Prothrombin Time-international Normalized Ratio Research Articles

Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K-Dependent Coagulation Factors Deficiency.

Vitamin K-dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K-dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.

Impact of Antibacterials on the Quality of Anticoagulation Control in Patients Initiating Warfarin Therapy.

Warfarin interacts with antibacterials to prolong the prothrombin time international normalized ratio (PT-INR) and increase the risk of bleeding. Patients initiating warfarin therapy often undergo precise dosage adjustments; however, the clinical implications of these interactions with antibacterials remain unclear. This study aimed to clarify the effect of antibacterials on PT-INR during the warfarin induction phase. This was a retrospective, observational study. Patients who were newly treated with warfarin after cardiovascular surgery were included. The primary endpoint was the comparison of the maximum PT-INR and time in therapeutic range (TTR) after warfarin initiation between the antibacterial-treated (ABx) and non-treated (non-ABx) groups. The maximum PT-INR was significantly higher in the ABx group (which included β-lactams, glycopeptides, quinolones, tetracyclines, and aminoglycosides) than in the non-ABx group (median [interquartile range] 2.37 [2.03-2.71] vs. 2.08 [1.93-2.33]; P = 0.005); however, the TTR did not differ significantly (65% [44-76] vs. 71% [43-85]; P = 0.150). The odds ratio for maximum PT-INR >2.6 with antimicrobial therapy was 2.51 (95% confidence interval 1.21-5.21). Antibacterial therapy was a risk factor for a maximum PT-INR >2.6. However, there was no association with the TTR, which is a marker of good outcomes. This was due to the strict warfarin dosing regimen according to the algorithm, which immediately and appropriately adjusted for PT-INR overexpansion. Antibacterials have been suggested to increase PT-INR during the induction phase of warfarin. However, with strict dose adjustments, the clinical impact on the PT-INR and TTR is likely limited.

Neutrophil Gelatinase-Associated Lipocalin (NGAL) as a Predictor for Sepsis Mortality in Children Admitted to Pediatric Intensive Care Unit (PICU): A Comparison With Prothrombin Time/International Normalized Ratio (PT/INR) and Urea/Creatinine Ratio

Neutrophil Gelatinase-Associated Lipocalin (NGAL) as a Predictor for Sepsis Mortality in Children Admitted to Pediatric Intensive Care Unit (PICU): A Comparison With Prothrombin Time/International Normalized Ratio (PT/INR) and Urea/Creatinine Ratio

Time-Dependent Association of Preinjury Anticoagulation on Traumatic Brain Injury-Induced Coagulopathy: A Retrospective, Multicenter Cohort Study

BACKGROUND AND OBJECTIVES: The impact of preinjury anticoagulation on coagulation parameters over time after traumatic brain injury (TBI) has remained unclear. Based on the hypothesis that preinjury anticoagulation significantly influences the progression and persistence of TBI-induced coagulopathy, we retrospectively examined the association of preinjury anticoagulation with various coagulation parameters during the first 24 hours postinjury in 5 periods. METHODS: Data from the Japanese registry of patients with TBI aged ≥65 years admitted between 2019 and 2021 were used. Time since injury was classified into 5 categories through a graphical analysis of coagulation parameters. We examined the association between preinjury anticoagulation and the platelet count, prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), D-dimer level, and fibrinogen level during each period by analysis of covariance using 10 clinical factors as confounding factors. RESULTS: Data from 545 patients and 795 blood tests were analyzed. The patients' mean age was 78.9 years, and 87 (16%) received anticoagulation therapy. The preinjury anticoagulation group had significantly greater Rotterdam computed tomography scores and poorer outcomes at discharge than the control group, with significantly lower D-dimer levels and higher fibrinogen levels. Analysis of covariance revealed significant associations between the D-dimer level and preinjury anticoagulation within 2 to 24 hours postinjury, APTT and preinjury anticoagulation within 1 to 24 hours, and PT-INR and preinjury anticoagulation throughout all periods up to 24 hours postinjury. CONCLUSION: Despite more severe TBI signs and poorer outcomes, the preinjury anticoagulation group had significantly lower D-dimer levels, especially within 2 to 24 hours postinjury. Thus, D-dimer levels during this period may not reliably represent TBI severity in patients receiving anticoagulation therapy before injury. Preinjury anticoagulation was also associated with an elevated PT-INR and prolonged APTT from early to 24 hours postinjury, highlighting the importance of aggressive anticoagulant reversal early after injury.

