International Normalized Ratio Values Research Articles

Оценка системы гемостаза кроликов после прижизненного экспериментального моделирования забрюшинной гематомы

The purpose of research is to study the dynamics of the hemostasis system in rabbits after intravital experimental modeling of retroperitoneal hematoma. The object of the study was 50 male rabbits of the Gray Giant breed, from which experimental and control groups of 25 individuals each were formed. Animals of the experimental group under non-inhalation anesthesia underwent intravital modeling of a retroperitoneal hematoma using a method we developed, including taking blood from the ear artery with the addition of an anticoagulant and subsequent injection of autologous blood into the retroperitoneal space. Animals in the control group were subjected to non-inhalational anesthesia only. Intravital experimental modeling of retroperitoneal hematoma in rabbits led to a number of significant changes in the hemostatic system, which were most pronounced in the first 14 days after the experiment. The international norma-lized ratio (INR) in the experimental group of animals had significantly low values compared to the control group only on the 1st, 3rd and 7th days, and the activated partial thromboplastin time (aPTT) – on the 1st, 3rd days , 7th and 14th days after the experiment. There were no significant differences in the level of fibrinogen in blood plasma between the animals of the experimental and control groups. Thrombin time (TT) in animals of the experimental group was significantly higher only on the 1st, 3rd, 7th and 14th days, and the D-dimer content was significantly higher in all studied periods after the experiment in comparison with the control group animals. The highest level of D-dimer in the blood plasma of animals in the experimental group was recorded on the 7th day and probably indicated that in retroperitoneal hematomas the most active processes of fibrinolysis occur at this time. Low values of INR in the first 7 days and aPTT in the first 14 days, as well as prolongation of TT in the first 14 days after the experiment, give reason to believe that with retroperitoneal hematomas, the threshold for the likelihood of thrombus formation increases during these periods.

Auditing plasma transfusion in intensive care: Use of decision time interval analysis.

To present a new method for displaying blood utilization data based on analysis of decision time intervals (DTIs). Retrospective study of patients treated in a medical intensive care unit (ICU), surgical ICU, or postcardiac surgery ICU at an academic hospital between January 2018 and June 2023. Each patient's episode of care was divided into a series of DTIs. Transfusions during each time interval were recorded. In total, 16,562 patients received 6980 units of plasma and 21,034 units of red blood cells during 111,557 time intervals of care. Patients had international normalized ratio (INR) values ranging from less than 1.0 to more than 4.0. Data on plasma transfusion at different INR values were displayed as the number of transfusion episodes, number of units given, or the proportion of DTIs with transfusion. Clinicians transfused plasma on 1.5% of occasions when the INR was 1.5 or less and on 2.2% of occasions when the INR was less than 2.0. Plasma was transfused without red blood cells in only 0.75% of DTIs. Transfusion practice was statistically different among the 3 ICUs. Compared with traditional methods of displaying the results of blood audits, DTI analysis displays information regarding the decision both to transfuse and to not transfuse. Utilization reviews that display data based on decision time analysis reveal clinical practice patterns very different from those suggested by traditional displays of plasma audit data.

Noncardiac Surgery in Patients with Left Ventricular Assist Devices: A 11-Year Institutional Experience.

Limited options in the end-stage treatment of heart failure have led to increased use of left ventricular assist devices. For this reason, the rate of non-cardiac surgeries in patients with left ventricular assist devices is also increasing. Our study aims to analyze surgical rate, anesthesia management, and results by reviewing our 11-year experience with patients who underwent non-cardiac surgery receiving left ventricular assist devices support. We retrospectively evaluated 57 patients who underwent non-cardiac surgery and 67 non-cardiac surgical procedures among 274 patients who applied between January 2011 and December 2022 and underwent left ventricular assist devices implantation with end-stage heart failure. Fifty (74.6%) patients with left ventricular assist devices admitted to the hospital for non-cardiac surgery were emergency interventions. The most common reasons for admission were general surgery (52.2%), driveline wound revision (22.3%), and neurological surgery (14.9%). This patient group has the highest in-hospital mortality rate (12.8%) and the highest rate of neurological surgery (8.7%). While 70% of the patients who underwent neurosurgery were taken to surgery urgently, the International Normalized Ratio values of these patients were between 3.5 and 4.5 at the time of admission to the emergency department. With a perioperative multidisciplinary approach, higher morbidity and mortality risks can be reduced during emergencies and major surgical procedures.

Exploring coagulation parameters as predictive biomarkers of Plasmodium infection: A comprehensive analysis of coagulation parameters.

