The Role of Heparin in Thromboembolic Complications Following Carotid Endarterectomy

The importance of platelets emerged from a local research programme, which aimed to reduce the stroke risk associated with carotid endarterectomy (CEA). It had been demonstrated that intra-operative heparinisation induced a transient reversal of aspirin inhibition; platelets were able to aggregate in response to arachidonic acid (AA). It was hypothesized that intra-operative anticoagulation with intravenous low molecular weight heparin (LMWH) instead of unfractionated heparin (UFH) might be associated with a reduction in pleiotropic platelet effects, and that this would result in a reduction of post-CEA embolization, a surrogate marker for stroke risk. A randomized controlled trial recruited 183 patients; 91 randomized to receive standard intra-operative anticoagulation with 5000IU UFH, and; 92 who received 2500IU LMWH intravenously. Studies conducted in sub-populations aimed to investigate the platelet aggregatory responses to AA and adenosine diphosphate (ADP) and the platelet pathways that were active (plasma and serum were assayed for the stable products of platelet metabolism; thromboxane (TXB2) from the cyclo-oxygenase-1 (COX-1) pathway and 12- hydroxyeicosatretraenoic acid (12-HETE) from the 12-lipoxygenase (12-LOX) pathway). To determine how heparin might interact with the platelet, lipase activity, the presence of heparin antibodies and anti-factorXa (FXa) activity were studied. Increases in platelet aggregation to AA and ADP were observed 3 minutes after heparinisation. In response to AA, these increases were similar for both UFH and LMWH, but patients who received UFH demonstrated significantly greater aggregation in response to ADP. Whilst there was no increase in the production of TXB2, there was a significant increase in the generation of 12-HETE. The increase in platelet response was associated with anti-FXa activity, but not with lipase or heparin antibody activity. The intra-operative substitution of LMWH for UFH was associated with a significant reduction in the risk of patients experiencing high-rate embolization post-operatively, and there is an argument for the re-evaluation of anticoagulation during CEA.