Although our results showed that anidulafungin, caspofungin and micafungin had significantly higher signal strength than triazoles and polyenes in coagulation dysfunction. At present, we can only find a small amount of research on the mechanism of micafungin leading to coagulation dysfunction, and caspofungin and anidulafungin are almost none.
The results of a case report show that the occurrence of TTP is most likely related to the use of micafungin by a mechanism that may be due to the fact that micafungin alters the function of ADAMTS13 or reduces the activity of ADAMTS13 through other pathways, which results in the circulation of von Willebrand factor (vWF), which in turn leads to the development of a platelet aggregant. ADAMTS13 works by cleaving vWF preventing it from forming large molecules, thus avoiding platelet aggregation [12]. Another view is that micafungin promotes thrombosis by causing eryptosis, which is accompanied by cell shrinkage [13] and cell membrane scrambling with phosphatidylserine translocation to the cell surface [14]. This view was confirmed in an in vitro cell trial [15]. It is worth noting that our results also showed a very strong signal between micafungen and TTP (ROR 20.43, 95%CI: 8.49–49.14) (Fig. 2). The patient in this report suffered cardiac arrest the day after the onset of TTP and subsequently died [12]. TTP is often fatal and if left untreated, usually results in death in 10–15 days [12]. Therefore, when necessary, patients using micafunzin should be monitored for laboratory indicators related to thrombosis, especially in the intensive care unit, because they are less able to describe their health than patients with mild disease. Although no relevant studies on micafungin and DIC were found, since it is clinically difficult to completely differentiate TTP from DIC [16], coupled with the fact that our results showed a very strong signal strength between micafungin and DIC (ROR 27.19, 95%CI 18.49–39.98), we believe that there is still a need to measure the coagulation parameters when using micafungin especially in patients with poor health.
In a multicentre phase IV clinical study, the AEs with the highest incidence in the micafungin group was decreased platelet count (8.2%) [17]. Results from another phase III clinical trial showed a 10% incidence of thrombocytopenia in the micafungin treatment group [10]. Our results also showed that positive signals were demonstrated between micafungin and both platelet count decreased (ROR 3.50, 95%CI: 2.36–5.19) and thrombocytopenia (ROR 2.87, 95%CI: 1.87–4.41). However, the exact mechanism is unclear.
Another case report documented that micafungin caused a patient to develop pure red cell aplasia (PRCA), which returned to normal levels after discontinuing micafungin [18]. The mechanism of its occurrence may be related to the immune response and metabolic pathways, but the exact mechanism is not known [19]. In addition, it has been reported that micafungin may cause immune complex type hemolytic anemia [20]. The main causes of drug-induced haemolytic anaemia include immunological or oxidative destruction of red blood cells (RBC). Drug-induced hemolysis of immune type can be divided into drug-dependent antibody mediated or drug-independent antibody mediated. The immune complex type is one of the drug-dependent antibody mediated types [21]. The evidence suggests that after the patient was given micafunzin, the body produced antibodies that could bind to micafunzin, and this complex caused the development of hemolytic anemia [20]. Although this type of hemolysis is very rare, it can be fatal. Therefore, as soon as micafungin is suspected of causing haemolysis in a patient, the drug should be discontinued and targeted treatment should be administered. There is a high degree of suspicion that the hemolysis caused by micafungine is closely related to bleeding at different sites. Our results also seem to support this hypothesis. The ROR (95%CI) between micafungine and gastrointestinal haemorrhage, cerebral haemorrhage and pulmonary haemorrhage were respectively: 3.17 (2.02–4.97), 4.95 (2.81–8.72), 5.53 (1.78–17.16). The results showed the strongest association between pulmonary haemorrhage and micafungin, followed by cerebral haemorrhage and gastrointestinal haemorrhage. This observation may be attributed to the location of fungal infection in the patient and the lungs are frequently susceptible to fungal infections.
