Changes in platelet function with inflammation in patients undergoing vascular surgery

Abstract

The role of platelets in ischaemic events is well established. Aspirin represents the default antiplatelet and blocks the metabolism of arachidonic acid (AA) at the cyclo-oxygenase enzyme (COX). AA is commonly used as a test of response to aspirin, but recent data raise uncertainty about the validity of this approach. Specifically, in some patients AA-induced clotting is not suppressed, but the level of COX-dependent AA metabolite, thromboxane B2 (TXB₂) is negligible. Furthermore, AA-induced whole blood clotting varies dynamically in individuals, who are aspirin responsive according to TXB₂ levels. The aim of this study was to assess the level of AA-, ADP- and thrombin-mediated platelet reactivity in patients on aspirin before, during, and after major vascular surgery, which represents a model of on/off vascular inflammation. Firstly, we hypothesised, that in association with this inflammatory episode AA-, ADP- and thrombin-induced clotting would change in a dynamic manner. Secondly, that AA-induced clotting will be modified despite complete suppression of platelet TXB₂ production by aspirin throughout the periprocedural period, possibly via a lipoxygenase-mediated mechanism. Fourty patients underwent major vascular surgery (open abdominal aortic aneurysm operation, infrainguinal bypass for subcritical limb ischaemia or peripheral aneurysm repair with bypass). They were all on 75 mg of aspirin prior to and throughout the perioperative period and received 5000 units of unfractionated heparin intraoperatively. AA-, ADP- and thrombin- induced clotting, AA metabolites (TXB₂ and 12-Hyroxyeicosatetraenoic acid (12- HETE)) and inflammatory markers (CRP, IL-6, TNF-α and CD40) were measured preprocedure and at 2, 24, 48 hours, 3 to 5 days and 3 months after surgery. AA-, ADP- and thrombin- induced platelet reactivity was assessed using thrombelastography. TxB2, 12- HETE, IL-6, TNF-α, CD40 were determined using the sequential competitive binding Enzyme-Linked ImmunoAssay technique and CRP was determined using an immune-turbidimetric test on human serum. There was a transient rise in inflammatory markers in the early perioperative period (CRP at 24, 48 hours and 3 to 5 days p<0.001 and IL-6 at 2, 24, 48 hours and 3 to 5 days p<0.001 as compared to baseline). Patients had negligible levels of TxB throughout, confirming a consistent therapeutic response to aspirin. There was a transient rise in thrombin-mediated clotting (MA_Thrombin at 48 hours p=0.001 and 3 to 5 days p<0.001) and a fall in AA- and ADP-induced clotting in the early post op period (both MA_AA and MA_ADP p=0.001 at 2 hours). At 3 months, the level of AA- and ADP-induced clotting was significantly higher than at baseline (p=0.008 for MA_AA and p=0.002 for MA_ADP), hence demonstrating a rebound effect.  These data demonstrate a novel dynamic variation in platelet aggregation with acute vascular inflammation, including AA-induced whole blood clotting which is apparently COX-1 independent.

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Identifiers

ORCID for Nicola Englyst: orcid.org/0000-0003-0508-8323

ORCID for Michael Mahmoudi: orcid.org/0000-0003-1293-8461

ORCID for Nicholas Curzen: orcid.org/0000-0001-9651-7829

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