Modifying perioperative blood loss

Modifying Perioperative Blood Loss

B. J. Hunt SUMMA R Y. Fears about the risks of disease transmission through the transfusion of homologous blood, as well as problems with blood supply and cost have increased the interest in reducing perioperative bleeding. This article discusses the causes of non-surgical perioperative bleeding and attempts to reduce perioperative bleeding with pharmacological agents. There is particular emphasis on tbe effects of cardiopulmonary bypass on haemostasis as the majority of studies have been conducted in this area. The agents discussed include the use of fibrin sealants, antiplatelet agents such as dipyridamole and prostacyclin analogues, antifibrinolytics and the effects of desmopressin and aprotinin. Currently high dose aprotinin would appear to be the most efficacious method of reducing perioperative bleeding in cardiac surgery, although a full risk benefit analysis is not yet possible. The effectiveness of aprotinin and tranexamic acid in reducing the ‘oozing’ seen in any surgical patient suggests the contribution of fibrinolysis in causing perioperative bleeding has not been fully evaluated. More research is required in this actively growing area.

Continued concerns over the risks of using homologous blood especially those of transfusion-transmitted infection, combined with occasional shortages of donor blood and increasing costs, have stimulated interest in perioperative blood conservation. Two broad approaches to blood conservation have been pursued. The first is to accept that blood loss is inevitable and to use measures to conserve the patients blood. Measures such as autologous blood pre-deposit’ have received increasing interest as have the use of autotransfusion, the venesection of one unit prior to cardiopulmonary bypass and reinfusion of residual oxygenator blood after bypass, the use of cell savers and the acceptance of a normovolaemic anaemia post-operatively.2 These measures have been poorly applied in the UK3 This is probably for two reasons. Firstly, a formal programme of blood conservation can be expensive, and the cost must be met B. J. Hunt, MRCP, MRCPath, Senior Research Fellow, Department of Research Haematology, Harefield Hospital. Harefield, Middlesex UB9 6JH, UK. Blood Reviews (1991) 5, 168-176 0 1991 Longman Group UK Ltd

from the surgical budget. In the UK, until recently, the use of donor blood had no financial consequence for either the patient or the surgical department. This contrasts with the USA where blood has a unit price and active conservation was found to be cost effective.4 Secondly, in the UK blood donated by volunteers is perceived as being relatively safe, in that HIV and Hepatitis B screening is performed and the risk of non-A/non-B hepatitis after a procedure such as cardiac surgery is cited as 2.4-3.9%sq6 compared to an incidence of 14.6 in the USA.’ This incidence is predicted to fall with direct screening of donors for Hepatitis C antibodies.* The second approach to blood conservation is to prevent blood loss at the time of surgery using pharmacological methods. This review will concentrate on this area and haemostatic changes seen perioperatively. Almost all of these studies have been performed in patients undergoing cardiopulmonary bypass and so the unique haemostatic problems seen during cardiopulmonary bypass are fully discussed.

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For a review of the management of patients with a pre-existing haemostatic abnormality the reader is advised to turn to a review by Bolan and Alving.g

Perioperative Bleeding Excessive bleeding can be due to surgical causes (i.e. suture deficiency) and/or derangement of haemostasis. The most important determinant of surgical blood loss is the surgeon. A few minutes of the surgeon’s attention to careful haemostatic control may well save a patient from returning to theatre for surgical reexploration to find a bleeding point. It will also save the development of haemostatic problems associated with continued bleeding, the consequent consumption of valuable units of blood products and increased risk of morbidity and mortality associated with excessive perioperative bleeding. There is a subset of patients, however in whom generalised oozing in the surgical field cannot be attributed to demonstrable bleeding vessels. There are no adequate definitions of an ‘excessive bleeder’ and yet many surgeons complain when it occurs. No consensus exists for the pathogenesis of nonsurgical perioperative bleeding. There are several reasons for this: (1) there is a failure to recognise the limitations of laboratory tests; (2) there may be shortcomings in the current concepts of haemostasis; (3) there are no quick and reliable laboratory assays to look at some components of haemostasis that may be causing a problem e.g. fibrinolysis; and (4) the investigative approach is often inappropriate e.g. the investigation of laboratory data following surgery should be based on not what is normal in the general population but on what is normal for patients who have undergone the procedure without excessive bleeding. Stated simply, a prolonged APTT postoperatively does not mean a patient will bleed. The lack of adequate, quick and reliable help from the laboratory in assessing haemostatic parameters has stimulated the use of equipment such as the thromboelastograph. lo Unlike the prothrombotic changes seen postoperatively, perioperative haemostatic changes have not been extensively studied although haemostatic activation is thought to occur as a result of the hyperadrenergic state induced by the stress of surgical stimulation. l1 When a blood vessel is cut and the normal endothelial cell barrier is disrupted, vasoconstriction occurs due to the release of vasoconstrictor such as serotonin and platelets are quickly recruited from the circulating blood to form an occlusive plug. Platelet activation is induced by adhesion to proteins such as collagen within the exposed subendothelial matrix of cut vessels and by agonists such as adrenaline. This occurs through a series of interactions between the platelets and subendothelial matrix (platelet adhesion) and among the platelets themselves (platelet aggre-

