Impact of Tigecycline on Coagulation in Severe Infections and Effect of Vitamin K1 Intervention: A Retrospective Single-Center Analysis

Introduction

At present, the Food and Drug Administration (FDA)-approved indications for tigecycline include complex abdominal infection, complex skin and soft tissue infection, and community-acquired pneumonia. Tigecycline is the first new type of glycyltetracycline antibacterial drug to be launched, which has advantages such as strong antibacterial activity, wide antibacterial spectrum, and good tolerance, safety, and effectiveness. At present, tigecycline is widely used in the treatment of infectious diseases caused by super-broad-spectrum β-lactamase-positive bacteria, carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and other drug-resistant bacteria [1,2].

Common adverse effects of tigecycline include rash, gastrointestinal reactions, pancreatitis, liver dysfunction, renal dysfunction, and coagulopathy. However, in fact, as early as 2010, Pieringer et al [3] reported a case of significant increase in activated partial thrombin time (APTT) and international normalized ratio (INR) after the patient received tigecycline treatment. Subsequently, there have been increasing reports of cases of coagulopathy caused by tigecycline both domestically and internationally, which have attracted clinical attention [4–6]. Researchers have found that tigecycline-induced coagulopathy reduced the effectiveness of anti-infection and increased mortality in severely infected patients [7]. In particular, hypofibrinogenemia associated with tigecycline can increase the occurrence of disseminated intravascular coagulation in critically infected patients [8,9]. Coagulation disorders after tigecycline treatment should receive considerable attention and be prevented in a timely manner, with an active search for alternatives.

At present, there are no unified data to support the incidence rate of tigecycline-induced coagulopathy [8–10]. Moreover, there are currently no studies on intervening in tigecycline-induced coagulopathy, with studies on the prevention of tigecycline-induced coagulopathy with vitamin K1 being in the theoretical stage only. Therefore, it is important to study the incidence rate and intervention measures of tigecycline-induced coagulopathy.

Severe infection itself is already a very serious condition for patients. If we can summarize the incidence rate of tigecycline-induced coagulopathy and the treatment experiences of vitamin K1, we could expect to avoid the occurrence of tigecycline-induced coagulopathy, to achieve safer medication and to improve patient prognosis on the basis of anti-infection. The objective of this study was to retrospectively analyze the clinical data of 920 patients with severe infection treated with tigecycline. We explored the incidence of tigecycline-induced coagulopathy and the effect of vitamin K1 on the improvement of coagulopathy, to provide a safer and more scientific clinical research basis for the application of tigecycline.

Material and Methods

PATIENTS AND METHODS:

This case-controlled retrospective study was conducted according to the principles of the Declaration of Helsinki. It was approved by the Ethics Committee of the Affiliated Hospital of Shandong University of Chinese Medicine, which exempted patients from informed consent (ethics review 2024 No. (041) KY). All cases were reviewed by a clinical pharmacist and 2 clinical doctors.

The study was conducted on 920 patients with severe infection treated with tigecycline in 3 Intensive Care Units (ICUs) of the Affiliated Hospital of Shandong University of Chinese Medicine from January 2017 to December 2022. Cases were selected according to inclusion and exclusion criteria. The inclusion criteria were as follows: (1) age over 18 years, (2) severely infected patients (Sequential Organ Failure Assessment, SOFA score ≥2), (3) treatment with tigecycline for 72 h or more, (4) integrity of coagulation indicators before and after tigecycline treatment, and (5) meeting at least 1 coagulation dysfunction criterion. The exclusion criteria were as follows: (1) age under 18 years (2) non-severely infected patients (SOFA score <2), (3) treatment with tigecycline for less than 72 h, (4) normal coagulation function, (5) underlying diseases that cause coagulopathy (such as hematological disorders, cirrhosis), (6) severe shock, disseminated intravascular coagulation, and end-stage renal disease, (7) lack of clinical data, and (8) using anticoagulants or other drugs that cause coagulopathy.

According to the inclusion and exclusion criteria, 220 patients were included and divided into a high-dose group and a normal-dose group. The dose of tigecycline in the high-dose group was 100 mg every 12 h, and a 200-mg loading dose was either used or not applicable. In the normal-dose group, the dose of tigecycline was 50 mg every 12 h, with or without a 100-mg loading dose. According to whether vitamin K1 treatment was used, 72 patients receiving vitamin K1 treatment were further included and grouped to high-dose and normal-dose groups. Vitamin K1 treatment lasted for at least 72 h.