Malaria affects the intravascular environment, leading to abnormal coagulation activation, prolonged prothrombin time, and activated partial thromboplastin time. Despite the high prevalence of malaria in the study area, there has been little published research on the effects of Plasmodium infection on coagulation parameters. The aim was to assess the effect of malaria on basic coagulation parameters among patients attending Dembia Primary Hospital and Makisegnit Health Center. A cross-sectional study was carried out from January to March 2020. The study involved 120 participants. Blood specimens were collected, which were analyzed using a Huma Clot Due Plus analyzer. The collected data were entered into EpiData and exported to SPSS version 21 for analysis. Non-parametric statistical methods were employed to analyze the data. The results were considered statistically significant if the p-value was less than 0.05. Individuals infected with Plasmodium exhibit coagulation disorders with elevated levels of PT (Prothrombin Time), APTT (Activated Partial Thromboplastin Time), and INR (International Normalization Ratio) in comparison to healthy controls. The median PT, APTT, and INR values for infected cases were measured at 20.5 [8.6], 39.5 [17.9], and 1.8 [0.9], respectively, while healthy controls had measurements of 15.1 [2.5], 28.8 [8.3], and 1.3 [0.2] (p ≤ 0.001). The severity of coagulation disorders increased with an increase in parasitemia levels. The type of Plasmodium species present had a significant impact on PT and INR values (p ≤ 0.001), whereas APTT did not show any significant impact across the Plasmodium species (p > 0.05). The results of this study found that malaria has a substantial impact on various blood clotting parameters, including PT, APTT, and INR. Parasitemia severity is significantly associated with extended PT and INR, implying that the higher the parasitemia, the longer it takes for blood to clot. Furthermore, the study discovered that the PT and INR levels differed based on the type of Plasmodium species responsible for the infection.

CoaguChek and Coag-Sense PT2 Meter Point of Care INR Device Validation

ObjectiveTo standardize international normalized ratio (INR) measurements and improve data integrity by enabling electronic result transmission for warfarin monitoring, two point-of-care (POC) devices were evaluated against an internal plasma INR reference method. MethodsA multicenter study was pursued (January 24, 2022, through October 19, 2022) to compare concordance of two commercially available POC devices, Coag-Sense PT2 Meter (Coag-Sense) and CoaguChek XS Pro and Plus devices (CoaguChek), against an internal plasma INR method among patients treated with warfarin. Bias and linear regression analysis were assessed for these devices including dosing decision accuracy compared with plasma INR reference. ResultsTwo hundred ninety-nine patients treated with warfarin across three Mayo Clinic sites agreed to participate. Atrial fibrillation (n=191, 63.9%), venous thromboembolism (n=65; 21.7%), and heart valve prosthesis (n=46; 15.4%) were common anticoagulant indications with a 2.5 INR target for 280 (93.6%) of patients. For the CoaguChek devices, 243 (81.3%) of values fell within 0.2 INR units with plasma INR referent and 285 (95.3%) within 0.4 units (R2=0.93). For the Coag-Sense device, 102 (34.1%) of values fell within 0.2 INR units and 180 (60.2%) within 0.4 INR units of plasma INR values, (R2=0.83; P<.0001). Using the plasma INR as the gold standard, appropriate dosing recommendations would have occurred for 292 (97.7%) of the CoaguChek and 244 (81.6%) of the Coag-Sense results. ConclusionCompared with a plasma referent, INR values obtained from the CoaguChek devices exhibited less systematic bias compared with Coag-Sense measures. This translates to a greater percentage of concordant management decisions between POC and laboratory INR methods.

The effect of administering preprocedural VITamin K on the international normalized ratio in patients anticoagulated with ACEnocoumarol (VITKACE-study): a prospective cohort study

BackgroundThe effect of the vitamin K antagonist acenocoumarol on coagulation needs to be reversed when patients undergo an invasive procedure with considerable bleeding risk. A strategy to achieve this is by administering oral vitamin K before a procedure while continuing acenocoumarol. ObjectivesTo assess the effect on periprocedural international normalized ratio (INR) values and safety using oral vitamin K as anticoagulant reversal method. MethodsIn this prospective cohort study, consecutive patients using acenocoumarol undergoing elective procedures between 2019 and 2022 were included. According to standard of care in our hospital, patients took 10 mg oral vitamin K 36 to 48 hours before the procedure while continuing their normal use of acenocoumarol. Effectiveness to lower INR to <1.8 preprocedural was assessed. Bleeding and thrombotic complications within 30 days after the procedure were assessed. Periprocedural course of INR was monitored by collecting additional blood samples. ResultsSeventy-four patients were included for analysis. On the day of the procedure, an adequate INR of <1.8 was achieved in 99% of patients. One clinically relevant nonmajor bleeding complication and no thrombotic complications were observed during the first 30 days after the procedure. INR gradually restored to therapeutic level during the days after the procedure. ConclusionUsing oral vitamin K while patients continue acenocoumarol intake is an effective way to adequately lower INR before an invasive procedure. Low amount of bleeding complications and absence of thromboembolic complications suggest that this is a safe strategy. The INR values returned gradually to therapeutic range after the procedure, probably contributing to the observed low bleeding rate.