169

gation). Platelets adhere through specific receptors including glycoprotein Ib receptor for von Willebrand Factor and several of the integrin superfamily of adhesion receptors for collagen, fibronectin laminin and vitronectin. The initial process of adhesion in contrast to aggregation does not require platelet metabolic activity. It leads however to the activation of platelets that secrete thromboxane A, and the contents of their granules. In addition activated platelets have a critical procoagulant role serving as a nidus for membrane based coagulation reaction involved in the generation of thrombin and the formation of fibrin. Increased fibrinolytic activity occurs during and shortly after an operation as Macfarlanei2 originally noted in 1937. He observed that blood removed from a patient immediately following cholecystectomy clotted normally but was ‘quite fluid’ when inspected the following day. Activation of fibrinolysis results in the production of plasmin and the subsequent digestion of fibrin. Fibrinolysis is activated mainly by two interacting systems (Fig. 1): the contact coagulation system (factor XII and pre-kallikrein) and tissue plasminogen activator (t-PA). The latter is synthesised and secreted by endothelial cells and binds avidly to fibrin and as a result plasminogen is maximally activated at the site of thrombus formation. Plasminogen activator inhibitor- 1 (PAI- 1), also produced from the endothelium, binds to t-PA stoichiometrically. PAI- is inhibited by activated protein C. The increase in understanding and the use of new assays of fibrinolysis have been poorly applied to the study of haemostatic changes in ‘simple’ surgical procedures. Such studies would be helpful in dissecting out the pathophysiological changes in more complex procedures. Haemostatic changes have been extensively studied however in cardiac surgery using cardiopulmonary bypass (see below). Increased levels of t-PA and PAI-1, with a net increase in free t-PA during and after an operation have been noted. l3 Several factors including vasoreactive agents, venous occlusion, anoxia, adrenaline, protein C, thrombin and the use of heparin during cardiopulmonary bypassi have been found to stimulate t-PA release from endothelial cells in vitro and in vivo, but the mechanisms underlying the increased release of t-PA in surgery has not been fully explored. Meninges, cerebral and prostatic tissue contain relatively high concentrations of tissue activators of plasminogen. Elimination of t-PA from the blood is mainly regulated by the liver with a normal half-life of 3-5 min.” Extremely high levels of t-PA occur during the anhepatic phase of orthotopic liver transplantation probably as a result of increased endothelial release and decreased hepatic clearance during the anhepatic stage. I6 This increase in fibrinolytic activity has been strongly implicated as the major cause of the bleeding diathesis seen in liver transplantation.17

170

MODIFIYING

PERIOPERATIVE

BLOOD LOSS

Contact activation \ i KALLIKREIN-

J

FACTOR XIIa

PLASMINOGEN

'

A

PLASMIN +----ALPHA-2

FIBRIN(OGEN)

I

ANTIPLASMIN

) FIBRINCOGEN) DEGREDATION PRODUCTS

Fig. 1 A simple scheme of fibrinolysis.

t-PA PAI - - NB

-tissue plasminogen activator -plasminogen activator inhibitor-l -inhibitory effect -activating effect Other agents stimulate the release of t-PA from the endothelium.

