Increase In INR Research Articles

Assessment of hemostatic changes after crystalloid and colloid fluid preloading in trauma patients using standard coagulation parameters and thromboelastography

Background:The choice of an ideal fluid administered post trauma and its subsequent influence on coagulation still poses a clinical dilemma. Hence, this study was designed to assess the influence of in vivo hemodilution with various fluid preparations (4% gelatin, 6% hydoxyethyl starch (HES), Ringer's lactate, 0.9% normal saline) on coagulation using standard coagulation parameters and real-time thromboelastography (TEG) in patients undergoing elective surgery post trauma.Methods:In a randomized, double-blind study, 100 patients of either sex and age, belonging to ASA Grades I and II, scheduled for elective surgeries were allocated into four groups of 25 each according to the type of fluid infused. Group G (4% gelatin), Group N (0.9% normal saline), Group R (Ringer's lactate), and Group H (6% HES) received preloading with 1 L of fluid according to the group. The coagulation status of the patients was assessed during perioperative period (before surgery, after fluid preloading, and at the end of the surgery) using both conventional coagulation analysis and TEG.Statistical Analysis:Analysis of variance (ANOVA), post hoc and Pearson Chi-square test were used.Results:In all the patients preloaded with gelatin, there was a significant increase in prothrombin time index (PTI; 14.88±0.90 vs. 13.78±3.01, P<0.001) and international normalized ratio (INR; 1.12±0.09 vs. 1.09±0.19, P<0.05) compared to the baseline value. An increase was observed in these parameters in the postoperative period also. In the HES group, there was statistically significant increase in PT time (15.70±1.51 vs. 13.74±0.75, P=0.01) and INR (1.20±0.15 vs. 1.03±0.17, P<0.001) as compared to the baseline. In the intergroup comparisons, the patients preloaded with HES had a significant increase in INR (1.20±0.15 vs. 1.12±0.09, P=0.04) and reaction time (R time; 6.84±2.55 min vs. 4.79±1.77 min, P=0.02) as compared to the gelatin group. The fall in coagulation time (k time; 2.16±0.98 vs. 3.94±2.6, P=0.02), rise in maximum amplitude (MA; 61.94±14.08 vs. 50.11±14.10, P=0.04), and rise in A20 (56.17±14.66 vs. 43.11±14.24, P=0.05) were more in patients preloaded with RL as compared to the HES group. 100% patients in the gelatin group, 84.2% patients in the NS group, 94.4% patients in the RL group, and 66.7% patients in the HES group had hypocoagulable (R time > 14 min) state in the postoperative period.Conclusion:Crystalloids are optimal volume expanders in trauma, with RL having beneficial effects on coagulation system (decrease in k time and increase in MA and A20). Among the colloids, HES 6% (130/0.4) affects coagulation parameters (increase in PTI, INR, R time, k time) more than gelatin. Trial registration (protocol number-IEC/NP-189/2011).

Amoxicillin/clavulanic acid‐warfarin drug interaction: a randomized controlled trial

To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy. In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo. The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P=0.94). The day 7-day 1 factor II, R(-) and S(-) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P=0.81, P=0.45, P=0.75, respectively). Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.

Interactions between Natural Health Products and Oral Anticoagulants: Spontaneous Reports in the Italian SurveillanceSystem of Natural Health Products

Introduction. The safety of vitamin K antagonists (VKA) use can be compromised by many popular herbal supplements taken by individuals. The literature reports that 30% of warfarin-treated patients self-medicates with herbs. Possible interactions represent an health risk. We aimed to identify all herbs-oral anticoagulants interactions collected in the Italian database of suspected adverse reactions to “natural health” products. Methods. The Italian database of spontaneous reports of suspected adverse reactions to natural products was analyzed to address herb-VKAs interactions. Results. From 2002 to 2009, we identified 12 reports with 7 cases of INR reduction in patients treated with warfarin (n = 3) and acenocoumarol (n = 4), and 5 cases of INR increase (all warfarin associated). It was reported 8 different herbal products as possibly interacting. Discussion. Our study confirms the risk of interactions, highlighting the difficulty to characterize them and their mechanisms and, finally, prevent their onset. The reported data underline the urgent need of healthcare providers being aware of the possible interaction between natural products and VKA, also because of the critical clinical conditions affecting patients. This is the first step to have the best approach to understand possible INR alterations linked to herb-VKA interaction and to rightly educate patients in treatment with VKA.

Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial

We investigated whether acetaminophen, given at 2 g/day and 3 g/day might potentiate the anticoagulant effect of warfarin. Forty-five patients on stable warfarin therapy, enrolled in this prospective, randomized, parallel (three arms), placebo-controlled study, received a 10-day regimen of acetaminophen (2 g/day or 3 g/day) or placebo. The mean maximal INR increase was 0.70 ± 0.49 and 0.67 ± 0.62 in patients receiving acetaminophen at 2 g/day and 3 g/day, respectively (P=0.01 for the respective comparisons versus placebo). The INR increase became significant on day 3 and was independently and significantly predicted by a maximal decrease in factor II (R(2)=0.36, P<0.0001), factor VII (R (2)=0.46, P<0.0001) and a maximal increase in acetaminophen plasma concentrations (R(2)=0.563, P<0.0001). Acetaminophen, at 2 g/day or 3 g/day, enhanced the anticoagulant effect of warfarin in stable patients, thus requiring close INR monitoring in the clinical setting.

Preliminary results of an open-label phase I pharmacokinetic/pharmacodynamic study of JNJ26481585: Early evidence of antitumor activity

e13504 Background: JNJ26481585 is a novel orally active pan-histone deacetylase inhibitor (HDACI) which showed potent antitumor efficacy in a wide range of animal tumor models. Methods: A 2-stage accelerated titration design Phase I trial was conducted to characterize safety, establish the maximum tolerated dose (MTD) and determine pharmacokinetics in patients (pts) with refractory solid tumors, of performance status &lt;2 and with adequate hematologic, renal, hepatic and cardiac function. The drug was administered orally, once daily in 3 weekly cycles. Results: To date, 9 pts (median age 59; range 32–74) have been treated at 4 dose levels (DL): 2 (2 pts), 4 (2 pts), 8 (3 pts), and 12 (2 pts) mg. The median number of cycles administered was 2 (range 1–9). Dose-limiting toxicity was seen at 12mg (CTCAE Grade [G] 3 non-sustained ventricular tachycardia [VT] [1 pt] and G3 fatigue [1 pt]) and the 8mg cohort is being expanded. Other toxicity observed at 12mg comprised G2 palpitations with QT prolongation (1 pt), G2 anorexia (1 pt), G2 vomiting (1 pt) and G2 dysgeusia (1 pt). At 8mg, 1 pt on warfarin developed a G2 INR increase. Non-specific ECG changes were observed from the 2mg DL onwards. The drug was generally well tolerated up to 8mg. Exposure to JNJ26481585 increased proportionally over the 2 to 12mg dose range, with a constant metabolite/parent ratio (3.5 for Cmax; 7 for AUC). Two partial responses (PR) and one stable disease (SD) have been observed. PR occurred in 2 pts with metastatic melanoma treated at 12mg : one pt had a PR in visceral and complete response in subcutaneous melanoma metastases after 22 days of drug and has ongoing response 5 months after stopping treatment; the second pt had PR in lymph nodes and reduction of cutaneous lesions of melanoma. One non small cell lung cancer pt treated at 4mg showed SD for 9 cycles. Assessment of histone acetylation as a pharmacodynamic biomarker in peripheral blood lymphocytes and hair follicles is ongoing. Conclusions: JNJ26481585 is generally well tolerated at doses up to 8mg daily. Evidence of promising antitumor activity has been observed with 2 PR to date in patients with metastatic melanoma. The 8mg cohort is being expanded with increased cardiac monitoring. Other schedules may be explored in the future. [Table: see text]

