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.

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.

Pulmonary embolism

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.