Effect of warfarin on activated partial thromboplastin time in patients receiving heparin

BACKGROUND: The activated partial thromboplastin time (APTT) is used to adjust heparin sodium dosage. However, warfarin sodium is often administered concomitantly with heparin and may also affect the APTT and, therefore, heparin dose. We performed a prospective cohort study to quantify the effect of warfarin on the APTT in patients who are being treated with heparin. METHODS: Serial assays of APTT, international normalized ratio, heparin levels, and functional levels of prothrombin (factor II) and factors VII and X were performed in 24 patients with acute venous thromboembolism who were treated with concomitant continuous intravenous heparin and warfarin. The effects of warfarin, as expressed by international normalized ratio and coagulation factor levels, on APTT were determined. RESULTS: Warfarin markedly affected APTT; for each increase of 1.0 in the international normalized ratio, the APTT increased 16 seconds (95% confidence interval, 10-22 seconds). The effects of warfarin and heparin on APTT were additive. Consequently, warfarin markedly altered the relationship between APTT and heparin levels; of the 29 blood samples with supratherapeutic APTT, 13 had a therapeutic heparin level and 10 had a subtherapeutic heparin level. CONCLUSIONS: In patients receiving concomitant heparin and warfarin therapy, APTT reflects the combined effects of both drugs. Because of the marked effect of warfarin on the APTT, decreasing heparin dose in response to a high APTT frequently results in subtherapeutic heparin levels.     

Evaluation of the activated partial thromboplastin time (APTT) sensitivity to heparin using five commercial reagents: implications for therapeutic monitoring

Heparin is an effective drug for prevention and treatment of thromboembolic conditions. Although several biological assays have been proposed for monitoring unfractionated heparin therapy, the measurement of the activated partial thromboplastin time (APTT) is the most widely employed test, and the overall risk of thromboembolic episodes was markedly reduced by maintaining APTT ratios above 1.5. However, the adjustment of the heparin therapy on the basis of APTT presents several questions which are still unresolved. Major discrepancies were found in APTTs performed using different reagents in both ex vivo and in vitro heparinized samples and occasionally with different lots of the same reagents; poor correlation was observed between APTT values and plasma heparin concentrations. In order to gain further insights into this phenomenon, we analysed the sensitivity to heparin of five commercial reagents for APTT measurement in 19 ex vivo heparinized samples. Differences were observed; correlation coefficients ranged from 0.820 to 0.985 and slopes of linear regressions from 0.26 to 1.14. Moreover, unsatisfactory correlations were obtained when APTT ratios were compared with heparin plasma concentrations in the same patients' samples. In the heparin therapeutic range of 0.35 - 0.70 U/ml, reagent-dependent differences were observed in the corresponding APTT values. These results point out a critical role of the assay methodology in monitoring heparin therapy by APTT. We suggest that reference materials and methods should be urgently identified, a universally agreed scale for reporting results should be established and reference ranges for the unfractionated heparin therapy should be reconsidered taking on account the reagent employed.     

Automated heparin-delivery system to control activated partial thromboplastin time: evaluation in normal volunteers

BACKGROUND: Unfractionated heparin is used widely; however, control of the level of anticoagulation remains its greatest problem, with fewer than 35% of patients having activated partial thromboplastin times (aPTTs) within a range of 55 to 85 seconds in recent trials. METHODS AND RESULTS: We developed and tested a prototype of an automated heparin control system (AutoHep) in which a computer-based titration algorithm adjusted the heparin infusion to reach a target aPTT. In 1 study, 12 healthy male subjects received an intravenous infusion of heparin with the rate determined by AutoHep and were randomized to receive an initial bolus or no bolus of heparin preceding the infusion. A second study evaluated the automated blood sampling system in 12 subjects. Of the 344 end-point aPTT measurements, 78% were within +/-10 seconds of the target (prespecified primary end point), and 89% were within a +/-15-second range. The time to achieve a target aPTT was 93 minutes without and 150 minutes with an initial heparin bolus. The total percentage of time within the target range +/-15 seconds was 46 of 48 hours (96%). The automatic blood sampling system successfully obtained 96% of all scheduled samples. CONCLUSIONS: These results suggest that the AutoHep system has the potential to significantly improve aPTT control of intravenous heparin compared with current clinical practice.     