Cardiopulmonary Bypass Haemorrhage is one of the most important complications of cardiac surgery. This is especially relevant now there are an increasing number of patients requiring reoperation and patients who have received anticoagulant, antiplatelet or thrombolytic therapy prior to surgery. New and more extensive surgical procedures such as combined heart and lung transplantation are also associated with an increased risk of haemorrhage. Cardiopulmonary bypass (CPB) involves extensive contact between blood and the synthetic surfaces of the membrane oxygenator which results in contact activation and thus the activation of a number of inflammatory systems including haemostasis (Fig. 2) such that heparin is an indispensable anticoagulant. Heparin by blocking the final steps of the coagulation cascade can prevent gross clotting of blood in the extracorporeal circuit but cannot inhibit the initial activation of factor XII. During CPB the activated clotting time is used to monitor anticoagulant therapy and is generally maintained above 350-400 s. This level of anticoagulation was originally empirically determined since gross clotting did not occur above

this threshold.” Subsequent clinical experience and studies of the production of fibrinopeptide A production support the use of this level of anticoagulation. lg Haemodilution is also a consequence of extracorporeal circulation but the fall in haematocrit, platelet count and plasma proteins including coagulation factor is about 30% and thus not of sufficient to cause bleeding.20 Harker et al” showed that the bleeding diathesis of CPB was associated with defects in platelet function. The degree of impairment in platelet function was proportional to the duration of CPB, and probably related to the level of hypothermia. Bypass produces thrombocytopenia,22’23 platelet fragmentation and several abnormalities of platelet function that include reduced responses to aggregation stimuli, loss of alpha granule contents,25 loss of platelet membrane fibrinogen receptor,26 alpha-adrenergic receptors2’ and glycoprotein Ib, the von Willebrand receptor. ‘* Scanning electron microscopy shows a rapid but transient transformation of smooth inactivated discoid platelets into activated platelets with pseudopodia. 2g These changes may p artially result from adhesion to surfaces of the extracorporeal circuit caused by the interaction between platelet fibrinogen Coagulation system

FACTOR XII

H.M.W KININOGEN Kinin generation h.+z;;z;;;ace

Angiotensin system RENIN

/

PLASMIN Fibrinolytic system

Cl

Complement system

/

/ I Cl

Fig. 2 The central role of contact activation in the inflammatory response

BLOOD REVIEWS

receptors associated with the glycoprotein IIb/IIIa complex and fibrinogen-coated surfaces of the membrane oxygenator.30 There has also been increasing emphasis on fibrinolytic activation as a cause of excessive bleeding associated with CPB. Tanaka et a131 have demonstrated the increased fibrinolytic activation during CPB is due to both an increase in extrinsic (t-PAO) and intrinsic (factor XIIa) activators. t-PA increases prior to bypass and reaches a maximum during CPB. Fibrinolytic activation occurs to a lesser extent by contact activation which is maximal at the time of the first passage of blood through the extracorporeal circuit. Enhanced fibrinolytic activity has been associated with post-operative blood 10ss..~‘*~~ The implications from these papers are that the increased amounts of free t-PA generated during CPB are incorporated into clots at that time and increased localised fibrinolytic activity occurs as a consequence of this in the immediate post-operative period. Some of the haemostatic problems associated with extracorporeal circulation have been overcome by the use of heparin bonded tubing but this is not widely available.

Identifying Those at Risk of Excessive Bleeding A history of previous bleeding problems in the patient and/or their family together with drug therapy and a full blood count are the usual prerequisites for a standard surgical procedure. The most important determinants of the haemorrhagic risk are the patient’s diagnosis, the procedure planned and whether previous surgery has been performed. Prior to cardiac surgery and/or in an unwell individual especially one actively bleeding, a prothrombin time, partial thromboplastin time and fibrinogen levels are also advised. It remains to be established whether additional routine investigations will provide an improved estimation of risk. In view of the relationship of post-CPB haemorrhage and altered platelet function, Burns34 et al studied bleeding time in patients undergoing elective aorto-coronary bypass surgery and found no relationship to blood loss, fall in haemoglobin levels, haematocrit or platelets requirements. Interestingly, Salzman found that patients with the higher blood loss after cardiac surgery were those with the lowest preoperative von Willebrand Factor (vWF) antigen levels.35

Pharmacological Agents to Reduce Blood Loss Pharmacological agents that have been used to reduce perioperative blood loss are reviewed below. The majority have been used in patients having cardiac surgery with CPB. The agents used can be broadly classified into four groups, fibrin sealants, those affecting platelet function, antifibrinolytics and desmopressin and aprotinin, drugs that affect both platelet function and fibrinolysis.