Factors Influencing Early Diagnosis and Poor Prognosis of Dysphagia After Senile Ischemic Stroke.

Dysphagia is often a long-term problem after ischemic stroke, which are often accompanied by complications and results in poor outcome. This study aimed to investigate the influencing factors associated with the prognosis of dysphagia after senile ischemic stroke and evaluate the diagnostic performance of crucial factors. A total of 192 elderly ischemic stroke patients (96 patients without dysphagia with average age of 69.81 ± 4.61years and 96 patients with dysphagia with average of 70.00 ± 6.66years) were enrolled in the retrospective study. The clinical factors of the patients were collected and recorded for chi-square analysis and logistic analysis. The receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic performance of international normalized ratio (INR) and homocysteine (Hcy) in senile ischemic stroke patients. The age, cough reflex, history of stroke, mechanical ventilation, eating posture, insufficient elevation of the larynx, standard swallowing assessment (SSA) score, Hcy value, and INR were closely related to endpoint events of patients with dysphagia. The joint model (combined INR and Hcy value) can increase the area under the curve (AUC) value (0.948) with higher sensitivity and specificity for predicting patients with dysphagia occurred endpoint events.The influencing factors for older ischemic stroke patients with dysphagia include age, cough reflex, history of stroke, mechanical ventilation, eating posture, insufficient elevation of the larynx, SSA score, Hcy value, and INR. INR and Hcy were independent risk factors for prognosis and diagnostic markers for patients with dysphagia after senile ischemic stroke.

Role of substance P in cerebral edema and association with an estimated specific gravity of the brain and an outcome prediction in post-traumatic cerebral edema

PurposeThe study aims to evaluate the role of substance P in cerebral edema and outcomes associated with acute TBI. MethodPatients with acute TBI who presented within 6 h and a CT scan showed predominantly cerebral edema were included in the study. Substance P level was assessed from a serum sample collected within 6 h of trauma. We also evaluated the brain-specific gravity using the Brain View software. ResultA total of 160 (128 male) patients were recruited. The median serum substance P concentration was 167.89 (IQR: 101.09–238.2). Substance P concentration was high in the early hours after trauma (p = 0.001). The median specific gravity of the entire brain was 1.04. Patients with a low Glasgow coma scale (GCS) at admission had a high concentration of the substance P. In the univariate analysis, low GCS, elevated serum concentrations of substance P level, high Rotterdam grade, high cerebral edema grade, a high international normalized ratio value, and high blood sugar levels were associated with poor outcomes at six months. In logistic regression analysis, low GCS at admission, high cerebral edema grade, and elevated blood sugar level were strongly associated with poor outcomes at six months. The area under the receiver operating characteristic curve was 0.884 (0.826–0.941). ConclusionSerum substance P is strongly associated with the severity of cerebral edema after TBI. However, brain-specific gravity does not directly correlate with posttraumatic cerebral edema severity. Serum substance P does not influence the clinical outcome of traumatic brain injury.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study*

Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

The Utilisation of INR to identify coagulopathy in burn patients.

Studies conflict on the significance of burn-induced coagulopathy. We posit that burn-induced coagulopathy is associated with injury severity in burns. Our purpose was to characterize coagulopathy profiles in burns and determine relationships between % total burn surface area (TBSA) burned and coagulopathy using the International Normalized Ratio (INR). Burned patients with INR values were identified in the TriNetX database and analyzed by %TBSA burned. Patients with history of transfusions, chronic hepatic failure, and those on anticoagulant medications were excluded. Interquartile ranges for INR in the burned study population were 1.2 (1.0-1.4). An INR of ≥ 1.5 was used to represent those with burn-induced coagulopathy as it fell outside the 3rd quartile. The population was stratified into subgroups using INR levels <1.5 or ≥1.5 on the day of injury. Data are average ± SD analyzed using chi-square; p < .05 was considered significant. There were 7,364 burned patients identified with INR <1.5, and 635 had INR ≥1.5. Comparing TBSA burned groups, burn-induced coagulopathy significantly increased in those with ≥20% TBSA; p = .048 at 20-29% TBSA, p = .0005 at 30-39% TBSA, and p < .0001 for 40% TBSA and above. Age played a significant factor with average age for those with burn-induced coagulopathy 59 ± 21.5 years and 46 ± 21.8 for those without (p < .0001). After matching for age, TBSA, and demographics, the risk of 28 day-mortality was higher in those with burn-induced coagulopathy compared to those without (risk difference 20.9%, p < .0001) and the odd ratio with 95% CI is 4.45 (3.399-5.825). Investigation of conditions associated with burn-induced coagulopathy showed the effect of heart diseases to be significant; 53% of patients with burn-induced coagulopathy had hypertension (p < .0001). Burn-induced coagulopathy increases with %TBSA burned. The information gained firmly reflects a link between %TBSA and burn-induced coagulopathy, which could be useful in prognosis and treatment decisions.

