S-Adenosylmethionine and Perioperative Bleeding Risk: A Case of Mohs Postoperative Hematoma and Scoping Review

1. Introduction

Over the counter (OTC) supplements are frequently used among patients undergoing procedures, yet their associated risks for bleeding remain under-recognized and poorly documented [1]. S adenosylmethionine (SAMe) is among popular OTC supplements, increasingly used for conditions such as depression, osteoarthritis, and liver disease [2]. Metabolites of SAMe including homocysteine have been associated with increased bleeding and spontaneous intracerebral hemorrhage [3,4]. Despite its widespread availability and physiologic potential for bleeding, risks associated with use of SAMe in surgical settings has not been evaluated [5]. We conducted a scoping review to assess clinical and mechanistic evidence regarding SAMe and perioperative bleeding following an unexpected postoperative hematoma in a patient taking SAMe.

1.1. Case Discussion

An 88-year-old man with a biopsy-proven stage IA melanoma (Figure 1A) underwent single-stage slow Mohs micrographic surgery resulting in a sizable surgical defect. Unexpected intraoperative bleeding was noted despite no known history of anticoagulant use or bleeding diathesis, and approximately 5 mL of blood was evacuated from the wound bed at the time of surgery. One week later, the defect was reconstructed with a cheek rotation flap and Burrow’s graft to optimize functional and cosmetic outcomes (Figure 1B).

Shortly after reconstruction, the patient developed a rapidly expanding postoperative hematoma that impaired vision (Figure 1C). Urgent decompression was performed using an improvised surgical drain technique, and more than 33 mL of blood was evacuated during several weeks of follow-up [6]. Upon further questioning, the patient disclosed that he had been splitting a SAMe tablet and taking one-half tablet twice daily. He denied alcohol use, prescription anticoagulants, antiplatelet agents, or other over-the-counter supplements associated with bleeding risk. Laboratory evaluation revealed mild macrocytic anemia with a normal platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT). The surgical drain was removed on postoperative day 16, and the patient subsequently healed without further bleeding complications. At four months of follow-up, the reconstruction remained successful requiring only minimal revision surgery (Figure 1D).

2. Materials and Methods

A focused literature review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Google Scholar, Cochrane Library, and ClinicalTrials.gov were searched (Table A1). Inclusion criteria encompassed English-language human clinical studies as well as studies evaluating physiological impacts or mechanistic effects relevant to perioperative bleeding. Eligible articles examined SAMe and SAMe metabolites including homocysteine, folate, and vitamin B12, and their association with perioperative bleeding. Exclusion criteria included animal-model studies and articles that did not report on perioperative or surgical bleeding outcomes. The level of evidence for each study was independently assessed by two investigators using a modified Oxford Centre for Evidence-Based Medicine framework; discrepancies were resolved by a third investigator (Table A2).

3. Results

Of 928 publications identified, 23 articles underwent full-text review (Figure 2). No original human clinical studies directly evaluating SAMe-associated perioperative or cutaneous postoperative bleeding were identified beyond the present index case. To provide mechanistic and physiologic context, ten studies examining homocysteine modulation and related effects on hemostasis were included. Several human studies evaluated SAMe metabolites and related one-carbon metabolic pathways; however, none assessed surgical bleeding outcomes (Table 2).

4. Discussion

With the widespread use of over the counter (OTC) supplements among surgical patients, it is increasingly important that preoperative histories and medication reconciliation extend beyond prescription medications to include dietary supplements and wellness products. During surgical evaluation, supplements such as vitamin E, ginkgo, fish oil, and garlic are commonly screened because of their recognized effects on platelet function and hemostasis [2,3,4,7]. In contrast, SAMe has received comparatively little attention despite its widespread availability in the United States and its biologic activity within pathways relevant to endothelial function, methylation, and vascular homeostasis [5,8]. Although marketed as an OTC supplement in the United States, SAMe is available as the prescription medication ademetionine in several European countries [7].

In our case, a significant postoperative hematoma developed following cutaneous surgery in a patient without traditional bleeding risk factors or a known coagulopathy. Further investigation revealed the chronic use of enteric-coated SAMe, a supplement that had not been initially disclosed during the preoperative medication review. This observation highlights a persistent challenge in performing medical assessments, as many patients do not consider supplements to be medications and therefore may not report them unless specifically asked [7]. The case underscores the importance of obtaining a detailed supplement history when evaluating patients prior to dermatologic surgery.

While no human clinical studies directly evaluated the association between SAMe and perioperative bleeding, several studies explore its metabolites in relation to hemostasis. SAMe supplementation may increase S-adenosylhomocysteine (SAH) and homocysteine concentrations, components of one-carbon metabolism, with downstream effects on endothelial function, vascular homeostasis, DNA methylation, and platelet signaling (Figure A1). The human literature identified in our review primarily demonstrated that folate and B-vitamin supplementation lower homocysteine, but this did not consistently result in corresponding changes in markers of vascular or coagulation function. Few studies found effects on pathways potentially relevant to hemostasis, including altered expression of coagulation-related proteins such as antithrombin following folic acid supplementation and improved endothelial reactivity following folinic acid supplementation. Notably, the only identified randomized trial directly evaluating SAMe supplementation did not demonstrate significant changes in homocysteine levels. Together, the available mechanistic evidence provides biologic context for our case of postoperative bleeding requiring surgical intervention and drain placement, while highlighting the need for further clinical investigation into the potential relationship between SAMe and perioperative bleeding.

5. Conclusions

Future studies should prioritize in-vitro platelet function assays and mechanistic studies evaluating the effects of SAMe on platelet activation, coagulation pathways, endothelial biology, and perioperative bleeding risk to establish causality and better define its effects on hemostasis. Given its plausibility to influence platelet behavior, a cautious approach would be to discontinue SAMe at least five days before cutaneous surgery, mirroring existing guidance for other OTC antithrombotic medications, until future studies can clarify its perioperative safety [3].