In contrast, data on caspofungin and anidulafungin in coagulation dysfunction are mainly clinical trials and a few case reports, and the sample sizes are small. Results of a safety study of caspofungin showed that thrombocytopenia occurred in < 4% of patients in the caspofungin treatment group [22]. One study found the presence of platelet antibodies in a patient with caspofungin-induced thrombocytopenia by laboratory examination, and the normal bone marrow examination suggests that peripheral destruction of platelets may be the mechanism of caspofungin-induced thrombocytopenia rather than inhibition of platelet production [23]. The fact that there is an overlap between platelet count decreased and thrombocytopenia also makes it difficult for spontaneous reporters to distinguish between the two. Another study showed that caspofungin prolonged prothrombin time, activated partial thromboplastin time (aPTT), and international normalized ratio (INR) in patients with moderate-to-severe hepatic dysfunction, where the mean time of aPTT was prolonged by up to 5 s [24]. A case report shows that a small-intestine transplant patient treated with caspofungin developed DIC and eventually died [25]. In the analysis of the risk factors for linezolid-induced thrombocytopenia, the use of caspofungin was shown to be an independent risk factor [26, 27]. Our results showed a strong signal between caspofungin and pulmonary haemorrhage (ROR 20.76, 95%CI 11.78–36.59), but we didn’t find any relevant case reports, perhaps the positive signal may be related to the disease itself, just like invasive aspergillosis usually involves the lungs and can lead to bleeding in the lungs and gastrointestinal tract [28]. Nevertheless, the exact mechanism by which caspofungin causes coagulation dysfunction remains inconclusive.
Similarly, the results of a clinical trial of anidulafungin in children under 2 years showed a 10.5% incidence of thrombocytopenia, which was the only AE associated with the blood and lymphatic system. Our results similarly showed that anidulafungin showed stronger signal strength only with thrombocytopenia (ROR 9.75, 95%CI 5.22–18.19), and the two results and seem to be in agreement with each other. In another clinical trial in patients aged 2–18 years, the incidence of epistaxis in the micafungin group was 16.3%. The incidence of platelet count decreased decline was 10.20% and the incidence of DIC, cerebral haemorrhage, gastrointestinal haemorrhage and coagulopathy were all 2.04% [29]. More other post-marketing safety data were not found. Thus, we summarized the current potential mechanisms by which antimicrobials cause coagulation dysfunction: (1) Reducing synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X by inhibiting vitamin K production of intestinal flora, e.g. cefoperazone [30, 31]. (2) Reducing fibrinogen by affecting liver function or gene expression, which causes coagulation dysfunction, such as tigecycline and fluconazole [32]. (3) Reducing platelet production by myelosuppression [33] or by immune-mediated increase in platelet clear [34]. (4) Drug interactions, such as fluconazole can lead to increased blood levels of superwarfarin and cause coagulation dysfunction [35]. These theories may be useful for further mechanistic studies.
An interesting topic is what is the risk of coagulation dysfunction in obese patients using echinocandins. More and more studies suggest that exposure to echinocandins is lower in obese patients compared to non-obese patients [36]. However, it has also been suggested that obese patients have a faster coagulation rate and greater antifibrinolytic capacity compared to the healthy population [37, 38]. These two conclusions may seem contradictory, and there are no studies on the risk of coagulation dysfunction in obese patients using echinocandins. This is worth exploring in depth.
In addition, considering that more than 70% AEs related with coagulation dysfunction in echinocandins occur in the first 10 days, coagulation parameters should be monitored regularly during the first week of drug use. Whether there is a causal relationship between high mortality and echinocandins needs to be explored in more rigorous studies, but it is certain that patients need to be alerted to a sudden deterioration in their health status during the use of echinocandins and amphotericin B. This is because once a coagulopathic event occurs, the patient is likely to die.
Although the study systematically predicted the risk of echinocandins and other antifungal drugs on coagulation dysfunction, there are still shortcomings. Firstly, the study does not prove a causal relationship between echinocandins and coagulation dysfunction, and the findings are only a speculation based on an algorithm. Second, the data included in the study may not fully reflect the real situation, as there are some errors or missing data in the self-reported reports. Third, the study was unable to determine the incidence of coagulation dysfunction because the total number of reports of the target patients as well as the target AEs were unknown. Lastly, the study could not rule out bias from the disease itself and drug interactions.
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