Increase In International Normalized Ratio Research Articles

Outcomes of endoscopic intervention for overt GI bleeding in severe thrombocytopenia

Gastrointestinal bleeding (GIB) in the setting of thrombocytopenia raises concerns about endoscopic procedure risk. We aimed to assess the safety and outcomes of endoscopy for overt GIB in the setting of severe thrombocytopenia in liver cirrhosis (LC) and non-liver cirrhosis (NLC). This is a retrospective study on inpatients who underwent endoscopy within 24 hours of presentation for overt GIB with a platelet count (PC) of 20 to<50× 103/mL. Outcomes included diagnostic and therapeutic yields, procedural adverse events, packed red blood cell (pRBC) and platelet transfusions, recurrent bleeding rate, and all-cause and GIB-related mortality. One hundred forty-four patients were identified. The median PC was 41× 103/mL and 61% had LC. The diagnostic yield was 68% (LC= 61%, NLC= 79%, P= .04). Therapeutic yield was 60% (59% vs 60%, P= 1.00). The initial hemostasis rate was 94% with one adverse event. The median number of pRBC and platelet transfusions decreased after intervention in the entire cohort. Recurrent bleeding rates were 22% at 1 month and 30% at 1 year, with no differences between groups. An increased international normalized ratio (INR) >2 was a predictor of recurrent bleeding. All-cause mortality was 19% at 1 month and 37% at 1 year, whereas GIB-associated mortality in our cohort was only 3% at 1 month and 4% at 1 year, with no significant difference between LC and NLC. Predictors of mortality were INR >2, activated partial thromboplastin time >38 seconds, hypotension, intensive care unit admission, and pulmonary comorbidities. In this study cohort, we observed that endoscopy for overt GIB in the setting of severe thrombocytopenia in patients with LC and NLC appears safe, has moderate diagnostic and therapeutic yields with high initial hemostasis rate, and is associated with a significant decrease in pRBC and platelet transfusions. Recurrent bleeding and all-cause mortality rates remain high.

Bilateral extensive multiple multi-layered retinal haemorrhage in a patient with alcoholic liver disease.

We report a rare case of bilateral multiple bilateral vitreous, pre-retinal and intra-retinal haemorrhages after bouts of coughing in a 47 year old female patient with high international normalized ratio (INR) due to alcoholic liver disease. Patient has been complaining of 2 weeks history of reduced vision to her liver physician who referred her to local eye unit. She reported that the vision deteriorated following intense coughing. She was found to have bilateral vitreous, pre-retinal and intra-retinal haemorrhages. liver disease. The patient was kept under ophthalmic observation. The vitreous, preretinal and intraretinal haemorrhages resolved spontaneously and his vision recovered fully Alcoholic liver disease is becoming more common. Clinicians should be aware that the combination of increased intravenous pressure due to persistent coughing and possible early portal hypertension and a pathological increase in INR can lead to severe multiple multi-layered retinal haemorrhage. The haemorrhages, however, will resolve spontaneously in most cases. In foveal involving pre-retinal haemorrhage, YAG- laser membranotomy was shown to speed up visual recovery in previous reports.

Coagulation after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a retrospective cohort analysis.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) benefit patients with peritoneal carcinomatosis. Nevertheless, this therapy is associated with considerable postoperative pain due to the extensive abdominal incision. While epidural analgesia offers efficacious pain control, CRS and HIPEC therapy is associated with perioperative coagulopathy that may impact its use. The purpose of this retrospective study is to characterize the postoperative coagulopathy in this patient subset and to develop a model that will help predict those at risk. Our database of patients treated with CRS and HIPEC (n = 171) was reviewed to assess perioperative changes in platelet count, international normalized ratio (INR), and partial thromboplastin time (PTT). Abnormal coagulation was defined by platelet count < 100 × 10-9·L-1, INR ≥ 1.5, or PTT ≥ 45 sec. Severe abnormality in coagulation was defined by platelet count < 50 ×10-9·L-1, INR > 2.0, and/or PTT > 60 sec. A logistic regression model was developed to determine if patient, disease, and/or surgical factor(s) were associated with the development of postoperative coagulopathy. Epidural catheter management in this patient population was also reviewed. Significant differences (adjusted P < 0.007) were noted between median preoperative and postoperative platelet and INR values on postoperative days (POD) 0 through 6 and days 0 through 3, respectively. Highest observed median differences between preoperative and postoperative values showed a decrease in platelet count of 94 × 10-9·L-1 (POD 2 and POD 3), an increase in INR of 0.2 (POD 0 to POD 2), and a decrease in PTT of 3.1 sec (POD 5). Coagulopathy and severe coagulopathy occurred in 38% and 4.7% of patients, respectively. Predictors of coagulopathy included intraoperative transfusion of packed red blood cells (PRBCs) and perhaps the peritoneal carcinomatosis index (PCI). Epidural catheters were inserted in 26 patients for a median [IQR] duration of 7.0 [5.0-7.0] days without complication. At the time of their removal, no blood products were required to correct abnormal coagulation values. Altered coagulation may appear during the postoperative period in approximately 40% of our patients treated with CRS and HIPEC. Intraoperative transfusion of RBCs and possibly increased PCI are associated with abnormal postoperative coagulation. Close monitoring of coagulation parameters is required to help ensure safe removal of an epidural catheter.

