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A Comparison of Coagulation Function in Patients Receiving Aspirin and Cefoperazone-Sulbactam With and Without Vitamin K1: A Retrospective, Observational Study
Address correspondence to: Hanbin Wu, Clinical Pharmacy, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Shanghai 200120, China.
The study objective was to explore whether prophylaxis with vitamin K1 improves abnormal coagulation function–associated cefoperazone-sulbactam in patients treated in the long term with low-dose aspirin.
Methods
This retrospective, observational study assessed patients treated with long-term low-dose aspirin in a naval military hospital in China from 2004 to 2018, including all patients treated concurrently with cefoperazone-sulbactam with or without vitamin K1. Differences in the coagulation index were analyzed statistically before and after receipt of cefoperazone-sulbactam.
Findings
The cohort included 227 patients. After cefoperazone-sulbactam treatment, the mean (SD) prothrombin time (PT) was 14.07 (3.07) seconds, activated partial thromboplastin time (aPTT) was 35.15 (4.78) seconds, and international normalized ratio (INR) was 1.49 (0.49) in the cefoperazone-sulbactam group, which was significantly higher than the PT of 11.55 (1.29), aPTT of 31.37 (2.20), and INR of 1.12 (0.35) before cefoperazone-sulbactam treatment. No significant difference was in the cefoperazone-sulbactam plus vitamin K1 group. In addition, no significant difference was found in the thrombin time or fibrinogen level between before and after cefoperazone-sulbactam treatment in both groups. The mean (SD) platelet counts of the 2 groups were 197.34 (71.82) × 109/L and 187.75 (72.66) × 1 09/L after cefoperazone-sulbactam treatment, respectively, which was significantly lower than 231.77 (77.05) × 109/L and 232.08 (84.48) × 109/L before cefoperazone-sulbactam treatment. There were greater proportions of coagulation disorders (prolongation of PT, aPTT, INR, and bleeding) after cefoperazone-sulbactam treatment in the cefoperazone-sulbactam group compared with that in the cefoperazone-sulbactam plus vitamin K1 group.
Implications
Results indicate that, after adding cefoperazone-sulbactam to the regimens of patients receiving long-term low-dose aspirin, therapy contributed to remarkable increase in abnormal coagulation function and coagulation disorders. Prophylaxis with vitamin K1 decreased the risk of these abnormalities in blood coagulation parameters associated with cefoperazone-sulbactam in patients taking long-term aspirin.
Low-dose aspirin (acetylsalicylic acid) has become one of the most commonly used pharmacologic therapies for primary or secondary prevention of cardiovascular and cerebrovascular diseases. However, hemorrhage may be particularly problematic in patients receiving low-dose aspirin antiplatelet therapy.
Cefoperazone-sulbactam, a third-generation cephalosporin, is a β-lactam/β-lactamase inhibitor combination and exhibits marked broad-spectrum activity against both gram-positive and -negative bacteria. It has been extensively used to treat various infectious diseases in clinical practice because of its efficacy and tolerability. However, increased risk of bleeding with the use of cefoperazone-sulbactam has been reported since the launch of this treatment.
Nevertheless, it is still a commonly used drug that is often coadministered in patients receiving long-term low-dose aspirin during the treatment of infections. Both cefoperazone-sulbactam and aspirin have an impact on coagulation function, although their targets are different links in the coagulation cascade. The interaction between aspirin and cefoperazone-sulbactam has not been established. Few data are available regarding whether the application of cefoperazone-sulbactam and aspirin together have an additive effect on coagulation function.
In a previous study, we found that cefoperazone-sulbactam was associated with prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT), and abnormal PT- and aPTT-induced cefoperazone-sulbactam was significantly improved after vitamin K1 intervention.
The cumulative effects on coagulation function caused by aspirin and cefoperazone-sulbactam were not further discussed in the previous study. The present study aimed to evaluate whether the use of cefoperazone-sulbactam was associated with an increased risk of coagulation disorders and prophylaxis with vitamin K1 during cefoperazone-sulbactam treatment and whether such treatment could produce a reduction in abnormal coagulation function in patients receiving long-term aspirin.
