in dose are required depending on the KCCT if under- or over-dosing is to be avoided (Box 23.1). Since the half-life of UFH is 1 h, it would take 5 h (five half-lives of the drug) to reach a steady state. A loading dose is, therefore, administered to reduce the time to achieve adequate anticoagulation. UFH in full dose can also be given by repeated subcutaneous injection, and in these circumstances the calcium salt appears to be less painful than the sodium salt. Opinions differ as to whether the subcutaneous or intravenous route is preferable. The subcutaneous route may take longer to reach effective plasma heparin concentrations but avoids the need for infusion devices.

Box 23.1 Guidelines to control unfractionated heparin (UFH) treatment

Source: Modified from Fennerty et al. (1986) and reproduced in British Committee for Standards in Haematology (1998)

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Jun 18, 2016 | Posted by admin in PHARMACY | Comments Off

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