Topical Antimycotics for Oral Candidiasis in Warfarin Users.

Treatment for oral candidiasis in warfarin users may be complicated by drug-drug interactions (DDIs) between warfarin and topically applied antimycotics. However, current knowledge of these putative DDIs is merely based on case series. We therefore performed a cohort cross-over study with the objective to evaluate the potential DDIs between warfarin and miconazole oral gel or nystatin oral solution. The cohort consisted of individuals using warfarin in the period of 1998-2012 (n ≈ 7400). We collected data on cohort members' measurements of the international normalized ratio (INR) from a clinical database, and obtained information on their use of topically applied miconazole and nystatin from a regional prescription register. Potential DDIs were assessed by comparing INR values before and after initiation of an antimycotic drug. Among 17 warfarin users exposed to miconazole oral gel, the mean INR increased from 2.5 (95% CI: 2.1-2.8) to 3.8 (95% CI: 2.8-4.8) after exposure, corresponding to a mean INR increase of 1.4 (95% CI: 0.3-2.4). Among 30 warfarin users exposed to nystatin oral solution, the mean INR was 2.7 (95% CI: 2.3-3.1) before and 2.5 (95% CI: 2.2-2.9) after exposure. In conclusion, we found evidence supporting a clinically relevant drug-drug interaction between warfarin and miconazole oral gel. In contrast, we did not find any indication of an interaction between warfarin and nystatin oral solution. Nystatin rather than miconazole should be preferred when treating warfarin users for oral candidiasis.

BPS 02–15 HIGHER INCIDENCE OF CARDIOHEPATIC SYNDROME IN PATIENTS WITH DECOMPENSATED HEART FAILURE AND ACUTE KIDNEY INJURY

Objective: Liver and kidney dysfunction is frequently encountered in heart failure and related to worse prognosis. Over the last several years interdependent feedback mechanisms involving the heart, kidney and liver have been discussed. The aim of the study was to assess the prevalence of acute kidney injury (AKI) and abnormal liver function tests (LFT) and their interrelations in acute decompensated heart failure (ADHF). Design and Method: In 322 ADHF patients (190 male, 69.5 ± 10.6years (M ± SD), arterial hypertension 87%, myocardial infarction 57%, atrial fibrillation 65%, diabetes mellitus 42%, known chronic kidney disease (CKD) 39%, chronic anemia 29%, ejection fraction (EF)38 ± 13%, EF <35% 39.1%) alanine transaminase (ALT), aspartate transaminase (AST), direct and total bilirubin (DB and TB), alkaline phosphatase (AP), gamma-glutamyl transpeptidase (GGT) and international normalized ratio (INR) were measured on admission. LFT were considered abnormal when levels exceeded local upper normal limit. Patients on warfarin were excluded from INR analysis. AKI was diagnosed based on KDIGO2012Guidelines. Mann-Whitney test and multivariate logistic regression analysis were performed, p < 0.05 was considered statistically significant. Results: Abnormal LFTs occurred in 274 (85.1%) patients. Increase of transaminases were detected in 68 (21.1%) patients (alone ALT/alone AST/both TA in 35.3, 26.5, 38.2% respectively), DB and/or TB in 264 (82%) patients (alone DB/alone TB/DB and TB – in 28, 0.8, 71.2% respectively), AP in 90 (27.9%) and GGT in 102 (31.7%) patients. AKI was diagnosed in 60 (18.6%) patients. Patients with versus without AKI had higher levels of ALT (60 ± 88 vs 29 ± 26U/l, p < 0.05), AST (52 ± 45 vs 31 ± 16U/l, p < 0.001), TB (29 ± 13 vs 25 ± 15 μmol/l, p < 0.01), DB (12 ± 7 vs 9 ± 7 μmol/l, p < 0.001), GGT (157 ± 117 vs 102 ± 68U/l, p < 0.001), AP (124 ± 74 vs 112 ± 88 U/l, p < 0.05), INR (1.49 ± 0.42 vs 1.29 ± 0.23, p < 0.01). Patients with vs without AKI had higher prevalence of increase of ALT (30 vs 12.3%, p < 0,001), AST (33.3 vs 9.2%, p < 0,001), TB (73.3 vs 56.2%, p < 0.05) and INR (60.8% vs 43.8%, p < 0,05). AKI was predictor for increase of ALT (OR 3.1,95%CI 1.6–5.9), AST (OR 4.9, CI 2.5–9.7), TB (OR2.1, CI1.2–4.0) and INR (OR 2.0, CI 1.0–3.9). Conclusions: Abnormal LFTs occurred in 85.1%, AKI-in 18.6% of patients admitted with ADHF. Patients with versus without AKI had higher prevalence of abnormal LFTs. In patients with ADHF increase of transaminases, total bilirubin and INR can directly contribute to AKI and vice versa.