Materials and Methods
The single-institution, retrospective, observational study using data from electronic medical records was conducted in China between 2004 to 2018 in the Hongkou Branch of First Affiliated Hospital of Naval Military Medical University. This observational research was conducted to compare the influence of cefoperazone-sulbactam with and without vitamin K1 on coaguIation function in patients treated with long-term aspirin. Adult patients (≥18 years of age) who continuously used injection forms of the study antibiotics for ≥72 hours in the inpatient department during January 1, 2004, to December 31, 2018 were eligible for inclusion. This study was conducted in accordance with the Declaration of Helsinki. The study was approved by the institutional review board of Naval Military Medical University and the First Affiliated Hospital of Naval Military Medical University Ethics Committee (reference 20200106012), and informed consent was not required because of the anonymous, observational nature of the study in China. The study does not involve human data or tissue. We took additional steps to protect the patient's privacy and have anonymized this article to the greatest possible extent.
The inclusion criteria were age <80 years, long-term (>6 months) aspirin (75–325 mg) therapy, and inpatients receiving cefoperazone-sulbactam with and without vitamin K1 during hospitalization. The exclusion criteria were as follows: (1) patients who were newly prescribed other anticoagulants or antiplatelet agents and any other antibiotics during the 7-day period before cefoperazone-sulbactam therapy until the end of treatment; (2) patients with tumors, bleeding, or severe liver and kidney diseases; (3) patients >80 years of age; (4) patients who underwent surgery during the 7-day period before cefoperazone-sulbactam therapy until the end of treatment; (5) outpatients; and (6) patients who changed antibiotics from cefoperazone-sulbactam to other antibiotic within 72 hours and multiple uses of antibiotics during hospitalization. If a patient was administered multiple rounds of antibiotics, only the first administration was included. We excluded patients who changed antibiotics from one study antibiotic to another during the observational period.
All patients had received aspirin (Bayaspirin; Bayer HealthCare Manufacturing S.r.l., Milan, Italy) antiplatelet therapy for >6 months and were continuing to receive therapy, and all patients received 1.5 to 3.0 g of cefoperazone-sulbactam BID (Sulperazon; Pfizer Inc, Shanghai, China) for antiinfection during therapy. The cefoperazone-sulbactam group was defined as a prescription for cefoperazone-sulbactam only, whereas the sulbactam plus vitamin K1 group was given 10 mg of vitamin K (Shanghai No. 1 Biochemical & Pharmaceutical Co Ltd, Shanghai, China) prophylaxis subcutaneously before each dose of cefoperazone-sulbactam during antibiotics therapy.
proposed criteria for the use of low-dose vitamin k supplementation in patients using vitamin k antagonists: a literature review of a clinical controversy.
To evaluate patient characteristics, we collected baseline data of age, sex, concomitant medications, underlying diseases, types of infections, and cephalosporin therapy duration. Coagulation studies were performed before administration of cefoperazone-sulbactam and after the last dose of the study antibiotics. The coagulation index includes PT, aPTT, thrombin time (TT), international normalized ratio (INR), fibrinogen, and platelet count, which were measured by standard techniques. The treatment period was defined as the first day of antibiotics treatment to 7 days after the last date of the course of antibiotics therapy. The types of infections were identified by text codes and classified as respiratory infections, genitourinary system infections, gastroenteritis, intra-abdominal infections, bacteremia, and other infections
We defined the coagulation index (PT, aPTT, or TT) prolongation as an increase by 25% and a decreased platelet count as a reduction by 25% from baseline after antibiotic treatment.
Bleeding events were defined as both diagnosis of bleeding events during cefoperazone-sulbactam therapy and 7 days after discontinuation of cefoperazone-sulbactam therapy but not at admission. Bleeding events include gastrointestinal bleeding, urinary tract bleeding, bleeding gums, epistaxis, oral mucosal bleeding, subcutaneous hematoma stasis, and intracerebral hemorrhage. All patients were treated in the ward.
This experiment uses MATLAB software, version 2020a (MathWorks Inc, Natick, MA) to analyze data. Continuous variables are reported as mean (SD) and interquartile range unless stated otherwise, and discrete variables are expressed as numbers. The 2-sample independent t test method is used to test the difference of the population means, in which it is assumed that the sample variances are not necessarily equal. P < 0.01 was considered to indicate a statistically significant difference.
Results
During the study period, a total of 1952 patients were identified. After detailed review, 1725 patients were excluded because of the reasons summarized in Figure 1. A total of 227 eligible patients were finally included in the analysis. Of those, 132 and 95 patients receiving aspirin and cefoperazone-sulbactam were treated with and without the vitamin K1, respectively.
Figure 1Flow chart of the process of patient selection.
The baseline characteristics of the 227 eligible patients are described in Table I. No significant differences were found between the 2 groups in sex, age, comorbidities, type of infections, and concomitant medications (Table I).
