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Background: Pediatric patients on extracorporeal membrane oxygenation (ECMO) often receive repeated red blood cell (RBC) transfusions. This study aims to quantify and characterize causes of RBC loss on ECMO. Methods: This retrospective, single‐center, observational study includes 91 ECMO patients (age 1 day–20 years). An RBC loss index (RLI), equal to ml RBCs lost per liter of patient + circuit volume per hour, was calculated from the changes in hematocrit and transfused RBCs. To measure the contribution of RBC injury/activation, RBC extracellular vesicle (REV) generation was measured by flow cytometry. Results: Median RLI on ECMO was 1.9 ml/L/h, 13‐fold higher than normal RBC production rate (0.15 ml/L/h) and equivalent to a 4.6 drop in hematocrit/day. Median RBC loss was higher in patients who died (2.95 ml/L/h) versus survived (1.70 ml/L/h, p =.0008). RLI correlated with transfusion rate (r2 = 0.71); however, transfusion rate (ml/kg) underestimated RBC loss in patients with large changes in hematocrit and over‐estimated RBC loss in neonates where the circuit volume is greater than the patient blood volume. In non‐bleeding patients, intravascular hemolysis represented 16% of total RBC loss and diagnostic phlebotomy 24%, suggesting that ~60% of RBC loss was due to other causes. REV generation was increased sevenfold to ninefold during ECMO. Discussion: RLI (ml/L/h) is a more reliable quantitative indicator of RBC loss than transfusion rate (ml/kg) for pediatric patients on ECMO. Phlebotomy and intravascular hemolysis only account for 40% of RBC loss in non‐bleeding ECMO patients. High REV generation suggests sublethal damage and extravascular clearance may be a cause of RBC loss on ECMO. See editorial on page 899–902, in this issue [ABSTRACT FROM AUTHOR]

Background: Most pediatric patients show a decline in platelet counts while on extracorporeal life support (ECLS) and require multiple platelet transfusions. To better understand platelet loss during ECLS, this study estimated platelet loss rates due to diagnostic phlebotomy, platelet activation, bleeding and other causes. Methods: We collected data on 91 patients (1d‐20y, 50 M, 41F). Platelet losses were estimated based on changes in platelet count, patient+circuit blood volume, and transfused platelet volumes. Platelet extracellular vesicles were measured by flow cytometry. Results: Median platelet loss was 2.8 × 109/L/hr, more than twice the normal rate of platelet removal and equivalent to a 67 000/μl decrease in platelet count per day. While platelet loss was correlated with platelet transfusion (r2 = 0.51), transfusion underestimated platelet loss in patients with large decreases in platelet count and over‐estimated platelet loss in neonates where the circuit volume > patient blood volume. Patients with disseminated intravascular coagulation before or significant bleeding during ECLS have double the rate of platelet loss. Platelet activation accounted for ~32% of total platelet loss, bleeding ~36% and phlebotomy 4%, with the remaining one‐third due to other causes. Annexin‐negative platelet extracellular vesicle release, a measure of platelet damage, was increased 9‐fold during ECLS. Conclusion: Our study is the first to quantitate total, phlebotomy and activation related platelet loss during ECLS. Platelet activation accounts for ~32% of total platelet loss, while bleeding doubles the platelet loss rate. The etiology of the remaining platelet loss is unknown. [ABSTRACT FROM AUTHOR]

Objectives: Activated partial thromboplastin time (aPTT) is the primary test used to monitor intravenous (IV) direct thrombin inhibitors (DTIs) but has many limitations. The plasma diluted thrombin time (dTT) has shown better correlation with DTI levels than aPTT. This study compared dose-response curves for dTT and aPTT in pediatric patients receiving argatroban and bivalirudin.Methods: A retrospective review of pediatric patients treated with argatroban (n = 45) or bivalirudin (n = 14) monitored with dTT and aPTT.Results: The dTT assay was calibrated to report DTI concentrations in µg/mL for argatroban and bivalirudin with good analytic sensitivity and specificity. The dTT was fivefold more likely to show a stable dose-response slope than the aPTT (P < .0002; odds ratio, 4.9). For patients in whom both dTT and aPTT showed a significant correlation between dose and assay results, dTT had a higher average correlation factor compared with aPTT (P = .007). Argatroban dose-response slopes showed more inter- and intrapatient variation than bivalirudin (dose-response slope coefficient of variation, 132% vs 52%).Conclusions: The dTT assay was more likely to show a stable dose response and have a stronger correlation with DTI dose than aPTT. Argatroban shows more variation in dose response than bivalirudin. [ABSTRACT FROM AUTHOR]