A Tutorial on Pharmacodynamic Scripting Facility inSimcyp.

The Simcyp Simulator provides a framework for mechanistic Physiologically‐Based Pharmacokinetic/Pharmacodynamic modeling of potentially interacting drugs. It also provides a scripting facility, using the Lua language, for developing customized pharmacodynamic and toxicity models driven by drug concentrations at the site of action. We present an overview of the scripting facility including the scripting language, the editor, and how scripts are embedded within the Simulator. Examples incorporating differential equations and including inter‐individual variability on parameters are presented.

Real-World Impact of Setting a Narrow International Normalized Ratio Target Range in the Management of Older Adult Patients on Warfarin

Elderly patients intrinsically have higher bleeding risks, deterring clinicians from prescribing them oral anticoagulants. Setting a narrow international normalized ratio (INR) target range might potentially mitigate some of these risks. This study sought to compare the outcomes of elderly patients who were assigned to either a narrow INR target range or the conventional INR target range in a real-world environment. This was a retrospective cohort study with the primary and secondary outcomes being the mean percentage time above INR 3.0 and the mean percentage time below INR 2.0 and the incidents of bleeding and thromboembolism associated with oral anticoagulant therapy, respectively. Patients and health care workers managing them had no prior knowledge of this study. Data of 150 patients with a narrow INR target range (2.0-2.5) and 164 patients with a conventional INR target range (2.0-3.0) were collected and analyzed. The narrow INR group had significantly higher underlying risks of bleeding than the conventional INR group. Patients in the narrow INR group had a significantly lower percentage time above INR 3.0 but no significant difference in the percentage time below INR 2.0. Adjusted incidence rate ratio (IRR) for bleeding events was significantly lower for the narrow INR group, while the adjusted IRR for thromboembolic events between both groups was similar. Patients assigned to a narrow INR target range in real-world practice spent a significantly lower amount of time below an INR of 3.0 compared to conventional INR target range with lower incidents of bleeding complications and no increase in subtherapeutic INRs.

Warfarin-induced raised international normalized ratio is further prolonged by pantoprazole.