Impact of antiplatelet and anticoagulant drugs on postoperative bleeding in reverse total shoulder arthroplasty

BackgroundThe decision to withdraw or continue antiplatelet and anticoagulant drugs would be balanced on the bleeding risk and the cardiovascular risk. The purpose of this study was to investigate perioperative bleeding in reverse shoulder arthroplasty (RSA) to determine the impact of oral antiplatelet and anticoagulant medications in the absence of drug withdrawal. The hypothesis was that the continuation of antiplatelet and anticoagulant drugs would increase postoperative bleeding but to a limited extent. MethodsDuring the study period, RSA cases were prospectively included and retrospectively reviewed. Cases of revision for arthroplasty, proximal fracture, and cemented stem fixation were excluded. Cases with dual therapy of aspirin and clopidogrel and cases with heparin bridges were also excluded. Age, gender, height, weight, American Society of Anesthesiologists physical status anesthesia risk (ASA), smoking status, preoperative diagnosis, preoperative blood sampling data within one month of surgery (estimated glomerular filtration rate (eGFR), Prothrombin Time-International Normalized Ratio (PT-INR), and activated partial thromboplastin time (APTT)), surgical time, stem length (standard or short stem), and use of tranexamic acid were identified. The presence of diabetes mellitus, rheumatoid arthritis, and hypertension were confirmed as comorbidities. Hemoglobin (Hb) and hematocrit (Ht) values were recorded preoperatively and on the third postoperative day, and estimated blood loss was calculated by Gross formula using the change in preoperative Ht and postoperative day 3 Ht values. Multiple regression models were used to determine predictors of the estimated blood loss. P values less than .05 were considered statistically significant. Results315 RSA cases were analyzed (172 females, a mean age of 77.2 years). The estimated blood loss was 819 ml. The regression equation was statistically significant (P < .0001, R2=0.21), and aspirin, direct oral anticoagulants (DOAC), tranexamic acid, height, and surgery time were statistically significant explanatory variables, showing the predicted changes in bleeding volume for each drug were +283 ml for aspirin, +180 ml for DOAC, and -237 ml for tranexamic acid, respectively. Warfarin and cilostazol were not employed due to P values and Akaike's Information Criterion. Two blood transfusions (without antiplatelet or anticoagulant medications) were administered. One patient on aspirin had a cardiovascular event. ConclusionsThe current study showed that the use of aspirin and DOAC were significant predictors of increased perioperative blood loss, but the amount of increase was in the acceptable range, suggesting that continued antiplatelet and anticoagulant were relatively safe in primary RSA. Administration of tranexamic acid was shown to reduce bleeding significantly.

Association between coagulation indicators and menorrhagia among women in Kenya.

Despite the significant burden of menorrhagia (bleeding > 80 mL every menstrual cycle) among women in Western Kenya, it remains unknown whether coagulation disorders are an important underlying cause of this condition in the region. This study assessed differences in coagulation profiles, associations between menorrhagia and coagulation profiles and compared morphological features of platelets among women attending Bungoma County Referral Hospital in Kenya. A comparative cross-sectional study of women with and without menorrhagia, aged 18-45 years, was performed between December 2022 and September 2023. Sociodemographic factors, prothrombin time (PT), activated partial thromboplastin time, thrombin time, fibrinogen, international normalised ratio (INR), and platelet count were compared between groups, and associations with menorrhagia were assessed. Prothrombin time and INR levels above normal references were deemed increased. A total of 428 (214 per group) women were included. Family history of bleeding disorders (p < 0.0001) was more frequent in menorrhagic than in non-menorrhagic women. Additionally, menorrhagic women had high PT (p < 0.0001) and high INR (p < 0.0001) levels. Menorrhagia was significantly associated with an increased PT (odds ratio = 2.129, 95% confidence interval = 1.658-2.734; p < 0.0001) and increased INR (odds ratio = 7.479, 95% confidence interval = 3.094-18.080; p < 0.0001). In this population in Western Kenya, menorrhagia was associated with a family history of bleeding disorders, increased PT, and increased INR. Routine assessment of the coagulation profile and family history of bleeding disorders is crucial for diagnosing and managing menorrhagia. Our findings suggest that menorrhagic and non-menorrhagic women differ in terms of PT and INR, which may be predictive of menorrhagia.