Chromogenic anti‐Xa assays for unfractionated heparin monitoring (heparin activity) are susceptible to interference from hemolysis and icterus. The purpose of this study was to better understand the effect of hemolysis and icterus on anti‐Xa heparin activity and to predict the magnitude of the error. Increasing levels of hemoglobin and unconjugated bilirubin were added to pooled normal plasma or buffer containing known levels of heparin. Increased plasma hemoglobin or bilirubin produced falsely increased residual factor Xa activity as measured by the absorbance change (OD/min) in the Stago heparin activity assay. This increased absorbance change slope resulted in falsely lower estimates of heparin activity. The falsely lower heparin activity measurement occurred even when heparin was not present, indicating it was not due to heparin neutralization. In a sample containing 0.62 ± 0.06 U/mL heparin and 228 mg/dL hemoglobin, the measured heparin activity was 0.41 ± 0.03 U/mL, underestimating heparin activity by 0.21 ± 0.07 U/mL. Interference occurred if plasma hemoglobin was above 70 mg/dL or bilirubin was above 16 mg/dL, which happened in 16%–26% of samples from pediatric patients on extracorporeal life support (ECLS). In conclusion, hemolysis and icterus were common in ECLS patients, leading to underestimates of unfractionated heparin activity and potentially higher doses of heparin than intended. The magnitude of the heparin activity measurement error could be predicted based on plasma hemoglobin and bilirubin levels until these levels exceeded the technical limits of the assay, ~230 mg/dL hemoglobin and 55 mg/dL bilirubin. [ABSTRACT FROM AUTHOR]

Objectives: To determine the relationship between baseline variations in the partial thromboplastin time (PTT) and the discordance between the PTT and anti-Xa heparin activity (anti-Xa) during heparin therapy.Methods: The baseline PTT on heparin was determined using automated heparin neutralization with protamine (prPTT). The prPTT was used to calculate a baseline-corrected PTT on heparin to reduce discordance with anti-Xa measurements.Results: The prPTT removed up to 1 U/mL of heparin, returning baseline values for normal, factor-deficient, and lupus inhibitor plasmas. A prolonged prPTT was seen in 97 (53%) of 182 samples from heparinized patients. The heparinized PTT was discordant compared with anti-Xa in 64 (35%) of 182 samples and 43 (67%) of 64 discordant samples, and 46% of concordant samples showed a prolonged prPTT. A baseline-corrected PTT reduced discordance with anti-Xa measurements by 64%.Conclusions: PTT/anti-Xa discordance due to baseline PTT prolongation could be reduced using a baseline-corrected PTT. [ABSTRACT FROM AUTHOR]

The article focuses on the need clinical risk assessment of patients with Pulmonary Embolism by the practicing physicians. It discusses an advice paper by Clinical Guidelines Committee of the American College of Physicians related to clinical algorithms of age-adjusted D-dimer. It also presents information on the approach of College of American Pathologists (CAP) and Clinical Laboratory and Standards Institute (CLSI) towards D-dimer.

Background: The pharmacokinetic properties of enoxaparin may lead to supratherapeutic antifactor Xa (anti-Xa) levels and increased bleeding when standard treatment doses are used in patients with morbid obesity. Objective: To evaluate the dose of enoxaparin needed to achieve therapeutic anti-Xa levels in a prospective, masked observational cohort of heterogeneous inpatients with morbid obesity and to determine whether patients with morbid obesity treated with 1 mg/kg of enoxaparin are at increased risk of supratherapeutic levels and bleeding events compared to patients receiving lower doses. Methods: Hospitalized patients with a body mass index ≥40 kg/m2 or actual body weight ≥140 kg and prescribed treatment doses of enoxaparin >60 mg per day were enrolled and consented to phlebotomy for determination of anti-Xa levels. Results: Forty-one patients were included for data analysis. The dose of enoxaparin that resulted in therapeutic and supratherapeutic anti-Xa levels at steady state was 0.83 mg/kg and 0.98 mg/kg (−0.11; 95% confidence interval [CI] −0.20 to −0.01, P = .02), respectively. Enoxaparin dose as mg/kg of actual body weight was an independent predictor of having a supratherapeutic anti-Xa level. Patients with doses <0.95 mg/kg versus ≥0.95 mg/kg were less likely to have supratherapeutic levels (odds ratio 0.21 [95% CI 0.05-0.84], P = .02) and had similar rates of subtherapeutic levels. Doses <0.95 mg/kg and ≥0.95 mg/kg resulted in similar bleeding rates of 17.9% and 22.2% (P = .71), respectively. Conclusion: Patients with morbid obesity required less than the recommended 1 mg/kg enoxaparin dose to achieve therapeutic peak anti-Xa levels; therefore, initiation with lower dosages is prudent and anti-Xa monitoring should guide dosage adjustments. [ABSTRACT FROM AUTHOR]

