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. There is a subset of patients, however, in whom generalised oozing in the surgical field cannot be attributed to demonstrable bleeding vessels.

No consensus exists for the pathogenesis of non-surgical perioperative bleeding. There are several reasons for this: (1) failure to appreciate the limitations of laboratory tests; (2) shortcomings in the current concepts of haemostasis; and (3) lack of reliable laboratory tests for some components of haemostasis, e.g., fibrinolysis.

Pharmacological agents to reduce blood loss

(1) Antifbrono/ytics203""219

Aprotinin: Is a potent anti-fibrinolytic agent. Its molar potency in vitro is 100- and 1000-times of tranexamic acid and epsilon amino-caproic acid (EACA). It directly inhibits kallikrein production and, therefore, activation of plasminogen by factor XIIa and indirectly inhibits t-PA release by bradykinin inhibition. Aprotinin can also mop up any plasmin by its direct powerful anti-plasmin action. Aprotinin inhibits activated Protein C, which is formed during CPB. Aprotonin is a bovine protein and, therefore, can provoke an immunological reaction.

The most dramatic reductions in perioperative blood loss have been associated with the administration of aprotinin. Royston et a/.,203,204,208 gave a high dose aprotinin regimen in patients undergoing "repeat" cardiac surgery. Postoperative drainage loss was reduced by 81%, total haemoglobin loss by 89%, and mean blood transfusion requirement was reduced by 91%. Further clinical studies have confirmed that high-dose aprotinin dramatically reduces blood loss after CPB. Shorter operating times are also seen in children, a probable consequence of the fact that the operative fields remain "bone dry''.

It is widely used in Europe including the UK. It is licensed for use in high risk cases, but most cardiac surgeons are reluctant to use it in first time CABG. This is due to the theoretical (but unproven) prothrombotic effects and the potential for the patient to develop anti-aprotinin antibodies that would prohibit their use in future surgery. The use of recombinant protein analogous to human protease nexin II has shown some efficacy in a sheep model.203 The majority of users of aprotinin in the UK do not use the full high-dose regimen, to reduce cost, and in the recognition that a lower dose does reduce bleeding, although possibly not to the same extent.208

Aprotinin has no effect on the fall in platelet count, but may have a minor effect on preserving platelet function by preserving platelet membrane receptors, possibly by inhibiting plasmin-mediated degradation. All trials have shown that there is a profound inhibition of fibrinolysis, suggesting that its main mechanism of action is through an anti-plasmin effect. The success of other anti-fibrinolytics in reducing bleeding supports this mechanism.203

(2) Other anti-fibrinolytic agents

Lysine Analogues: When plasminogen and plasmin bind to fibrin it is thought their lysine-binding sites. In the presence of lysine analogues epsilon amino-caproic acid (EACA) and tranexamic acid, the binding is reduced and fibrinolysis delayed.210--216

EACA has been used successfully in the control of bleeding due to hyperfibrinolysis following transurethral resection, but others found no significant benefit in patients undergoing cardiac surgery. In one randomised study on patients undergoing CABG, tranexamic acid reduced the blood loss in the first 10 hours by a third.215

Desmopressin acetate or DDAVP:

It is a synthetic vasopressin analogue that is relatively devoid of vasoconstrictor activity. It increases the plasma concentration and activity of vWF probably by inducing its release in the endothelium. vWF mediates platelet adhesion to damaged endothelium and also to act as a carrier molecule for factor VIII;C. Plasma levels of vWF increase 2- to 5-fold 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.188 Two studies of patients undergoing ''re-do'' cardiac operations showed that 0.3mg/kg of DDAVP given after CPB reduced blood loss, elevated vWF levels, and shortened bleeding times.188 In three trials using DDVAP in doses 0.3 mg/kg after the termination of CPB in uncomplicated CABG, the changes in plasma levels of vWF were studied. In the control group there was a doubling of vWF level and a greater rise in levels of vWF in the DDAVP treated group. This was, however, not accompanied by enhanced platelet aggregation or increased functional activity compared with the placebo treated group. The blood loss was similar. To conclude, it appears that DDAVP is not beneficial in uncomplicated CABG patients.

DDAVP increases the release of t-Pa from the endothelial cell, and this may reduce the beneficial effects of increasing vWF.

(3) Fibrin sealants

The sealants mimic the final part of the coagulation cascade in that a source of thrombin is added to the 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. In one retrospective study, it reduced blood loss significantly. There is no licensed fibrin sealant in the US or UK, but they are available on a named patient basis. Initially, thrombin was of bovine origin, which led to the development of a bleeding diathesis postoperatively, due to the formation of cross-reactive antibodies to bovine thrombin that inhibit factor V. Despite extensive clinical experience with fibrin sealants, the data available is mainly descriptive and randomised clinical trials are needed to fully assess their contribution to reducing bleeding. The other concern, as with any other product produced from plasma, is transfusion-transmitted diseases. Methods for producing autologous fibrin sealants are, however, being evaluated.220

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