Impact of Dietary Vitamin K Intake on Anticoagulation Therapy in Patients With Left Ventricular Assist Device During the 2018 Osaka Earthquake.

Background: The 2018 Osaka earthquake caused severe damage to the National Cerebral and Cardiovascular Center, and the interruption to the delivery of hospital food in particular had a significant effect on patients with left ventricular assist devices (LVAD). Methods and Results: We retrospectively assessed 10 patients who had been provided with emergency rations on the day of earthquake and the next day for breakfast. Catered foods were provided thereafter. Vitamin K content was largely reduced due to emergency rations; the prothrombin time-international normalized ratio (PT-INR) on day 2 was significantly higher than on day 1. Conclusions: Close monitoring of PT-INR and assessing vitamin K content may be important for preventing complications in patients with a LVAD during a disaster.

NEED OF EXTERNAL QUALITY ASSESSMENT SCHEME – AN EXPERIENCE IN CENTRAL LABORATORY AT RNTMC, UDAIPUR

Objectives: The objectives of the study are to periodically assess the quality of the external quality assessment scheme (EQAS) with the aim of enhancing laboratory performances. Methods: An observational study was done at our central laboratory at RNTMC, Udaipur, after approval from the institutional review board. Our laboratory receives quarterly blood samples and already prepared slides from AIIMS, Delhi, for complete blood count (CBC). In addition, lyophilized blood samples for fibrinogen, prothrombin time/international normalized ratio (PT/INR), and activated partial thromboplastin time (APTT) analysis are received quarterly from CMC, Vellore, through courier package. As for cytopathology, the third package includes already prepared 10 slides of 2 cycles for cytopathology analysis along with a brief clinical history. Results: CBC, peripheral blood film examination findings, and reticulocyte count results were consistently acceptable, except in August 2021, December 2022, and March 2023 when some parameters of CBC were deemed unacceptable. Results for PT/INR, APTT, and fibrinogen were within consensus at all-time except in March 2022, when they were out within consensus and deemed unacceptable. Similarly, results for cytopathology evaluation were in concordance with the results of the provider except for a few occasions were deviations were seen for some diagnoses due to interpretation error. Conclusion: Engaging in EQAS has facilitated the enhancement of test result accuracy, thereby improving the overall quality of laboratory practices and minimizing erroneous outcomes.

The historical origins of modern international normalized ratio targets

Prothrombin time (PT) and its derivative international normalized ratio (INR) are frequently ordered to assess the coagulation system. Plasma transfusion to treat incidentally abnormal PT/INR is a common practice with low biological plausibility and without credible evidence, yet INR targets appear in major clinical guidelines and account for the majority of plasma use at many institutions. In this article, we review the historical origins of INR targets. We recount historical milestones in the development of the PT, discovery of vitamin K antagonists (VKAs), motivation for INR standardization, and justification for INR targets in patients receiving VKA therapy. Next, we summarize evidence for INR testing to assess bleeding risk in patients not on VKA therapy and plasma transfusion for treating mildly abnormal INR to prevent bleeding in these patients. We conclude with a discussion of the parallels in misunderstanding of historic PT and present-day INR testing with lessons from the past that might help rationalize plasma transfusion in the future.

Pre-operative Serum Albumin Predicts Native Liver Survival in Biliary Atresia.

To predict native liver survival (NLS) after Kasai portoenterostomy (KP) for biliary atresia (BA) using pre-operative clinical data. Pre-operative data were collected from 29 patients with BA who underwent KP at our department between 1989 and 2017 and were analysed including serum albumin, bilirubin, prothrombin time-international normalised ratio, body height, body weight, age at KP, paediatric end-stage liver disease score calculated using the pre-operative data and the period of NLS. The 10-year NLS rate of all patients was 51%. A multivariate analysis revealed that among all factors, the pre-KP serum albumin level was the only independent predictor of NLS ( P = 0.04, hazard ratio = 0.269, 95% confidence interval = 0.077-0.934). The area under the receiver operating characteristic curve for NLS, determined using pre-KP serum albumin was 0.760 and 3.75 mg/dl was selected as the cut-off value. There was a significant difference in NLS between patients with high (≥3.8 mg/dl) and low (≤3.7 mg/dl) pre-KP serum albumin (90.0% vs. 31.5%, P < 0.01). Decreased pre-KP serum albumin may reflect not only functional impairment of the liver, but also the inflammatory process, which is hypothesized to occur during its advancement. The pre-KP serum albumin level may be a good prognostic factor for NLS in post-KP BA patients.

