Tigecycline is one of the few therapeutic options for the treatment of multi drug resistant and extensively drug resistant bacterial infections[16–19]. A total of 50 patients who received tigecycline were enrolled in our study. The majority of patients were admitted in the intensive care unit (ICU) and over 50% were diagnosed by sepsis. Mixed infection was common, with the most common sites of infection being lower respiratory tract, followed by abdominal and skin and soft tissues.
After treatment with tigecycline, hypofibrinogenemia occurred in 26 out of 50 patients (52%). This similar phenomenon had been mentioned in other literature[5, 6, 13], and gastrointestinal bleeding occurred in three cases that were noteworthy. In addition, the recovery of fibrinogen concentration after stopping treatment also reflected a causal relationship, which was similar to some previous research conclusions[5, 6, 13]. In the clinical trial, hypofibrinogenemia was a less detected adverse reaction, which may be due to the fact that the subjects did not receive high-dose and/or long-term tigecycline treatment [1]. As adverse drug reactions were the most common reason for poor adherence to treatment and even termination of treatment, we explored the independent risk factors for hypothrombinemia in patients treated with tigecycline. Our study showed that the independent risk factors included the baseline direct bilirubin > 0.4mg/dL and the cumulative dose, and the baseline fibrinogen level might be a protective factor.
Fibrinogen is a glycosylated acute-phase protein synthesized by liver parenchymal cells that has a half-life of 3 to 4 days. The normal range of the fibrinogen level in the bloodstream is 2 to 4 g/L. Hypofibrinogenemia can occur in patients with chronic inherited diseases such as afibrinogenaemia, dysfibrinogenaemia, or hypodysfibrinogenemia, and patients with acquired hepatic dysfunction such as cirrhosis, hepatitis, and metastatic hepatoma, and patients with severe malnutrition. Acute hypofibrinogenemia is associated with disseminated intravascular coagulation, severe sepsis, malignancy, and drug administration such as valproic acid, allopurinol [6]. Through the multivariate logistic regression analysis, we found that the higher direct bilirubin may be another risk factor. Because tigecycline is mainly metabolized by the liver, the abnormality of blood coagulation routine may be aggravated with the aggravation of liver injury. Therefore, we recommended strengthening the monitoring of patients with liver dysfunction during the use of tigecycline, especially those defined as Child-Pugh C.
In this study, the cumulative dose of tigecycline has been considered as one of the risk factors, some studies showed that it often developed on the 5th–10th day after tigecycline was used[6–9, 20], In this study, the fibrinogen level of 87.5% of the patients (21/24) was restored to the normal range after drug withdrawal, and it's time ranged from 1 to 9 days. This is also in accord with previous cases[7–10].At the same time, it was reported that receiving high-dose tigecycline was related to a decrease of fibrinogen in other studies [5, 7, 21]. In this study, only 4 patients received high-dose tigecycline, so no similar conclusion was obtained. The daily dose of tigecycline specified in the manual is 100 mg. However, in clinical practice, it was found that the low dose of tigecycline was not effective for some patients with severe infection, and it was easy to lead to the production of drug-resistant bacteria[7, 11, 12]. Increasing the dose can enhance the antibacterial ability of the drug[22]. Therefore, the clinical application of high-dose tigecycline was also very common. In addition, some studies reported that there was no significant difference in the incidence of adverse reactions, such as coagulation abnormalities between high-dose tigecycline and the standard dose[11, 12]. Therefore, we consider that after tigecycline therapy, when the daily dose is exceeded and the cumulative dose is large, there is a greater need to strengthen the monitoring of coagulation indicators.
Since urine excretion accounts for 33% of tigecycline elimination[1], renal impairment might not cause drug accumulation and higher toxicity. As a lipophilic drug, tigecycline is more widely distributed in the body tissues of elderly patients, which leads to the prolongation of tigecycline's retention time in the body and increased exposure; The metabolism and excretion of liver and kidney function in the elderly will also slow down, which will further increase the exposure of tigecycline in the body, causing abnormal blood coagulation. Other factors, such as intra-abdominal infection and high protein C levels were identified as risk factors for tigecycline associated hypofibrinogenemia in other studies[5, 6]. In addition, it has been reported that hemoglobin level is a protective factor leading to abnormal coagulation of tigecycline[23]. The decrease in hemoglobin may reduce the oxygen carrying capacity of blood, slow down the metabolism of cells in the body, and slow down the metabolism of tissues. However, tigecycline is widely distributed in tissues, so it may slow down the metabolism of tigecycline, leading to an increase in the concentration of tigecycline.
Hypofibrinogenemia associated with tigecycline is usually characterized by dose-dependent prolongation of prothrombin time and activated partial prothrombin kinase time, as well as decreased fibrinogen levels. Tigecycline and its metabolites might have multiple effects on blood coagulation, affecting external or internal pathways, or even common pathways. At present, the severe coagulation dysfunction caused by tigecycline can only be reversed by stopping it and infusion of fibrinogen. At the same time, there is a lack of effective preventive measures. In this study, it was found that there is no difference combining vitamin k1 injection in the group with or without hypoprothrombinemia. It has been suggested that tigecycline plays a role in reducing the gastrointestinal flora, resulting in reduced production of vitamin K[24]. However, this cannot explain the plasma fibrinogen reduction.