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Objectives: The optimal method for monitoring of anticoagulation in patients on extracorporeal life support (ECLS) is unknown. The objective of this study was to assess the relationship between anti-factor Xa level (anti-Xa; IU/mL) and activated partial thromboplastin time (aPTT; seconds) for monitoring intravenous unfractionated heparin anticoagulation in adult ECLS patients. Methods: Charts of all adult patients cannulated for ECLS from 2015 through 2017 were reviewed and laboratory and heparin infusion data were extracted for analysis. Time matched pairs of anti-Xa and aPTT were considered concordant if both laboratory values were within the same clinically utilized range. A hierarchical logistic regression model was used to determine factors associated with discordance while accounting for patient level effects. Results: A total of 1016 paired anti-Xa and aPTT values from 65 patients were evaluated. 500 (49.2%) paired samples were discordant with a degree of variability on linear regression (r 2 = 0.315). The aPTT fell into a higher therapeutic range compared to the anti-Xa in 31.6% and lower in 17.3%. Logistic regression demonstrated that discordance was independently associated with time from initiation of ECLS (OR 1.17 per day, p < 0.001), average heparin infusion rate (OR 1.25 per U/kg/hr, p < 0.001), and INR (OR 3.22, p < 0.001). Conclusions: Nearly half of all aPTT and anti-Xa values were in discordant ranges and discordance is more likely as the time on ECLS and the INR level increase. The use of either assay in isolation to guide heparin anticoagulation may lead to misestimation of the degree of anticoagulation in complex ECLS patients. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated associations of estradiol (E2) dose and serum E2 levels with coagulation/anti-coagulation measures in early (<6 years) compared with late (≥10 years) postmenopausal women.Methods: Postmenopausal women from the REPLENISH trial tested four formulations of oral combined E2 and progesterone compared with placebo. Mixed-effects linear models tested the association of E2 dose and serum E2 levels with the prothrombin time (PT), the activated partial thromboplastin time (APTT), antithrombin (ATHRM), fibrinogen (FIBRINO), protein C (PROTC), and protein S (PROTS), assessed five times over 12 months.Results: Among 1215 early and 297 late postmenopausal women, the E2 dose was statistically significantly inversely associated with the APTT in early postmenopause, PROTC in late postmenopause, and with the PT, ATHRM, and PROTS in both groups. Serum E2 levels were statistically significantly inversely associated with the APTT, PROTS, and FIBRINO in early postmenopause, the PT in late postmenopause, and ATHRM and PROTC in both groups. With longer time since menopause, the inverse E2 dose effect and serum E2 effects became stronger.Conclusion: Increasing E2 dose and serum E2 levels were associated with changes in coagulation/anti-coagulation measures. The associations were stronger among women ≥10 years since menopause when initiating E2. The timing of E2 therapy, E2 dose, and serum E2 levels relative to time since menopause may modify the venous thromboembolism risk. [ABSTRACT FROM AUTHOR]

Dabigatran etexilate (Pradaxa) is approved in the EU for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and one or more risk factors. Dabigatran etexilate is a prodrug of dabigatran, a direct inhibitor of thrombin. In patients with NVAF in the phase III RE-LY trial, dabigatran etexilate dosages of 110 and 150 mg twice daily were noninferior to warfarin with regard to the risk of stroke or systemic embolism (primary efficacy endpoint). The higher dosage was associated with a significantly lower risk of stroke or systemic embolism than warfarin, with no significant between-group difference in the risk of major bleeding (primary safety endpoint). Both dosages of dabigatran etexilate were associated with significantly lower rates of haemorrhagic stroke, intracranial bleeding and life-threatening major bleeding than warfarin. Dabigatran etexilate was also effective and generally well tolerated across various patient subgroups. The efficacy and tolerability of dabigatran etexilate was maintained for up to 6.7 years in the RELY-ABLE extension study. Routine anticoagulation monitoring is not required in patients receiving dabigatran etexilate, and it is currently the only non-vitamin K antagonist oral anticoagulant (NOAC) with a specific reversal agent available. Although direct comparisons with other NOACs would be beneficial, dabigatran etexilate is a useful option for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background: Lower activated partial thromboplastin times are associated with higher levels of some coagulation factors and may represent a procoagulant tendency.Methods: In the Atherosclerosis Risk in Communities study, we studied the 13-year risk of venous thromboembolism in relation to baseline activated partial thromboplastin time in 13,880 individuals. We also studied 258 venous thromboembolism cases and 589 matched controls with measurements of additional coagulation factors.Results: After adjustment for demographics and procoagulant factors reflected in the activated partial thromboplastin time (fibrinogen, factors VIII, IX, and XI, and von Willebrand factor), participants in the lowest 2 quartiles of activated partial thromboplastin time compared with the fourth quartile had 2.4-fold (95% confidence interval [CI], 1.4-4.2) and 1.9-fold (95% CI, 1.1-3.2) higher risks of venous thromboembolism. The risk associated with activated partial thromboplastin times below the median was higher for idiopathic (odds ratio 5.5; 95% CI, 2.0-15.5) than secondary venous thromboembolism (odds ratio 1.74; 95% CI, 0.88-3.43). Subjects with both activated partial thromboplastin times below the median and factor V Leiden were 12.6-fold (95% CI, 5.7-28.0) more likely to develop venous thromboembolism compared with those with neither risk factor (P interaction<.01). A lower activated partial thromboplastin time also added to the thrombosis risk associated with obesity and elevated D-dimer.Conclusion: A single determination of the activated partial thromboplastin time below the median increased the risk of future venous thromboembolism. Findings were independent of coagulation factor levels, and a low activated partial thromboplastin time added to the risk associated with other risk factors. [ABSTRACT FROM AUTHOR]