Sir, Drug–drug interactions are important to know so that any complication arising can be avoided, especially when it is life-endangering. We present a case where pantoprazole further increased the warfarin-induced raised International normalized ratio (INR) by potentiating warfarin effect. This increase in INR attenuated after stopping the pantoprazole, and a stable INR target was achieved. Pantoprazole is commonly used in Pediatric Intensive Care Unit (ICU) for prophylaxis of stress-induced ulcers. It probably can interact with warfarin and further prolong INR, which can result in life-threatening bleeding. A 14-year-old patient was admitted in our ICU in view of sepsis with pneumonia and later developed deep vein thrombosis of circumflex vein, common femoral vein, superficial vein, and popliteal vein. Heparin was started, later followed by warfarin in a dose of 0.2 mg/kg (8 mg/day) to maintain a target INR of 2.5. On day 3, her INR rose to 6, but the patient was stable, and there was no bleeding. Hence, we decreased the warfarin dose by 20%. After 2 days, INR was still raised at 5.0. We again decreased the dose and monitored INR. High INR led to a reduction of warfarin to a total dose of 1 mg/day. This usually does not happen in our practice, so we looked for drug interactions which can cause raised INR in patients on warfarin therapy and checked that our patient was not receiving any such drugs or dietary items such as garlic, mango, papaya, or fish. Our patient was receiving ceftriaxone, vancomycin, and pantoprazole. We could not change/stop antibiotics and so decided to stop pantoprazole. After 3 days, INR decreased to 1.4. We had to increase the warfarin dose to increase INR to 2.5. Final dose of warfarin now was 8 mg/day. We observed a 87.5% reduction in dose of warfarin when given concomitantly. Warfarin is a racemic mixture of stereoisomers where S-warfarin is 3–5 times more potent inhibitor of the Vitamin K epoxide reductase complex than R-warfarin. It undergoes extensive metabolism by the cytochrome P450 (CYP) isoforms. CYP2C9is responsible for the metabolism of S-warfarin, while R-warfarin is metabolized by CYP1A2, CYP2C19, and CYP3A4.[1] Any drug which can inhibit these cytochrome isoenzymes can lead to decreased metabolism of warfarin and thus prolonged effect of the drug.[2] In a study from Sweden, pantoprazole was shown to strongly inhibit CYP2C9 activity in vitro.[3] This may form the basis for the interaction between these two drugs. As warfarin has a low therapeutic index such interaction may lead to life-threatening bleeding. This interaction has also been reported in postmarketing period. However, one study clearly showed a lack of interaction between pantoprazole and warfarin.[4] On application of DIPS scale for drug–drug interaction, this case scored 5 points which shows that interaction between pantoprazole and warfarin is probable and caused a rise in INR.[5] We did not rechallenge/made alterations in the dose of pantoprazole. CYP2C9 polymorphism is unlikely as on stopping the pantoprazole INR again decreased to nontherapeutic range. In conclusion, in spite of a good rationale, there is small evidence for interaction between pantoprazole and warfarin; it would be pragmatic to monitor INR when pantoprazole and warfarin are used concomitantly to avert any serious bleeding. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Characterization of a porcine model for associating liver partition and portal vein ligation for a staged hepatectomy

BackgroundPublications using the ALPPS (associating liver partition and portal vein ligation for a staged hepatectomy) procedure have demonstrated a future liver remnant growth of 40–160% in only 6–9 days. The present study aimed to develop and describe the first large animal model of ALPPS that can be used for future studies. MethodsA total of 13 female domestic pigs underwent ALPPS stage 1 (portal vein division and parenchymal transection) followed by ALPPS stage 2 (completion left‐extended hepatectomy) 7 days later. An abdominal computed tomography (CT) scan was performed immediately prior to ALPPS stage 1 surgery and again 7 days later to assess hypertrophy immediately prior to ALPPS stage 2 surgery. Blood samples, as well as tissue analysis for Ki‐67, were performed. ResultsOn CT volumetric analysis, the mean size of the future liver remnant (FLR) prior to ALPPS stage 1 was 21 ± 2% and 40 ± 6% prior to ALPPS stage 2. The median degree of growth was 75% with a mean kinetic growth rate of 11% per day. Liver weights at autopsy correlated well with CT volumetric analysis (r = 0.87). There was no significant difference in mean lab values [asparate aminotransferase (AST), alanine aminotransferase (ALT), ammonia, International Normalized Ratio (INR) or bilirubin] from baseline until immediately prior to ALPPS stage 2. Post ALPPS stage 2 there was a significant increase in INR from baseline 1.1 to 1.6 (P = 0.012). No post‐operative deaths secondary to liver failure were observed. ConclusionThe present study describes the first reproducible large animal model of the ALPPS procedure. The degree of liver growth and the kinetic rate of growth were similar to that which has been demonstrated in human publications. This model will be valuable as future laboratory studies are performed.

Evaluation of clotting factor activities early after severe multiple trauma and their correlation with coagulation tests and clinical data