Influence of CYP2C9 and VKORC1 on warfarin response during initiation of therapy

Background Although multiple reports have documented the influence of CYP2C9 and VKORC1 variants on warfarin dose, risk of over-anticoagulation and hemorrhage, their influence on anticoagulation maintenance and individual proportion of time spent in target INR range (PPTR) is limited. Moreover the potential benefit of genotype-guided dosing implemented after initiation of therapy in a racially diverse population has not been explored. Herein we present the influence of CYP2C9 and VKORC1 C1173T on warfarin response during the first 30 days of therapy. Methods Warfarin dose was empirically determined in 250 African Americans 271 European Americans. The influence of CYP2C9 and VKORC1 on rate of INR increase, anticoagulation maintenance, risk of over-anticoagulation, and change in dose over 30 days was evaluated after adjustment for socio-demographic, lifestyle and clinical factors. Possession of variant VKORC1 (± variant CYP2C9) genotype was associated with a more rapid attainment of target INR and higher frequency of dose adjustments. Patients possessing variant genotypes spent less time in target range. However adjustment for rate of INR increase rendered the association non-significant. European Americans (but not African Americans) possessing variant VKORC1 (± variant CYP2C9) genotype had a higher risk of over-anticoagulation. Neither CYP2C9 nor VKORC1 influenced the risk of minor hemorrhage. CYP2C9 and VKORC1 explained 6.3% of the variance in dose change over the first 30 days of therapy demonstrating that the usefulness of genotype-guided dosing may extend beyond first day of therapy. Conclusion The benefit of genotype-based dose prediction may extend beyond first few days of therapy. Whether genotype-guided dosing will decrease the risk of over-anticoagulation, improve anticoagulation control and most importantly improve outcomes for chronic warfarin users remains to be proven.

Tibolone (Livial ®) enhances warfarin-induced anticoagulation in postmenopausal women

Objective To investigate the potential drug interaction between tibolone and warfarin in healthy postmenopausal women. Methods and results The study was designed as a double-blind, randomized, placebo-controlled, two-way crossover study in postmenopausal women. After stabilization of the International Normalized Ratio (INR; a standardized prothrombin time, PT) between 1.4 and 2.0 with warfarin, subjects were randomized to receive either tibolone (2.5 mg/day) or placebo for 21 days. After a 7-day wash-out period (during which warfarin treatment was continued) the treatments were crossed over. Primary efficacy parameters were INR and coagulation Factors II, VII, VIIa and X (means of measurements at Days 18 and 20 and Days 46 and 48). Treatment with tibolone induced a statistically significant increase in INR (estimate of mean difference = 0.40; P = 0.002), and a statistically significant decrease in coagulation factors. Treatments were generally well tolerated and no clinically significant adverse events were observed. Conclusions Tibolone enhances warfarin-induced anticoagulation in postmenopausal women, as reflected by increases in INR and decreases in coagulation Factors II, VII, VIIa and X, compared to placebo. It is advisable to monitor for changes in coagulation status during (and after discontinuation of) simultaneous use of tibolone and warfarin.

Interaction between Paracetamol and Warfarin: A Double-Blind Placebo-Controlled Randomised Study.

