Role of international normalized ratio in nonpulmonary sepsis screening:An observational study

Currently,there is a lack of sepsis screening tools that can be widely used worldwide.Pulmonary sepsis can be of sufficient concern to physicians due to their noticeable symptoms,which usually rely less on screening tools.AIM To investigate the efficiency of the international normalized ratio(INR)for the early rapid recognition of adult nonpulmonary infectious sepsis.METHODS This is a prospective observational study.A total of 108 sepsis patients and 106 nonsepsis patients were enrolled according to relevant inclusion and exclusion criteria.Commonly used clinical indicators,such as white blood cell,neutrophil count,lymphocyte count,neutrophil-lymphocyte count ratio(NLCR),platelets(PLT),prothrombin time,INR,activated partial thromboplastin time,and quick Sequential“Sepsis-related”Organ Failure Assessment(qSOFA)scores were recorded within 24 h after admission.The diagnostic performances of these clinical indicators were analyzed and compared through multivariate logistic regression analysis,Spearman correlation,and receiver operating characteristic curve analysis.The INR value of the sepsis group was significantly higher than that of the nonsepsis group.INR has superior diagnostic efficacy for sepsis,with an area under the curve value of 0.918,when those preexisting diseases which significantly affect coagulation function were excluded.The diagnostic efficacy of the INR was more significant than that of NLCR,PLT,and qSOFA(P<0.05).Moreover,INR levels of 1.17,1.20,and 1.22 could be used to categorize the relative risk of nonpulmonary infections sepsis into three categories:low,medium and high risk,respectively.CONCLUSION The INR is a promising and easily available biomarker for diagnosis,and it can be used as one of the indicators for early screening of adult nonpulmonary infectious sepsis.When its value is higher than the optimal cutoff value(1.22),high vigilance is required for adult nonpulmonary infectious sepsis.

International normalized ratio as a predictor of mortality in trauma patients in India

BACKGROUND:Hemorrhage is the second leading cause of death in trauma patients preceded only by traumatic brain injury. But hemorrhagic shock is the most common cause of preventable death within 6 hours of admission. Traumatic coagulopathy is a hypocoagulable state that occurs in the most severely injured. International normalized ratio(INR) and its relationship with trauma mortality have not been studied specifi cally. This study aimed to establish a predictive value of INR for trauma-related mortality.METHODS:A total of 99 trauma patients aged 18–70 years were included in the study. Their INR was determined and patient progression was followed up till death/discharge. According to previous retrospective studies,the cutoff value for INR in our study was kept at 1.5.RESULTS:The total mortality rate of the patients was 16.16%(16/99). The mean INR was 1.45 with a SD of 1.35. INR was deranged in a total of 14 patients(14.14%). Of these patients,11 died(78.57%) and 3 survived. INR was deranged in 11(68.75%) of the 16 patients who died,but 5 deaths(31.25%) had normal INR values. The sensitivity of INR was 69%(95%CI 41%–88%) and the specificity 96%(95%CI 90%–99%). The diagnostic accuracy of INR was 92%(95%CI 85%–96%). Positive predictive value and negative predictive value were 79%(95%CI 49%–95%) and 94%(95%CI 87%–98%),respectively.CONCLUSION:Our results showed that INR is a good predictor of mortality in trauma patients.

Optimal INR level in elderly and non-elderly patients with atrial fibrillation receiving warfarin: a report from the COOL-AF nationwide registry in Thailand

Background Asian population are at increased risk of bleeding during the warfarin treatment,so the recommended optimal international normalized ratio(INR)level may be lower in Asians than in Westerners.The aim of this prospective multicenter study was to determine the optimal INR level in Thai patients with non-valvular atrial fibrillation(NVAF).Methods Patients with NVAF who were on warfarin for stroke prevention were recruited from 27 hospitals in the nationwide COOL-AF registry in Thailand.We collected demographic data,medical history,risk factors for stroke and bleeding,concomitant disease,electrocardiogram and laboratory data including INR and antithrombotic medications.Outcome measurements included ischemic stroke/transient ischemic attack(TIA)and major bleeding.Optimal INR level was assessed by the calculation of incidence density for six INR ranges(<1.5,1.5–1.99,2–2.49,2.5–2.99,3–3.49,and≥3.5).Results A total of 2,232 patients were included.The mean age of patients was 68.5±10.6 years.The mean follow-up duration was 25.7±10.6 months.There were 63 ischemic stroke/TIA and 112 major bleeding events.The lowest prevalence of ischemic stroke/TIA and major bleeding events occurred within the INR range of 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.Conclusions The INR range associated with the lowest risk of ischemic stroke/TIA and bleeding in the Thai population was 2.0–2.99 for patients<70 years and 1.5–2.99 for patients≥70 years.The rates of major bleeding and ischemic stroke/TIA were both higher than the rates reported in Western population.