Preparation of lyophilized partial thromboplastin time reagent composed of synthetic phospholipids: usefulness for monitoring heparin therapy

To contribute to the development of a reference reagent for monitoring heparin therapy, a lyophilized partial thromboplastin time (PTT) reagent was prepared from synthetic dioleoylphosphatidylcholine, dioleoylphosphatidylserine, and dioleoylphosphatidylethanolamine, with colloidal silica as activator. The reagent, coded 91/558, was contained in sealed glass ampoules; it deteriorated in a heat degradation experiment, but its activity remained constant for at least 4 years when stored at -70 degrees C. Within- and between-run precision with this reagent complied with the requirements proposed by the International Committee for Standardization in Haematology (ICSH) Panel on PTT. The response of this reagent and of two other reagents to heparin added to pooled normal plasma was nonlinear. Citrated samples from 58 patients receiving intravenous heparin and from 24 apparently healthy volunteers were tested with reagent 91/558, with Automated APTT (Organon Teknika), with Manchester APTT reagent, with an antifactor Xa assay, and with an anti-factor IIa assay. The correlation of APTT with anti-Xa and anti-IIa activity was poor. The best correlation was observed between reagent 91/558 and the Organon Teknika reagent. Correlations were improved when individual patients' samples were replaced by pooled plasmas from heparinized patients, in whom the effect of oral anticoagulation was minimal. These results suggest that preparation of a lyophilized synthetic phospholipid reagent is feasible for use in monitoring heparin therapy.     

Use of bedside activated partial thromboplastin time monitor to adjust heparin dosing after thrombolysis for acute myocardial infarction: results of GUSTO-I. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries

Multiple five-day testing of rats in the open field and elevated plus-maze revealed a regressive dynamics of the integral characteristics of the exploratory behavior. The integral quantitative indices of searching activity in Henderson's test of extrapolation deliverance (modified by N. A. Bondarenko) and in active shock avoidance in N. R. Grigor'ev's problem box, on the contrary, displayed a progressive dynamics, like quantitative characteristics of cognitive activity. We established the differences between the determinants and control mechanisms of exploratory behavior and searching activity. This allowed us to differentiate these forms of behavior as different functional states.     

On the value of the activated partial thrombo-plastin time (aptt) in monitoring heparin therapy

Of 1068 blood samples referred for evaluation of the haemostatic mechanism 135 contained heparin as judged by the polybrene titration method. Of the 57 samples with a heparin concentration in the defined therapeutic range, 65 per cent had APTT values in the "therapeutic range". Of the samples from patients who had not received any anticoagulant, 213 (24 per cent) had prolonged APTT, and 48 of these samples had APTT values in the "therapeutic range" for heparin therapy. It is suggested that the APTT test is of limited value in monitoring heparin therapy.     

Activated partial thromboplastin time after heparin removal (aPTT/HR) in a new scheme of anticoagulant monitoring

Activated partial thromboplastin time after heparin removal (aPTT/HR), a test employing anion exchange chromatography, was devised as an alternative to the prothrombin time after heparin removal (PT/HR) to monitor simultaneous anticoagulation with heparin and coumarins. The potential utility of the aPTT/HR was assessed by performing parallel PTs and aPTTs on 62 consecutive plasmas from coumarin-treated outpatients. All samples had 0.2 units/ml of heparin added and then removed to see if the maneuver influenced therapeutic group assignment. In no instance did reassignment occur. A conditional Irwin-Fisher test (P = 0.000604) and a special multinomial trial analysis (P = 0.002) indicated that the aPTT would be at least comparable to the PT for following coumarin antithrombotic prophylaxis. Since the heparin removal procedure had no influence on therapeutic categorization, the same statistical proof could be applied to the relationship between aPTT/HR and PT/HR. This study indicates that the aPTT can be used to monitor all stages of heparin and /or coumarin anticoagulation.     