Background: Paracetamol is the gold standard antalgic and antipyretic therapy for patients receiving oral anticoagulants. Paracetamol and anticoagulant are therefore often concomitantly prescribed. The literature reports conflicting data about this association, concluding sometimes to the existence of an interaction and sometimes not. The primary objective of the study is to assess the effect of paracetamol on the anticoagulant effect of warfarin in usual conditions.Methods: Patients on stable oral anticoagulation (warfarin with a target INR between 2 and 3) for at least 1 month have been included in a prospective randomised double blind study, cross-over controlled versus placebo. They randomsuccessively received for a 14 days-period paracetamol (at 1g four times daily) and placebo. Both periods were separated by a wash-out period lasting at least 2 weeks. INR, factors II, V, VII, X were measured during each period before the intake of the study-treatment and 12h after the intake at day 2, 4, 7, 9, 11 and 14.Results: 20 patients were included. On paracetamol, the mean maximal INR increase observed was 1.01 ± 0.45 versus 0.27 ± 0.28 on placebo, p=0.003. The mean maximal INR was higher on paracetamol than on placebo (3.45 vs 2.66, p=0.01). A clinically significant increase of INR (above 0.5) was observed in 17 out of 19 patients on paracetamol as compared to 3 out of 19 patients on placebo. Factor II, VII, X levels were significantly decreased on paracetamol while there was no difference in factor V levels.Discussion: Paracetamol at 4g/d induced a significant increase in INR in patients on a stable anticoagulation with warfarin. It results in an increase in the risk of bleeding of the warfarin. The mechanism of the interaction may be a metabolit of the paracetamol, inhibiting of enzymes involved in the synthesis of the vitamino-K dependent clotting factors.

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Aims: To assess the effects of surgery and ANH on coagulation. Methods: A total of 33 patients randomized to ANH (n = 17)/no ANH (n = 16), undergoing major gastrointestinal surgery, were prospectively studied. Coagulation tests included aPTTR, INR, platelets, fibrinogen and thromboelastography (TEG). Results: There was no significant difference between groups at entry. In ‘no ANH’, as operation progressed, there was a decrease in platelet count (P < 0.001) and fibrinogen (P = 0.001), and increase in aPTTR (P = 0.002) and INR (P = 0.001). The TEG confirmed this; decrease in alpha angle (P = 0.006), MA (P = 0.003) and G (P = 0.001), increase in K (P = 0.008). Prior to knife to skin, ANH reduced platelet count (P = 0.003) and fibrinogen (P = 0.001), and increased aPTTR (0.003) and INR (P = 0.001). R time was shortened (P = 0.001) but MA (P = 0.001) and G (P < 0.001) decreased. Re-transfusion of autologous blood increased platelet count (P = 0.03) and fibrinogen (P = 0.004), decreased aPTTR (P = 0.017) and INR (P = 0.002), without affecting the TEG. Between the groups, at the time of knife to skin, the ANH group had a lower platelet count (P < 0.001), increased INR (P = 0.006), reduced MA (P = 0.010) and G (P = 0.011), but shortened R time (P = 0.004). At 1 h into operation, the platelet count remained lower (P = 0.002), the INR (P = 0.005) and aPTTR (P = 0.008) significantly prolonged. Immediately prior to re-transfusion the only difference was a prolonged INR (P = 0.023). By the end of the operation there was no difference between groups. In addition there was no difference in estimated blood loss. Conclusions: Coagulation is significantly impaired as operation progresses. Acute normovolaemic haemodilution impairs coagulation; this remains significantly impaired throughout operation.

Heparin and Low Molecular Weight Heparin Prolong Prothrombin Times in Patients on Warfarin Treatment