171

Fibrin Sealants The sealants mimic the final part of the coagulation cascade in that a source of thrombin is added to fibrinogen concentrates in the presence of calcium and a clot forms. Fibrin glue has been used to secure haemostasis in patches and suture lines during congenital heart surgery. 36 In one retrospective study it reduced blood loss significant1y.j’ Tisseel, a commercially available fibrin sealant is available on a named patient basis in the UK. In the USA the sealant has not been licensed by the Food and Drug Administration and some investigators have used a combination of cryoprecipitate and thrombin to achieve a similar effect.38 A quick method of preparing autologous fibrin glue prepared by an alcohol precipitation technique has been described.39 Tisseel is prepared from the pooled products of screened donors. Preparation of the product also includes a thermal inactivation step so that transfusion-transmitted infection has not been a problem. Currently the source of thrombin is of bovine origin, human thrombin will shortly be available. Despite the extensive clinical experience with fibrin sealants, the data available is descriptive and randomised clinical trials are needed to fully assess the contribution to reducing bleeding.

Platelet-inhibiting Agents Perioperative anti-platelet agents such as aspirin and dipyridamole have been shown to act as antithrombotic agents and improve immediate graft patency.@ It seems paradoxical to assess the effect of a plateletinhibiting agent in reducing post-operative blood loss when one of the cited causes of bleeding is inhibition of platelet function. It was argued that plateletinhibiting agents would ‘preserve’ platelets during CPB by preventing their activation and thus make them available post-operatively. However the obvious risk is that blocking ‘harmful’ platelet function will also block ‘beneficial’ platelet function. Prostacycfin. Prostacyclin stimulates platelet adenylate cyclase, increases platelet cyclic adenosine monophosphate and thus inhibits platelet aggregation. Epoprostenol was given either before or during CPB, to patients undergoing uncomplicated coronary artery bypass grafting4i in two studies. There were no differences between intraoperative or total blood losses and major problems with hypotension preclude their use.42 Iloprost another analogue of prostacyclin partially protected platelets during simulated extracorporeal circulation, during experimental cardiopulmonary bypass in dogs and in patients during CPB where dangerous hypotension occurred. Dipyridamofe. Dipyridamole limits platelet aggregation and granular release by inhibiting platelet phosphodiesterase activity and thus increasing cyclic adenosine monophosphate. Teoh et al studied43 the

172 MODIFIYING PERIOPERATIVE BLOOD LOSS effects of dipyridamole on perioperative bleeding of patients during open-heart surgery. 58 patients acted as controls or were given either perioperative oral or intravenous dipyridamole. The patients who received dipyridamole maintained a higher platelet count and had a significantly smaller blood loss (~~0.05) than the controls. There have been no other studies of using dipyridamole for reducing blood loss, these findings bear repeating. Disintegrins. The ‘disintegrins’ are a newly described

class of proteins isolated from viper venoms, so called because they interfere with the interaction of adhesive ligands with their integrin receptor.& In a simulated extracorporeal circuit they prevent platelet adhesion to the surface of the extracorporeal circuit, because they block fibrinogen interactions with platelet receptors. The data supports the theory that the interaction of platelet glycoprotein IIb/IIIa complex with surface absorbed fibrinogen is a major factor for platelet adhesion to these surfaces.45 Disintegrins also blocked the loss of beta-thromboglobulin from platelets into circulating plasma which suggests that release of platelet constituents takes place on the surface of the circuit after platelets adhere. However in animal studiess6 disintegrins interfere with the formation of platelet haemostatic plugs and thromboemboli suggesting although this type of therapy may protect platelets from damage in the bypass equipment they will also prevent platelet adhesion required to seal holes in the patients. Attempts to block the platelet binding sites of surface absorbed fibrinogen have not been extended to clinical trials. Antzfibrinolytics Lysine Analogues. When plasminogen

and plasmin bind to fibrin it is through their lysine-binding sites. In the presence of the lysine analogues epsilon aminocaproic acid (EACA) and tranexamic acid, the binding is reduced and fibrinolysis delayed. EACA has been used successfully in the control of bleeding due to hyperfibrinolysis following transurethral resection. 47 However, others 48-50 evaluated EACA therapy in 340 patients undergoing cardiac surgery and concluded there was no significant benefit. All these studies have used lysine analogues to treat established post-operative bleeding. One recent study51 randomised 38 coronary artery bypass patients to receive a placebo or tranexamic acid perioperatively. The dose given was 10 mg/kg over 20 min followed by 1 mg/kg for 10 h. Blood loss in the first 10 h was reduced by a third from a mean of 750-500 mls (p < 0.001). Desmopressin. Desmopressin