Thirty-year outcomes of low-intensity anticoagulation for mechanical aortic valve.

The long-term safety, efficacy, and outcomes of low-intensity anticoagulation for mechanical heart valves remain unclear. This study aimed to evaluate the long-term outcomes of low-intensity anticoagulation therapy after aortic valve replacement (AVR) with a mechanical prosthesis. This retrospective cohort study consulted medical records and conducted a questionnaire to investigate 519 patients who underwent single AVR with the St. Jude Medical bileaflet valve and were in sinus rhythm. All patients were followed up with an international normalized ratio (INR) target of 1.6-2.5, and their INR values were checked throughout the follow-up period. The survival rate, incidence of major adverse cardiac and cerebrovascular events (MACCE), and risk factors for cardiac death and MACCE were investigated. The total follow-up was 9793 patient-years, and the follow-up periods were 19.9 (standard deviation [SD]: 7.9) years. The mean INR was 2.03 (SD: 0.54). Survival rates from cardiac death were 93.6% in 20years and 85.2% in 30years. Advanced age ≥ 70years was the only significant risk factor for cardiac death and MACCE, and the INR < 2.0 was not significant risk factor for MACCE including thromboembolism or bleeding events. Low-intensity anticoagulation with an INR of 1.6-2.5 for patients with sinus rhythm after AVR with a bileaflet mechanical valve is safe and effective, even over 30years.

Effects of sodium ferulate for injection on anticoagulation of warfarin in rats in vivo

BackgroundHerb-drug interactions may result in increased adverse drug reactions or diminished drug efficacy, especially for drugs with a narrow therapeutic index such as warfarin. The current study investigates the effects of sodium ferulate for injection (SFI) on anticoagulation of warfarin from aspects of pharmacodynamics and pharmacokinetics in rats and predicts the risk of the combination use.MethodsRats were randomly divided into different groups and administered single- or multiple-dose of warfarin (0.2 mg/kg) with or without SFI of low dose (8.93 mg/kg) or high dose (26.79 mg/kg). Prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected by a blood coagulation analyzer, and international normalized ratio (INR) values were calculated. UPLC-MS/MS was conducted to measure concentrations of warfarin enantiomers and pharmacokinetic parameters were calculated by DAS2.0 software.ResultsThe single-dose study demonstrated that SFI alone had no effect on coagulation indices, but significantly decreased PT and INR values of warfarin when the two drugs were co-administered (P < 0.05 or P < 0.01), while APTT values unaffected (P > 0.05). Cmax and AUC of R/S-warfarin decreased but CL increased significantly in presence of SFI (P < 0.01). The multiple-dose study showed that PT, APTT, INR, and concentrations of R/S-warfarin decreased significantly when SFI was co-administered with warfarin (P < 0.01). Warfarin plasma protein binding rate was not significantly changed by SFI (P > 0.05).ConclusionsThe present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.

Effect of combination of molnupiravir with clarithromycin on blood biomarkers in patients with mild-to-moderate COVID-19

Background: Molnupiravir is a type of medication used to treat coronavirus disease 2019 (COVID-19). However, no evidence regarding the therapeutic effect of molnupiravir combined with clarithromycin (CAM) on blood biomarkers is available. Methods: Of the 156 rehabilitation patients, 124 patients with mild-to-moderate COVID-19 were treated with molnupiravir. Among these 124 patients, 54 were treated with CAM. The remaining 28 rehabilitation patients were negative for COVID-19. Blood biomarkers were assessed after administration of molnupiravir in patients receiving molnupiravir plus CAM or molnupiravir alone. Results: Among the measured blood biomarkers, lactate dehydrogenase, potassium, white blood cells, C-reacted protein, neutron–lymphocyte ratio, fibrin degradation product, and prothrombin time–international normalized ratio values were significantly higher (P &lt; 0.05) in the molnupiravir alone group than in the molnupiravir plus CAM group, and lymphocytes were significantly lower (P &lt; 0.05) on day 5 after admission. In the molnupiravir plus CAM group, immunoglobulin (Ig) A levels increased and soluble interleukin 2-receptor levels (sIL2R) decreased (P &lt; 0.05) on day 14 after admission. In addition, COVID-19-negative patients had higher IgA levels and lower sIL2R levels compared to infected patients (P &lt; 0.05). The concomitant administration of molnupiravir plus CAM resulted in fewer sequelae after 12 months, and the incidence of venous thromboembolism was significantly reduced (P &lt; 0.05). Conclusion: In patients with mild-to-moderate COVID-19, concomitant administration of molnupiravir plus CAM showed several non-worsening blood biomarkers, elevated immune activity, and reduced post-infection sequelae. Relevance for Patients: After administration of molnupiravir to patients with mild-to-moderate COVID-19, administration of CAM to patients suffering from secondary macrolide-sensitive bacterial infection was compared with administration of molnupiravir alone. D-dimer, IgA, and sIL2R are potential predictive factors of disease severity in critically ill patients with COVID-19.

