Discussion

This case illustrates a rare but clinically significant instance of cefazolin-associated coagulopathy. The rapid rise in INR following cefazolin initiation, combined with decreased activity of vitamin K-dependent clotting factors and prompt correction with vitamin K, strongly supports a drug-induced mechanism. Cefazolin’s MTD side chain is hypothesized to inhibit vitamin K epoxide reductase, producing a warfarin-like effect that reduces synthesis of clotting factors II, VII, IX, and X. ^{Reference Wu, Wang and Guo1,Reference Park, Kim and Lee2} Although this phenomenon is well described with NMTT-containing cephalosporins, reports involving cefazolin remain sparse. ^{Reference Wu, Wang and Guo1,Reference Park, Kim and Lee2,Reference Beckstrom, Wong and LaDow6,Reference Smith, Doyle and Crane7} In 2019, Strazzulla et al. ^{Reference Strazzulla, Chakvetadze and Picque8} conducted a retrospective chart review of all patients treated with cefazolin with monitored coagulation markers. They found that there was a slight increase in PTT in patients that received cefazolin, but no change in their INR. Additionally, bleeding only occurred in 5% of the total population. Ngiam et al. ^{Reference Ngiam, Liong and Tham9} reported a cefazolin-associated INR elevation in a patient with MSSA endocarditis with end-stage renal disease (ESRD) that was also responsive to vitamin K therapy. Wang et al. ^{Reference Wang and Hecht5} published a case report detailing a patient with MSSA endocarditis that received cefazolin and rifampin dual therapy for treatment. This patient had a recent large weight loss and developed renal failure with a need for renal replacement therapy. It was thought that these events were provoking factors of cefazolin toxicity which may worsen coagulopathy. A 2026 case report by Beckstrom et al. ^{Reference Beckstrom, Wong and LaDow6} described a similar occurrence to the one in this case report. The patient developed a seemingly unprecipitated INR increase that was rapidly corrected with 5 mg of oral vitamin K therapy. Finally, Smith et al. ^{Reference Smith, Doyle and Crane7} described another case of cefazolin-associated INR elevation in a patient with a MSSA infection. However, unlike other case reports, this patient only had a mild elevation in their serum creatinine compared to renal failure requiring renal replacement therapy. Application of the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 4, consistent with a possible adverse drug reaction. ^{Reference Naranjo, Busto and Sellers11} Points were assigned for prior published reports, the temporal relationship to cefazolin initiation, improvement following discontinuation and phytonadione administration, and objective confirmation by factor assays and TEG, with a point deducted for the presence of concurrent ischemic hepatitis as an alternative cause. Several items could not be scored in this setting, including rechallenge, dose-response, and measurement of cefazolin concentrations, which are not routinely available. The presence of concurrent hepatic injury complicates interpretation. The patient’s marked transaminase elevation and rapid normalization are consistent with ischemic hepatitis. Importantly, hepatic synthetic dysfunction typically does not respond to vitamin K administration, as the liver is unable to produce new clotting factors. ^{Reference Saja, Abdo and Sanai10} In contrast, this patient demonstrated a rapid INR correction following phytonadione, supporting a functional vitamin K deficiency rather than isolated hepatic failure. The reduction in factor V activity suggests that hepatic injury likely contributed to the overall coagulopathy. Therefore, this case is best explained by a multifactorial process, with cefazolin-induced inhibition of vitamin K-dependent clotting factor synthesis as the primary driver, compounded by transient hepatic dysfunction.