acetate or DDAVP is a synthetic vasopressin analogue that is relatively devoid of vasoconstrictor activity. It increases the plasma concentrations and activity of vWF probably by inducing the release of vWF from Weibel Palade

bodies in the endothelium. vWF mediates platelet adhesion to damaged endothelium and also to act as a carrier molecule for factor VIIIC. Plasma levels of vWF increase from two to five times from the baseline within an hour and are associated with a shortening of the bleeding time in patients with von Willebrand’s disease, platelet function defects and uraemia.s2*53 Two studies of patients undergoing ‘re-do’ cardiac operations35*54 showed that 0.3 ug/kg of DDAVP given after CPB reduced blood loss, elevated vWF levels and shortened bleeding times. The methodology of both trials can be criticised for Czer et al selected only patients with excessive post-operative mediastinal bleeding using historical controls, while Salzman et al excluded all uncomplicated coronary artery bypass patients and their controls had a more extensive blood loss before receiving desmopressin. (It is noticeable in Czer’s study that in the 12 patients who continued bleeding and required reoperation a localised bleeding source was identified emphasising the need for exquisite surgical haemostasis at initial operation.) In three trials using DDAVP in doses of 0.3 ug/kg after the termination of CPB in uncomplicated coronary artery bypass patients, 55-57 the changes in plasma levels of vWF were studied. In the control group there was a doubling of vWF levels and a greater rise in levels of vWF in the DDAVP treated groups. This was not however accompanied by enhanced platelet aggregation or increased functional activity compared with the placebo treated group. The blood loss in both studies was similar in both the placebo treated and control groups. In conclusion it appears that DDAVP is not beneficial in uncomplicated coronary artery bypass patients but it cannot be excluded that it may be beneficial in patients with greater alterations in the haemostatic system. Little attention has been paid to the effect of desmopressin in stimulating fibrinolysis. It increases the release of t-PA from the endothelial cell and this may reduce the beneficial effects of increasing vWF. A trial of a combination of desmopressin and an antifibrinolytic agent would be interesting. The risk of increased graft thrombosis and post-operative thromboembolic disease has not been formally studied with perioperative DDAVP. It may be small however for in 1988, only seven thrombotic events were recorded for 217 000 recipients5’ of desmopressin for various indications. Aprotinin. The most dramatic reductions in perioper-

ative blood loss have been associated with the administration of aprotinin. In 1973 at a low dose of 200 000 kallikrein inactivating units (KIU) aprotinin reduced blood loss in patients undergoing transurethral resection of the prostate.5v At the same time a higher dose of 20 000 KIU/kg given at the start of cardiopulmonary bypass during cardiac surgery reduced blood loss by 21°h.60 More recently Royston et a161 gave a high dose aprotinin regime in patients

BLOOD REVIEWS

undergoing ‘repeat’ cardiac surgery (Table). Postoperative drainage loss was reduced by 81%, and total haemoglobin loss by 89%. The mean blood transfusion requirement was reduced by 91%, and 7 of the 11 patients who required aprotinin did not require any donor blood. Further studies62-64 have confirmed that aprotinin given in this way does dramatically reduce blood loss perioperatively not only in open-heart surgery but also vascular surgery65 and liver transplantation.66*67 Shorter operating times were also seen, this may result from the striking reduction of oozing that is normally seen, the operative fields remain ‘bone dry’. Aprotinin is now widely used in Europe and in 46 cardiothoracic centres in the UK as part of an open trial. Aprotinin is a basic polypeptide of 58 amino acid residues and was originally found in bovine organs in 1930.68 It is a serine protease inhibitor or serpin i.e. by forming reversible stoichiometric complexes it is able to inhibit proteases which have serine residues in their active site. Aprotinin is an unusual serpin in that it inhibits a wide range of serine proteases with varying affinity. In low concentrations aprotinin is a powerful inhibitor of plasmin and in high doses (150200 KIU) will also inhibit kallikrein.69 It also inhibits other serine proteases such as trypsin and chymotrypsin, which inspired studies of it’s use in pancreatitis. It’s functional activity is measured in kallikrein inhibitory units: one unit of aprotinin will inhibit two Dosage regime for high dose aprotinin according to Royston et al. Lancet 1987; ii: 1289-91