According to the results in Table II, a comparison of the coagulation function of patients between the 2 groups found no significant difference in the PT, TT, aPTT, INR, fibrinogen, and platelets before cefoperazone-sulbactam treatment. No significant difference were found in PT, TT, INR, and fibrinogen before and after cefoperazone-sulbactam treatment in the cefoperazone/sulbactam plus vitamin K1 group. No significant difference was found in TT and fibrinogen before and after cefoperazone-sulbactam treatment in the cefoperazone-sulbactam group. In the cefoperazone-sulbactam group after cefoperazone-sulbactam treatment, the mean (SD) PT was 14.07 (3.07) seconds, aPTT was 35.15 (4.78) seconds, and INR was 1.49 (0.49), which were significantly higher than the PT of 11.55 (1.29) seconds, the aPTT of 31.37 (2.20) seconds, and the INR of 1.12 (0.35) before cefoperazone-sulbactam treatment (P < 0.001). The platelet counts of the 2 groups were 197.34 (71.82) × 109/L and 187.75 (72.66) × 109/L after cefoperazone-sulbactam treatment, respectively, which were significantly lower than the platelet counts of 231.77 (77.05) × 109/L and 232.08 (84.48) × 109/L before cefoperazone-sulbactam treatment (P < 0.001).
Table IIComparison of coagulation indexes of the 2 groups of patients before and after treatment with antibiotics.
According to the results in Table III, compared with that in the cefoperazone-sulbactam plus vitamin K1 group, there were greater proportions of coagulation disorders (prolongation of PT, aPTT, INR, and bleeding) after cefoperazone-sulbactam treatment in the cefoperazone-sulbactam group.
Table IIISummary of coagulation disorders in the full cohort after treatment with antibiotics.
To the best of our knowledge, this is the first retrospective, observational study evaluating the influence of cefoperazone-sulbactam with and without vitamin K1 on coagulation function in patients receiving long-term aspirin treatment. In this study, we found that the PT and aPTT were significantly prolonged, INR was significantly elevated, and coagulation disorders events (prolongation of PT and aPTT, increase in INR values, and bleeding) had relatively higher proportions among patients receiving long-term aspirin therapy after being treated with cefoperazone-sulbactam. We also found that prophylaxis with vitamin K1 normalized most of these abnormalities in blood coagulation parameters associated with cefoperazone-sulbactam in patients receiving long-term aspirin treatment. Of note, treatment with prophylaxis with vitamin K1 was linked to a decreased proportions of coagulation disorders induced by cefoperazone-sulbactam combination aspirin compared with no vitamin K1 intervention.
Cefoperazone, a semisynthetic third-generation cephalosporin, contains the N-methylthiotetrazole side chain at the 3 position of the cephalosporin nucleus. Although the potential mechanism of cefoperazone-associated coagulopathy is unclear,
proposed criteria for the use of low-dose vitamin k supplementation in patients using vitamin k antagonists: a literature review of a clinical controversy.
N-methylthiotetrazole inhibits vitamin K 2,3-epoxide reductase, a key player in the production of clotting factors. Cephalosporin antibiotics, such as cefoperazone, inhibit the growth of important intestinal bacteria that are a source of vitamin K. Because the human body obtains vitamin K from the 2 sources, vitamin K–epoxide reductase inactivation or lack of normal gut flora, they alone cause a vitamin K insufficiency. Vitamin K deficiency impairs the carboxylation and activation of vitamin K–dependent clotting factors II (prothrombin), VII (proconvertin), IX (antihemophilic factor B), and X (Stuart-Prower factor), which require vitamin K as a cofactor in its reduced form, causing functional deficiencies of these factors.
Therefore, cefoperazone can induce hypoprothrombinemia and further bleeding. According to the above pathologic mechanism, vitamin K supplementation can resolve both.
proposed criteria for the use of low-dose vitamin k supplementation in patients using vitamin k antagonists: a literature review of a clinical controversy.
Our previous study and earlier clinical studies suggest that coagulopathy-associated cefoperazone-sulbactam could be prevented by vitamin K supplementation. In addition, another possible hypothesis is that sulbactam may also exhibit effects on coagulopathy.
proposed criteria for the use of low-dose vitamin k supplementation in patients using vitamin k antagonists: a literature review of a clinical controversy.