DATA COLLECTION:

The collected general demographic characteristics included underlying diseases, SOFA score, infection location, tigecycline dosage, treatment duration, antiplatelet/anticoagulant drugs, and bleeding events. Collect coagulation function indicators, such as PT, APTT, and fibrinogen, were collected 1, 3, 5, and 7 days after tigecycline treatment, as well as before and after 72 h of vitamin K1 treatment.

DIAGNOSTIC CRITERIA:

The normal ranges of coagulation function are PT of 11–15 s, APTT of 28–43.5 s, and fibrinogen of 2–4 g/L (Stago automated coagulation instrument). According to the experimental coagulation method detection standard, PT and APTT exceeding 3 s and 10 s of the normal upper limit, respectively, are defined as abnormal. Hypofibrinogenemia is defined as fibrinogen levels below 2 g/L. Regarding infection, according to “The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)” [11], a SOFA score ≥2 was defined as severe infection.

STATISTICAL ANALYSIS:

SPSS software was used for data analysis (version 26.0, IBM Corp, Armonk, NY, USA). The continuous variables were expressed as mean±standard deviation, and categorical variables were presented as numerical values and percentages. The distributions of age, sex, infection site, and underlying diseases were expressed by percentage proportion. ANOVA for repeated measures were used to compare the temporal changes of coagulation function indicators in different treatment dose groups. The t test was used to analyze the changes in coagulation function indicators before and after treatment with vitamin K1. P<0.05 was considered to express a statistically significant result.

The detailed patient screening process is shown in Figure 1.

Results

CASE INCLUSION:

The case inclusion and research process are shown in Figure 1. The data on 920 patients with severe infection were collected, and 220 patients were eligible for the study, including 135 patients in high-dose group and 85 patients in the normal-dose group. The indexes of coagulation function were collected 1, 3, 5, and 7 days after treatment in both groups. The onset time of coagulation dysfunction was 5.350±2.12 days in the high-dose group and 6.34±2.24 days in the normal-dose group. A total of 72 patients with coagulation disorders were treated with vitamin K1 injection, including 56 patients in the high-dose group and 16 patients in the normal-dose group. The coagulation indicators were collected before and 72 h after treatment with vitamin K1.

BASIC DISEASE AND INFECTION SITE DISTRIBUTION:

The underlying diseases were distributed as follows: 85 cases of infection (38.63%), 36 cases of cerebrovascular disease (16.36%), 25 cases of fracture (11.36%), 18 cases of cardiovascular disease (8.18%), 8 cases of tumor (3.63%), and 48 cases (21.82%) of other diseases, such as acute exacerbation of chronic obstructive pulmonary disease, pulmonary fibrosis, rheumatic diseases, multiple injuries, and gastrointestinal bleeding. The infection site distribution was as follows: 137 patients had pulmonary infections (62.27%), 48 had abdominal infections (21.82%), 18 had bloodstream infections (8.19%), 15 had complicated skin and soft tissue infections (6.82%), and 2 had intracranial infections (0.9%). The antibiotic susceptibility test results showed 125 cases of multidrug-resistant Acinetobacter baumannii, 45 cases of multidrug-resistant Klebsiella pneumoniae, 34 cases of multidrug-resistant Serratia marcescens, 16 cases of Enterococcus faecium, and 10 cases of Escherichia coli. Fourteen patients showed 2 pathogenic bacteria, while 4 patients did not cultivate pathogenic bacteria and used empirical medication. The basic disease type and infection site distribution are shown in Table 1 and Figure 2.

AGE AND SEX DISTRIBUTIONS:

A total of 135 patients were included in the high-dose group, including 75 men, with an average age of 77.54±8.23 years. Eighty-five patients were included in the normal-dose group, including 57 men, with an average age of 79.11±8.02 years. In the high-dose and normal-dose groups, 81–90 year olds accounted for the largest proportion, 51.11% and 54.12%, respectively. The age and sex distributions are shown in Table 2 and Figure 3.

