Heightened Procoagulation after Post-Operative Thromboprophylaxis Completion in Patients with Metastatic Bone Disease from Primary Colorectal Cancer.

Abstract

Platelets play a role in venous thromboembolism (VTE) and in mediating colorectal cancer (CRC) progression. Still, platelets' role in hypercoagulability after surgical intervention for metastatic bone disease (MBD) is ill-defined. In this quantitative observational study, we utilized a high-resolution imaging approach to temporally examine platelet procoagulant membrane dynamics (PMD) in four patients with MBD from primary CRC (CRC/MBD), before and after surgical intervention, over a 6-month period. We coupled this investigation with thrombelastography, quantitative plasma shotgun proteomics, and biochemical analysis. The plasma of CRC/MBD patients was enriched in ADAM1a, ADAMTS7, and physiological ligands for platelet glycoprotein-VI/spleen tyrosine kinase (GPVI/Syk) activation. Thromboprophylaxis attenuated procoagulation upon its initial prescription (post-operative day one, POD1); however, all patients experienced rebound procoagulation between POD3 and POD14, which was associated with Syk activation (Y525/Y526) in all patients, and a VTE event in two patients. Plasma levels of DNA-histone complexes increased steadily after surgery and remained elevated throughout the study period. Additionally, we increasingly sighted both homotypic and heterotypic platelet microaggregates after surgery in CRC/MBD patients, but not in healthy control participants' plasma. Our data elucidates the cell biology of a prothrombo-inflammatory state caused by disease and vascular injury, and recalcitrant to thromboprophylaxis. New mechanistic insights into hypercoagulability in CRC/MBD patients may identify novel drug targets for effective thromboprophylaxis type and duration after orthopaedic surgery.