International Normalized Ratio Predicts Recurrence and Bleeding in Patients With Acute Venous Thromboembolism Who Undergo Direct Oral Anticoagulants.

Prothrombin time/international normalized ratio (PT/INR) is related to both antithrombotic effect and risk of bleeding. Its role in the prediction of venous thromboembolism (VTE) recurrence and bleeding for patients with acute VTE who undergo direct oral anticoagulants (DOACs) treatment is unclear, despite previous studies revealed some association between them. The predictive efficiency of INR for VTE recurrence and bleeding were analyzed in a retrospective cohort with VTE patients who underwent DOACs treatment. Then its predictive efficiency for VTE recurrence and bleeding were validated in a prospective cohort with the acquired cutoffs range, and compared with anti-Xa level, DASH and VTE-BLEED scores. In the retrospective cohort (n = 1083), the sensitivity and specificity of INR for the prediction of VTE recurrence were 79.4% and 92.8%, respectively. The area under the curve (AUC) was 0.881 (0.803-0.960)(P = .025). The cutoff value of INR was 0.9. The sensitivity and specificity of INR for the prediction of bleeding were 85.7% and 77.9%, respectively. The AUC was 0.876 (0.786-0.967)(P < .001). The cutoff value of INR was 2.1. In the prospective cohort (n = 202), the calibration showed that there were 4 (50%) patients with VTE recurrence, 156 (97.5%) patients with non-recurrence and bleeding (non-R&B), and 20 (58.8%) patients with bleeding in the low (INR < 0.9)(n = 8), intermediate (0.9 ≤ INR ≤ 2.1)(n = 160), and high (INR > 2.1)(n = 34) groups, respectively. The baseline PT/INR value at the initiation of DOACs treatment is an independent predictor for VTE recurrence and bleeding in patients with acute VTE who undergo DOACs treatment.

Extremely elevated international normalized ratio in a patient using dabigatran etexilate: a case report

Background: We present the case of a patient who was administered dabigatran and showed an extremely elevated prothrombin time-international normalized ratio (PT-INR).Case report: A 79-year-old man was referred due to PT-INR 12.6. The patient was taking 110 mg of dabigatran twice daily in capsule form. On admission, blood urea nitrogen level was 23 mg/dL, creatinine was 1.51 mg/dL, and the estimated glomerular filtration rate was 44.8 mL/min/1.73 m2. Coagulation tests revealed PT 96.8 seconds, PT-INR 12.46, and activated partial thromboplastin time 125.5 seconds. Dabigatran was discontinued, PT-INR on the day after admission was 8.96. PT-INR recovered to 1.61 on the fourth day without any treatment.Conclusion: The PT-INR was not directly correlated with dabigatran activity. Regular monitoring of coagulation was not necessary in all patients taking dabigatran. However, it may be useful to regularly perform coagulation tests in patients with renal impairment or in those at a high risk of bleeding.

Kinetic-pharmacodynamic model of warfarin for prothrombin time-international normalized ratio in Japanese patients.

Genotype-guided dosing algorithms can explain about half of the interindividual variability in prothrombin time-international normalized ratio (PT-INR) under warfarin treatment. This study aimed to refine a published kinetic-pharmacodynamic model and guide warfarin dosage for an optimal PT-INR based on renal function. Using a retrospective cohort of adult patients (>20 years) who were administered warfarin and underwent PT-INR measurements, we refined the kinetic-pharmacodynamic model with age and the genotypes of cytochrome P450 2C9 and vitamin K epoxide reductase complex subunit 1 using the PRIOR subroutine in the nonlinear-mixed-effect modelling programme. We searched the significant covariates for parameters, such as the dose rate for 50% inhibition of coagulation (EDR50 ), using a stepwise forward and backward method. Monte Carlo simulation determined a required daily dose of warfarin with a target range of PT-INR (2.0-3.0 or 1.6-2.6) based on the significant covariates. A total of 350 patients with 2762 PT-INR measurements were enrolled (estimated glomerular filtration rate [eGFR]: 47.5 [range: 2.6-199.0] mL/min/1.73 m2 ). The final kinetic-pharmacodynamic model showed that the EDR50 changed power functionally with body surface area, serum albumin level and eGFR. Monte Carlo simulation revealed that a lower daily dose of warfarin was required to attain the target PT-INR range as eGFR decreased. Model-informed precision dosing of warfarin is a valuable approach for estimating its dosage in patients with renal impairment.

