Drugs and haemostasis

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Chapter 29 Drugs and haemostasis

The coagulation system

Coagulation initiates with tissue factor (TF), a cell membrane protein that binds activated factor VII (indicated by adding the letter ‘a’, i.e. factor VIIa). Although there is a small fraction of circulating factor VII in the activated state, it has little or no enzymatic activity until it is bound to TF. Most non-vascular cells express TF in a constitutive1 fashion, whereas de novo TF synthesis can be induced in monocytes and damaged endothelial cells. Injury to the arterial or venous wall exposes extravascular TF-expressing cells to blood. Lipid-laden macrophages in the core of atherosclerotic plaques are particularly rich in TF, thereby explaining the propensity for thrombus formation at sites of plaque disruption. Once bound to TF, factor VIIa activates factor IX and factor X (to IXa and Xa, respectively), leading to thrombin generation and clot formation (Fig. 29.1).

The classical view of blood coagulation with separate ‘extrinsic’ and ‘intrinsic’ pathways initiated by either TF or contact with an anionic surface does not reflect physiological coagulation. It is now evident that coagulation does not occur as linear sequential enzyme activation pathways but rather by a network of simultaneous interactions, which undergo regulation and modulation during the thrombin generation process itself.

In the current model, blood coagulation starts with a transient release of tissue factor by damaged endothelium, resulting in the formation of sub-nanomolar amounts of thrombin via TF/VIIa-driven Xa formation (extrinsic-tenase). The initial thrombin activity is necessary to prime the system for a full thrombin explosion. Tissue factor pathway inhibitor (TFPI) rapidly shuts down this priming pathway and the full thrombin explosion is then dependent on factor IXa-driven Xa formation. Factor IXa-driven Xa formation (intrinsic-tenase) is amplified by the thrombin explosion itself, as thrombin forms a positive feedback loop by activating factor XIa (not shown in Fig. 29.1), which converts more IX to IXa.

Thrombin converts soluble fibrinogen into insoluble fibrin monomers, which spontaneously polymerise to form the fibrin mesh that is then stabilised and cross-linked by activated factor XIII (factor XIIIa), a thrombin-activated transglutaminase. Thrombin amplifies its own generation by:

Procoagulant drugs

Vitamin K

Vitamin K (‘Koagulation’ vitamin) is essential for normal coagulation. It occurs naturally in two forms. Vitamin K1 (phylloquinone) is widely distributed in plants and K2 includes vitamin synthesised in the alimentary tract by bacteria, e.g. Escherichia coli (menaquinones). Leafy green vegetables are a good source of vitamin K1. Bile is required for the absorption of the natural forms of vitamin K, which are fat soluble. The storage pool of vitamin K is modest and can be exhausted in 1 week, although gut flora will maintain suboptimal production of vitamin K-dependent proteins. A synthetic analogue, menadione (K3), is water soluble.

Vitamin K is necessary for the final stage in the synthesis of coagulation proteins in the liver: the procoagulant factors II (prothrombin), VII, IX and X, and anticoagulant regulatory proteins, proteins C and S. The vitamin allows γ-carboxylation of glutamic acid residues in their structure; this permits calcium to bind to the molecule, mediating the conformational change required for enzymatic activity, and binding to negatively charged phospholipid surfaces, e.g. platelets. Membrane binding is required for full enzymatic potential.

During γ-carboxylation of the proteins, the reduced and active form of vitamin KH2 converts to an epoxide, an oxidation product. Subsequently vitamin K epoxide reductase converts oxidised vitamin K back to the active vitamin K, i.e. there exists an interconversion cycle between vitamin K epoxide and reduced vitamin K (Fig. 29.2).

When the vitamin is deficient or where drugs inhibit its action, the coagulation proteins produced are unable to associate with calcium in order to form the necessary three-dimensional configuration and associated membrane-binding properties that are required for full enzymatic activity. Their physiologically critical binding to membrane surfaces fails to occur, and this impairs the coagulation mechanism. These proteins are called ‘proteins induced in vitamin K absence’ or PIVKAs.