Most commercially available prothrombin (PT) as says are stated to be insensitive to heparin in therapeutic doses. These conclusions are, however, based on studies using normal plasma samples. The aim of the present study was to study the effect of unfractioned heparin, three low molecular heparins, and a heparinoid on six prothrombin assays using plasma samples from patients on warfarin. Plasma samples from 30 patients on warfarin were heparinized in vitro with unfrac tioned heparin, three different low molecular weight heparins (Fragmin® [Pharmacia/Upjohn Inc., Delaware, U.S.A.], Klex ane® [Rhone Poulenc Rorer, Halte, Denmark], and Logiparin- Dinnohep®, [Leo Biological Products, Ballerup, Denmark]) and the heparinoid Org 10172 (Orgaran [Organon, Oss, The Netherlands]) to obtain 0.50-1.50 U/ml plasma. The PT time was then determined with four PT reagents stated to be insen sitive to heparin (Innovin [Dade, Miami, Florida, U.S.A.], Ny coplastin [Nycomed Pharma, Oslo, Norway], Nycotest PT [Ny comed Pharma], and Stago Prothrombin Complex Assay [SPA 50, Diagnostica Stago, Franconville, France]) and two reagents stated to be sensitive to heparin (Manchester Reagent [Manchester Comparative Reagent, Ltd., Stockport, Great Brit ain] and Thrombotest [Nycomed]). All PT assays except Inno vin were sensitive to the heparins. With a heparin concentration of 0.5 U/ml plasma, the increase in INR ranged from 18-55% with Thrombotest and 0-44% with the other assays. The in crease in INR values by 1.5 U/ml plasma differed among the heparins used; Manchester Reagent 6-297%, Thrombotest 43- 247%, Nycoplastin 48-81%, SPA 50 20-74%, Nycotest PT 17-36%, and Innovin 0-5%. Orgaran did not prolong the clot ting time with the Manchester Reagent. With the other five PT assays, Innohep (Leo Biological Products, Ballerup, Denmark) and Orgaran gave the largest increase in INR value. Fragmin, Klexane, and unfractioned heparin caused a similar low in crease in INR. A 3-h delay in testing prolonged the prothrom bin times with the simple PT assays (Manchester Reagent and Nycoplastin). The other assays were little affected. Concomi tant heparin therapy prolongs the PT clotting times with all reagents, except Innovin, to the extent that with three of the assays examined this may lead to underdosing of warfarin.

How do we manage the hemorrhagic risk on hypovitaminosis K and treatments with antivitamin K

Vitamin K deficiency leads to a deficit in vitamin K-dependent factors, resulting in either hypocoagulability and a decrease in the Quick one-stage prothrombin time expressed as the prothrombin time (PT), or in an increase in INR in patients receiving oral anticoagulation. The anesthesiologist's objective is to bring these values back into the safety range before surgery, i.e., above 50% for PT and below 1.5 for INR. The method to be used will be chosen according to the urgency of the correction. Safety ranges may be reached in 6-12 h following oral or parenteral administration of vitamin K. A 5-mg dose is usually sufficient. If the deficit in vitamin K-dependent factors requires immediate correction, intravenous administration of PPSB should be done. The minimum time during which antivitamin K treatment may be disrupted after surgery depends on both the possibility of restarting oral treatment and the risk of postoperative haemorrhage. During this period, the need for an anticoagulation treatment using heparin should be discussed according to the risk of thrombosis.

Effects of long scotophase and cold acclimation on heat production in two diurnal rodents

Heat production $$(\dot V_{O_2 } )$$ of two diurnal rodents,Rhabdomys pumilio andLemniscomys griselda was measured in long scotophase-LS (8L: 16D; 25°C) acclimated and long scotophase and cold — LSAC (8L: 16D; 6°C) acclimated animals and compared to a control group (12L: 12D; 25°C). LS increased $$\dot V_{O_2 } $$ in both species. Further acclimation of LSAC increased $$\dot V_{O_2 } $$ inR. pumilio and decreased $$\dot V_{O_2 } $$ inL. griselda. LS increased body temperature (T b) inL. griselda only. LS increased overall thermal conductance in both species. LSAC caused a further increase in this parameter inR. pumilio. A singificant (P<0.001) increase in the magnitude of maximal nonshivering thermogenesis (NST) was observed in both species due to LS acclimation. LSAC did not change this maximal NST but increased its obligatory part (minimal $$\dot V_{O_2 } $$ , P<0.05, inL. griselda, andP<0.001, inR. pumilio). The results of this study show that winter acclimatization of heat production mechanisms, in both species, may be due to extension of scotophase.