CHANGES OF COAGULATION INDICATORS AFTER TIGECYCLINE TREATMENT:

The incidence of blood coagulation disorders due to tigecycline treatment was 23.91%. Intra-group comparison showed that on days 5 to 7, APTT and PT were significantly prolonged (P<0.05 or P<0.01), and fibrinogen was significantly decreased in both groups (P<0.01), indicating that coagulation dysfunction occurred 5 to 7 days after tigecycline treatment. Compared with in the normal-dose group, APTT and PT in the high-dose group were significantly prolonged on day 7 (P<0.05), and fibrinogen was significantly decreased on days 5 to 7 (P<0.05), indicating that high-dose tigecycline was more likely to cause coagulation dysfunction than the normal dose. The results are shown in Table 3 and Figure 4.

CHANGES OF COAGULATION INDICATORS BEFORE AND AFTER VITAMIN K1 TREATMENT:

Of the patients with tigecycline-induced coagulopathy, 32.72% were treated with vitamin K1. Compared with before treatment, APTT and PT were significantly shortened (P<0.05 or P<0.01), and fibrinogen levels were significantly increased (P<0.05 or P<0.01) in both groups. The coagulation indicators of the 2 groups before and after vitamin K1 intervention are shown in Table 4 and Figure 5.

Discussion

TIGECYCLINE CAN INDUCE COAGULOPATHY:

In our study, the incidence of tigecycine-related coagulation disorders was 23.91%, which appeared 5 to 7 days after tigecycline treatment, manifested as significantly prolonged APTT and PT, and significantly reduced fibrinogen. The changes in fibrinogen were more significant than those in APTT and PT, and the fibrinogen levels in both groups decreased by 50%, compared with the initial fibrinogen levels. Previous studies have reached the same conclusion. Campany-Herrero et al [14] found that tigecycline caused significant changes in fibrinogen (average decrease of 1.76 g/L) and INR (average increase of 0.11). The study of Liu et al [9] showed that the average values of APTT, PT, and thrombin time increased 95.9% (142/148) of patients experienced a decrease in fibrinogen during treatment with tigecycline, and 60.8% (90/148) of patients experienced hypoalbuminemia (fibrinogen <2.0 g−L−1). Leng et al [6] retrospectively analyzed 50 patients with severe infection who received tigecycline treatment and found that the fibrinogen decreased and APTT and PT increased within 3 to 4 days after tigecycline treatment.

The instructions for tigecycline describe that it can lead to prolonged APTT, prolonged PT, increased INR, and decreased platelets [4]. Also, tigecycline can cause hypofibrinogenemia, and fibrinogen changes more significantly than APTT, PT, and other indicators [8,15]. The causes of the coagulation dysfunction caused by tigecycline are unknown. At present, the main arguments are as follows. (1) In the physiology state, the synthesis of fibrinogen is affected by interleukin-6, and tigecycline can reduce the plasma fibrinogen level by inhibiting the synthesis of interleukin-6 [16,17]. (2) The level of microRNA-122 in the blood of patients with severe infection is correlated with the thrombin index APTT, antithrombin III, and fibrinogen levels. Tigecycline can affect the coagulation function by influencing the level of microRNA-122 [18–20]. (3) Tigecycline can destroy the balance of intestinal flora and inhibit the synthesis of vitamin K, thus affecting the coagulation response. Tigecycline itself can inhibit the activity of vitamin K, and may also cause coagulation dysfunction. (4) The molecular structure of tigecycline is similar to that of tetracycline antibiotics, and it can bind to some sites of liver cell ribosomes to interfere with the synthesis of fibrinogen and other coagulation indicators [21]. Also, tigecycline-induced coagulopathy is associated with infection, liver dysfunction, disseminated intravascular coagulation, active bleeding, hypothermia, and acidosis [22].

EFFECT OF TIGECYCLINE DOSAGE ON COAGULOPATHY:

In the present study, tigecycline-induced coagulopathy was dose-dependent. Our research showed that, with longer tigecycline treatment, the coagulation function of the high-dose group was worse than that of the normal-dose group. Compared with the normal-dose group, APTT and PT in the high-dose group were significantly prolonged on day 7 (P<0.05), and fibrinogen was significantly decreased on days 5 to 7 (P<0.05), indicating that high-dose tigecycline was more likely to cause coagulation dysfunction than the normal dose. Some researchers have found that the coagulopathy caused by tigecycline has nothing to do with dose, and high-dose tigecycline does not increase the occurrence of coagulopathy [6,23]. However, some studies have come to the same conclusion as our research. Brandtner et al [24] found that after taking a super-therapeutic dose of tigecycline, mitochondrial activity of hepatocytes was rapidly lost, and APTT was gradually prolonged with the increase of blood concentration of tigecycline. Treml et al [25] found that patients in the fibrinogen reduction group received a higher total dose of tigecycline.

