Perioperative management of aspirin resistance after off-pump coronary artery bypass grafting: possible role for aprotinin

Abstract

Background: Aspirin is the only drug proven to reduce saphenous vein graft (SVG) failure, but aspirin resistance (ASA-R) frequently occurs after off-pump coronary artery bypass grafting (OPCAB). The factors, mechanism, and best means for preventing and/or treating ASA-R have not been established. This study hypothesizes that thrombin production during OPCAB stimulates this acquired ASA-R.

Study design and methods: A nonrandomized prospective cohort of 255 patients (n=465 SVG) who underwent OPCAB with varied use of aprotinin (21%) and different SVG preparation techniques (standard, 56% vs. low-pressure, 44%) was analyzed. A surplus SVG segment was obtained to assess endothelial integrity. ASA-R was determined at baseline, after surgery, and on Days 1 and 3 by three assays. The effects of aprotinin on thrombin responsiveness were analyzed by means of whole-blood aggregometry, SVG tissue factor (TF) activity, and transcardiac thrombin production (i.e., F1.2 levels in aorta versus coronary sinus). SVG patency was assessed on Day 5 with multichannel CT angiography.

Results: ASA-R developed in 42 percent of patients after OPCAB. Multivariate analysis showed that ASA-R, endothelial integrity, and target size independently predicted early SVG failure. Aprotinin use was associated with: 1) reduced postoperative ASA-R (15%); 2) decreased platelet (PLT) response to thrombin; 3) reduced TF activity within SVG segments; 4) decreased transcardiac thrombin gradient; and 5) improved SVG patency.

Conclusion: ASA-R is a common post-OPCAB event whose frequency may be reduced by intraoperative use of aprotinin, possibly via TF and thrombin suppression. Improved perioperative PLT function after OPCAB may also inadvertently enhance the clinical relevance of these potential antithrombotic effects.

Fig. 1

Aprotinin inhibits thrombin-induced PLT aggregation and preserves proteolysis-independent pathways of PLT activation. Citrated whole blood was untreated or treated with 200 KIU per mL aprotinin immediately before the addition of thrombin at low (0.25 U/mL) or high doses (0.5 U/mL), followed by the addition of collagen (5 μg/mL) at 6 minutes. After a strong aggregation response to thrombin, illustrated in this representative example by the strong change in impedance (ohms at 6 min), the untreated blood showed a much weaker subsequent response to collagen. In contrast, the aprotinin treatment blocked the response to thrombin while preserving the ensuing aggregation response to collagen.

Fig. 2

Aprotinin blocks the activity of TF expressed on the luminal surface of pressure-injured SVG. SVGs were prepared for grafting with two techniques (pressure-controlled or syringe injection). Surplus SVG segments were analyzed for TF expression with immunohistochemistry and a functional assay. TF was constitutively expressed in the adventitia (thick arrows) but not on the luminal surface of SVG (thin arrows) procured by the pressure-controlled technique. Uncontrolled pressure (syringe injection) resulted in a significant increase in TF expression (arrowheads) and activity, which was blocked by the addition of 500 KIU per mL aprotinin (n = 5/group).

Fig. 3

Aprotinin administration reduced thrombin formation in the bypass graft. In vivo thrombin generation in the bypass graft was estimated by measuring the gradient of prothrombin fragment F1.2 across the heart (coronary sinus vs. aortic sample) after protamine administration. Patients who received aprotinin showed a significantly lower transcardiac gradient of thrombin (p < 0.05).

Fig. 4

Aprotinin limits the burst in thrombin formation that occurs in SVG at high risk for thrombosis. The transcardiac gradients of thrombin formation, defined by the percentage difference in coronary sinus (CS) versus aortic (Ao) levels of F1.2, were measured in OPCAB patients after protamine administration. Only the subgroup of patients who had a graft with low intraoperative flow (<20 mL/min) and poor endothelial integrity (<25% luminal coverage with CD31) showed a significant gradient of thrombin formation and this gradient was reduced by aprotinin use. In contrast, other OPCAB groups developed very little postoperative gradient of F1.2. There was also little transcardiac gradient noted in preoperative OPCAB and postoperative heart transplant patients who served as controls for the influence of coronary artery disease and reperfusion injury, respectively.