Efficacy and safety of Nafamostat mesylate in patients with end-stage renal failure.

Recent studies on dialysis anticoagulation therapy in patients with renal failure have shown that Nafamostat mesylate, a broad-spectrum potent serine protease inhibitor, has strong anticoagulation and anti-fiber activity. To evaluate the efficacy and safety of Nafamostat mesylate in patients with end-stage renal failure. Seventy-five patients with end-stage renal failure who received hemodialysis at our hospital between January 2020 and August 2021 were selected and divided into the observation group (Nafamostat mesylate for injection, n = 33) and control group (heparin sodium injection, n = 32). General patient data, indicators of clinical efficacy, dialyzer hemocoagulation parameters, coagulation function indices, and hemoglobin concentration and platelet count before and after treatment, and the occurrence of adverse reactions after treatment were compared between the two groups. The two groups showed no significant differences in general patient data (P > 0.05). The post-treatment effectiveness rate in the control group was lower than that in the observation group (P < 0.05). The two groups showed no significant difference in the number of patients in grade I (P > 0.05), while the number of patients in grade 0 was lower in the control group, and the number of patients in grades II and III was higher in the control group (P < 0.05). The post-treatment prothrombin time, activated partial thromboplastin time, thrombin time, and international normalized ratio values in the control group were higher than those in the observation group, while the fibrinogen level in the control group was lower than that in the observation group (P < 0.05). The two groups showed no significant difference in the platelet count and hemoglobin level before and after treatment (P > 0.05). The total number of post-treatment adverse reactions in the observation group was lower than that in the control group (P < 0.05). Treatment of patients showing end-stage renal failure with Nafamostat mesylate can significantly improve therapeutic efficacy and has high safety and clinical value.

Effect of High Altitude Environment on Pharmacokinetic and Pharmacodynamic of Warfarin in Rats.

High altitude environment affects the pharmacokinetic (PK) parameters of drugs and the PK parameters are an important theoretical basis for guiding the rational clinical use of drugs. Warfarin is an oral anticoagulant of the coumarin class commonly used in clinical practice, but it has a narrow therapeutic window and wide individual variation. However, the effect of high altitude environment on PK and pharmacodynamic (PD) of warfarin is unclear. The objective of this study is to investigate the effect of a high altitude environment on PK and PD of warfarin in rats. Rats were randomly divided into plain group and high altitude group and blood samples were collected through the orbital venous plexus after administration of 2 mg/kg warfarin. Warfarin concentrations in plasma samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and PK parameters were calculated by the non-compartment model using WinNonlin 8.1 software. Meanwhile, the expression of PXR, P-gp and CYP2C9 in liver tissues was also determined by western blotting. The effect of high altitude environment on PD of warfarin was explored by measuring activated partial thromboplastin time (APTT) and prothrombin time (PT) values and then calculated international normalized ratio (INR) values based on PT. Significant changes in PK behaviors and PD of warfarin in high altitude-rats were observed. Compared with the plain-rats, the peak concentration (Cmax) and the area under the plasma concentration-time curve (AUC) increased significantly by 50.9% and 107.46%, respectively. At the same time, high altitude environment significantly inhibited the expression of PXR, P-gp and CYP2C9 in liver tissues. The results of the PD study showed that high altitude environments significantly prolonged PT, APTT and INR values. High altitude environment inhibited the metabolism and increased the absorption of warfarin in rats and increased the effect of anticoagulant effect, suggesting that the optimal dose of warfarin for patients at high altitude should be reassessed.