Background: The VA Northeast Ohio Healthcare System introduced a new nurse-driven anti-factor Xa (anti-Xa) protocol for monitoring unfractionated heparin to replace the previous activated partial thromboplastin time protocol., Objective: To design, implement, and evaluate the efficacy of the anti-Xa monitoring protocol., Methods: An interdisciplinary team of providers collaborated to develop and implement a nurse-driven, facility-wide anti-factor Xa protocol for monitoring unfractionated heparin therapy. The effectiveness of this protocol was evaluated by retrospective analysis., Results: We reviewed 100 medical records for compliance with the new anti-Xa monitoring protocol. We then evaluated 178 patients whose anticoagulation was monitored with the anti-Xa assay to determine the time to therapeutic range. We found that 80% of patients receiving the anti-Xa protocol achieved therapeutic anticoagulation within 24 hours, as compared with 54% of patients receiving the activated partial thromboplastin time protocol (P < .001). Protocol conversion also yielded a decrease in blood draws, dose adjustments, and potential calculation errors., Conclusions: Monitoring intravenous heparin therapy with the anti-Xa assay rather than activated partial thromboplastin time resulted in a shorter time to therapeutic anticoagulation, longer maintenance of therapeutic levels, and fewer laboratory tests and heparin dosage changes. We believe the current practice of monitoring heparin treatment with activated partial thromboplastin time assays should be reexamined., (©2020 American Association of Critical-Care Nurses.)

Background: Mortality prediction aids clinical decision making and is necessary for quality improvement initiatives. Validated metrics rely on prespecified variables and often require advanced diagnostics, which are unfeasible in resource-constrained contexts. We hypothesize that machine learning will generate superior mortality prediction in both high-income and low- and middle-income country cohorts., Methods: SuperLearner, an ensemble machine-learning algorithm, was applied to data from three prospective trauma cohorts: a highest-activation cohort in the United States, a high-volume center cohort in South Africa (SA), and a multicenter registry in Cameroon. Cross-validation was used to assess model discrimination of discharge mortality by site using receiver operating characteristic curves. SuperLearner discrimination was compared with standard scoring methods. Clinical variables driving SuperLearner prediction at each site were evaluated., Results: Data from 28,212 injured patients were used to generate prediction. Discharge mortality was 17%, 1.3%, and 1.7% among US, SA, and Cameroonian cohorts. SuperLearner delivered superior prediction of discharge mortality in the United States (area under the curve [AUC], 94-97%) and vastly superior prediction in Cameroon (AUC, 90-94%) compared with conventional scoring algorithms. It provided similar prediction to standard scores in the SA cohort (AUC, 90-95%). Context-specific variables (partial thromboplastin time in the United States and hospital distance in Cameroon) were prime drivers of predicted mortality in their respective cohorts, whereas severe brain injury predicted mortality across sites., Conclusions: Machine learning provides excellent discrimination of injury mortality in diverse settings. Unlike traditional scores, data-adaptive methods are well suited to optimizing precise site-specific prediction regardless of diagnostic capabilities or data set inclusion allowing for individualized decision making and expanded access to quality improvement programming., Level of Evidence: Prognostic and therapeutic, level II and III.

Objective: Mobile applications for improving diagnostic decision making often lack clinical evaluation. We evaluated if a mobile application improves generalist physicians' appropriate laboratory test ordering and diagnosis decisions and assessed if physicians perceive it as useful for learning., Methods: In an experimental, vignette study, physicians diagnosed 8 patient vignettes with normal prothrombin times (PT) and abnormal partial thromboplastin times (PTT). Physicians made test ordering and diagnosis decisions for 4 vignettes using each resource: a mobile app, PTT Advisor, developed by the Centers for Disease Control and Prevention (CDC)'s Clinical Laboratory Integration into Healthcare Collaborative (CLIHC); and usual clinical decision support. Then, physicians answered questions regarding their perceptions of the app's usefulness for diagnostic decision making and learning using a modified Kirkpatrick Training Evaluation Framework., Results: Data from 368 vignettes solved by 46 physicians at 7 US health care institutions show advantages for using PTT Advisor over usual clinical decision support on test ordering and diagnostic decision accuracy (82.6 vs 70.2% correct; P < .001), confidence in decisions (7.5 vs 6.3 out of 10; P < .001), and vignette completion time (3:02 vs 3:53 min.; P = .06). Physicians reported positive perceptions of the app's potential for improved clinical decision making, and recommended it be used to address broader diagnostic challenges., Conclusions: A mobile app, PTT Advisor, may contribute to better test ordering and diagnosis, serve as a learning tool for diagnostic evaluation of certain clinical disorders, and improve patient outcomes. Similar methods could be useful for evaluating apps aimed at improving testing and diagnosis for other conditions.