IntroductionTraumatic injuries are amongst the leading causes of death worldwide, frequently as a result of uncontrolled hemorrhage. Critical deficiencies in clotting factors have been noted in trauma-induced coagulopathy. However, the exact underlying conditions that result in devastating coagulopathies remain unclear. The purpose of this study was to elucidate these underlying deficiencies.MethodsBlood samples were drawn from 45 severely injured trauma patients on their arrival at the resuscitation room, and the activities of all soluble clotting factors and routine coagulation tests were assessed. The Mann–Whitney-U-test was used to assess differences in coagulation activity between the patients and healthy controls. Furthermore, Spearman’s rank correlation was used to analyze the blood work.ResultsAfter severe trauma the levels of serum fibrinogen and calcium were significantly reduced. Furthermore, traumatized patients had a significantly increased International Normalized Ratio (INR) compared to healthy controls. The median activities of all clotting factors were reduced after severe multiple trauma, with the exception of factor VIII, which was increased. Statistically significant differences were observed for factors II (80 vs. 122 %, P < 0.0001), V (76 vs. 123 %, P < 0.0001), VII (90 vs. 114 %, P = 0.002), VIII (200 vs. 108 %, P < 0.0001), and X (86 vs. 122 %, P < 0.0001). Spearman’s correlation indicated a significant negative correlation between INR on arrival with fibrinogen and levels of factors II, V, and VII, whereas Partial Thromboplastin Time was significantly negatively correlated with factor VIII (all P < 0.0001).ConclusionsThese findings suggest a general but rather moderate impairment of clotting factor activities following severe multiple trauma. In the concept of a calculated coagulation therapy, this could demand for the use of factor concentrates with higher ratios of clotting factors. Finally, the physiological importance of strongly elevated factor VIII activity remains unclear, but a possible interference with ex vivo measurements of Partial Thromboplastin Time has to be considered.

Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy

Coagulopathy has a high prevalence in critically ill patients. An increased International Normalized Ratio (INR) is a common trigger to transfuse fresh frozen plasma (FFP), even in the absence of bleeding. Therefore, FFP is frequently administered to these patients. However, the efficacy of FFP in correcting hemostatic disorders in non-bleeding recipients has been questioned. To assess whether INR prolongation parallels changes in the results of other tests investigating hemostasis, and to evaluate the coagulant effects of a fixed dose of FFP in non-bleeding critically ill patients with a coagulopathy. Markers of coagulation, individual factor levels and levels of natural anticoagulants were measured. Also, thrombin generation and thromboelastometry (ROTEM) assays were performed before and after FFP transfusion (12 mL kg(-1) ) to 38 non-bleeding critically ill patients with an increased INR (1.5-3.0). At baseline, levels of factor II, FV, FVII, protein C, protein S and antithrombin were reduced, and thrombin generation was impaired. ROTEM variables were within reference ranges, except for a prolonged INTEM clot formation time. FFP transfusion increased the levels of coagulation factors (FII, 34% [interquartile range (IQR) 26-46] before vs. 44% [IQR 38-52] after; FV, 48% [IQR 28-76] before vs. 58% [IQR 44-90] after; and FVII, 25% [IQR 16-38] before vs. 37% [IQR 28-55] after), and the levels of anticoagulant proteins. Thrombin generation was unaffected by FFP transfusion (endogenous thrombin potential, 72% [IQR 51-88] before vs. 71% [IQR 42-89] after), whereas ROTEM EXTEM clotting time and maximum clot firmness slightly improved in response to FFP. In non-bleeding critically ill patients with a coagulopathy, FFP transfusion failed to induce a more procoagulant state.

Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies.

This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin. We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus® and Innovin® reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR. The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0-3.0, the INR contribution of rivaroxaban with Neoplastin Plus® was 0.5-1.2, decreasing to 0.3-0.6 with Innovin® at median trough rivaroxaban plasma concentrations (38 μg l(-1) ). The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin® is preferable to Neoplastin Plus® because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR.

Continuous molecular adsorbent recirculating system treatment in 69 patients listed for liver transplantation

Objective. The molecular adsorbent recirculating system (MARS) is used to purify blood from albumin-bound toxins in patients with liver failure. However, the application of MARS has not demonstrated improved survival in randomized clinical trials and the clinical utility has not been finally established. In our department, the use of MARS is now restricted to the most critically ill patients with acute or acute on chronic liver failure. Material and methods. Since 2005, we have treated 69 patients (30 males/39 females with median age of 49 years ranging from 1 months to 70 years) listed for liver transplantation (LT) with MARS. Median model of end-stage liver disease score in patients older than 12 years of age (n = 56) was 33 (interquartile range 26–39). The flow rate was 35–40 mL/kg/h and treatment kits were changed every 8–12 h. The patients were treated for a median of 27 h (range 1–144 h). Results. Fifty-six patients (81%) were transplanted. Nine died before they could be transplanted, and four patients recovered without transplantation. Forty-six (82%) of the transplanted patients were alive 30 days after transplantation. Ammonium decreased modestly from a median of 148 to 124 µM (p = 0.03) during MARS treatment. We detected worsening of coagulopathy with significant decreases in platelet count and fibrinogen concentrations, and increase in International Normalized Ratio. Phosphate and magnesium decreased significantly during MARS treatment. Conclusion. Continuous MARS therapy may bridge liver failure patients to LT under close observation and treatment of coagulopathy and electrolyte disturbances.