We performed coagulation tests, including aPTT, PT, TT, INR, and fibrinogen, during treatment with cefoperazone. aPTT is used for assessing the contact factor (intrinsic) pathway of blood coagulation. Prolonged aPTT is caused by deficiencies of factors VIII, IX, and XI and contact factor deficiencies, such as factor XII, prekallikrein, and also present in certain diseases, including vitamin K deficiency, disseminated intravascular coagulation, and liver disease. PT reflects the extrinsic and common pathways of blood coagulation. Prolonged PT is caused by deficiencies of factors II, V, VII, and X and low fibrinogen concentrations. PT can vary with different thromboplastin reagent preparations even when using the same plasma. Therefore, one attempt to solve this problem has been the introduction of the INR as applied to the PT.
Vitamin K- reversible hypoprothrombinemia in rats, I: sex differences in the development of hypoprothrombinemia and the effects of beta-lactam antibiotics.
TT reflects the conversion of fibrinogen to fibrin after the addition of a thrombin reagent. TT is very sensitive to the presence of heparin and direct thrombin inhibitors in the sample. Prolonged TT indicates hyperfibrinolysis.
Fibrinogen, a soluble clotting protein synthesized by hepatocytes, is converted by thrombin into fibrin and then cross linked by factor XIII to form blood clot in blood clotting but is also an important secretory glycoprotein in inflammatory processes that control bacterial infection.
Normal concentrations of fibrinogen, which is a multifunctional clotting protein, are usually 1.5 to 4.0 g/L. Activation of fibrinogen by thrombin leads to the formation of an effective clot. As an acute-phase protein in physiologic and pathologic response to infection, plasma fibrinogen could increase in inflammatory states, such as trauma and pregnancy, that increase thrombotic risk.
A new study reveals that the major metabolite of aspirin (salicylic acid) acts at the level of transcription to downregulate the production of fibrinogen in staphylococcal disease.
We did not observe that the level of fibrinogen decreased after the infection was controlled in our patient. We speculated that fibrinogen in 2 phases of the acute-phase response to microbial infection is at a high level and has a long t½ of 4 to 6 days. The effect of aspirin on fibrinogen had always existed and did not change before and after infection in our patient. The specific mechanism needs further investigation.
This study indicated that our patient had prolongation of aTT and PT and increase of INR after receiving cefoperazone-sulbactam treatment, but no significant difference was found in fibrinogen and TT before and after cefoperazone -sulbactam treatment. This result is in line with the popular opinion (hypothesis) that cefoperazone-sulbactam interferes with vitamin K metabolism and synthesis, further disrupts synthesis of multiple vitamin K–-dependent coagulation factors, and does not affect the synthesis and secretion of fibrinogen and other coagulation factors.
Aspirin that prevents platelet aggregation decreases the incidence of adverse cardiac events in patients who are at high risk for cardiovascular occlusion. With the advent of an aging society, aspirin is widely used in China. However, administration of long-term aspirin increases the risk of hemorrhagic events.
The reason for aspirin-associated bleeding is that long-term use of aspirin inhibits cyclo-oxygenase 1 in platelets and leads to impaired platelet aggregation and drastic reduction in thromboxane A2 production. Aspirin is often coadministered with antibiotics during the treatment of infections. The use of antibiotics can have an additive effect on increasing the risk of hemorrhage of aspirin. In addition to its antiplatelet effect, aspirin has been reported to have fibrinolytic and hypoprothrombinemic effects and can acetylate fibrinogen and enhance fibrinolysis. Patients taking aspirin had a lower resting fibrinopeptide level.
Salicylic acid, a metabolite of aspirin, can inhibit quinone reductases and produce an elevation of the ratio of vitamin K epoxide to vitamin K in the liver, thus antagonizing the vitamin K–dependent biosynthesis of clotting factors in the rat. The inhibitory effect of salicylate was prevented by pretreatment of rat liver donors with supplemental vitamin K injected 24 hours before sacrifice.
There are intimate connections among the events of platelet activation, aggregation, secretion, and blood coagulation. Recent research developments indicate that activated platelets participate in exposing receptors for the assembly of enzyme-cofactor-substrate complexes at all stages of the blood coagulation cascade. Platelets can control thrombin generation, support fibrin formation, and regulate fibrin clot retraction.
Because aspirin affects the activation of platelets, it can affect blood coagulation.
On the other hand, coadministration of antibiotics can modulate the metabolism and pharmacokinetic properties of aspirin via suppression of metabolic activity of gut microbiota. Pharmacodynamic investigations have found that ampicillin treatment significantly prolongs the bleeding time in aspirin-dosed rats.