Background: A substantial fraction of all American healthcare expenditures are potentially wasted, and practices that are not evidence-based could contribute to such waste. We sought to characterize whether Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT) tests of preoperative patients are used in a way unsupported by evidence and potentially wasteful., Methods and Findings: We evaluated prospectively-collected patient data from 19 major teaching hospitals and 8 hospital-affiliated surgical centers in 7 states (Delaware, Florida, Maryland, Massachusetts, New Jersey, New York, Pennsylvania) and the District of Columbia. A total of 1,053,472 consecutive patients represented every patient admitted for elective surgery from 2009 to 2012 at all 27 settings. A subset of 682,049 patients (64.7%) had one or both tests done and history and physical (H&P) records available for analysis. Unnecessary tests for bleeding risk were defined as: PT tests done on patients with no history of abnormal bleeding, warfarin therapy, vitamin K-dependent clotting factor deficiency, or liver disease; or aPTT tests done on patients with no history of heparin treatment, hemophilia, lupus anticoagulant antibodies, or von Willebrand disease. We assessed the proportion of patients who received PT or aPTT tests who lacked evidence-based reasons for testing., Conclusions: This study sought to bring the availability of big data together with applied comparative effectiveness research. Among preoperative patients, 26.2% received PT tests, and 94.3% of tests were unnecessary, given the absence of findings on H&P. Similarly, 23.3% of preoperative patients received aPTT tests, of which 99.9% were unnecessary. Among patients with no H&P findings suggestive of bleeding risk, 6.6% of PT tests and 7.1% of aPTT tests were either a false positive or a true positive (i.e. indicative of a previously-undiagnosed potential bleeding risk). Both PT and aPTT, designed as diagnostic tests, are apparently used as screening tests. Use of unnecessary screening tests raises concerns for the costs of such testing and the consequences of false positive results.

Background: Trauma-induced coagulopathy following severe injury is associated with increased bleeding and mortality. Injury may result in alteration of cellular phenotypes and release of cell-derived microparticles (MP). Circulating MPs are procoagulant and support thrombin generation (TG) and clotting. We evaluated MP and TG phenotypes in severely injured patients at admission, in relation to coagulopathy and bleeding., Methods: As part of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, research blood samples were obtained from 180 trauma patients requiring transfusions at 5 participating centers. Twenty five healthy controls and 40 minimally injured patients were analyzed for comparisons. Laboratory criteria for coagulopathy was activated partial thromboplastin time (APTT) ≥ 35 sec. Samples were analyzed by Calibrated Automated Thrombogram to assess TG, and by flow cytometry for MP phenotypes [platelet (PMP), erythrocyte (RMP), leukocyte (LMP), endothelial (EMP), tissue factor (TFMP), and Annexin V positive (AVMP)]., Results: 21.7% of patients were coagulopathic with the median (IQR) APTT of 44 sec (37, 53), and an Injury Severity Score of 26 (17, 35). Compared to controls, patients had elevated EMP, RMP, LMP, and TFMP (all p<0.001), and enhanced TG (p<0.0001). However, coagulopathic PROMMTT patients had significantly lower PMP, TFMP, and TG, higher substantial bleeding, and higher mortality compared to non-coagulopathic patients (all p<0.001)., Conclusions: Cellular activation and enhanced TG are predominant after trauma and independent of injury severity. Coagulopathy was associated with lower thrombin peak and rate compared to non-coagulopathic patients, while lower levels of TF-bearing PMPs were associated with substantial bleeding., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: There are no guidelines for thrombolysis in stroke patients taking dabigatran, or dabigatran reversal strategies in patients with ICH. We sought to assess how vascular neurologists plan to care for these patients., Methods: An Internet-based questionnaire was sent to US board-certified vascular neurologists. Case scenarios for patients on dabigatran with acute ischemic stroke or ICH were presented; questions assessed preferred treatment strategies., Results: In all, 221 vascular neurologists responded. For a typical ischemic stroke patient eligible for intravenous (IV) tissue plasminogen activator (tPA) except for use of dabigatran (time of last dose unknown), 49% would not treat with tPA regardless of PTT, 28% would treat if PTT was normal, 9% would treat if PTT was less than 40 seconds, and 4% would treat regardless of PTT. Even more variability in responses was seen when presented with a normal PTT but variable times from last dabigatran dose. Between 8%-14% of respondents were not sure what they would do. For catheter-based thrombolysis, 25% indicated they would treat with IV tPA but would prefer catheter thrombolysis, 30% would use IV tPA and consider catheter thrombolysis as for any patient, 36% would only use catheter thrombolysis, and 9% would not use IV tPA or catheter thrombolysis. For a patient with dabigatran-associated ICH, 73% said they would attempt reversal of dabigatran with the following modalities: FFP 53%; factor VIIa 24%; prothrombin complex concentrates 61%; platelet transfusion 7%; and hemodialysis 24%., Conclusions: There is a remarkable lack of consensus among vascular neurologists regarding the assessment and treatment of acute stroke patients on dabigatran., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The United States Pharmacopeia recently changed the standards for unfractionated heparin (UFH) resulting in reduction in potency by about 10 %. Despite the reduction in potency, no new recommendations for UFH dosing were recommended. A retrospective review was conducted on patients receiving UFH and at least one activated partial thromboplastin time (aPTT) after start of infusion. Patients receiving UFH prior to April 2010 were collected as old UFH potency patients versus those receiving UFH after May 1st, 2010 were defined as new UFH potency patients. The primary endpoint was time to a therapeutic aPTT. Secondary endpoints included the number venous thrombotic events (VTE) and bleeding events during hospitalization through 30 days post discharge. Thrombotic events were defined as acute coronary syndrome, ischemic stroke, and VTE. Bleeding was defined in accordance with the GUSTO bleeding scale. A total of 359 patients were included for evaluation, 181 in the old UFH group and 178 in the new UFH group. The primary endpoint was similar between groups with an average time of 18.8 ± 25.4 versus 20.8 ± 22.2 h in the old and new UFH groups respectively (p = 0.092). Patients receiving old UFH and an initial bolus had higher aPTTs (96.6 ± 43.7 s) than those receiving new UFH and an initial bolus (76.7 ± 34.5 s) (p = 0.003). There was no difference found between groups in regards to bleeding or thrombotic events during hospitalization or through 30 days. In patients receiving UFH, dosed per the institutions' nomogram, no clinically significant outcomes were found between the old and new UFH potencies.