Analysis of laboratory parameters before the occurrence of hepatic sinusoidal obstruction syndrome in children, adolescents, and young adults after hematopoietic stem cell transplantation

PurposeHepatic sinusoidal obstruction syndrome (SOS) is a serious complication following hematopoietic stem cell transplantation (HSCT) in which early diagnosis improves patient outcome. The aim of our study was to detect laboratory parameters following HSCT that can predict the occurrence of SOS.MethodsThis retrospective study included 182 children, adolescents, and young adults who underwent allogeneic or autologous HSCT for the first time (median age 7.2 years). The diagnosis of SOS was based on the pediatric criteria of European Society for Blood and Marrow Transplantation (EBMT). We investigated 15 laboratory parameters after HSCT before the onset of SOS.ResultsThe overall incidence of SOS was 14.8%. SOS developed in 24 of 126 allogeneic (19.1%) and in 3 of 56 autologous (5.4%) HSCT patients at a median time of 13 days after HSCT. We observed a low SOS mortality rate of 11.1% within 100 days after HSCT. International normalized ratio (INR) ≥ 1.3, activated partial thromboplastin time (aPTT) ≥ 40 s, reptilase time ≥ 18.3 s, factor VIII ≤ 80%, antithrombin III ≤ 75%, protein C ≤ 48%, D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L showed significant associations with the onset of SOS in the univariate analyses. In the multivariate analysis, INR ≥ 1.3 [odds ratio (OR) = 8.104, p = 0.006], aPTT ≥ 40 s (OR = 10.174, p = 0.001), protein C ≤ 48% (OR = 5.215, p = 0.014), and ferritin ≥ 3100 µg/L (OR = 7.472, p = 0.004) could be confirmed as independent risk factors after HSCT before SOS. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters were changed according to the cut-off values. The values of factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), protein S, fibrinogen, and alanine aminotransferase (ALT) were not relevant for the occurrence of SOS.ConclusionIn summary, the laboratory parameters INR, aPTT, protein C, and ferritin were very useful to predict the occurrence of SOS. In addition, this is the first report on a significant association between SOS and high values of INR and aPTT after HSCT before SOS.

OUTCOMES OF WARFARIN THERAPY FOR SECONDARY PREVENTION OF ISCHEMIC STROKE: A RETROSPECTIVE, FOLLOW-UP STUDY

Aim: Anticoagulant prophylaxis is recommended because cardioembolic ischemic stroke is associated with worse functional outcomes, increased recurrence rates, and higher mortality. This study aimed to investigate the rates of recurrent ischemic attacks and bleeding complications in patients receiving warfarin following ischemic stroke. Method: In this retrospective analysis, a total of 181 individuals who were initiated on warfarin therapy following an ischemic stroke were included in the study. These patients were subsequently monitored for a duration spanning from 1 month to as long as 16 years. The acute ischemic stroke diagnosis was established using the Trial of Org 10172 in Acute Stroke Treatment classification criteria. Patient follow-up periods, international normalized ratio (INR) levels, ischemic events, and bleeding were recorded and evaluated. Results: In the patient cohort, 97 (53.6%) were women and 84 (46.4%) were men. The recurrent ischemic stroke rate was 7.2%, major bleeding rate was 3.3%, and minor bleeding rate was 12.7%. While the average INR value during recurrent ischemic stroke was 1.69±0.31, the average INR value during bleeding complications was observed to be 3.15±1.38. The rate of minor bleeding was related to duration of warfarin use and non-valvular atrial fibrillation. Conclusion: Our results show that long-term warfarin use and non-valvular atrial fibrillation are risk factors for bleeding.

Utilization of International Normalized Ratio-Derived Formula to Predict Plasma Rivaroxaban Level - Validation Study and Real-World Experience