Activated partial thromboplastin time is a predictive parameter for further miscarriages in cases of recurrent fetal loss

OBJECTIVE: To determine whether clinically routine clotting tests such as activated partial thromboplastin time (aPTT), prothrombin time (PT), or fibrinogen can be used to predict further miscarriages. DESIGN: Prospective study. SETTING: Nagoya City University Hospital, Nagoya, Japan. PATIENT(S): A total of 261 patients with a history of two consecutive first-trimester spontaneous abortions who had no antiphospholipid antibodies or other autoimmune diseases and no anatomic anomalies were examined for aPTT, PT, and fibrinogen before becoming pregnant again. INTERVENTION(S): Blood tests were performed before pregnancy. Patients then were followed up during subsequent pregnancy and their outcomes were compared with their previous blood test results. MAIN OUTCOME MEASURE(S): Activated partial thromboplastin time, PT, and fibrinogen were measured by coagulation time methods. RESULT(S): Fifty-eight of 261 patients (22.2%) had a subsequent miscarriage. Mean (+/-SD) values for preconception aPTT in individuals whose subsequent pregnancies ended in success and failure were 88.2%+/-23.4% and 99.3%+/-26.4%, respectively. The difference was statistically significant. Respective values were 106.8%+/-22.8% and 106.3%+/-21.4% for PT and 245+/-61.1 mg/dL and 259.1+/-57 mg/dL for fibrinogen. These findings were not significantly different. CONCLUSION(S): A shortened aPTT before conception is associated with further miscarriages in patients with a history of recurrent spontaneous abortions who have no antiphospholipid antibodies.     

Time consumption at an orthopedic operating theatre. Physicians' ability to predict their own time consumption

The aim of the study was to investigate the time spent on different procedures in an orthopaedic operating theatre, and to evaluate the ability of doctors to predict their own time consumption. Time schedules were registered for 146 operations, of these 104 were either knee or hip replacements. Sixty percent of the total time was spent on surgery. The median misjudgment was 15 minutes for surgeons and five minutes for anaesthetists. An improvement in the doctors' ability to predict their own time consumption in the course of the study period could not be demonstrated. Comparing the study period with the similar period the year before it was not possible to demonstrate a change in the number of cancelled operations or the number of days with overtime. Epidural anaesthesia with bupivacaine was the most time consuming anaesthesia, the differences between the other forms of anaesthesia used were insignificant.     

Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial

BACKGROUND: Although intravenous heparin is commonly used after thrombolytic therapy, few reports have addressed the relationship between the degree of anticoagulation and clinical outcomes. We examined the activated partial thromboplastin time (aPTT) in 29,656 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial and analyzed the relationship between the aPTT and both baseline patient characteristics and clinical outcomes. METHODS AND RESULTS: Intravenous heparin was administered as a 5000-U bolus followed by an initial infusion of 1000 U/h, with dose adjustment to achieve a target aPTT of 60 to 85 seconds. aPTTs were collected 6, 12, and 24 hours after thrombolytic administration. Higher aPTT at 24 hours was strongly related to lower patient weight (P < .00001) as well as older age, female sex, and lack of cigarette smoking (all PT< .0001). At 12 hours, the aPTT associated with the lowest 30-day mortality, stroke, and bleeding rates was 50 to 70 seconds. There was an unexpected direct relationship between the aPTT and the risk of subsequent reinfarction. There was a clustering of reinfarction in the first 10 hours after discontinuation of intravenous heparin. CONCLUSIONS: Although the relationship between aPTT and clinical outcome was confounded to some degree by the influence of baseline prognostic characteristics, aPTTs higher than 70 seconds were found to be associated with higher likelihood of mortality, stroke, bleeding, and reinfarction. These findings suggest that until proven otherwise, we should consider the aPTT range of 50 to 70 seconds as optimal with intravenous heparin after thrombolytic therapy.     

Time allocated and time spent relative to time needed for learning as determinants of achievement.