With the emergence of drug-resistant bacteria, especially carbapenem-resistant Acinetobacter baumannii, clinical treatment cannot be limited to the standard dose of tigecycline but should rely more on the super-standard dose of tigecycline [26]. Some studies have shown that as dosage increased, tigecycline showed positive pharmacokinetic characteristics and better clinical outcomes [27,28]. The blood concentration of tigecycline is a more accurate predictor of coagulopathy than is dosage. In patients with severe infection, especially in patients with septic shock, early hemodynamic abnormalities, renal hypoperfusion, hypoalbuminemia, multiple organ dysfunction, continuous renal replacement therapy, extracorporeal membrane oxygenation, fluid resuscitation, and other factors increase or decrease the apparent volume of distribution and clearance of drugs in the body, thus affecting the blood drug concentration. Blood concentrations of tigecycline vary widely among patients, and exposure in vivo is a more accurate predictor of efficacy than is dose and may have a better correlation with the occurrence of adverse reactions [29,30]. Yu et al [31] divided 40 severely infected patients treated with tigecycline into a high-dose group and standard-dose group and detected the blood concentration of tigecycline. They found that the plasma peak concentration of tigecycline in the high-dose group (2.46±0.43 μg/mL) was significantly higher than that in the normal-dose group (1.25±0.16 μg/mL). Bai et al [32] divided 45 severely infected patients treated with tigecycline into a high-dose group and standard-dose group. The median trough concentration of tigecycline in the high-dose group was 0.56 ug/mL, which was higher than that of the normal-dose group (0.21 ug/mL). The level of fibrinogen decline in the high-dose group was significantly higher than that of normal-dose group (−3.05±1.67 vs −1.75±1.90). Therefore, efficacy and coagulation dysfunction are factors to consider when choosing tigecycline, and monitoring blood drug concentration is crucial to avoid coagulation dysfunction caused by high-dose tigecycline.

EFFECT OF THE APPLICATION TIME OF TIGECYCLINE ON COAGULOPATHY:

Besides dosage, treatment duration was also a risk indicator for tigecycline-related coagulopathy [10]. Due to study limitations, we observed the changes in coagulopathy after only 1 week of tigecycline treatment. We found that coagulopathy caused by tigecycline occurred 5 to 7 days after treatment, and the changes increased with the prolongation of treatment time, which was consistent with some research results [6,33]. A retrospective study [9] of 426 severely infected patients treated with tigecycline found that regardless of the normal dose or high dose, more patients with prolonged treatment (>14 days) developed hypoalbuminemia. By searching 16 years of data from the FDA Adverse Event Reporting System, Guo et al [22] found that the incidence of tigecycline-induced coagulopathy was 14.7%, and 80.72% of coagulation-related adverse events occurred within the first 14 days after the start of tigecycline treatment. A retrospective cohort study involving 311 cases found that treatment with tigecycline for more than 7 days was an independent risk factor of tigecycline-related coagulopathy [7]. Campany-Herrero et al [14] identified that with the duration of tigecycline treatment >4 weeks, high dosage was an independent risk factor associated with hypofibrinogenemia. However, a retrospective analysis found that coagulopathy can occur on any day after the application of tigecycline, even on day 39 [34]. Therefore, the onset time of tigecycline-related coagulopathy was not the same in different studies. This is because many factors affect tigecycline-related coagulopathy, including the degree of infection, organ function, comorbidities, and hemodynamics. Therefore, due to sample selection bias, the occurrence time of coagulation disorders caused by tigecycline is not the same in different studies.

The correlation between the duration of treatment and tigecycline-induced coagulopathy can be related to the cumulative dosage. A retrospective study involving 9 hospitals in China found that treatment duration ≥6 days was a risk factor for tigecycline-induced coagulopathy, which was related to the cumulative dose (≥1000 mg) [15]. However, the treatment time with tigecycline is closely related to the site of infection, severity of the infection, and sensitivity of the pathogen [35]. The more severe the infection, the longer the treatment with tigecycline. Low tissue concentration and insensitivity to pathogenic bacteria can be the contributing factors for the prolonged administration of tigecycline.