Anticoagulation early after mechanical heart valve replacement

Objective： To explore the changes of coagulation activity and the characters of anticoagulation early after mechanical heart valve replacement. Methods： All patients only took warfarin orally for anticoagulation. The predicted international normalized ratio （INR） was 1.5 to 2.0. Several coagulation markers were monitored early after valve replacement. Complications associated with anticoagulation were recorded and analyzed. The patients were divided into three groups based on the number and position of mechanical valve prothesis, including group M （mitral valve replacement）, group A （aortic valve replacement） and group D （mitral and aortic valve replacement）.Comparison was made between the three groups. Results： Three events of mild cerebral embolism and five events of mild bleeding occurred during the early postoperative period. One patient suffered from mild cerebral embolism on the 4th day after operation, accompanied by large volume of pericardial drainage. Two patients with bleeding had lower INRs than predicted range. However, INR in one patient with mild cerebral embolism was in the predicted range. There was no significant difference in thrombo time （TT）, activated partial thromboplastin time （APTT） and 1NR on the 3rd day after operation compared to those before operation; meanwhile, plasma fibrinogen （FIB） concentration was higher than that before operation （P〈0.05）. 1NR had no significant changes on the 2nd day after the beginning of anticoagulation compared to that before operation; however, 1NR was significantly elevated on the 4th day （P〈0.05）. Warfarin doses and INRs were similar among the three groups, but FIB concentrations in plasma were higher in groups M and D than in group A （P〈0.01）. Conclusion： Hypercoagulabale state exists early after mechanical heart valve replacement. When anticoagulation begins is determined by the change of coagulation markers, not by the volume of chest or pericardial drainage. INR can not accurately reflect the coagulation state sometimes, especially during the first 3 days after anticoagulation. The number and position of mechanical valve prothesis could affect coagulation state. Therefore, anticoagulation therapy should be regulated accordingly.

Patients’time in therapeutic range on warfarin among atrial fibrillation patients in Warfarin Medication Therapy Adherence Clinic

BACKGROUND The quality of warfarin therapy can be determined by the time in the therapeutic range(TTR)of international normalized ratio(INR).The estimated minimum TTR needed to achieve a benefit from warfarin therapy is≥60%.AIM To determine TTR and the predictors of poor TTR among atrial fibrillation patients who receive warfarin therapy.METHODS A retrospective observational study was conducted at a cardiology referral center in Selangor,Malaysia.A total of 420 patients with atrial fibrillation and under follow-up at the pharmacist led Warfarin Medication Therapeutic Adherence Clinic between January 2014 and December 2018 were included.Patients’clinical data,information related to warfarin therapy,and INR readings were traced through electronic Hospital Information system.A data collection form was used for data collection.The percentage of days when INR was within range was calculated using the Rosendaal method.The poor INR control category was defined as a TTR<60%.Predictors for poor TTR were further determined by using logistic regression.RESULTS A total of 420 patients[54.0%male;mean age 65.7(10.9)years]were included.The calculated mean and median TTR were 60.6%±20.6%and 64%(interquartile range 48%-75%),respectively.Of the included patients,57.6%(n=242)were in the good control category and 42.4%(n=178)were in the poor control category.The annual calculated mean TTR between the year 2014 and 2018 ranged from 59.7%and 67.3%.A high HAS-BLED score of≥3 was associated with poor TTR(adjusted odds ratio,2.525;95%confidence interval:1.6-3.9,P<0.001).CONCLUSION In our population,a high HAS-BLED score was associated with poor TTR.This could provide an important insight when initiating an oral anticoagulant for these patients.Patients with a high HAS-BLED score may obtain less benefit from warfarin therapy and should be considered for other available oral anticoagulants for maximum benefit.