171 Ss in Grades 4 and 5 who read at grade level were given 3 task presentations, each of which yielded a trials score (trials needed, trials spent, trials allocated) as well as a retention score. In addition to these scores, degree of learning or achievement scores were obtained. Degree of learning was the level of accuracy attained by the last learning trial of each task presentation. Achievement was set for 100% for the time-needed presentation; 91% of Ss reached this criterion. Degree of learning under the time-spent and time-allocated presentations varied from 30 to 100%. The trials-spent:trials-needed ratio scores were calculated for each S. Results show that spending and/or allocating insufficient learning time had a direct negative effect on achievement. Both degree of initial learning and 1-wk retention dropped significantly when Ss spent or were given fewer trials than needed to learn the experimental task. (30 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Aprotinin prolongs activated and nonactivated whole blood clotting time and potentiates the effect of heparin in vitro

This study was designed to evaluate the effect of aprotinin on activated versus nonactivated whole blood clotting time using two different on-site methods and to quantify these anticoagulant properties when compared to heparin in a controlled, in vitro environment. Blood specimens were obtained prior to heparin administration from 56 patients undergoing cardiac surgery. Specimens obtained from the first consecutive 20 patients were mixed with either normal saline (NS) or aprotinin (400 kallikrein inhibiting units (KIU)/mL), inserted into Hemochron tubes containing either NS or heparin (0.3 or 0.6 U/mL) and then used to measure celite-activated (celite ACT) and nonactivated whole blood clotting time (WBCT1) using four Hemochron instruments. Accordingly, specimens obtained from the second consecutive 20 patients were mixed with either NS or aprotinin, inserted into Automated Clot Timer cartridges containing either NS or heparin (0.06, 0.13, or 0.25 U/mL) and then used to measure kaolin-activated (kaolin ACT) or nonactivated whole blood clotting times (WBCT2) using four Automated Clot Timer instruments. Specimens obtained from the last 16 patients were mixed with either incrementally larger doses of aprotinin (0, 100, 200, 300, or 400 KIU/mL) or heparin (0, 0.12, 0.24, 0.36, 0.48, or 0.72 U/mL) and were then used for measurement of whole blood clotting time (WBCT2) using six Automated Clot Timer instruments. Aprotinin significantly prolonged activated or nonactivated whole blood clotting time and potentiated the prolongation of whole blood clotting time by heparin. The linear relationship between whole blood clotting time and either heparin concentration (WBCT2 = H x 357 + 280, mean adjusted r2 = 0.88) or aprotinin concentration (WBCT2 = A x 0.97 + 300, mean adjusted r2 = 0.94) was variable among patients. On average, 200 KIU/mL of aprotinin prolonged WBCT2 to the same extent as 0.69 +/- 0.28 U/mL of heparin using linear regression models within each patient. Aprotinin significantly prolongs activated or nonactivated whole blood clotting time measurements in a dose-dependent manner. Since prolongation of whole blood clotting time by heparin is potentiated by aprotinin in vitro, aprotinin's anticoagulant properties may in part account for the prolonged celite activated clotting time values observed in the presence of aprotinin.     

Antithrombin III during cardiac surgery: effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation

This study was designed to determine if, and to what extent, antithrombin III (AT) levels affect the response of the activated clotting time (ACT) to heparin in concentrations used during cardiac surgery, and to characterize the relationship between AT levels and markers of activation of coagulation during cardiopulmonary bypass (CPB). After informed consent, blood specimens obtained from eight normal volunteers (Phase I) were used to measure the response of the kaolin and celite ACT to heparin after in vitro addition of AT (200 U/dL) and after dilution with AT-deficient plasma to yield AT concentrations of 20, 40, 60, 80, and 100 U/dL. In Phase II, blood specimens collected before the administration of heparin and prior to discontinuation of CPB, were used to measure the response of the kaolin ACT to heparin (preheparin only), AT concentration, and a battery of coagulation assays in 31 patients undergoing repeat or combined cardiac surgical procedures. In Phase I, strong linear relationships were observed between kaolin (slope = 1.04 AT - 2, r2 = 0.78) and celite (slope = 1.36 AT + 6, r2 = 0.77) ACT slopes and AT concentrations below 100 U/dL. In the pre-CPB period of Phase II, only factors V (partial r = -0.49) and VIII (partial r = -0.63) were independently associated with heparin-derived slope using multivariate analysis; an inverse relationship was observed between AT and fibrinopeptide A levels (r = -0.41) at the end of CPB. Our findings indicate that the responsiveness of whole blood (ACT) to heparin at the high concentrations used with CPB is progressively reduced when the AT concentration decreases below 80 U/dL. Because AT is variably, and sometimes extensively, reduced in many patients before and during CPB, AT supplementation in these patients might be useful in reducing excessive thrombin-mediated consumption of labile hemostatic blood components, excessive microvascular bleeding, and transfusion of blood products. IMPLICATIONS: Heparin, a drug with anticoagulant properties, is routinely given to patients undergoing cardiac surgery to prevent clot formation within the cardiopulmonary bypass circuit. However, when levels are reduced, heparin is not as effective. Findings within this study indicate that administration of antithrombin III may help to preserve the hemostatic system during cardiopulmonary bypass.     