Low Doses of Acetaminophen Prolonged Prothrombin Time and Increased International Normalized Ratio in Patients Receiving Long-Term Therapy

Abstract Objectives: Acetaminophen is one of the safest and effective antipyretic and analgesic medications. Long term administration of this medication appeared to interfere with the activity of two key enzymes of the vitamin K cycle. The primary end point of this study was to evaluate the chronic effect of acetaminophen on Prothrombin Time (PT) and International Normalized Ratio (INR) parameters. Methods: Prospective, longitudinal , double-blind, placebo-controlled study was performed in Kurdistan region of Iraq, patients suffering from mild headache were prepared to take acetaminophen 500 mg twice daily for at least (8) months. PT, INR, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured for both patient and control groups before drug administration and then every month. Results: The main consequence of the study was the difference in mean PT and INR between control group and group receiving acetaminophen long term therapy for 8 months. In patients on acetaminophen (1 g/day), the mean observed PT and INR were significantly elevated during therapy period. The significant differences in mean PT started from the second month of therapy (12.910 ± 0.098) in patients on acetaminophen versus (12.083 ± 0.077) in control participants (P<0.01). The maximum variations of mean PT was observed after eight months in patients on acetaminophen compared with the control participants (18.903 ± 0.184 vs. 12.300 ± 0.066, P< 0.01). Likewise the mean observed INR was significantly increased after the second month of treatment (1.123 ± 0.013) in patients on acetaminophen versus (1.006 ± 0.101) in control subjects (P<0.01). As well, maximum variations of mean INR observed after eight months in patients on acetaminophen compared with the control participants (2.084 ± 0.033 vs. 1.036 ± 0.008, P<0.01). There was a significant difference of mean ALT observed during the latest three months of study period in patients on acetaminophen compared with the control participants (P<0.01). However a significant value of both PT and INR in all patients rose markedly during the eight months of acetaminophen therapy. Conclusion: The clinical findings of this study support that chronic administration of acetaminophen at low dose (Ig/day) induce a highly significant elevation of PT and INR parameters in all patients participated in this study.

How safe is acetaminophen use in patients treated with vitamin K antagonists? A systematic review and meta-analysis

IntroductionAcetaminophen is a commonly prescribed and over-the-count used drug, and is considered to be the preferred treatment choice for anticoagulated patients requiring analgesic drug therapy. However, observational data have suggested that this drug combination may increase the International Normalized Ratio (INR) values and bleeding events in patients taking Vitamin K antagonists (VKAs). Still, the clinical impact of this putative effect remains unknown. Therefore, we performed a systematic review of randomized controlled trials (RCTs) to estimate the impact of concomitant use of acetaminophen and VKA in the INR measurements MethodsSystematic review and meta-analysis of RCTs comparing acetaminophen versus placebo or no treatment, in VKA-treated patients and reporting INR estimates. Medline and Cochrane Library were searched up to April 2014. Primary outcome was the mean difference (MD) between the greatest INR elevations in each treatment arm. Random-effects meta-analysis was performed to derive pooled estimates and 95% Confidence Interval (CI). Heterogeneity was evaluated with I2 test. ResultsSeven RCTs (n=225 patients) were included. Acetaminophen was associated with a mean 0.62 INR increase (95%CI: 0.46 to 0.78; I2=25%) compared to placebo in VKA-treated patients. Studies did not report any major bleeding event. Meta-regression showed a significant 0.17 mean increase of the INR per each daily gram of acetaminophen (95%CI: 0.004 to 0.33). ConclusionAcetaminophen is associated with a statistically significant and possible clinically relevant increase in the INR, with a dose dependent relationship. Patients treated concomitantly with VKA and acetaminophen should be monitored more regularly for possible VKA dosage adjustment.

