4. Drugs Affecting Coagulation

The process of coagulation ends with a haemostatic plug that forms following platelet activation subsequently reinforced by fibrin This final step involves the conversion of soluble fibrinogen to insoluble strands of fibrin reaction catalysed by thrombin. Thrombin (factor IIa) is one of several important serine proteases that are present in the coagulation cascade, and is formed from prothrombin (factor II) in the presence of activated factor X Both coagulation pathways activate factor X, which, as Xa (the suffix ‘a’ denotes ‘active’), converts prothrombin to thrombin.

The newer model of coagulation suggests that thrombin is generated initially by the extrinsic pathway in a process that involves the activation of factors IX and X by a tissue factor-factor VIIa ->forms in response to damaged vascular endothelium. Factor Xa binds with prothrombin (factor II) to form thrombin (factor IIa). Thrombin + positive feedback = thrombin activates factors V and VIII activate factor IX (to IXa) and X (to Xa) with the generation of more thrombin (IIa). Enzyme complexes, such as prothrombinase further activate platelets and accelerate continued thrombin formation factor XIII (fibrin stabilizing factor) links fibrin polymers via covalent bonds, while thrombin itself activates an inhibitor of fibrinolysis.

the two classically described pathways are the ‘intrinsic’, or contact, pathway, all of whose components are present within blood, and the ‘extrinsic’ pathway, in which some components are found outside blood. The intrinsic system is triggered by contact with exposed collagen in endothelium, and the extrinsic system is activated by the release of tissue thromboplastin. he pathways converge on the activation of factor X. The protein coagulation factors are present in blood as inactive precursors, which are then activated by proteolysis, particularly of serine moieties. The cascade is amplified, with each step producing greater quantities of activated clotting factors than the one preceding it. The process in health is held in check by antithrombin III, which neutralizes all the serine proteases involved in the cascade.

warfarin is a competitive inhibitor of vitamin K reductase, and so prevents the regeneration of the reduced active form and the addition of the essential carboxyl moiety to the four coagulation factors coumarins The elimination half-life of factor VII is only 6 hours, whereas that of factor II is 60 hours (the t½ of factors IX and X are 24 and 40 hours, respectively). The effect of warfarin on the prothrombin time (or international normalized ratio, [INR]) starts at 12–16 hours and lasts for 4–5 days is metabolized by the hepatic mixed function oxidase P450 system, and there are a number of drugs which can interfere with its metabolism potentiated by agents that inhibit hepatic drug metabolism - cimetidine, metronidazole and amiodarone attenuated by dietary vitamin K and by drugs such as barbiturates and carbamazepine which induce hepatic cytochrome P450.

Heparins: heparin is not a single homogenous substance. Heparins are a family of sulphated glycosaminoglycans Heparin fragments, low-molecula rweight heparins (LMWHs), are much more commonly used than unfractionated preparations. Heparins inhibit coagulation by potentiating the action of antithrombin III (ATIII). ATIII inactivates thrombin and other serine proteases by binding to the active serine site and so inhibits factors II, IX, X, XI and XII The larger molecules of unfractionated heparin bind both to the enzyme and to the inhibitor, but the smaller LMWHs such as tinzaparin, dalteparin and enoxaparin increase the action of ATIII only on factor Xa. The in vitro effect of unfractionated heparin is measured by the APTT, which is not prolonged by LMWHs.)

Aspirin (acetyl salicylic acid) is the original example of this class of drug. Aspirin and the non-selective COX inhibitors such as diclofenac and ibuprofen inactivate the enzyme cyclo-oxygenase (COX) by binding to COX-1 Aspirin binds irreversibly; the others exhibit competitive antagonism which is reversible. Platelet synthesis of thromboxane (TXA2), which promotes platelet aggregation, then falls. TXA2 also reduces the synthesis of prostaglandin PGI2 (also known as epoprostenol or prostacyclin) in vascular endothelium. This substance inhibits platelet aggregation The persistent inhibition of platelet aggregation results from the fact that vascular endothelium is able to synthesize new PGI2, whereas platelets are unable to produce new TXA2

Clopidogrel. This is a thienopyridine which binds covalently to the P2Y12 ADP receptor on platelet cell membranes, induces a conformational change which renders it inactive and thereby prevents receptor-mediated platelet aggregation Receptor blockade inhibits fibrin cross-linking by preventing activation of the glycoprotein IIb/IIIa pathway. Clopidogrel acts within 2 hours of oral administration, and its irreversible effects last for the lifetime of the platelet (usually 7–10 days).

Ticagrelor. This is a nucleoside analogue which also blocks the P2Y12 ADP receptor but at a site separate from that of ADP agonism. Unlike clopidogrel therefore it is a reversible allosteric antagonist.

Aspirin (acetyl salicylic acid). The effect of aspirin is dose-dependent. At the commonly prescribed low dose of 75 mg daily, the drug acetylates serine residues on COX-1 in a reaction that is irreversible. This inhibition blocks the generation by platelets of thromboxane A2 with a consequent reduction in thrombocyte aggregation and a prolongation of bleeding time. 650 mg daily, aspirin also blocks COX-2, which thereby mediates its anti-inflammatory, antipyretic and analgesic effects.

