The purpose of the research was to develop an improved solid phase microextraction (SPME)-based sampling protocol for the therapeutic drug monitoring of tranexamic acid (TXA) from plasma and urine of patients with chronic renal dysfunction (CRD) in order to correct the current dosing schedule to accommodate these patients. A 12-fold improvement in sampling efficiency (25 min for 96 samples -22 s per sample) was achieved with the use of hydrophilic-lipophilic balance (HLB)-coated SPME devices, thereby enabling high throughput profiling of TXA in the plasma and urine of 49 CRD patients undergoing cardiac surgery. A limit of quantification of 10 μg/mL and 25 μg/mL was obtained for plasma and urine respectively while a method accuracy of 103–105% and a precision of less than 8% was achieved. The results from this study were ultimately used by clinicians at the Toronto General Hospital to design a corrective pharmacokinetic dosing schedule for CRD patients. This green method further presents potential application in the clinical field for the fast high throughput monitoring of TXA not only in plasma but also in urine – a biological matrix seldom explored for the analysis of TXA – without the need for solvent-assisted extraction, extensive sample pre-treatment or clean-up, derivatization or excessive pH adjustment to improve amenability for analytical separation. Display omitted ⁃Biocompatible TFME used for tranexamic acid profiling in urine and plasma⁃TFME devices directly exposed to native, unprocessed complex biological samples⁃Rapid high throughput TFME protocol produces clean LC-MS amenable extracts⁃No additional sample cleanup, pre-treatment or compound derivatization required⁃First SPME protocol for TXA quantitation from urine