The mortality of hospitalized patients with COVID-19 and non-cirrhotic chronic liver disease: a retrospective multi-center study

Background Patients with chronic liver disease (CLD) have a higher risk of mortality when infected with severe acute respiratory syndrome coronavirus 2. Although the fibrosis-4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and albumin-bilirubin grade (ALBI) score can predict mortality in CLD, their correlation with the clinical outcomes of CLD patients with coronavirus disease 2019 (COVID-19) is unclear. This study aimed to investigate the association between the liver severity and the mortality in hospitalized patients with non-cirrhotic CLD and COVID-19. Methods This retrospective study analyzed 231 patients with non-cirrhotic CLD and COVID-19. Clinical characteristics, laboratory data, including liver status indices, and clinical outcomes were assessed to determine the correlation between liver status indices and the mortality among patients with non-cirrhotic CLD and COVID-19. Results Non-survivors had higher levels of prothrombin time-international normalized ratio (PT-INR), alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein (hs-CRP) and lower albumin levels. Multivariable analysis showed that ALBI grade 3 (odds ratio (OR): 22.80, 95% confidence interval (CI) [1.70–305.38], p = 0.018), FIB-4 index ≥ 3.25 (OR: 10.62, 95% CI [1.12–100.31], p = 0.039), PT-INR (OR: 19.81, 95% CI [1.31–299.49], p = 0.031), hs-CRP (OR: 1.02, 95% CI [1.01–1.02], p = 0.001), albumin level (OR: 0.08, 95% CI [0.02–0.39], p = 0.002), and use of vasopressors (OR: 4.98, 95% CI [1.27–19.46], p = 0.021) were associated with the mortality. Conclusion The ALBI grade 3 and FIB-4 index ≥ 3.25, higher PT-INR, hsCRP levels and lower albumin levels could be associated with mortality in non-cirrhotic CLD patients with COVID-19. Clinicians could assess the ALBI grade, FIB-4 index, PT-INR, hs-CRP, and albumin levels of patients with non-cirrhotic CLD upon admission.

Role of electrode configuration and morphology in printed prothrombin time sensors

Patients on long-term anticoagulation therapy require frequent testing of prothrombin time/international normalized ratio (PT/INR) to ensure therapeutic efficacy. Point-of-care (POC) PT tests for at-home monitoring eliminate the burden of visiting the clinic, but realizing a cost-effective and robust at-home POC test for PT has remained elusive. Recent demonstrations of printed PT sensors show promise for addressing the cost concerns; however, the printed sensors have lacked quality control to ensure reliability between tests. In this work, on-chip redundancy is introduced with fully printed impedimetric PT sensors by incorporating simultaneous testing with a single fingerstick volume of blood (8 µL). The influence of electrode dimensions and composition were studied, revealing an optimal electrode spacing of 200 µm and an unexpected dependence on the morphology of the electrodes. Three distinct silver morphologies were studied: aerosol jet printed silver nanoparticles (AgNPs), aerosol jet printed silver nanowires (AgNWs), and evaporated silver (Ag). In general, AgNPs exhibited the best PT sensor performance, due to relatively low conductance and high porosity. Overall, the printed impedimetric PT sensor functionalization was improved by incorporating simultaneous testing and, when combined with a handheld control device, shows promise for leading to a system that overcomes the challenges of commercial PT/INR coagulometers.

Effect of fibrinogen concentrate on the initial fibrinogen level in trauma and postpartum hemorrhage.

