The blood sparing effect and the safety of aprotinin compared to tranexamic acid in paediatric cardiac surgery☆

Breuer, Tamás; Martin, Klaus; Wilhelm, Markus J.; Wiesner, Gunther; Schreiber, Christian; Hess, John; Lange, Rüdiger; Tassani, Peter

doi:10.1016/j.ejcts.2008.09.038

Cited by 81 publications

(57 citation statements)

References 26 publications

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“…Furthermore, KD1-L17R did not cause any detectable histopathologic changes in any other major organ, including heart, lungs, brain, and liver. KD1-L17R (and BPTI) also did not cause any seizures as indicated for TE (71,72).…”

Section: Nature Of Residues 73 and 143 In Pm Andmentioning

confidence: 76%

Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis

Bajaj¹,

Ogueli

Kumar

et al. 2011

Journal of Biological Chemistry

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Tissue factor pathway inhibitor-2 (TFPI-2) inhibits factor XIa, plasma kallikrein, and factor VIIa/tissue factor; accordingly, it has been proposed for use as an anticoagulant. Fulllength TFPI-2 or its isolated first Kunitz domain (KD1) also inhibits plasmin; therefore, it has been proposed for use as an antifibrinolytic agent. However, the anticoagulant properties of TFPI-2 or KD1 would diminish its antifibrinolytic function. In this study, structure-based investigations and analysis of the serine protease profiles revealed that coagulation enzymes prefer a hydrophobic residue at the P2 position in their substrates/inhibitors, whereas plasmin prefers a positively charged arginine residue at the corresponding position in its substrates/inhibitors. Based upon this observation, we changed the P2 residue Leu-17 in KD1 to Arg (KD1-L17R) and compared its inhibitory properties with wild-type KD1 (KD1-WT). Both WT and KD1-L17R were expressed in Escherichia coli, folded, and purified to homogeneity. N-terminal sequences and mass spectra confirmed proper expression of KD1-WT and KD1-L17R. Compared with KD1-WT, the KD1-L17R did not inhibit factor XIa, plasma kallikrein, or factor VIIa/tissue factor. Furthermore, KD1-L17R inhibited plasmin with ϳ6-fold increased affinity and effectively prevented plasma clot fibrinolysis induced by tissue plasminogen activator. Similarly, in a mouse liver laceration bleeding model, KD1-L17R was ϳ8-fold more effective than KD1-WT in preventing blood loss. Importantly, in this bleeding model, KD1-L17R was equally or more effective than aprotinin or tranexamic acid, which have been used as antifibrinolytic agents to prevent blood loss during major surgery/trauma. Furthermore, as compared with aprotinin, renal toxicity was not observed with KD1-L17R.

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Section: Nature Of Residues 73 and 143 In Pm Andmentioning

confidence: 76%

Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis

Bajaj¹,

Ogueli

Kumar

et al. 2011

Journal of Biological Chemistry

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“…In 2009, Breuer et al [27] reported data of 199 patients with a weight less than 20 kg undergoing open heart surgery in a single institution comparing aprotinin and tranexamic acid. The dosing for aprotinin was a bolus of 50 000 KIU/kg 100 000 KIU/100 ml priming solution in the CPB system and a continuous infusion of 10 000 KIU/ kg/h until chest closure.…”

Section: Tranexamic Acid and Epsilon-aminocaproic Acid In Pediatric Cmentioning

confidence: 98%

Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era

Koster

Schirmer

2011

Current Opinion in Anaesthesiology

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“…In three studies 7,22,23 that primarily investigated the hemostatic effects of aprotinin versus TA, patients receiving aprotinin had fewer seizures Results are the number of patients unless otherwise stated TA = tranexamic acid; CT = computed tomography; ICU = intensive care unit; EEG = electroencephalography (0-1.2%) than those having received TA (2.7-4.6%). 7,22,23 It is noteworthy that seizures were not reported by the BART investigators, although seizure was not an a priori defined endpoint in that trial. 12 There have been two recent reports that have specifically examined TA and seizures after cardiac surgery.…”

Section: Discussionmentioning

confidence: 99%

Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors

Manji

Grocott

et al. 2011

Can J Anesth/J Can Anesth

144

132

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Background Seizures after cardiac surgery are a serious complication. The antifibrinolytic agent tranexamic acid (TA), which has known proconvulsant properties, may be associated with postoperative seizures. We sought to determine the association between TA and other risk factors for seizures after cardiac surgery. In all, 58.1% were grand mal, 14.5% were associated with a stroke, and 58.1% recurred in hospital. Altogether, 48.3% of the patients were able to discontinue anticonvulsant medications prior to discharge. Compared to the non-seizure group, seizure patients had an increased rate of postoperative neurological complications, defined as delirium and/or stroke (3.2% vs 19.6%, P \ 0.001), increased intensive care unit (ICU) length of stay (1.0 vs 4.7 days, P < 0.001), and increased ICU mortality (1.4 % vs 9.7 %, P = 0.001). Conclusions Our data suggest that multiple risk factors, including TA, are associated with seizures after cardiac surgery. Thus, the TA dose may be a readily modifiable risk factor for postoperative seizures. Methods and results Résumé

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The blood sparing effect and the safety of aprotinin compared to tranexamic acid in paediatric cardiac surgery☆

Abstract: Aprotinin administration bears no additional risks compared to tranexamic acid and it has a stronger blood sparing effect in paediatric cardiac surgery. There were fewer rethoracotomies and less postoperative red blood cell transfusion in patients who received aprotinin.

Cited by 81 publications

References 26 publications

Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis

Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis

Re-evaluation of the role of antifibrinolytic therapy with lysine analogs during cardiac surgery in the post aprotinin era

Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors

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