VITAMIN K1 IMPROVED COAGULOPATHY INDUCED BY TIGECYCLINE:

The FDA approved injectable vitamin K1 for bleeding caused by vitamin K deficiency and mentioned that tigecycline can reduce the population of microorganisms colonizing the colon and the distal ileum, which normally synthesize vitamin K. In addition, tigecycline itself can inhibit the activity of vitamin K and cause coagulopathy [5]. In the present study, the effects of blood diseases, cirrhosis, severe shock, disseminated intravascular coagulation, and end-stage renal disease on coagulation function were excluded. After treatment with vitamin K1, the fibrinogen increased and APTT and PT were shortened in both groups. The fibrinogen level of the high-dose group and the normal-dose group increased by 34.75% and 34.85%, respectively, with the most significant changes. Comparing the groups, after vitamin K1 treatment, the improvement of coagulation indices in the normal-dose group was more obvious than in the higher-dose group, which may be related to the slight coagulation disorder in the normal-dose group.

Studies on vitamin K1 in the treatment of tigecycline-induced coagulopathy are very few and mainly focused on case reports. In single-center or multi-center retrospective studies, cases involving vitamin K1 therapy were often combined with the use of plasma or fibrinogen or with the discontinuation of tigecycline. Lei et al [36] studied 20 patients with hypofibrinogenemia after treatment with tigecycline, and found that fibrinogen levels gradually decreased from 3.98±2.05 g/L to 0.87±0.45 g/L. In their study, 35% of patients discontinued tigecycline therapy and were given vitamin K1, and fibrinogen levels returned to normal within 4 days. Whether the improvement of hypofibrinogenemia was due to discontinuation of tigecycline or vitamin K1 infusion has not been further investigated. The literature review by Cui [34] of tigecycline-induced coagulopathy included 13 case reports and 4 retrospective studies. Five of the 13 patients were treated with vitamin K1, and treatment in 2 patients was judged to be ineffective; however, both patients had end-stage renal disease and severe liver disease. Since liver disease can aggravate coagulation dysfunction, and kidney disease can cause tigecycline to accumulate, the therapeutic effect of vitamin K1 could not be accurately evaluated. Among the 4 retrospective studies, 2 involved vitamin K1. In one of those studies, 148 patients were treated with tigecycline, and only 1 patient was treated with vitamin K1. In the other study, of 50 patients, none were treated with vitamin K1, and the author analyzed in only the discussion section that the coagulopathy caused by tigecycline combined with cefoperazone sulbactam may be related to vitamin K deficiency. Therefore, Cui’s conclusion that vitamin K1 was ineffective in tigecycline-induced coagulopathy was not accurate. Therefore, some large-scale prospective controlled studies are still needed to investigate the effect of vitamin K1 on tigecycline-induced coagulation dysfunction.

Our study has several advantages. First, compared with previous case reports, we used different dose groups to explore coagulopathy. Second, we conducted a cohort study and analysis on the relevant indicators to ensure the reliability of the results. Third, we excluded the influence of underlying diseases and anticoagulant drugs on coagulation dysfunction, and no patients stopped using tigecycline during vitamin K1 treatment. This study also has certain limitations. First, as a single-center retrospective study, there can be selection bias. Second, the complexity and heterogeneity of ICU patients can affect the study results. Again, in terms of research methods, no negative control group was set up, and subgroup analysis was not conducted on many influencing factors. Finally, although all cases were reviewed by a clinical pharmacist and 2 clinical doctors, the diagnosis of tigecycline-related coagulopathy can still be confused for other reasons.

Conclusions

In conclusion, we found statistically significant differences in fibrinogen reduction and APTT and PT prolongation in patients taking tigecycline. These changes usually occurred within 5 to 7 days of tigecycline treatment. Tigecycline-induced coagulopathy is dose-dependent and has a causal relationship with a long course of treatment. The higher the dose or the longer the course, the more severe the coagulopathy. After vitamin K1 treatment, coagulation function improved significantly, especially in fibrinogen levels. Based on these results, we recommend routine monitoring of coagulation function after tigecycline administration, and adjusting treatment regimens according to the monitoring results. Prophylactic use of vitamin K1 can reduce the incidence of coagulopathy.