Abciximab. This is a monoclonal antibody and specific GPIIb/IIa receptor antagonist which inhibits all pathways of platelet activation. It is given by infusion and has a long duration of action, which means that platelet function will not be restored until at least 12 hours after discontinuing the infusion. It provokes an antibody response so repeated administration is not possible.

does not depend on other proteins but rather target a specific molecule. Compared with warfarin, the DOACs have a more rapid onset and offset of action with more predictable anticoagulation profiles. There are two main classes of DOAC: activated thrombin inhibitors and activated factor X inhibitors

Dabigatran. This a direct thrombin inhibitor whose effects peaks at 2–3 hours with an elimination half-life of 12–14 hours. It is unusual in that it has a specific reversal agent in the form of idarucizimab, which is a monoclonal antibody that restores coagulation to normal within minutes. Bivalirudin. This is an analogue of hirudin (a natural anticoagulant peptide found in the salivary glands of leeches). Bivalirudin is a synthetic 20 residue peptide which is an irreversible thrombin inhibitor. It is an intravenous preparation

Rivaroxaban, apixaban. These are examples of orally active direct factor Xa inhibitors. The peak effect of rivaroxaban is at 4 hours, and as factor Xa activity takes 24 hours to normalize, the drug can be given once daily. Apixaban has a similarly selective, reversible direct action on factor Xa but needs twice daily dosing.

Fondaparinux. This is a synthetic pentasaccharide that is chemically similar to heparins and which binds to the same high-affinity binding sites on antithrombin III (ATIII) to potentiate its effect on activated factor X. The drug is given subcutaneously.

this will need to be adapted according to the specific clinical situation, but before elective surgery warfarin is usually stopped 4–5 days preoperatively. If the INR remains unacceptably high, then the patient should be given vitamin K (1.0 mg intravenously) and fresh frozen plasma (FFP; 15 ml kg−1). After minor surgery, the warfarin can be resumed on the first postoperative day. After major surgery, anticoagulation should be maintained by heparin infusion (typically at a rate of 1,000–2,000 units h−1) or by subcutaneous low-molecularweight heparin (LMWH). If necessary, the actions of heparin can be reversed by protamine (1 mg for every 100 units of heparin), whose positive charge neutralizes the negatively charged heparin.

Vitamin K: clotting factors II, VII, IX and X are glycoproteins which contain glutamic acid. Reduced vitamin K (named from the German word ‘Koagulation’) acts as an essential co-factor in this hepatic γ-carboxylation reaction, during which vitamin K is oxidized from the reduced active hydroquinone form to the inactive 2,3-epoxide. In the presence of vitamin K reductase, this process is then reversed.

70-year-old man requires inguinal hernia repair. He is on long-term warfarin for atrial fibrillation with an INR of 2.8. Plan: aim for an INR <2.0. Stop warfarin without substituting another anticoagulant and restart normal dose after surgery. There is no need for bridging anti-coagulation in these patients. Sample scenario (2): a 65-year-old man requires colonic resection. After mechanical mitral valve replacement, his INR has been kept between 3.0 and 4.0. Plan: stop warfarin early enough to allow the INR to fall below 2.0, and follow one of two main options. (1) Heparin: infuse intravenous heparin to maintain activated partial thromboplastin time (APTT) at 1.5–2.5, stop 2 hours prior to surgery and then restart 6 hours postoperatively. Restart warfarin as soon as oral intake is restored (2) LMWH: for example, tinzaparin 100 units kg−1 daily, increasing to 175 units kg−1 postoperatively

If surgery is urgent, then a high INR should be reduced by FFP and vitamin K and possibly by prothrombin complex concentrate (PCC). Restart warfarin as soon as oral intake is restored.

FFP and PCC. FFP does not contain sufficient quantities of the vitamin K–dependent clotting factors for complete reversal of warfarin-induced bleeding, although it does reduce the INR. Prothrombin complex concentrate (PCC, Beriplex) contains factors II, VII, IX and X and in a dose of 25–50 units kg−1 will correct such acquired coagulation factor deficiencies within 1 hour. A single treatment for a 70 kg patient costs around £550

Surgery: neurosurgery requires normal coagulation; cataract surgery may be performed safely with an INR of up to 2.5. Some surgeons will sometimes undertake emergency procedures such as hemiarthroplasty in patients whose INR is similarly high. They do so because clinical experience suggests that, contrary to expectation, blood loss under these circumstances is not excessive. Many surgeons would be prepared to perform routine surgery such as day-case arthroscopy on a patient with an INR of 2.0.

Incidence. The third National Audit Project (NAP) of the Royal College of Anaesthetists (Br J Anaesth 2009, 102: 179–90), which examined major complications of neuraxial blockade, identified eight cases of vertebral canal haematoma, all of which were associated with epidural analgesia. Seven out of those eight had received antithrombotic drugs. NAP 3 estimated an incidence of permanent harm of 1 in 20,000 epidurals and 1 in 140,000 subarachnoid (spinal) blocks.

UFH 4hours if prophylacis - check aptt LMWHs (prophylactic) 12 hr 2–4 hr LMWHs (treatment) 24 hr 2–4 hr Clopidogrel 7 days No delay needed Aspirin None No delay needed Coumarins (e.g. warfarin) INR <1.4 No delay needed

Rivaroxaban 24 hr 2–4 hr Apixaban 24h wait 2-4h Dabigatran - prev C/I AoA 96-120h Fondaparinux 36 hr 6–12 hr Ticagrelor 72 hr No delay needed Bivalirudin 10 hr 2–4 hr

Vascular surgery. One special circumstance is in vascular surgery during which some anaesthetists are nervous about siting an epidural catheter in patients who may receive large doses of intravenous unfractionated heparin intraoperatively. There is no prospective evidence which attests to the safety of this practice, but observational studies in large numbers of patients (3,000) have found no increased incidence of epidural haematoma formation.