Oral vitamin K antagonists exert an anticoagulant effect by interrupting the vitamin K cycle. There are two classes of drugs: the coumarins, including warfarin and acenocoumarol, and the indanediones such as phenindione. The anticoagulant effect of oral vitamin K antagonists is expressed as the International Normalised Ratio (INR).

Vitamin K deficiency may arise from:

The following preparations of vitamin K are available:

Coagulation factor concentrates

Bleeding due to deficiency of specific coagulation factors is treated by either elevating the deficient factor, e.g. treatment of mild factor VIII deficiency with desmopressin (see below), or replacement of the missing factor. Recombinant factor VIII and IX are now available in some countries for patients with congenital deficiency of these factors. For patients with rare coagulation factor deficiencies or multiple acquired deficiencies (liver disease, massive blood loss with dilutional coagulopathy or DIC), replacement therapy requires human-derived fresh frozen plasma (FFP) or factor concentrates containing factors II, VII, IX and X (Beriplex, Octaplex).

Solvent–detergent virally inactivated FFP (Octaplas) is currently given to selected patients in the UK, for example those with rare bleeding disorders and patients with thrombotic thrombocytopenic purpura who require repeated exposure to FFP. Methylene blue-treated single donor unit FFP is also available as a virally inactivated product.

Use of coagulation factor concentrates

Management of haemophilia A and haemophilia B (deficiency of factor VIII and IX, respectively) requires special expertise but the following points are notable:

FEIBA is a human donor-derived factor concentrate for patients with inhibitory antibodies to factor VIII or IX. It contains a mixture of coagulation factors and produces thrombin generation even in the presence of inhibitors to factor VIII or IX.

Recombinant factor VIIa (NovoSeven) is effective for patients with inhibitory antibodies to factor VIII or IX or deficiency of factor VII. A pure synthetic activated coagulation factor, it generates thrombin even in the presence of inhibitors to factor VIII or IX. Owing to its short duration of action, three doses (90 μg/kg) are usually necessary at 2-h intervals. Alternatively a single large dose can be used (270 μg/kg).

Desmopressin (DDAVP)

Desmopressin is a vasopressin analogue that increases the plasma concentrations of factor VIII and von Willebrand factor, and directly activates platelets. DDAVP is usually given subcutaneously or intravenously, but unwanted effects (headache, flushing and tachycardia) are less severe after subcutaneous use. A concentrated form is available for intranasal use.

DDAVP is useful for treating patients with mild haemophilia A and von Willebrand’s disease, especially for short-term therapy. For dental extraction, a single injection of 0.3 micrograms/kg 1–2 h before surgery, combined with the oral antifibrinolytic drug, tranexamic acid, for 5–7 days after the procedure (see Antifibrinolytic drugs, p. 492), will produce normal haemostasis and prevent secondary haemorrhage.

Patients with Type 3 (severe) or some forms of Type 2 von Willebrand’s disease (VWD) and some with Type 1 with severe haemorrhage, or patients who require major surgery, need replacement therapy with human-derived intermediate-purity factor VIII concentrate known to contain high molecular weight von Willebrand factor (vWF) multimers. The larger multimers are required for normal haemostatic function. Cryoprecipitate that is rich in factor VIII and vWF is not virally inactivated and should not be used for patients with VWD or mild to moderate factor VIII deficiency.

DDAVP shortens the bleeding time in patients with renal or liver failure.

Anticoagulant drugs

Anticoagulant drugs act principally to reduce the activity of thrombin, the enzyme that is mainly responsible for blood clotting. The following discussion will show that drugs do so by:

Oral vitamin K antagonists (VKA)

Warfarin and other oral vitamin K antagonists (VKA) reduce the activity of zymogens.

