Systemic anti-fibrinolytic agents
Systematic reviews of randomised controlled clinical trials, mainly in cardiac and orthopaedic surgery, indicate that use of these drugs is associated with a reduction in the proportion of patients transfused and the number of units of red cells administered to them.(CD001886)
Tranexamic acid or epsilon-aminocaproic acid
Inhibits fibrinolysis by blocking a lysine-binding site on plasmin. Generally considered contra-indicated where formation of a large insoluble clot is undesirable, e.g. haemorrhage in the bladder. Systematic reviews of clinical trials in cardiac and orthopaedic surgery indicate that tranexamic acid may have similar effectiveness to aprotinin. Tranexamic acid is much cheaper than aprotinin; it is a pure chemical rather than a bovine tissue extract, and is not associated with the risk of allergic reactions.
Dose: In cardiac surgery, a dose of 2 g iv pre-bypass and 2 g iv post-bypass is used in some units. This is not a licensed indication. In other situations with haemorrhage, a dosage of 1 g iv repeated six hourly in adults may help control bleeding (dose frequency must be modified in renal failure). A large multi-country trial of tranexamic acid in the early management of traumatic haemorrhage is in progress: www.crash2.lshtm.ac.uk
A bovine protein that inhibits plasmin and other serine proteases. There is a risk of allergic reaction, especially if the patient has been previously exposed to this foreign protein. The first five millilitres should be infused slowly. Aprotinin reduces allogeneic transfusion requirements in cardiac bypass surgery and is often used where blood losses are predictably high, e.g. repeat operations to replace valves in patients with infective endocarditis. Some clinicians remain concerned about a possible effect on graft patency.
Dose: A single dose of 0.5−1 million Kallikrein Inhibitor Units (50−100 ml) followed by infusion of 0.2 million units (20 ml) per hour may be used. The ‘Hammersmith’ protocol is widely used for cardiac surgery (two million units bolus followed by 0.5 million units per hour). Two recent reports of risks of aprotinin have been widely challenged. A prospective randomised controlled clinical trial of aprotinin, tranexamic acid and epsilon aminocaproic acid is in progress.
Binds and neutralises the acidic heparin molecule. A strongly basic protein prepared from fish sperm. Neutralises unfractionated heparin but low-molecular-weight heparins are only partially neutralised. Protamine also binds to platelets. A fall in platelet count may occur immediately after administration but is usually short lived. Allergic reactions including anaphylaxis are recorded but are rare. The manufacturers recommend caution in those with fish allergy, vasectomy and previous exposure, and in diabetics who have taken the older protamine-containing insulin preparations.
Dose: 1 mg protamine per 100 units heparin. Reduce dose per unit of heparin by 50% for every hour post-heparin administration. If laboratory tests suggest persistence of heparin effect, give a further 50 mg and repeat the laboratory tests.
Releases stores of factor VIII and von Willebrand factor from endothelial cells and may have other pro-haemostatic effects. In patients who have already lost a large amount of blood its effectiveness may be limited as these stores may be exhausted. DDAVP may also improve platelet function in patients with liver or renal failure. When used in cardiac surgery or von Willebrand’s disease, it has been associated with coronary artery thrombosis.(PMID14973974)
Dose: Typically 0.3 μg/kg given subcutaneously and repeated if necessary at six-hour intervals. It is useful in patients with milder forms of haemophilia and von Willebrand’s disease (see Recombinant factor VIIa).
Local haemostatic agents
Provide a locally administered coagulum.
Bovine and/or human origin. Pooled plasma derivatives (e.g Tisseal®).(PMID12804501)
Bovine origin (Bioglue®).
Local coagulation promoters
Locally applied thrombin (e.g. FloSeal®).
Tranexamic acid. May be useful in nose packs for epistaxis, or orally for gum bleeding, or at surgical site.
Procoagulant swabs, etc. (e.g. Spongestan®).