The response of Quick''s prothrombin time test to oral anticoagulation. Influence of thromboplastin source and calcium chloride concentration

A hypothesis is presented suggesting that nicotinamide (NIC) is an initial signal substance in the response of eukaryotic cells to conditions which cause DNA-strand breakage, especially in connection with oxidative stress. In the stressed cell, NIC is released as a result of the activity of poly(ADP-ribose)polymerase (PADPRP). PADPRP is known to be activated by DNA-strand breakage, caused by e.g. oxidative stress or mutagens. NIC and its metabolite trigonelline (N-methylnicotinic acid) can induce defensive metabolism at the gene level. Connections between NIC and DNA-methylation are also considered. This hypothesis is discussed in the light of own observations and literature reports.     

Conformational conversion of antithrombin to a fully activated substrate of factor Xa without need for heparin

Regulation of the inhibitory activity of antithrombin, the principal inhibitor of the blood-clotting proteinases factor Xa and thrombin, is accomplished by binding to heparin. We report here an antithrombin variant in which serine at position 380, 14 residues N-terminal from the reactive bond and at a hinge point in the structure, was replaced by cysteine to test a proposed mechanism of heparin activation of antithrombin as an inhibitor of factor Xa. By derivatization of this cysteine with a bulky group, fluorescein, the antithrombin became permanently and fully activated toward reaction with factor Xa in a manner analogous to heparin activation, albeit as a substrate. These findings establish a structural basis for the mechanism of heparin activation of antithrombin against factor Xa in agreement with that proposed from an X-ray structure of antithrombin.     

Using the theory of planned behavior to predict leisure time physical activity among people with chronic kidney disease.

Objective: To evaluate the utility of the theory of planned behavior (TPB) for explaining and predicting leisure time physical activity (LTPA) in the chronic kidney disease population. Study Design: Prospective correlational design. Participants: Eighty men (n=52) and women (n=28) with chronic kidney disease (mean serum creatinine=310.55 [±148.75] μmol/L). Method: Baseline interview assessing attitude, subjective norm, perceived behavioral control, and intention to engage in LTPA. Telephone interview 1 week later assessing frequency and intensity of LTPA. Results: Perceived behavioral control (β=.69) but not attitude (β=.17) or subjective norm (β=.02) was associated with intention to engage in LTPA. Intention (β=.53) but not perceived behavioral control (β=.18) predicted LTPA. Conclusion: These findings provide partial support for the utility of the TPB for explaining LTPA among people with chronic kidney disease. Additional research is required to determine if targeting perceived behavioral control may be an effective means for increasing LTPA in this population. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

To predict some of the people some of the time: In search of moderators.

This study tested the prediction that 3 variables—self-reported trait relevance, consistency, and observability—would moderate correlations between self-ratings and peer ratings. These predictions received considerable support when the 3 moderators were measured by ranking procedures (i.e., rank ordering traits in terms of their standing on each moderator) and very litle support when the 3 moderators were measured by rating scales (i.e., rating each trait in terms of its standing on each moderator). The advantage of the ranking measure may indicate an advantage for moderators that distinguish among traits across or within individuals (intertrait and intraindividual moderators) as opposed to moderators that distinguish among individuals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Speciality guidelines for the delivery of services.

Presents the Specialty Guidelines, which are based on the generic Standards for Providers of Psychological Services originally adopted by the American Psychological Association (APA) in September 1974 and revised in January 1977. (PsycINFO Database Record (c) 2010 APA, all rights reserved)