These findings suggest that the alteration of gut microbiota after antibiotic treatment could potentiate the therapeutic potency of aspirin. Our findings suggest that the bleeding rate among patients treated with aspirin and cefoperazone-sulbactam is significantly increased compared with that reported in patients receiving aspirin alone.
Cumulative effects of combination of cefoperazone-sulbactam and aspirin on abnormal coagulation function increase the risk for coagulation disorder events. This result supports the above theory.
One of strengths of our study was that the platelet count statistically significantly decreased in patients after cefoperazone-sulbactam treatment both with and without vitamin K1. To explain this phenomenon, 3 potential mechanisms should be considered. First, platelets are key mediators of hemostasis. In addition, platelets play a key role in preventing infection. Consequently, platelets arrive as first responders at sites of injury and/or inflammation. On encountering a microbe, platelets bind, contain, and kill bacteria directly. These processes cause the platelet to be irreversibly consumed. In general, infection can form autoantibodies against platelet surface proteins, which mediated destruction of platelets. On the other hand, platelets are activated in response to inflammation during infection. The activated platelets can bind to leukocytes or to endothelial cells, and platelets subsequently are removed from circulation. The decrease in platelet count is a frequent finding in infected patients.
The patients in our study all went through the process of infection, so a decrease in platelet count after infection occurred. Even after treatment of cefoperazone-sulbactam, it did not recover within a certain period. Second, cefoperazone-sulbactam can induce thrombocytopenia in 3 to 12 days.
There are 2 reasons for the decrease in platelet count caused by cefoperazone-sulbactam. The direct toxic damage of cefoperazone-sulbactam to the bone marrow causes a decrease in platelet production. On the other hand, cefoperazone-sulbactam can combine with the macromolecular proteins in the plasma to form a complete antigen. The whole antigen stimulates the production of antibody IgG in the body. This antibody can destroy the platelets bound to the cefoperazone-sulbactam but not normal platelets, resulting in the decrease in platelet count. Third, a few studies have reported on the association between decrease in platelet count in individuals taking aspirin medication.
An alternative explanation for the decrease in platelet count in our patients was that the treatment of cefoperazone-sulbactam potentiated the pharmacologic potency of aspirin via the modification of gut microbiota.
Coadministration of cefoperazone-sulbactam and aspirin in our patients reduced gut microbial aspirin-metabolizing activity, and systemic exposure to aspirin and its primary metabolite was significantly increased. Thus, increased concentration of aspirin could be attributed to an enhanced rate of platelet apoptosis.
Because most of our patients were middle-aged and elderly, we selected patients <80 years of age. For various baseline diseases, we eliminated patients with severe liver and kidney diseases. Concomitant treatment might affect the development of coagulation function in the patients included in the study; therefore, we excluded those receiving any anticoagulants or antiplatelet agents. The drugs the patients received in the study did not interact with cefoperazone-sulbactam or aspirin on coagulation function. Hence, baseline diseases and concomitant medicine had no major impact on the clinical presentation of the interaction in this study.
There are several limitations to this study. First, it was a small retrospective case–control study; thus, effects of selection bias may be present. Second, we analyzed all patients as a group but not individually. Other different confounding variables could not be controlled for in the analysis. If we had analyzed the coagulation factors of individuals in the study, a confounding bias might have been avoided. Third, we also may not fully capture full dose and course of cefoperazone-sulbactam and vitamin K1 and not establish an association between the drugs dose and the coagulation function. We believe we have done our best to control for the potential differences in covariates among the study groups.
Conclusions
In this study, we found that the combination of cefoperazone and aspirin can produce cumulative effects on abnormal coagulation function and prophylaxis with vitamin K1 normalizing most of these abnormalities in blood coagulation parameters associated with cefoperazone-sulbactam in patients receiving long-term aspirin therapy. Therefore, close monitoring of coagulation function in patients treated concurrently with cefoperazone-sulbactam and aspirin plus prophylactic use of vitamin K1 is recommended.
Acknowledgments
We declared that materials described in the manuscript, including all relevant raw data, will be freely available to any scientist wishing to use them for non-commercial purposes, without breaching participant confidentiality.
Disclosure
The authors have indicated that they have no conflicts of interest regarding the content of this article.
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Zheng SL
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Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis.
proposed criteria for the use of low-dose vitamin k supplementation in patients using vitamin k antagonists: a literature review of a clinical controversy.
Vitamin K- reversible hypoprothrombinemia in rats, I: sex differences in the development of hypoprothrombinemia and the effects of beta-lactam antibiotics.
Data are presented as number (percentage) of patients unless otherwise indicated.
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