Massive hemorrhage is a serious event that threatens the lives of patients. Fibrinogen concentrate (FC) can control bleeding without causing viral complications and without volume loading, which can happen in transfusion-associated circulatory overload and transfusion-associated acute lung injury. FC application is easy and does not require dissolution or extra devices. It is a cost-effective agent when considering the blood and products used in large quantities. A total of 67 postpartum hemorrhage (PPH) and trauma patients' medical records, who had ASA I-III classification (The American Society of Anesthesiologists classification of physical status), were obtained. Patients were divided into two groups (fibrinogen level ≤ 100 mg/dl and ≥ 101 mg/dl). The following information was obtained from patient files: demographic parameters, history of operations, and laboratory findings (i.e., complete blood counts, coagulation tests, and fibrinogen levels). Also, the duration of intensive care unit stays and mechanical ventilation application days, the administration of fresh frozen plasma (FFP), erythrocytes, platelets, and FC numbers, and tranexamic acid infusion were recorded. There was no mortality in PPH patients in either group (fibrinogen level ≤ 100 mg/dl and ≥ 101 mg/dl). The mortality rate in trauma patients was significantly higher in the group with fibrinogen levels ≤ 100. A total of 170 g of FC were given to PPH patients and 92 g to trauma patients. There were statistically significant differences between the preoperative PT (prothrombin time), postoperative APTT (activated partial thromboplastin time), postoperative PT, and postoperative INR (international normalized ratio) levels of the patients in the group with fibrinogen levels ≤ 100. Mortality rates were also significantly higher, and hospital stays significantly longer in trauma patients in the group with fibrinogen levels ≤ 100. Therapy may be considered during massive bleeding and transfusion, as it can help to increase fibrinogen levels quickly and efficiently. Compared with FFP, fibrinogen concentrate may have some advantages in reducing the risk of fluid overload. FFP contains a range of clotting factors, including fibrinogen. It also contains other proteins and fluids that can lead to fluid overload, especially when given in large volumes during massive transfusions.

The prothrombin time/international normalized ratio predicts prognosis in cardiogenic shock.

The study investigates the prognostic impact of the prothrombin time/international normalized ratio (PT/INR) in patients with cardiogenic shock. Despite ongoing improvements regarding the treatment of cardiogenic shock patients, intensive care unit (ICU)-related mortality in cardiogenic shock patients remains unacceptably high. Limited data regarding the prognostic value of the PT/INR during the course of cardiogenic shock treatment is available. All consecutive patients with cardiogenic shock from 2019 to 2021 were included at one institution. Laboratory values were collected from the day of disease onset (day 1) and days 2, 3, 4 and 8. The prognostic impact of the PT/INR was tested for 30-day all-cause mortality, as well as the prognostic role of PT/INR changes during course of ICU hospitalization. Statistical analyses included univariable t -test, Spearman's correlation, Kaplan-Meier analyses, C-Statistics and Cox proportional regression analyses. Two hundred twenty-four cardiogenic shock patients were included with a rate of all-cause mortality at 30 days of 52%. The median PT/INR on day 1 was 1.17. The PT/INR on day 1 was able to discriminate 30-day all-cause mortality in cardiogenic shock patients [area under the curve 0.618; 95% confidence interval (CI), 0.544-0.692; P = 0.002). Patients with PT/INR > 1.17 were associated with an increased risk of 30-day mortality [62% vs. 44%; hazard ratio (HR) = 1.692; 95% CI, 1.174-2.438; P = 0.005], which was still evident after multivariable adjustment (HR = 1.551; 95% CI, 1.043-2.305; P = 0.030). Furthermore, especially patients with an increment of the PT/INR by ≥10% from day 1 to day 2 were associated with an increased risk of 30-day all-cause mortality (64% vs. 42%; log-rank P = 0.014; HR = 1.833; 95% CI, 1.106-3.038; P = 0.019). Baseline PT/INR and an increase of the PT/INR during the course of ICU treatment were associated with the risk of 30-day all-cause mortality in cardiogenic shock patients.

Effect of fat emulsion administration on blood coagulation in terminal lung cancer patients.