Effect of rifampicin on anticoagulation of warfarin:A case report

BACKGROUND The drug interaction between warfarin and rifampicin is widely known,but there are still some difficulties in managing the combination of the two drugs.CASE SUMMARY A patient with brucellosis received strict monitoring from a Chinese pharmacist team during combination of warfarin and rifampicin.The dose of warfarin was increased to 350%in 3 mo before reaching the lower international normalized ratio treatment window.No obvious adverse reaction occurred during the drugadjustment period.This is the first case report of long-term combined use of rifampicin and warfarin in patients with brucellosis and valve replacement in China based on the Chinese lower warfarin dose and international normalized ratio range.CONCLUSION Anticoagulation for valve replacement in Chinese patients differs from that in other races.Establishment of a pharmacist clinic provides vital assistance in warfarin dose adjustment.

Thrombus precursor protein for monitoring anticoagulation in patients with mechanical valve prosthesis

Objective: To evaluate the plasma concentration of thrombus precursor protein (TPP) in patients after mechanical heart valve replacement, and to explore whether it can be used as a marker for monitoring anticoagulation. Methods: Totally 60 patients who took warfarin after mitral valve replacement and 20 control patients with non-valvular heart diseases were subjected in this study. Their plasma TPP concentration and international normalized ratio (INR) were determined, and compared not only between the anticoagulant patients and the control patients, but also between the patients with atrial fibrillaiton (AF, n=37) and the patients with sinus rhythm (SR, n=23) after mechanical valve replacement. The relationship between plasma TPP concentration and INR in the 60 anticoagulant patients was analyzed with linear regression. Results: It was found that the anticoagulant therapy effectively decreased plasma TPP concentration and elevated INR. In the anticoagulant group, the patients with AF had higher plasma TPP concentration than the others with sinus rhythm (P<0.05), although there was no significant difference in INR level between these 2 groups of patients (P>0.05). No significant correlation was found between plasma TPP concentration and INR in the anticoagulant patients (P>0.05). INR did not accord with plasma TPP concentration in several patients. Conclusion: INR can’t reflect the coagulation status and guide the anticoagulation correctly sometimes; TPP may be a valuable assistant marker for monitoring anticoagulation in patients with mechanical heart valve prothesis; Patients with AF may require higher density of anticoagulation and TPP is strongly suggested to be monitored in these patients.

VKORC1 genotypes are associated with response to warfarin but free warfarin concentration during initial anticoagulation in healthy Chinese volunteers

Background The genetic variations in VKORC1 modulate the stable responses to warfarin administration. But the role of VKORC1 polymorphisms during the initial anticoagulation and elimination period in the Hart Chinese population is not clear. Methods Twenty-four healthy Chinese volunteers were grouped according to their VKORC1 genotype. Twelve subjects were in the 3 mg group and 12 in the 6 mg group. VKORC1 genotypes were determined by a polymerase chain reaction （PCR） based restriction fragment length polymorphism （RFLP） assay and sequencing. The international normalized ratio （INR） was measured with an ACL9000 coagulation analyser. Plasma free warfarin concentration was measured with LC/MS/MS. Results In the initial anticoagulation period, the -1639AG and 1173TC carriers compared with the -1639AA and 1173TT carriers had a low INR value. The differences between genotypes with regard to INR values were more obvious in the 3 mg subjects （P 〈0.05）, and were not significantly different among the 6 mg subjects （P〉0.05）. On the contrary, no significant difference of plasma free warfarin concentration between genotypes was observed in each dosage group. It took 96 hours for the INR value and 144 hours for the free warfarin plasma concentration to come back to baselines after the last dose. No significant difference among genotypes and dosing groups was detected in the elimination phase （P〉0.05）. Conclusion VKORC1 polymorphisms are associated with differences in the initial response to warfarin when given at fixed doses, without affecting, as expected, its plasma concentration.