Introduction: Specific assay of plasma rivaroxaban level are not always readily available with short turn-around-time which hampered the management of urgent clinical situations. The response of routine coagulation screening tests show huge lot-to-lot differences with the plasma rivaroxaban level. International normalized ratio (INR) is a standardized measurement taking into account of lot-to-lot variations of PT reagents. In this study, we aimed to build a predictive formula of plasma rivaroxaban levels from INR value and validated in real world clinical situations. Method: The study period was 1 st January 2018 to 31 st December 2021. Ninety-four patients who taking rivaroxaban participated in the study. Patients were randomized into testing cohort and validation cohorts. The prediction formula was built from the testing cohort and then validated in validation cohort. The predictive performance was further validated on real-world clinical requests. Results: The baseline characteristics of both cohorts were well-balance. There was significant correlation between the plasma rivaroxaban level and PT in both the testing and validation cohorts (Testing cohort: R square 0.838, p &amp;lt; 0.01; Validation cohort: R square 0.836, p &amp;lt; 0.01). The plasma rivaroxaban level showed significant correlation with APTT in both the testing and validation cohorts (Testing cohort: R square 0.744, p &amp;lt; 0.01; Validation cohort: R square 0.654, p &amp;lt; 0.01). There was also significant correlation between INR and plasma rivaroxaban levels in both the testing and validation cohorts (Testing cohort: R square 0.819, p &amp;lt;0.01; Validation cohort: R square 0.816, p &amp;lt; 0.01). Both INR and plasma rivaroxaban levels were undergone natural logarithmic transformation. We choose the quadratic model to determine the relationship between the natural log of plasma rivaroxaban level and the natural log of INR as it had highest R square value (R square 0.850, p&amp;lt;0.01). The formula is: ln (plasma rivaroxaban level) = 2.96+7.87 X ln (INR) - 5.04X (ln (INR))^2. The root mean square error (RMSE) of the predictive formula for the testing and validation cohorts were 61.81 ng/ml and 69.32 ng/ml, respectively. We received a total of 43 requests for plasma rivaroxaban assay involved 29 patients during the study period (Table 1). Three patients had multiple requests for plasma DOAC level assays during this period. The cut-off INR value was 1.3 for administration of antidote for rivaroxaban, which corresponded to a rivaroxaban level of 75 ng/ml. The sensitivity and specificity for using this INR cut-off value to determine the threshold plasma rivaroxaban level (75 ng/ml) for administration of reversal agents were 95% (95%CI: 85.4 -100%) and 87.5% (95%CI:71.3-100%) respectively in real world clinical situations (Table 2). Conclusion: Plasma rivaroxaban level can be calculated from prediction formula by INR value with satisfactory accuracy and the INR cut-off value derived from it can be used to guide the decision for administration of reversal agents with excellent sensitivity and specificity.

Antiphospholipid Antibody Syndrome (APS) Pediatric Patient Outcomes on Warfarin

Background: Antiphospholipid antibody syndrome (APS) is an acquired thromboembolism (TE) risk factor and places patients at very high risk of recurrent TE. APS diagnosis requires venous (deep vein thrombosis (DVT) or pulmonary embolism (PE)) or arterial thromboembolism and laboratory diagnosis including persistently positive lupus anticoagulant (LA) or elevated anticardiolipin (aCL) and/or beta 2 glycoprotein I (B2GPI) antibodies tested 12 weeks apart. Vitamin K antagonist (warfarin) is the standard of care anticoagulant to reduce risk of TE recurrence in APS patients. Warfarin is dosed based on the International Normalized Ratio (INR) with established therapeutic ranges for optimal efficacy and safety. The reported time in therapeutic range (TTR) varies greatly across specialties with an average TTR of 50-55%. However, it is often difficult to maintain target INR in APS. Furthermore, there is limited data evaluating pediatric patients with APS and their TTR on warfarin and outcomes. Aim: To evaluate the relationship of APS status to TTR and outcomes of patients &amp;lt; 21 years of age with APS who are on warfarin anticoagulation. Methods: This was a single center analysis of APS patients between July 2019 and May 2022 who were enrolled in a multi-center prospective study of pediatric patients on warfarin therapy, eKITE (electronic KidClot Thrombophilia Education). The study included an online learning series regarding warfarin management. Home INR meters and test strips were provided to all patients to perform INR testing. INR values were reported by patients and recorded. Demographic and clinical data was extracted from the electronic medical record, target INR was set by the treating provider, and TTR was calculated as a surrogate for safe, effective warfarin management. Results: Nine patients (n=9) with APS were identified for this analysis, mean age 16.7 years (range 12-19 years). Demographic and laboratory findings are summarized in Table 1. Most patients had secondary APS due to systemic lupus erythematous (SLE) 78% (n=7) and 22% (n=2) had other primary diagnoses. APS antibody status included single positive in 67% (n=6), double positive in 22% (n=2), and triple positive in 11% (n=1). More specifically, APS criteria were met by persistently elevated LA in 78% (n=7), aCL IgM in 22% (n=2) with overall mean aCL IgM of 34.4 MPL^ (range 9.9-127.9), B2GPI IgG in 11% (n=1) with overall mean B2GPI IgG SGU* of 13.1 (range 0.9-63.3), and B2GPI IgM in 22% (n=2) with overall B2GPI IgM mean of 32.5 SGU (range 3.3-190.9). At time of presentation 67% (n=6) of patients had DVT, 44% (n=4) had PE, 11% (n=1) had arterial TE, and 22% (n=2) presented with DVT &amp; PE. Mean TTR for all patients was 56%. TTR for single positive APS was 66%, double positive APS 39%, and triple positive APS 33%. TTR for secondary APS (SLE) and non-SLE diagnoses was 53% and 68% respectively. Mean dose changes were 11 (range 0-48) with one single positive LA patient requiring 48 dose changes, and two patients with single positive LA not requiring any dose changes. Two patients (22%) developed recurrent clot. One triple positive APS patient developed two DVTs and one non-SLE patient developed recurrent arterial TE. Three patients (33%) had minor bleeding events including mild epistaxis and hematemesis not requiring intervention. One patient (11%) had a major bleeding event, hemoperitoneum from pseudoaneurysm extravasation, while resuming warfarin during post-operative period, and required takeback surgery with sub-therapeutic INR 1.5 at the time of event. Conclusion: The mean TTR for pediatric patients with APS is similar to what is reported in other populations despite the challenge of managing warfarin in this group where the INR may be affected by primary disease modifying medications or disease flares. The risk of recurrent TE remains high in APS patients. Home INR monitors are a safe and effective strategy in managing warfarin anticoagulation in APS patients, reducing time and laboratory monitoring burden for frequent dose changes, which ultimately improves quality of life.Optimizing TTR is important to decrease risk of recurrent TE or bleeding in these high risk APS patients.