Table

1. Test dose. 2. Loading dose. 2 million K.I.U. over 20 min before sternotomy. 3. Priming of the oxygenator with 2 million K.I.U. 4. Continuous infusion following loading dose until skin closure of 500 000 K.I.U. per hour.

contact

biological units of kallikrein by 50%. The currently recommended doses are designed to achieve blood levels that inhibit kallikrein (about 200 KIU/ml). Kallikrein is formed during the activation of coagulation by negatively changed surfaces such as exposed subendothelial surfaces and cardiopulmonary bypass equipment. Kallikrein has an important central role in the activation of the inflammatory response, so if kallikrein is inhibited there is a decrease in activation of complement, renin, bradykinin, coagulation and fibrinolysis (Fig. 2). Aprotinin is a potent antifibrinolytic agent (Fig. 3), it’s molar potency in vitro is lOO- and lOOO-times that of tranexamic acid and EACA”. It directly inhibits kallikrein production, and thus activation of plasminogen by factor XIIa and probably as shown during liver transplantation71 indirectly inhibits t-PA production, for inhibition of kalIikrein will inhibit bradykinin production, a stimulator of t-PA release. Aprotinin can also mop up any plasmin still formed by it’s direct powerful antiplasmin action. Finally in vitro studies show that aprotinin inhibits activated Protein C72 which is formed during CPB. Activated Protein C promotes fibrinolysis by stoichiometrically inhibiting plasminogen activator inhibitor and stimulating the release of t-PA. There are no studies of changes of protein C in vivo as yet. It seems aprotinin is incorporated into a fibrin clot and may prevent later fibrinolytic activity. As platelet defects are often blamed for bleeding after CPB it was felt that aprotinin may have a major effect on platelet function. If high dose aprotinin is used the prolongation of the bleeding time normally seen after CPB is not seen62 although there is a usual fall in platelet count, suggesting aprotinin preserves platelet function in some way, Glycoprotein Ib, a platelet membrane receptor for vWF, is responsible for mediating platelet adhesion, is lost during CPB,

acfivation

PLASMINOGEN

’

d-LASMIN

+

+----ALPHA-2 ~_----~A FIBRIN(OGEN)

Fig. 3 A simple scheme of aprotinin’s antifibrinolytic effect Key t-PA PAI - A

-tissue plasminogen activator -plasminogen activator inhibitor-l -inhibitory effect -activating effect -DIRECT EFFECT OF APROTININ -indirect effects of aprotinin

173

tFIBRIN(OGEN)

ANTIPLASMIN

DEGREDATION

PRODUCTS

174 MODIFIYING PERIOPERATIVE BLOOD LOSS however this loss may be inhibited by aprotinin.28 How this occurs is uncertain. Plasmin, elastase and calpain are all enzymes that strip glycoprotein Ib receptors from the platelet and all are inhibited by aprotinin.75 Aprotinin also inhibits the coagulation pathway, for in the coagulation cascade kallikrein once formed operates a positive feedback loop on factor XII. In the presence of aprotinin there is prolongation of ex vivo tests of the intrinsic system such as the activated clotting time and APTT. 76 As heparin therapy during cardiopulmonary bypass is monitored by the ACT, in order to ensure that adequate levels of heparin are used, the ACT timer should be run at a higher level than normal. Most anaesthetists monitor heparin levels by running the activated clotting time at times greater than 400 s. If aprotinin is used the activated clotting time should be run at greater than 750 s to allow for ‘normal’ heparin levels.” From the data available at present, it appears that high dose aprotinin offers a potential for a major reduction in perioperative blood loss and transfusion requirements in cardiac surgery and probably in noncardiac surgery, further work is required in understanding it’s mechanism of action and an appropriate dose. The risks of using a prothrombotic agent perioperatively especially those of increased post-operative thromboembolic disease and in particular graft patency after coronary artery bypass grafting have not been defined. Until these risks are defined the use of aprotinin should be limited to operations with a large perioperative bleeding risk.

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Conclusions The practise of using pharmacological agents to reduce blood loss is in it’s infancy, and highlights the deficiencies in our understanding of why patients bleed perioperatively. The mechanisms of aprotinin and tranexamic acid suggest we may be underestimating the importance of the perioperative activation of fibrinolysis. Future work in this actively growing area may increase our understanding of haemostasis and hopefully will reduce the dependence of surgical centres on the blood transfusion service.

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