Predictive genetic factors for bleeding in cardiac surgery patients with cardiopulmonary bypass
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KeywordsPlasminogen Tranexamic Acid Spurious Association Population Substructure Neutral Marker
The incidence of excessive postoperative bleeding and transfusion requirements for major cardiac surgical interventions varies between 10% and 70%. Not all the mechanisms involved are as yet understood.
To investigate the possible role of several genetic polymorphisms associated with coagulation, fibrinolysis and inflammation, in patients with excessive bleeding after elective cardio-pulmonary bypass (CPB).
Patients and methods
We performed a cross-sectional study of 26 patients, from a clinical trial of 50 CPB patients, who did not receive antifibrinolytic prophylaxis. For these patients we recorded clinical variables associated with bleeding, and the following polymorphisms: insertion/deletion (I/D) of angiotensin-converting enzyme (ACE) gene; G1691A of the Leiden factor gene; G20210A of the factor II gene; 4G/5G of plasminogen activator inhibitor-1 (PAI-1); Alu repeat I/D of the plasminogen tissular activator (tPA) gene; and finally the first intron of TNF-β (TNF-β + 250). In addition, seven neutral markers were genotyped to follow genomic control strategies that would detect spurious associations due to population substructure . The neutral markers chosen are biallelic Alu repeats distributed in different chromosomes. We used SPSS-12.2 software for statistical purposes.
Greater bleeding in the 24-hour postoperative period was associated with: ACE (DD: 891 [SD 531] ml; ID: 512 [SD 458] ml, II: 1125 [SD 735] ml; P = 0.046), TNF-β + 250 (AA: 747 [SD 459] ml; AG: 568 [SD 482] ml; GG: 1350 [SD 775] ml; P = 0.029), and PAI-1 (4G/4G: 792 [SD 477] ml; 4G/5G: 554 [SD 376] ml; 5G/5G: 1036 [SD 694] ml; P = 0.037). Homozygous 5G showed lower levels of PAI-1 (36.98 [7.68] vs 120.3 [14.3], P = 0.02), lower levels of leptins preoperatively (11.15 [2.15] vs 25.56 [3.93], P = 0.016), at admission (3.54 [0.84] vs 18.67 [3.72], P = 0.02), and at 4 hours (3.43 [1.12] vs 15.48 [3.27], P < 0.001) and 24 hours postoperatively (11.12 [4.36] vs 29.57 [4.82], P = 0.013) and greater coagulation factors consumed. Those patients achieved a greater advantage of antifibrinolytic prophylaxis with tranexamic acid.
We found three polymorphisms associated with excessive postoperative bleeding. This may enable us to identify patients at risk before CPB intervention and to optimize prophylactic therapy.