Patients with cancer, especially those with lung cancer, are at high risk of developing thrombosis. Intralipos® infusion 20% is contraindicated for thrombosis, and there is no consensus on whether it can be safely used in cases of advanced cancer. We conducted a retrospective observational study to elucidate the impact of fat emulsion administration on blood coagulation in patients with terminal lung cancer. The subjects were patients with terminal lung cancer in the Department of Surgery and Palliative Medicine, Fujita Health University Nanakuri Memorial Hospital between January 2016 and December 2019. We compared changes in their blood coagulation profile before hospitalization and one month later. There were a total of 213 patients with lung cancer-139 who were administered fat emulsion and 74 who were not-with no significant differences in baseline characteristics. In the fat emulsion administration group (n=27), the prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), respectively, were 1.17±0.26 (mean±standard deviation) and 30.5±5.0s at hospitalization and 1.16±0.12 and 31.2±4.2s one month later with no significant differences. In the non-administration group (n=6), the PT-INR and APTT, respectively, were 1.44±0.43 and 30.6±5.2s before hospitalization and 1.28±0.18 and 33.0±7.5s one month later with no significant differences. We did not identify any changes in PT-INR and APTT after fat emulsion administration in patients with terminal lung cancer. There were also no new cases of thrombosis, suggesting that fat emulsions were administered safely in patients with terminal lung cancer.

Effects of changing the timing of warfarin administration in combination with fluconazole on prolongation of the PT-INR: a case report

BackgroundFluconazole (FLCZ) inhibits cytochrome P450 (CYP) 2C9, 2C19, and 3A4 and has a drug-drug interaction that potentiates the effects of warfarin and prolong the prothrombin time-international normalized ratio (PT-INR). Although a drug-drug interaction have been reported between FLCZ and warfarin, the effects of the timing of their administration on this interaction have not yet been investigated.Case presentationA female patient in her 30s with Marfan syndrome had undergone the Bentall procedure with a mechanical valve and total arch replacement for acute aortic dissection Stanford A type and rupture of the ascending aorta. Warfarin was administered to prevent thromboembolism. She was hospitalized 1 year ago for graft infection caused by Candida albicans, and treatment with FLCZ was initiated. She received FLCZ 200 mg once a day in the morning and warfarin 1.75 mg once a day in the evening, and the PT-INR remained stable at approximately 2.0 and within the therapeutic range. However, 42 days after changing the timing of administration of warfarin from evening to morning, the PT-INR was prolonged by approximately 3-fold to 6.25. The PT-INR then decreased to the previous level by changing the timing of administration of warfarin from morning to evening.ConclusionsThe timing of administration of FLCZ and warfarin may affect the magnitude of drug-drug interaction.

Time-to-event modeling for achieving a stable warfarin dose using genetic and non-genetic covariates.

Time-to-event modeling is gaining importance in drug dosage determination, particularly using pharmacometrics approaches. To evaluate the various time-to-event models for estimating the time to achieve a stable warfarin dose in the Bahraini population. A cross-sectional study evaluating the non-genetic and genetic covariates (single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1 and CYP4F2 genotypes) was conducted in patients receiving warfarin for at least 6 months. Time to achieving a stable dose of warfarin was defined as the duration (in days) from the day of initiating warfarin until 2 consecutive prothrombin time-international normalized ratio (PT-INR) values were observed in the therapeutic range with a gap of at least 7 days. Exponential, Gompertz, log-logistics, and Weibull models were tested, and the model with the lowest objective function value (OFV) was chosen. The covariate selection was carried out using the Wald test and OFV. A hazard ratio (HR) with a 95% confidence interval (95% CI) was estimated. A total of 218 participants were included in the study. The Weibull model was observed to have the lowest OFV (1989.82). The expected time to reach a stable dose in the population was 21.35 days. The CYP2C9 genotypes were identified as the only significant covariate. The HR (95% CI) for achieving a stable warfarin dose within 6 months of initiation for individuals with CYP2C9 *1/*2 was 0.2 (0.09, 0.3), 0.2 (0.1, 0.5) for CYP2C9 *1/*3, 0.14 (0.04, 0.6) for CYP2C9 *2/*2, 0.2 (0.03, 0.9) for CYP2C9 *2/*3, and 0.8 (0.45, 0.9) for those with the C/T genotype for CYP4F2. We estimated the population time-to-event parameters for achieving a stable warfarin dose in our population and observed CYP2C9 genotypes to be the main predictor covariate followed by CYP4F2. The influence of these SNPs needs to be validated in a prospective study and an algorithm to predict a stable warfarin dose and the time to achieve it needs to be developed.