Bleeding risk and thrombosis in cirrhosis:a paradox with a need to address them

Patients with cirrhosis have a state of“rebalanced hemostasis”where there is a simultaneous reduction in both qualitative and quantitative properties of procoagulants and anticoagulants,i.e.,platelets,fibrinogen,coagulation factors,protein C,S,and antithrombin and conversely,there is an increase in the levels of von Willebrand factor,endothelial factor VIII,tissue plasminogen activator(t-PA),and plasminogen activator inhibitor type 1(PAI-1)(1).Laboratory tests,such as INR,involving these coagulation proteins have been used for the prognostication of patients with cirrhosis/liver failure and have historically been part of several severity scores(2,3).Spontaneous bleeding due to clotting factor deficiencies is less frequent in the absence of mechanical trauma,while thrombosis is not uncommon and may merit anticoagulation therapy(4).However,the management of patients with cirrhosis with abnormalities in the hemostasis system is unclear.To meet this unmet need,the European Association for the Study of the Liver(EASL)developed new guidelines for the prevention and management of bleeding and thrombosis in patients with cirrhosis(5).The bleeding here is referred to mucocutaneous and visceral bleeding events.

Obstructive Sleep Apnea Hypopnea Syndrome as a Reason for Active Management of Pulmonary Embolism

Background：Obstructive sleep apnea hypopnea syndrome （OSAHS） constitutes an independent factor for high warfarin dose for patients with pulmonary embolism （PE）.The aim of this study was to investigate whether the 6-month anticoagulation treatment by warfarin is enough for patients with PE complicated by OSAHS.Methods：We investigated 97 PE patients,32 of them had OSAHS and 65 non-OSAHS.Warfarin was administered for 6-month if no abnormal circumstances occurred.All patients were followed up for 18 months.Adverse events （AE） included death,major bleeding,hospitalization due to heart failure or pulmonary hypertension,and recurrence or aggravation of PE （including deep vein thrombosis）.Recurrence rate of PE after warfarin cessation was compared between the two groups.Results：OSAHS patients required a significantly higher dose of warfarin than their non-OSAHS counterparts （4.73 mg vs.3.61 mg,P 〈 0.001）.During warfarin treatment,no major bleeding and aggravation of PE occurred among OSAHS patients,and the rates of various AE were not significantly different between the OSAHS and non-OSAHS groups.PE recurrence was higher in OSAHS than non-OSAHS groups after withdrawal of warfarin （21.43% vs.6.78%,P =0.047）.Compared with non-OSAHS patients,OSAHS group had lower international normalized ratio （INR） value but higher plasminogen on baseline and INR resumed to a relatively low level after warfarin discontinuation.Conclusions：OSAHS patients may present with hypercoagulation and relatively high-risk of recurrence of PE after cessation of 6-month warfarin treatment.

Low standard oral anticoagulation therapy for Chinese patients with St.Jude mechanical heart valves

Objective To study the efficacy of the low standard oral anticoagulation therapy following St Jude Medical (SJM) valve implantation for Chinese patients.Methods Totally 805 patients with a mean age of 42.70±11.09 years,enrolled into this study. Among them,230 underwent aortic valve replacements (AVR),381 mitral valve replacements (MVR),189 double valve replacements (DVR) and 5 tricuspid valve replacememts (TVR). All patients received postoperative oral anticoagulation therapy based on a low standard of international normalized ratio (INR,2.0-2.5). Of the 805 patients,710 were followed up for 0.25-13 years (a median,4.15 years). Results Postoperatively,17 adverse events occurred. Operative mortality was 2.11%. The most frequent cause of operative mortality was a low cardiac output. During follow-up,there were 47 anticoagulant-induced hemorrhages [1.59%/patient-year (pt-yr)],10 cases of thromboembolism (0.34%/pt-yr),and 3 mechanical valve thromboses (0.19%/pt-yr). There were 44 late deaths and the linearized late mortality rates were 0.51%pt-yr. Estimates of actuarial survival for all patients at 5 and 10 years was 97.45% (0.70%) and 77.96% (17.44%),respectively.Conclusions A low target INR range of 2.0-2.5 is preferable for Chinese patients so as to reduce the severe bleeding complications in those with conventionally higher levels of INR. The long-term results were satisfactory in terms of the numbers of those who suffered thrombosis,embolism and bleeding.