Introduction: Prothrombin G20210A (PT20210) carriers have increased prothrombin levels and increased risk for venous thrombosis. We hypothesized PT20210 carriers would have decreased PT, aPTT, and dRVVT clotting times., Methods: We reviewed 1186 thrombotic risk panels that included PT, aPTT, dRVVT, and PT20210 genotype with potential confounding variables, excluding samples consistent with anticoagulant therapy or lupus anticoagulant presence. We examined relationships of PT20210 with PT, aPTT, and dRVVT correcting for covariates using multivariate regression. We confirmed associations in 1876 separate panel results and a group of homozygotes for PT20210 and used general linear models to determine if associated tests predict PT20210 status., Results: Neither PT, aPTT, nor dRVVT was shorter in PT20210 carriers. Contrary to our hypothesis, PT20210 was significantly associated with higher dRVVT (p=0.001), but not PT or aPTT. dRVVT differences were significant in a replicate sample p=0.035 and an additional sample of PT20210 homozygotes (p=0.02). Of all variables available, only dRVVT predicted PT20210 carrier status (p=0.0008, AUC=0.64)., Conclusions: We observed an association between longer dRVVT and the prothrombin G20210A mutation in a retrospective observational study. These findings merit further study in large well-characterized clinical cohorts and laboratory research experiments., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Object: The utility of preoperative hemostasis screening to predict complications is uncertain. The authors quantified the screening rate in US neurosurgery patients and evaluated the ability of abnormal test results as compared with history-based risk factors to predict hemostasis-related and general outcomes., Methods: Eleven thousand eight hundred four adult neurosurgery patients were identified in the 2006-2009 American College of Surgeons National Surgical Quality Improvement Program database. Multivariate logistic regression modeled the ability of hemostatic tests and patient history to predict outcomes, that is, intra- and postoperative red blood cell [RBC] transfusion, return to the operating room [OR], and 30-day mortality. Sensitivity analyses were conducted using patient subgroups by procedure., Results: Most patients underwent all 3 hemostatic tests (platelet count, prothrombin time/international normalized ratio [INR], activated partial thromboplastin time), but few had any of the outcomes of interest. The number of screening tests undergone was significantly associated with intraoperative RBC transfusion, a return to the OR, and mortality; an abnormal INR was associated with postoperative RBC transfusion. However, all tests had low sensitivity (0.09-0.2) and platelet count had low specificity (0.04-0.05). The association between patient history and each outcome was approximately the same across all tests, with higher sensitivity but lower specificity. Combining abnormal tests with patient history accounted for 50% of the mortality and 33% of each of the other outcomes., Conclusions: This is the first study focused on assessing preoperative hemostasis screening as compared with patient history in a large multicenter sample of adult neurosurgery patients to predict hemostasis-related outcomes. Patient history was as predictive as laboratory testing for all outcomes, with higher sensitivity. Routine laboratory screening appears to have limited utility. Testing limited to neurosurgical patients with a positive history would save an estimated $81,942,000 annually.

We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 μg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

Background: Thrombin is an enzyme that is essential for the acceleration of the coagulation cascade and the conversion of fibrinogen to clottable fibrin., Objectives: We evaluated the relationship of basal peak thrombin generation with the risk of future venous thromboembolism (VTE), and determined whether associations were independent of other coagulation markers., Methods: The Longitudinal Investigation of Thromboembolism Etiology (LITE) study investigated VTE in two prospective population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS). Peak thrombin generation was measured on stored plasma in a nested case-control sample (434 cases and 1004 controls). Logistic regression was used to estimate the relationship of peak thrombin generation with VTE, adjusted for age, sex, race, center, and body mass index. Mediation was evaluated by additionally adjusting for factor VIII and D-dimer., Results: Relative to the first quartile of peak thrombin generation, the odds ratio (OR) of VTE for those above the median was 1.74 [95% confidence interval (CI) 1.28-2.37]. The association was modestly attenuated by adjustment for FVIII and D-dimer (OR 1.47, 95% CI 1.05-2.05). Associations appeared to be stronger for idiopathic than for secondary VTE. Elevated peak thrombin generation more than added to the VTE risk associated with FV Leiden or low activated partial thromboplastin time., Conclusions: In this prospective study of two independent cohorts, elevated basal peak thrombin generation was associated with subsequent risk of VTE, independently of established VTE risk factors.

Context: Appropriate laboratory monitoring of unfractionated heparin therapy promotes effective anticoagulation while minimizing hemorrhagic complications., Objectives: To measure heparin therapy monitoring in a "real-world" setting and to assess the degree of anticoagulation achieved., Design: One hundred forty institutions abstracted laboratory and pharmacy data from up to 30 inpatients receiving standard-dose unfractionated heparin therapy for 72 hours. Institutions also reported their therapeutic ranges and described heparin prescribing and monitoring policies., Results: Activated partial thromboplastin times or anti-factor Xa levels were measured at least once within the first 12 hours of administration for 95% of 3431 heparinized inpatients. Eighty-seven percent of patients had a platelet count performed within 72 hours of heparin administration. Seventy-eight percent of heparinized inpatients achieved therapeutic anticoagulation within 24 hours, but more than one third of patients entered the supratherapeutic range on at least 2 occasions during the first 72 hours. We found moderate variation in performance among the 140 institutions participating in the study, with more consistency in monitoring patients but less consistency in achieving therapeutic levels of anticoagulation. In one fourth of hospitals, more than half of the heparinized patients entered the supratherapeutic range on 2 or more occasions during the first 72 hours of therapy. None of 20 institutional practices we examined were meaningfully associated with more thorough monitoring of patients or with a higher percentage of patients achieving therapeutic anticoagulation. There was moderately wide variation in therapeutic ranges among the 140 sites., Conclusions: The prevention of heparin over-anticoagulation represents an important opportunity for improving patient safety in a significant number of institutions.