Fasting and warfarin

Recently, we reported the findings of a study on the effects of Ramadan fasting on a group of 32 Muslim patients taking warfarin.13 Weekly INR (international normalized ratio) readings were taken from subjects with previously stable INRs over a three-month period spanning pre-Ramadan to post-Ramadan. We found a statistically significant increase in the mean INR by 0.23 (p=0.006) during Ramadan from the pre-Ramadan month and decreased by 0.28 (p<0.001) after Ramadan. There was no significant difference (p=1.000) in mean INR between the non-Ramadan months. Importantly, there was a decline in the time within therapeutic range (TTR) during Ramadan with a corresponding increase in TTR above the therapeutic target range. %TTR declined from 80.99% before Ramadan to 69.56% during Ramadan (p=0.453). The first out-of-range INR was seen around 12.1 days (95% CI 9.0-15.1) after the start of fasting and returned within range about 10.8 days (95% CI 7.9-13.7) after Ramadan. Time above range increased from 10.80% pre-Ramadan to 29.87% during Ramadan (p=0.027), while time below range increased from 0.57% during Ramadan to 15.49% post-Ramadan (p=0.006). This observation is directly attributable to the effects of fasting.

Successful anesthetic management of a patient with thyroid carcinoma invading the trachea with tracheal obstruction, scheduled for total thyroidectomy

We report a case of large thyroid carcinoma with tracheal and esophageal invasion who presented with preoperative stridor scheduled for total thyroidectomy and segmental tracheal resection. Careful and comprehensive preoperative anesthetic planning was done. Extracorporeal circulation membrane oxygenation (ECMO) was set up and running prior to induction under local anesthesia, due to an increased international normalized ratio (INR) and fear of bleeding in the airway. Fiberoptic bronchoscopy (FOB) is the first choice in many circumstances of difficult airway. However, we twice failed to intubate under FOB guidance. Successful intubation was done with traditional laryngoscopy and a Glidescope. The operative course was smooth. The oral endotracheal tube (ETT) was changed to a nasal ETT after surgery with the Glidescope. FOB-assisted intubation carries a chance of failure, and in critical patients, the presence of other intubating modalities such as video-assisted or fiberoptic-assisted technology or safety measures, including ECMO, will greatly increase the safety of anesthesia and surgery.

Peripheral vein infusion of autologous mesenchymal stem cells in Egyptian HCV-positive patients with end-stage liver disease.

IntroductionWe have assessed the utility of autologous mesenchymal stem cell (MSC) peripheral vein infusion as a possible therapeutic modality for patients with end-stage liver diseases.MethodsForty patients with post-hepatitis C virus (HCV) end-stage liver disease were randomized into two groups: Group 1 (GI): 20 patients who received granulocyte colony-stimulating factor (G-CSF) for 5 days followed by autologous MSCs peripheral-vein infusion and group 2 (GII): 20 patients who received regular liver-supportive treatment only (control group).ResultsIn MSC-infused patients (GI), 54% showed near normalization of liver enzymes and improvement in liver synthetic function. Significant changes were reported in albumin (P = 0.000), bilirubin (P = 0.002), increased international normalized ratio (INR) (P = 0.017), prothrombin concentration (P = 0.029) and alanine transaminase (ALT) levels (P = 0.029), with stabilization of clinical and biochemical status in 13% of cases. None of the patients in GII showed any significant improvement. Hepatic fibrosis was assessed in GI by detection of procollagen IIIC peptide level (PIIICP) and procollagen III N peptide level (PIIINP). The pretreatment values of s-PIIICP and s-PIIINP were 9.4 ± 4.2 and 440 ± 189, respectively, with a decrease to 8.1 ± 2.6 and 388 ± 102, respectively, 3 months after MSC therapy. However, the difference was statistically nonsignificant (P = 0.7). A significant correlation coefficient was reported after 3 months between the s-PIIINP and prothrombin concentration (P = -0.5) and between s-PIIICP and ascites (P = 0.550).ConclusionsFirst, autologous MSC infusion into a peripheral vein is as effective as the previously reported intrahepatic infusion. Second, MSCs have a supportive role in the treatment of end-stage liver disease, with satisfactory tolerability and beneficial effects on liver synthetic functions and hepatic fibrosis. Third, IV infusion of MSCs after G-CSF mobilization improves s-albumin within the first 2 weeks and prothrombin concentration and alanine Taransaminase after 1 month. According to the data from this current study and those previously reported by our group, we recommend further studies on patients’ infusion with pure CD133 and CD34 followed by IV infusion of in vitro-differentiated MSCs within 1 week and another infusion after 3 months.Trial registrationClinicalTrials.gov NCT01729221. Registered 17 November 2012.

