INTRODUCTION
Gastrointestinal bleeding is a common clinical manifestation with various etiologies[1]. According to the site of bleeding, it can be classified into upper, middle, and lower gastrointestinal bleeding. Additionally, depending on the speed of blood loss, it can be categorized into acute, occult, and chronic gastrointestinal bleeding[2]. Upper gastrointestinal bleeding often presents as hematemesis, melena, or coffee-ground vomitus, among which variceal bleeding accounts for a significant proportion, representing 30% of all acute gastrointestinal bleeding cases and up to 90% in cirrhotic patients[3]. Hence, prompt diagnosis and treatment by clinicians are needed[4]. Hemocoagulase, a protein-based hemostatic agent extracted from snake venom, has been commonly used in the clinical treatment of various hemorrhagic diseases[5-7]. As has been evidenced previously[8,9], hemocoagulase selectively acts on damaged blood vessels without affecting the normal physiological coagulation system. However, with the widespread clinical application of snake venom-derived hemocoagulase, certain rare adverse reactions have become increasingly evident. In 2016, the Respiratory Medicine Branch of the Chinese Medical Association published a consensus[10], emphasizing the dual role of hemocoagulase in both hemostasis and coagulation. The consensus points out that long-term or high-dose use of hemocoagulase can gradually lower fibrinogen levels, eventually inducing acquired hypofibrinogenemia. In recent years, there have been numerous clinical reports of hemocoagulase-resulted hypofibrinogenemia, although most are individual case reports[11-13]. Zou et al[14] have a retrospectively analyzed 109 gastrointestinal bleeding patients and identified key hazards of hypofibrinogenemia caused by hypofibrinogenemia, providing valuable insights for future clinical practice and treatment strategies.
DIVERSE RISK FACTORS AND FINDINGS VARY ACROSS DIFFERENT STUDIES FOR HEMOCOAGULASE-ASSOCIATED HYPOFIBRINOGENEMIA IN PATIENTS WITH GASTROINTESTINAL BLEEDING
In a study by Zou et al[14], a total of 109 patients were enrolled based on specific inclusion and exclusion criteria and grouped [acquired hypofibrinogenemia (n = 36), non-hypofibrinogenemia (n = 73)]. Hypofibrinogenemia refers to plasma fibrinogen level below 2.0 g/L. Hazards of hemocoagulase-related hypofibrinogenemia were analyzed through logistic regression and the model's accuracy was evaluated through receiver operating characteristic analysis. The results showed that patients with hypofibrinogenemia had a higher probability of being sent to intensive care unit (P = 0.021). Additionally, female patients were more likely to develop acquired hypofibrinogenemia when using hemocoagulase to treat gastrointestinal bleeding (P = 0.005). Patients with hypofibrinogenemia also had a higher in-hospital mortality rate (P = 0.027). Furthermore, these patients received a higher total dose of hemocoagulase (P = 0.026) and required more packed red blood cell transfusions (P = 0.024), with low-level baseline fibrinogen (P < 0.000). The regression analysis determined a higher total dose of hemocoagulase and female sex, along with low-level baseline fibrinogen as hazards of hypofibrinogenemia resulted from hemocoagulase in gastrointestinal bleeding cases.
Zhang et al[15] have demonstrated consistent findings with the above results that high total hemocoagulase dosage is a hazard factor. However, Huang et al[16] have proved different conclusions, suggesting that age, treatment duration, and route of administration were the key risk factors for hemocoagulase-associated hypofibrinogenemia, and cumulative dosage was not a significant risk factor. The discrepancy in these results may be attributed to the following factors. First, the study by Zou et al[14] is a retrospective single-center study with a small sample size, potentially leading to data bias. Second, the influencing factors and reference ranges used by these two research centers are different, which may lead to divergent outcomes. Specifically, regarding the effect of total hemocoagulase dosage on hypofibrinogenemia, the results of these two studies are even contradictory. As noted in the conclusion of the study, this study is a single-institution retrospective study with a limited number of patients, and the results may have certain limitations. Furthermore, there may have been factors affecting study accuracy, leading to selective bias in the results.
The authors identified higher total hemocoagulase dosage and female sex, along with low-level baseline fibrinogen as influencing factors of hypofibrinogenemia resulted from hemocoagulase. Through further literature review, we found that Ma et al[17] have suggested that factors such as sex, age, the type of hemocoagulase used, cumulative dosage, treatment duration, and albumin levels were potential risk factors for hemocoagulase-associated hypofibrinogenemia. Unfortunately, the authors does not provide a comprehensive explanation for these risk factors, but they emphasize that hemocoagulase types and albumin levels are also important contributors to hypofibrinogenemia development. Through comparing the baseline data from both studies, it's evident that Zou et al[14] fail to include these variables, which may be a critical factor for the inconsistent results between the two studies.
Additionally, this study also pointed out that low-level baseline fibrinogen was one of the risk factors. Zhang et al[15] have shown consistent results, who treat 460 patients with cirrhosis and esophageal variceal bleeding (EVB) using Agkistrodon acutus hemocoagulase in combination with somatostatin. They compared the baseline data of patients (age, baseline fibrinogen levels, and baseline plasma prothrombin time) who developed severe hypofibrinogenemia following hemocoagulase treatment with those who did not, and demonstrated statistically significant differences between these variables (P < 0.05). Further analysis revealed that, regardless of whether severe hypofibrinogenemia occurred during treatment, both groups exhibited a downward trend in fibrinogen levels. This suggests that the use of Agkistrodon acutus hemocoagulase may deplete plasma fibrinogen, leading to a gradual decline in fibrinogen levels[18]. However, this study only focused on patients treated with Agkistrodon acutus hemocoagulase and may not represent all types of hemocoagulase. Additionally, since the study participants had EVB, further investigation is needed to determine whether EVB has a greater impact on fibrinogen levels.
CONCLUSION
Potential risk factors for hemocoagulase-associated hypofibrinogenemia include age, gender, low-level baseline fibrinogen levels, route of administration, hemocoagulase type, cumulative dose, treatment duration, and albumin levels. Therefore, when using hemocoagulase for gastrointestinal bleeding, clinicians should be aware of both intrinsic and extrinsic risk factors of patients and be vigilant for the development of hemocoagulase-induced hypofibrinogenemia.