Delays in processing statium (STAT) blood samples have led to the production of an increasing number of point-of-care tests. Product inserts recommend measuring blood samples immediately after procurement, suggesting that delays may invalidate the test results. We studied the effect of the age of blood samples on point-of-care (POC) prothrombin time (PT) and an activated partial thromboplastin time (aPTT) result. Informed consent was obtained from 11 patients undergoing cardiopulmonary bypass (CPB). Blood samples (40 mL) were taken from each patient. Each blood sample was used to perform five PT tests and six aPTT tests on five POC devices (Gem PCL, Hemochron 801, Hemochron Jr. Signature, Hemochron Response, Rapidpoint Coag) at three different sample ages [< 60 s (fresh blood), 10 and 18 min after sample collection]. Blood samples were procured in a plastic syringe devoid of air bubbles, which was left undisturbed between tests but was gently agitated before initiating the 10- and 18-min tests. For tests requiring citrated whole blood, a fraction of each sample was anticoagulated (3.8% citrate) at each age. Statistical analysis was used for comparison of test results for fresh blood to aged samples (10 and 18 min). Test values were recorded as International Normalized Ratio (INR) and seconds for PT and aPTT, respectively. Two devices, the Hemochron 801 and Hemochron response showed statistically, although not clinically, significant variation in PT test results when the samples were aged to 10 and 18 minutes. As for aPTT results, Hemochron 801, Hemochron response, Hemochron Jr. signature, and Gem PCL showed statistically significant variation at 18 minutes. One device (Hemochron 801) reported results with 10-min aged blood that were statistically different from fresh blood. None of the aPTT tests results from any device produced results with aged blood that were clinically different from fresh blood. This study suggests that, in the tests evaluated, blood samples that have aged 10 or 18 min will produce clinically relevant aPTT and PT results, respectively.

The European Pharmacopoeia Biological Reference Preparation Batch 3/Mega 2 (United States/Food and Drug Administration) (Ph. Eur. BRP Batch 3/Mega 2 (US/FDA)) was developed as an internationally available, common working standard to replace the dwindling stocks of Mega 1 (the current US standard) and Ph. Eur. BRP Batch 2 (the current European standard). The potency was assigned in an international collaborative study with reference to four currently established standards, Ph. Eur. BRP batch 2, WHO 5th and 6th International Standard and Mega 1. Thirty-eight laboratories participated in the collaborative study. Each laboratory was asked to perform four independent assays. Participants used either the one stage clotting assay or the chromogenic assay or both. This publication reports the results obtained with both assays. The summary and conclusion, however highlight the results mainly with respect to the chromogenic assay, which is the assay prescribed in the European Pharmacopoeia. Data were analysed for both assays separately. A consensus potency value was calculated as the unweighted average of mean potencies determined against the four standards. A potency of 8.6 IU/vial as determined in the chromogenic substrate method was assigned to the candidate standard. Inter-laboratory agreement as assessed by calculation of the geometric coefficient of variation was below 10% for mean potencies against all four calibrators for the chromogenic assay. Ph. Eur. BRP Batch 3/Mega 2 (US/FDA) is a freeze-dried, plasma derived, high-purity concentrate. The material was filled into approximately 100,000 vials and lyophilised to a final residual moisture of < or = 2%. Approximately 90,000 vials of the standard are available, equally shared between the two co-ordinating centers. Based on the stability studies, the predicted mean percentage loss per year at -20 degrees C is 0.000% and thus the candidate standard appears to be stable. The Ph. Eur. BRP batch 3 was adopted by the European Pharmacopoeia Commission in November 2001.

Objective: Our objective was to evaluate whether selected hemostasis variables, some of which may reflect inflammation or endothelial dysfunction, are independently associated with the development of diabetes., Research Design and Methods: We studied a biethnic cohort of 12,330 men and women, 45-64 years of age, of the Atherosclerosis Risk in Communities Study. New cases of diabetes were diagnosed by a reported physician diagnosis, hypoglycemic medication use, or a casual or fasting serum glucose level of > or = 11.1 or > or = 7 mmol/l, respectively., Results: Over an average follow-up of 7 years, 1,335 new cases of diabetes were detected. The odds ratios (4th versus 1st quartile) of developing diabetes, adjusted by logistic regression for age, sex, race, study center, family history of diabetes, fasting glucose, physical activity, and smoking, were 1.2 (95% CI 1.0-1.5) for fibrinogen and 1.4 (1.1-1.6) for factor VII. Associations for factor VIII, von Willebrand factor, and activated partial thromboplastin time were found to be 1.8 (1.3-2.3), 1.4 (1.1-1.8), and 0.63 (0.49-0.82), respectively, in women. Although further adjustment for BMI and waist-to-hip ratio diminished the relationships, a highly statistically significant association (P = 0.001) remained for factor VIII (1.6 [1.2-2.1]) in women., Conclusions: Factor VIII and other hemostasis variables are associated with the development of diabetes in middle-aged adults. These findings support a role for inflammation and, particularly in women, endothelial dysfunction in the pathogenesis of type 2 diabetes.