Analysis of Laboratory Parameters before the Occurrence of Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients after Hematopoietic Stem Cell Transplantation

Introduction: Hepatic sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease of the liver, is a serious complication following hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment with defibrotide can improve patient outcome. The pathogenesis is not fully understood, but it is obvious that some laboratory parameters are already changed before the onset of SOS. The aim of our retrospective study was to detect laboratory parameters following HSCT that can predict the occurrence of SOS. Methods: We analyzed 182 children with a median age of 7.2 years who underwent allogeneic or autologous HSCT for the first time and without defibrotide prophylaxis. Our study population consisted of 126 patients who received allogeneic HSCT (69.2%) and 56 patients who underwent autologous HSCT (30.8%). The stem cell sources were peripheral blood stem cells (50.5%) or bone marrow (49.5%) and the most frequent underlying diseases were solid tumors (34.1%), genetic diseases (19.2%), acute lymphoblastic leukemia (18.1%), and acute myeloid leukemia (13.7%). The diagnosis of SOS was based on the pediatric criteria of European Society for Blood and Marrow Transplantation. We investigated the following 15 laboratory parameters after HSCT before the onset of SOS: international normalized ratio (INR), activated partial thromboplastin time (aPTT), reptilase time, factor VIII, factor XIII, von Willebrand factor (vWF), von Willebrand factor activity (vWF activity), fibrinogen, antithrombin III, protein C, protein S, D-dimer, alanine aminotransferase (ALT), bilirubin, and ferritin. The last laboratory values within one week before the onset of SOS were analyzed in the SOS patient group. In the non-SOS patient group, we investigated the parameters for four weeks after transplantation and calculated the median. We selected cut-off values for the continuous parameters based on receiver operating characteristic curves analyses and existing reference values. We performed Mann-Whitney U test, univariate and multivariate analyses to find significant ( P &amp;lt; .05) associations between the values of laboratory parameters and the occurrence of SOS. The probability of developing SOS was calculated using the significant independent variables. Results: The overall incidence of SOS was 14.8% at a median time of 13 days after HSCT. SOS developed in 24 of 126 allogeneic (19.1%) and in 3 of 56 autologous (5.4%) HSCT patients. Only 3 out of 27 patients (11.1%) who suffered from very severe SOS died within 100 days after HSCT. In the univariate analysis, we found significant associations between the onset of SOS and the following parameters: INR ≥ 1.3, aPTT ≥ 40 sec, reptilase time ≥ 18.3 sec, factor VIII ≤ 80%, antithrombin III ≤ 75%, protein C ≤ 48%, D-dimer ≥ 315 µg/L, bilirubin ≥ 9 µmol/L, and ferritin ≥ 3100 µg/L. In multivariate analysis, we confirmed INR ≥ 1.3 [odds ratio (OR) = 8.104, P = .006], aPTT ≥ 40 sec (OR = 10.174, P = .001), protein C ≤ 48% (OR = 5.215, P = .014), and ferritin ≥ 3100 µg/L (OR = 7.472, P = .004) as independent risk factors after HSCT before SOS. If three of the four significant cut-off values were present, the probability of developing SOS was more than 70%. The probability of SOS was 96%, if all four laboratory parameters were changed according to the cut-off values. The values of factor XIII, vWF, vWF activity, protein S, fibrinogen, and ALT were not relevant for the occurrence of SOS. Conclusions: In summary, the laboratory parameters INR, aPTT, protein C, and ferritin were very useful to predict the occurrence of SOS. These four parameters can enable earlier diagnosis and treatment leading to an improved outcome. In addition, this is the first report on a significant association between SOS and high values of INR and aPTT after HSCT before SOS.