HAEMOSTATIC AGENTS

2014

HAEMOSTATIC AGENTS enhance the process of haemostasis, which is the arrest of blood loss from damaged blood vessels, and is essential to life. It involves three key components and their processes: platelets, blood vessels (the vascular endothelium and smooth muscle of the wall), and the blood-borne coagulation cascade system. To an extent, these components can be separated, but proper formation of the haemostatic plug in vivo requires interaction of all. For instance, blood coagulation in vitro is rapid and efficiently forms a clot as such, but it is not the same entity as the thrombus of platelets enmeshed in fibrin that constitutes the functional haemostatic plug which is required in haemostasis to prevent haemorrhage. Similarly, in vivo, in a patient with a deficiency of platelets, there may be spontaneous bleeding giving a purple coloration in the skin (thrombocytopenic purpurea); though the clotting time of the blood is unchanged, the bleeding time is prolonged.

The processes involved in formation of fibrin are described in more detail at ANTITHROMBINS and ANTICOAGULANTS. Briefly, some agents are direct-acting thrombin antagonists, binding avidly to this enzyme and thus preventing the key stage in blood coagulation (e.g. hirudin and certain other agents still being evaluated, including hirugen, hirulog-1 and argatroban). Other agents work as indirect-acting thrombin antagonists in as much as their action involves enhancement of the actions of the endogenous anticoagulant factor, antithrombin III, which inhibits thrombin by binding to the active serine of this serine protease. Agents such as heparin enhance the rate of this reaction by binding to antithrombin III and producing a conformational change (see antithrombins). Other, even more indirect agents, act essentially as vitamin K antagonists, so preventing its key role in the formation of clotting factors (e.g. dicoumarins, notably warfarin).

The role of platelets in the clotting process is discussed in more detail at platelet aggregation inhibiting agents. Such agents include aspirin, a cyclooxygenase inhibitor that reduces synthesis by platelets of thromboxane A2 (TXA2), which is thrombotic and a vasoconstrictor. Similarly, TXA2-synthase inhibitors (e.g. dazoxiben) and TXA2-receptor antagonists (e.g. vapiprost) have been investigated with a view to their use as antiplatelet agents, as have drugs that combine these activities (e.g. ridogrel). Also, prostacyclin (available as epoprostenol) is a potent inhibitor of platelet aggregation, and can help disintegrate platelet clumps. It inhibits the transduction mechanisms for the expression of membrane glycoprotein receptors (GPIIb/IIIa), which are critical for aggregation. Similarly, ticlopidine inhibits expression of the platelet GPIIb/IIIa receptors into the high-affinity ligand-binding state; also, monoclonal antibodies to GPIIb/IIIa receptors are effective inhibitors of platelet function.

The formation of fibrin – coagulation – and the degradation of fibrin – fibrinolysis – are in balance in normal physiology. Clotting, and the subsequent repair of blood vessel walls and other tissue elements, is part of a continuing process. Therapeutically, most aspects of these processes need to be modified in certain circumstances. One very extensive use of haemostatic agents is in the treatment of myocardial infarction, and the possible sequelae where fragment break-off from thrombi can cause stroke. Various combinations of antiplatelet agent (aspirin), anticoagulant or antithrombin agents (heparin) and fibrinolytic agents (streptokinase, anistreplase or t-PA) are very effective, halving mortality.

Genetically, determined clotting diseases include classical haemophilia, which is due to lack of factor VIII, and there is another form of haemophilia due to deficiency of factor IX (Christmas factor). These are treated by giving fresh donor blood or plasma, preparations of factor VIII or factor IX, or increasingly as one of the recombinant versions which are becoming available.

Acquired coagulation defects are more common, and may be due to liver disease (since bile is required for absorption of vitamin K), dietary deficiency of vitamin K, or ingestion of oral anticoagulant agents. Most of these can be treated by giving vitamin K and its congeners, menadiol sodium phosphate or phytomenadione.

Protamine can be used as an antidote in heparin overdose. Ethamsylate reduces capillary bleeding, and is used in the treatment of menorrhagia and probably works by correcting impaired platelet adhesion.

The role of the blood vessels themselves, is an important part of haemostasis. Both the vascular endothelium and smooth muscle are important. The damaged endothelium releases agents (e.g. the prostanoids) that affect both platelet aggregation and/or act on smooth muscle to constrict the vessel. Further, damage to the endothelium exposes collagen which promotes, and provides a substrate, for platelet adhesion. Activated platelets release a number of vasoactive substances (e.g. 5-hydroxytryptamine) that affect the tone of the blood vessels. In general, a profound local vasoconstriction is an important factor in haemostasis in preventing blood loss and enhancing the effectiveness of the haemostatic plug. Sometimes such vasoconstrictors (vasopressin, adrenaline, noradrenaline and 5-hydroxytryptamine) are administered therapeutically to suppress bleeding. See 5-hydroxytryptamine receptor agonists; prostanoid receptor agonists; vasopressin receptor agonists.