Objectives: The purpose of this study was to determine the incidence and demographic characteristics of patients experiencing cardiac rupture after thrombolytic and adjunctive anticoagulant therapy and to identify possible associations between the mechanism of thrombin inhibition (indirect, direct) and the intensity of systemic anticoagulation with its occurrence. BACKGROUND Cardiac rupture is responsible for nearly 15% of all in-hospital deaths among patients with myocardial infarction (MI) given thrombolytic agents. Little is known about specific patient- and treatment-related risk factors. METHODS Patients (n = 3,759) with MI participating in the Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9A and B trials received intravenous thrombolytic therapy, aspirin and either heparin (5,000 U bolus, 1,000 to 1,300 U/h infusion) or hirudin (0.1 to 0.6 mg/kg bolus, 0.1 to 0.2 mg/kg/h infusion) for at least 96 h. A diagnosis of cardiac rupture was made clinically in patients with sudden electromechanical dissociation in the absence of preceding congestive heart failure, slowly progressive hemodynamic compromise or malignant ventricular arrhythmias. RESULTS A total of 65 rupture events (1.7%) were reported-all were fatal, and a majority occurred within 48 h of treatment Patients with cardiac rupture were older, of lower body weight and stature and more likely to be female than those without rupture (all p < 0.001). By multivariable analysis, age >70 years (odds ratio [OR] 3.77; 95% confidence interval [CI] 2.06, 6.91), female gender (OR 2.87; 95% CI 1.44, 5.73) and prior angina (OR 1.82; 95% CI 1.05, 3.16) were independently associated with cardiac rupture. Independent predictors of nonrupture death included age >70 years (OR 3.68; 95% CI 2.53, 5.35) and prior MI (OR 2.14; 95%, CI 1.45, 3.17). There was no association between the type of thrombin inhibition, the intensity of anticoagulation and cardiac rapture. CONCLUSIONS Cardiac rupture following thrombolytic therapy tends to occur in older patients and may explain the disproportionately high mortality rate among women in prior dinical trials. Unlike major hemorrhagic complications, there is no evidence that the intensity of anticoagulation associated with heparin or hirudin administration influences the occurrence of rupture.

Background: Therapy with intravenous unfractionated heparin improves clinical outcome in patients with active thromboembolic disease, but achieving and maintaining a therapeutic level of anticoagulation remains a major challenge for clinicians., Methods: A total of 113 patients requiring heparin for at least 48 hours were randomly assigned at 7 medical centers to either weight-adjusted or non-weight-adjusted dose titration. They were separately assigned to either laboratory-based or point-of-care (bedside) coagulation monitoring., Results: Weight-adjusted heparin dosing yielded a higher mean activated partial thromboplastin time (aPTT) value 6 hours after treatment initiation than non-weight-adjusted dosing (99.9 vs 78.8 seconds; P =.002) and reduced the time required to exceed a minimum threshold (aPTT >45 seconds) of anticoagulation (10.5 vs 8.6 hours; P =.002). Point-of-care coagulation monitoring significantly reduced the time from blood sample acquisition to a heparin infusion adjustment (0.4 vs 1.6 hours; P <.0001) and to reach the therapeutic aPTT range (51 to 80 seconds) (16.1 vs 19.4 hours; P =.24) compared with laboratory monitoring. Although a majority of patients participating in the study surpassed the minimum threshold of anticoagulation within the first 12 hours and reached the target aPTT within 24 hours, maintaining the aPTT within the therapeutic range was relatively uncommon (on average 30% of the overall study period) and did not differ between treatment or monitoring strategies., Conclusions: Weight-adjusted heparin dosing according to a standardized titration nomogram combined with point-of-care coagulation monitoring using the BMC Coaguchek Plus System represents an effective and widely generalizable strategy for managing patients with thromboembolic disease that fosters the rapid achievement of a desired range of anticoagulation. Additional work is needed, however, to improve on existing patient-specific strategies that can more effectively sustain a therapeutic state of anticoagulation.

Although coronary thrombosis is thought to play a pivotal role in the pathogenesis of unstable angina and non-Q wave myocardial infarction and antithrombotic therapy is a mainstay in the early management of these patients, the relation between measures of systemic anticoagulation and clinical events has not been defined clearly. In the Thrombolysis in Myocardial Ischemia III trial, 1473 patients with ischemic chest pain at rest evaluated within 24 hours of symptom onset were randomized to (1) tissue plasminogen activator (TPA) or placebo and (2) an early invasive or an early conservative strategy. All patients received a full complement of anti-ischemic medication, aspirin, and continuous intravenous heparin titrated to an activated partial thromboplastin time (aPTT) of 1.5 to 2.0 times control for 72 to 96 hours. The median aPTT in all study groups exceeded the minimum threshold (45 seconds) by 24 hours and remained within the designated range during the protocol-directed heparin infusion. No differences in median aPTT values for the 72- to 96-hour study period were observed between groups (p=not significant). Median 12-hour heparin concentrations were >0.2 U/ml in all groups; however, values <0.2 U/ml were common thereafter, particularly in TPA-treated patients. Time-dependent covariate analyses failed to identify statistically significant differences in either aPTT or heparin levels between patients with in-hospital clinical events (spontaneous ischemia, myocardial infarction, or death) and those without events (p=0.27). Furthermore, early clinical events occurred in a similar percentage of patients with optimal anticoagulation (all aPTTs >60 seconds, all heparin levels>0.2 U/ml), and those with aPTTs or heparin levels below these thresholds. Aggressive (high-intensity) anticoagulation with heparin to achieve aPTTs >2.0 times control does not appear to offer additional clinical benefit to lower levels (1.5 to 2.0 times control) among patients with unstable angina and non-Q wave myocardial infarction receiving intravenous heparin and oral aspirin. Therefore, the optimal level of anticoagulation in this common clinical setting is between 45 and 60 seconds when heparin is included in the treatment strategy. Direct plasma heparin measurement does not offer an advantage to routine aPTT monitoring. The occurrence of spontaneous ischemia, myocardial infarction, and death in spite of antischemic therapy and optimal anticoagulation (as it is currently defined) with heparin supports ongoing efforts to develop more effective antithrombotic agents.