Pharmacodynamics

During the γ-carboxylation of factors II (prothrombin), VII, IX and X (and also the natural anticoagulant proteins C and S), active vitamin K (KH2) is oxidised to an epoxide and must be reduced by the enzymes vitamin K epoxide reductase and vitamin K reductase to become active again (see the vitamin K cycle, p. 483). Coumarins3 are structurally similar to vitamin K and competitively inhibit vitamin K epoxide reductase and vitamin K reductase, so limiting availability of the active reduced form of the vitamin to form coagulant (and anticoagulant) proteins. The overall result is a shift in haemostatic balance in favour of anticoagulation because of the accumulation of clotting proteins with absent or decreased γ-carboxylation sites (PIVKAs).4

This shift does not take place until functioning vitamin K-dependent proteins, made before the drug was administered, have been cleared from the circulation. The process occurs at different rates for individual coagulation factors (VII t½ 6 h, IX and X t½ 18–24 h, prothrombin t½ 72 h). The anticoagulant proteins C and S have a shorter t½ than the pro-coagulant proteins and their more rapid decline in concentration may create a transient hypercoagulable state. This can be dangerous in individuals with inherited protein C or S deficiency who may develop thrombotic skin necrosis during initiation of oral anticoagulant therapy with vitamin K antagonists. Anticoagulation with heparin until the effect of warfarin is well established reduces the risk of skin necrosis when rapid induction of anticoagulation is required.

The therapeutic anticoagulant effect of warfarin develops only after 4–5 days. Furthermore, the INR does not reliably reflect anticoagulant protection during this initial phase, as the vitamin K-dependent factors diminish at different rates and the INR is particularly sensitive to the level of factor VII, which is not a principal determinant of thrombotic or bleeding risk.

Warfarin is the oral anticoagulant of choice, for it is reliably effective and has the lowest incidence of adverse effects. Because of the delay in onset of anticoagulant effect with oral vitamin K antagonists (VKAs) there is a need for an immediate-acting anticoagulant, such as a heparin, in the first few days of therapy if rapid anticoagulation is required.

The response to warfarin, and other coumarins, varies within and between individuals and therefore regular monitoring of dose is essential. The pharmacokinetics (absorption and metabolism) and pharmocodynamics (haemostatic effect) are influenced by vitamin K intake and absorption, by heritable functional polymorphisms affecting metabolism such as P450 CYP 2 C9 polymorphisms, by rates of synthesis and clearance of coagulation proteins, and by drugs. The effectiveness of anticoagulant therapy with oral VKAs is determined by the INR, a standardised method derived from the prothrombin time that permits comparison between different laboratories.

Adverse effects

The major complication of treatment with warfarin is bleeding. As well as a risk of haemorrhage after trauma or surgery, spontaneous bleeding may occur. Each year a patient is on treatment there is a 1 in 20 (5%) risk of minor haemorrhage. The annual risk of major bleeding is 1 in 100, of which one-quarter are fatal. The risk of bleeding relates to the INR, not the dose of warfarin: the higher the INR, the greater the chance of bleeding. The risk of over-anticoagulation increases with intercurrent illness and interaction with other drugs, and is more likely in patients whose anticoagulant control is unstable. Therefore, it is essential to:

Warfarin is a small molecule that crosses the placenta and can produce harmful effects in the developing fetus.

Warfarin embryopathy develops only after exposure to oral anticoagulant during the first trimester of pregnancy. The most common feature is chondrodysplasia punctata, characterised by abnormal cartilage and bone formation (with stippling of epiphyses visible on radiography) in vertebrae and femur, and the bones of the hands and feet during infancy and early childhood; these disappear with age (warfarin is not the only cause of this abnormality). Other less common skeletal abnormalities include nasal hypoplasia and hypertelorism (wide-set eyes).

Bleeding into the central nervous system is a danger throughout pregnancy but particularly at the time of delivery.

As a consequence of the above, warfarin is contraindicated in the first 6–12 weeks of pregnancy and should be replaced by heparin before the anticipated date of delivery, as the action of the latter drug can be terminated rapidly prior to the birth.

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