The Lesser Known Side-Effect of Warfarin: Warfarin-Induced Venous Limb Gangrene

An 84-year-old woman receiving warfarin for antiphospholipid antibody syndrome and who had a history of bilateral lower extremity amputations presented to the emergency department with severe bilateral necrotic changes over her legs and arms (Figures 1 and 2). She had begun warfarin therapy 3 months earlier for newly diagnosed antiphospholipid antibody syndrome. Her International normalized ratio (INR), which had been 6.04 six days prior to admission, was 3.63 on admission. Skin biopsy specimens revealed necrosis secondary to vascular thrombosis. A warfarin-induced etiology was suspected, and the drug was discontinued.Figure 2Additional ischemic changes on patient's right elbow. There were no ischemic changes noted on patient's breasts or abdomen, as would normally present in warfarin-induced skin necrosis.View Large Image Figure ViewerDownload (PPT) Unlike warfarin-induced skin necrosis, which classically presents centrally over adipose tissue approximately 3 days after starting warfarin in the setting of congenital protein C deficiency,1Warkentin T.E. Elavathil L.J. Hayward C.P. Johnston M.A. Russett J.I. Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.Ann Intern Med. 1997; 127: 804-812Crossref PubMed Scopus (427) Google Scholar warfarin-induced venous limb gangrene is a less well-described side-effect of warfarin and presents in the distal extremities2Haimovici H. Bergan J.J. Coumadin-induced skin necrosis versus venous gangrene of the extremities.J Vasc Surg. 1987; 5: 655-656Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and paradoxically with a supratherapeutic INR.3Warkentin T.E. Venous limb gangrene during warfarin treatment of cancer-associated deep venous thrombosis.Ann Intern Med. 2001; 135: 589-593Crossref PubMed Google Scholar It can occur in patients with hypercoagulable states, such as heparin immune thrombocytopenia1Warkentin T.E. Elavathil L.J. Hayward C.P. Johnston M.A. Russett J.I. Kelton J.G. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia.Ann Intern Med. 1997; 127: 804-812Crossref PubMed Scopus (427) Google Scholar or antiphospholipid antibody syndrome.4Grim Hostetler S. Sopkovich J. Dean S. Zirwas M. Warfarin-induced venous limb gangrene.J Clin Aesthet Dermatol. 2012; 5: 38-42PubMed Google Scholar The increase in INR has been shown to reflect a concurrent depletion of protein C,3Warkentin T.E. Venous limb gangrene during warfarin treatment of cancer-associated deep venous thrombosis.Ann Intern Med. 2001; 135: 589-593Crossref PubMed Google Scholar which is normally balanced by warfarin's ability to prevent thrombin formation by depleting other procoagulant factors. However, in patients with warfarin-induced venous limb gangrene, warfarin does not adequately prevent thrombin-antithrombin complex formation.3Warkentin T.E. Venous limb gangrene during warfarin treatment of cancer-associated deep venous thrombosis.Ann Intern Med. 2001; 135: 589-593Crossref PubMed Google Scholar This patient's hypercoagulability from her antiphospholipid antibody syndrome, abrupt depletion of protein C as reflected by her elevated INR, and failure of warfarin to prevent thrombin-antithrombin formation, likely led to formation of multiple microthrombi in the distal extremities. It is unclear why this phenomenon occurs in some patients but not others.

Comments to Prediction of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: An Enhanced Model of BARD Score

Dear Editor, I read with interest this paper which introduces an enhanced scoring model to predict advanced fibrosis in nonalcoholic fatty liver disease. The new model added the international normalized ratio (INR) as a risk factor apart from the three factors of body mass index, aspartate transaminase/alanine aminotransferase ratio, and diabetes mellitus (BARD score).1 INR is a measure of the extrinsic pathway of coagulation and status of liver damage. It is influenced by vitamin K intake and availability, tobacco consumption, and other variables.2,3 Common digestive disorders, such as vomiting and malabsorption, create fluctuations in INR. Warfarin resistance has been reported with rapid increase in INR due to interaction with prednisone, vitamin C, leflunomide, and herbal-drug interaction.4-6 And there are several case reports about Warfarin-cranberry juice interaction.7 In addition, value of INR increases significantly with time from plasma stored at -40℃ or -20℃.8 The new model presented here maintains the simplicity and strength of the BARD score, and the combination of INR and BARD score reduces the occurrence of false positives. Nevertheless, the INR is influenced by multiple variables as stated above, especially the use of warfarin, which is prescribed worldwide. More studies have been suggested to assess the INR, which is influenced by many variables, before the establishment of a new model. Additionally, the authors state in the introduction section the importance of the diagnosis of fibrosis in the early stage, rather than the advanced stage as mentioned in the title.