Heparin and its derivatives have been widely used in anticoagulation therapy after digital replantation to reduce thrombotic events and ensure robust blood flow [1]. There is no consensus among microsurgery centers due to lack of standardized protocols. The protocols used are mainly based on subjective clinical experience rather than evidence-based guidelines. Some institutions use unfractionated heparin (UFH) as the main anticoagulant after free tissue transfer, whereas others use low-molecular-weight heparin (LMWH), acetylsalicylic acid, thrombolytics, dextran, or prostaglandin E1 [1-6]. We only found one relevant systematic review in the Cochrane database. However, few studies have reviewed and compared the success rates of LMWH vs. UFH. Nevertheless, the methodological and statistical limitations of these studies have led to the lack of conclusions [7]. Moreover, the complication rates associated with LMWH or UFH were unclear, making it difficult for microsurgeons to choose between them [7]. In other words, the protocols are reliant on individual clinical experience, which can be biased.

We focused on hepatotoxicity among the complication of anticoagulant use. In our institution, we routinely perform liver function or anticoagulation panel tests perioperatively to monitor hepatotoxicity based on our clinical experience. Although well described in the literature, hepatotoxicity is often overlooked due to its asymptomatic nature, with a rare possibility of sequelae; however, aggravated symptoms can sometimes occur [2,8-13]. The rates of hepatotoxicity vary among studies, with most authors reporting higher rates with LMWH. However, this finding has not been statistically proven [10,14,15].

In previous studies, the comparison of hepatotoxicity rates between LMWH and UFH has been limited to particular instances, such as prophylaxis or treatment of pulmonary embolism. However, a comparison of hepatotoxicity rates between perioperative LMWH and UFH administration after digital replantation has not been presented. By comparing the hepatotoxicity, success rate, and complication rate between patients who received LMWH or UFH, the study aimed to promote the usage of LMWH over UFH as the main anticoagulant.

A total of 44 patients underwent digital replantation and perioperative anticoagulation therapy. Ten patients were classified into LMWH group and 34 patients into UFH group. The patient demographics are summarized in Table 1. Representative cases are shown in Figs. 1 and 2. The median patient age was 44.0±14.8 years. Among the patients, 59.1% were non-smokers and 40.9% were smokers. Regarding medical history, none of the patients had a history of hepatic diseases, and most patients had no comorbidities (59.1%). Most patients underwent replantation of one digit (72.7%), whereas a small number of patients underwent operations for more than one digit (27.2%). The success rate was 100% in the LMWH group, whereas one replantation failed in the UFH group (2.9%; category 3, microvascular insufficiency due to arterial and venous occlusions). There was no statistically significant difference in the success rates between the two groups (p>0.999) (Table 2, Fig. 3). No major complications, including systemic bleeding or thrombocytopenia, were observed in either group. The rate of hepatotoxicity was higher in the UFH group than in the LMWH group. The proportion of patients with elevated AST levels (50.0% and 10.0%, respectively; p=0.031) and the rate of ALT elevation (47.1% and 10.0%, respectively; p=0.027) were higher in the UFH group than in the LMWH group (Table 3, Fig. 4).

LMWH is a relatively new class of anticoagulants compared to UFH and is derived from UFH. The anticoagulant activity of LMWH originates from the inhibition of activated coagulation factor X (factor Xa), whereas the anticoagulant activity of UFH originates from its binding to the antithrombin III molecule [17,18]. Since its introduction in the 1970s, LMWH has gradually replaced UFH in clinical practice and has been used to prevent deep venous thrombosis, pulmonary embolism and to treat unstable angina and ST-elevation myocardial infarction [17,18].

However, many institutions still use UFH as the main anticoagulant therapy for perioperative anticoagulation in the microsurgical domain. Recently, there have been changes based on advances in the knowledge of flap dynamics and LMWH [1]. However, it is interesting to consider the advantages of LMWH compared to those of UFH. Some of the advantages of LMWH include: (1) improved predictability of dose-response relationships due to the lower rate of binding to plasma proteins [19], (2) increased plasma half-life due to a lower rate of binding to macrophages and endothelial cells, and (3) lower incidence of heparin-induced thrombocytopenia [20].

The hepatotoxicity of heparin and heparin-derived products has been described in several studies. However, heparin-related hepatotoxicity is often neglected due to its asymptomatic nature. Although heparin-related hepatotoxicity does not cause any sequelae in most cases, it should be closely monitored since it can result in elevated levels of liver enzymes and sometimes shows aggravated symptoms [11].

Our results showed that although patients who were administered UFH had a higher rate of hepatotoxicity than those who were administered LMWH, the success rate was not different. This finding is in agreement with a previous study [7], which showed no statistically significant differences between the two groups in terms of patient demographics. This could indicate that the hepatotoxicity of LMWH described in the literature could be exaggerated. There is no evidence to suggest that LMWH is associated with a high risk of hepatotoxicity in clinical settings. The results section does not include details of other liver function test panel results, such as bilirubin or ALT levels, since these were normal. Although there has been a recent case report regarding the elevation of bilirubin and ALT levels, neither is usually considered to be related to heparin-associated or enoxaparin-related hepatotoxicity [9].

The risk of hepatotoxicity due to UFH and LMWH was high in our results compared to that in other reports, which reported hepatotoxicity risks of 8% and 4%–13%, respectively [14,21]. This could be due to the small sample size or the underreported nature of heparin-derivative-induced hepatotoxicity. The mechanism underlying the different results is unknown, and further research is necessary.

Only enoxaparin was used in this study, despite the availability of several classes of LMWH in the market. This helped to reduce the burden of creating subgroups. Other classes of LMWH might have introduced additional variables, contributing to different results. Further, multicenter and double-blind clinical trials are needed to confirm our results.

A limitation of this study is the small sample size, and missing medical records owing to the retrospective nature of the study making the study underpowered. Moreover, the number of patients in the LMWH group was smaller than that in the UFH group. The use of LMWH in anticoagulant therapy in the perioperative period of digital replantation has only occurred recently at our institution. The indications for the use of LMWH are gradually expanding in almost all patients who undergo microsurgery, including digital replantation and tissue transfer. More detailed results, including a larger number of patients, will be presented in a subsequent prospective study.

LMWH resulted in no significant difference in the success rate, but the risk of hepatotoxicity was significantly lower than that with UFH. Considering the advantages of LMWH, its extensive use is highly recommended for anticoagulation therapy in patients after digital replantation.