A wide variety of haemostatic variables were measured in healthy male subjects predominantly blood donors residing in Riyadh, the capital city of Saudi Arabia. Subjects were divided according to ethnic origin: Saudi Arabs n = 487, Westerners (Europeans and Americans) n = 300, South East Asians (Koreans and Filipinos) n = 360, and West Africans n = 82. There were no significant differences in prothrombin time, partial thromboplastin time, thrombin time, reptilase time, plasma fibrinogen, antithrombin, plasminogen and platelet count between Saudis, Westerners and Asians. Africans exhibited significantly lower plasma levels of fibrinogen, platelet count and plasminogen than other ethnic groups. Arabs and Africans had higher levels of FVIII:C and vWF:ristocetin cofactor than Westerners. On the other hand, FX was significantly higher in Westerners than in other ethnic groups. Smokers had higher fibrinogen levels than non-smokers. These variations, which could not be related to blood group distribution, physical parameters of height and weight, may be due to genetic and/or dietary habits. In conclusion, this study established the existence of racially determined variations in haemostatic variables, with Black Africans showing changes consistent with a lesser tendency towards atherosclerosis and cardiovascular disease than other ethnic groups. These variations should be taken into account when investigating the haemostatic system in patients.

We studied African-American Factor (FVII)-deficient variants and carriers in Georgia by measuring their levels of FVII antigen (FVIIAG) and FVII procoagulant (FVIIC). Factor VIIAG was determined using enzyme-linked immunoassay (ELISA), whereas FVIIC was measured in two ways: 1) by fibrin clotting methods that employed human recombinant (HRFVIIC), human placental (HPFVIIC), rabbit brain (RBFVIIC), and bovine brain (BBFVIIC) thromboplastins; and 2) by an amidolytic method (AMFVIIC). Prothrombin time tests (PT) were also performed by standard methods. These 4 FVII-deficient patients and 3 carriers demonstrated the following results: PT: 18.2 +/- 6.5 sec; FVIIAG: 73.0 +/- 14.9%; HRFVIIC: 30.6 +/- 20.3%; HPFVIIC: 30.5 +/- 21.4%; RBFVIIC: 25.3 +/- 21.4%; BBFVIIC: 30.6 +/- 17.5%; AMFVIIC: 44.1 +/- 18.3%. We conclude that a group of clinically mild African-American FVII-deficient variants exists in Georgia. This group is characterized by the presence of FVIIAG and decreased FVIIC, using a variety of thromboplastins; and excellent correlation was noted for both human thromboplastins.

Prothrombin time (PT) and partial thromboplastin time (PTT) tests are commonly ordered for hospitalized patients. A significant reduction in laboratory workload and expense can be achieved if these tests are ordered appropriately. The likelihood that the patient will benefit from these tests is small.

A 42-year-old Mexican migrant laborer with a previous history of neurofibromatosis presented with a stuffy nose and chronic ulceration of his soft palate. Multiple subcutaneous nodules were found on his skin, and laboratory investigation revealed an elevated activated partial thromboplastin time (APTT). Further laboratory evaluation showed a lupus-like circulating anticoagulant deemed IgM by quantitative immunoglobulin studies. Although coagulation defects in lepromatous leprosy are rare, the preoperative preparation of a patient with leprosy may require a screening prothrombin time (PT), APTT and platelet count. Abnormalities in these values may indicate the need for specific factor assays and a search for circulating anticoagulant.

Hereditary factor IX deficiency (hemophilia B) is among the more common hereditary bleeding disorders and factor IX assays are among the more common specific factor assays performed by coagulation laboratories. To assess the sensitivity of various reagents used for performance of activated partial thromboplastin times and factor IX assays, a series of samples with varying levels of factor IX were included in the 1988 College of American Pathologists Survey Program. We found significant differences in the sensitivity of reagents to factor IX deficiency. Surprisingly, the least sensitive reagents were among the most commonly used reagents. Significant differences in the classification of activated partial thromboplastin times as abnormal were noted between H1 and H2 survey participants. As with factor VIII assays, significant differences in the dose-response curves for factor IX deficiency were noted between reagents, with more responsive reagents giving more precise results for factor IX assays. Comparison of factor IX assay performance in 1988 with 1980 performance indicates a substantial improvement in assay precision. However, a further improvement in assay performance could be expected if current recommendations were followed.

Data from the 1978 CAP Hematology Survey were analyzed for the effect of sodium and calcium salts of heparin on the activated partial thromboplastin time (APTT). The results indicate that the sodium salt of heparin prolongs the APTT more than the calcium salt at a heparin concentration of 0.2 units/ml. Furthermore, there was a variable response of the different APTT reagents to the different heparin salts. Data from the 1979 CAP Hematology Survey showed a greater sensitivity of the Automated APTT reagent and the Platelin Plus Activator of General Diagnostics compared with Actin (Dade) and Thrombofax (Ortho) at therapeutic heparin levels of 0.2 units/ml to 0.4 units/ml. The 1979 CAP heparin questionnaire results are presented and analyzed.

Conventionally, heparin has been evaluated for its anticoagulant effect by various nonspecific, poorly standardized coagulant methods such as the U.S. Pharmacopeial and other global (APTT) tests. However, these assays are relatively insensitive to heparin fractions and fragments, and give varying with the newer modes of heparin administration. It has become necessary, therefore, to develop other methods able to detect a proper therapeutic/prophylactic level and to evaluate a standard potency for these agents. Newer amidolytic assays utilizing synthetic substrates provide for specific anti-factor Xa or anti-factor IIa evaluation. Although these factors are believed to reflect the antithrombotic effect of heparin and its fractions/fragments, conclusive clinical studies are not available at this time. Interactions with non-AT-III-mediated pathways, the contact, kallikrein-kinin, and fibrinolytic system, other coagulant factors, endothelium, and eicosanoid system all can contribute to the overall antithrombotic response of heparin. Some of these actions are not measurable by current in vitro test methods. Amidolytic, immunochemical, and physical assays using various activators to generate endogenous factor Xa, as well as assays for the detection of metabolic or release products of each of these systems, may be more relevant to in vivo conditions. Specific low molecular weight markers such as fibrinopeptide A, which provide the earliest detection of hemostatic activation, can be measured directly, or an in vitro system can be developed to quantitate the relative generation of these markers. These methods can then be modified to assay the in vitro potency of heparin preparations. With proper consideration of reagent specificity and concentration, molecular interactions, reaction time and temperature, ionic type and concentration, reliable accurate methods for a true in vitro representation of in vivo events may be developed. Clinical assays must measure an endogenous response to therapy and not merely an absolute circulating level of drug. However, a standardized pure enzyme system may be ideal to evaluate the potency of these agents. The development of heparin derivatives necessitates a reassessment of currently practiced laboratory technology. Furthermore, well-defined biochemical methods are required for a standardized evaluation of potency and clinical monitoring of these agents.

Data from the 1976-1979 CAP Surveys for Factor VIII assays are reviewed. Beginning in 1979, Factor IX assays were also performed by survey participants. Data was obtained from approximately 2500 laboratories and the different instrument-reagents are ranked according to precision and sensitivity. Also, the results of questionnaires on specific assay techniques (1977 through 1979) are analyzed. A trend was noted indicating an increasing number of laboratories are now performing factor assays. There is poor correlation between precision and sensitivity of most systems (i.e., instrument and reagent combination). For any given system, there was considerable variation in precision from a normal Factor VIII levels specimen to a low Factor VIII specimen. This was also the case with respect to Factor IX assays. With respect to the technical aspects of factor assays there was marked interlaboratory variation (i.e., dilution of normal plasma used to construct standard curve, etc.). The need for standardization of factor assays is evident from the survey data.

Plasma samples of 125 patients from 80 kindreds with hereditary plasma thromboplastin antecedent (PTA, factor XI) deficiency were tested by factor XI radioimmunoassay (RIA) and electroimmunoassay (EIA) in an attempt to detect variant molecules. Ninety-six patients (70 kindreds) were Jewish, and 29 (10 kindreds) were of other ethnic backgrounds, namely, Japanese, black American, Korean, Arab, Indian, and English. Seventy-eight patients were homozygotes, and 47 were heterozygotes. Both non-Jewish homozygotes and heterozygotes had lower factor XI activity than respective Jewish subjects. Twenty-eight homozygotes whose factor XI clotting activities (XI:C) were 1.5% to 13% had factor XI-related antigen (XI:RAG) levels less than 10% by EIA. In 72 homozygotes, including 22 patients who were also tested with EIA, XI:C was 2.9% +/- 3.0% (mean +/- SD) and XI:RAG tested by RIA, 2.9% +/- 3.0%. In 47 heterozygotes, XI:C and XI:RAG tested by RIA were 51.9% +/- 16.6% and 51.0% +/- 16.2%, respectively. Similar results were obtained when only unrelated patients (62 homozygotes and 27 heterozygotes) were analyzed. There was a highly significant correlation between XI:C and XI:RAG (RIA) in 38 homozygotes and 47 heterozygotes (r = 0.94, n = 85, P less than 0.001). Thus, we failed to identify functionally abnormal factor XI molecules (CRM+ variant) in these patients with hereditary factor XI deficiency.

It has become apparent that mild factor deficiency states (i.e., Factor VIII, IX, and von Willebrand's syndrome) are frequent causes of postoperative bleeding and hemorrhagic complications following trauma. Despite their incidence, they frequently are not diagnosed or in some instances are misdiagnosed. In an attempt to improve the level of performance of factor assays, the College of American Pathologists recently has introduced factor-deficient plasmas into their proficiency testing program. Initially, plasmas deficient in Factor VIII were evaluated and more recently, plasmas deficient in Factors IX and XI were included. The results of the initial survey programs indicated a lack of precision and accuracy of Factor VIII and IX assays. Similar difficulties also were encountered with plasmas deficient in Factor XI. Extensive information also was gathered on the fundamentals of laboratory performance of factor assays. This information included data regarding preparation of the standard activity curves, source of deficient substrate plasmas, number of patient sample dilutions, etc. Also, it was evident that various thromboplastins have different degrees of sensitivity to the various deficiency states. A portion of this variability may be attributable to the choice of activator, however, it would appear that the phospholipid content of the partial thromboplastins is of equal importance.