The authors discuss a study by S. Bloemen and colleagues, published within the issue which described development of reference intervals for thrombin generation assay (TGA) in whole blood, platelet-rich plasma, and platelet-poor plasma. Topics include clinical situations where altered TGA results have been described, problems that limit the clinical use of TGA, and development of fully automated TGAs by manufacturers on coagulation instruments.

Objectives: Thromboelastography Platelet Mapping (TEGPM) is an assay designed to detect platelet inhibition due to aspirin or clopidogrel-like drugs. The purpose of this study was to evaluate potential causes of error in the design or operation of the assay. Methods: We evaluated percent inhibition of platelets due to aspirin or clopidogrel using TEGPM, which measures clot viscoelastic maximum amplitude (MA) after activation with adenosine diphosphate (ADP) or arachidonic acid (AA) and subtraction of MA due to fibrin (MAFibrin). Results: MAFibrin measured in heparinized blood showed an unstable increasing pattern in 28% of samples (16 of 58). The platelet aggregation inhibitor eptifibatide corrected increasing MAFibrin in 14 of 16 cases, while the thrombin inhibitor argatroban corrected increasing MAFibrin in six of 16 cases, suggesting that unanticipated platelet activation/ aggregation was a more important cause of unstable rising MAFibrin than uninhibited thrombin. The unstable increased MAFibrin falsely increased percent ADP inhibition on average from 19% to 38% and percent AA inhibition from 29% to 58%. Heparinized samples showed platelet clumping and had procoagulant platelet microvesicle levels double those in citrate anticoagulant. Conclusions: Unanticipated platelet activation/aggregation occurring in the heparinized TEGPM samples lead to erroneous percent inhibition results. [ABSTRACT FROM AUTHOR]

Aim Phosphatidylserine-rich microparticles derived from endothelial cells, platelets and leukocytes have been implicated as surrogate markers of cellular activation in systemic lupus erythematosus ( SLE). Because microparticles have also been associated with many primary neurologic diseases, this study investigated whether cellular-derived microparticles are also implicated in neuropsychiatric SLE ( NPSLE). Method Plasma microparticles were measured in 51 SLE patients and 22 age- and gender-matched controls. Acute NPSLE was defined as major NPSLE (acute stroke, transient ischemic attack, psychosis, isolated seizures, major cognitive disorder, or acute confusional state) and NPSLE disease activity was measured with the neurologic components of the SLE Disease Activity Index (Neuro- SLEDAI). Results Neuro- SLEDAI levels varied widely in SLE patients, consistent with variable NPSLE activity. When considering all patients with SLE, there was no difference in total microparticles relative to matched controls, 2158/μL (interquartile range [ IQR] 1214-3463) versus 2782/μL ( IQR 1586-2990; P = 0.57) nor differences in microparticles derived from either platelets ( P = 0.40), monocytes ( P = 0.15) or endothelial cells ( P = 0.32). However, levels of circulating monocyte-derived microparticles significantly and independently correlated with NPSLE ( r = −0.28; P = 0.045), corticosteroid dosage ( r = −0.38; P = 0.006) and levels of circulating C5a ( r = 0.54; P < 0.0001). Non-neurologic SLE disease activity was not associated with microparticles. Conclusion Circulating cell-derived microparticles are reduced in active NPSLE, although the relative contribution of reduced microparticle production, increased consumption or intravascular sequestration, remain uncertain. [ABSTRACT FROM AUTHOR]

An international normalized ratio (INR) higher than 9 is associated with a high risk of bleeding, yet most studies have focused on outpatients with lower INR. We retrospectively analyzed diagnosis, bleeding, treatment, and mortality in 162 patients with INR higher than 9, including inpatients and outpatients with and without warfarin treatment. Patients without anticoagulant treatment with INR higher than 9 had a poor prognosis, 67% experienced bleeding and 74% died. Among outpatients receiving warfarin with INR higher than 9, 11% had bleeding, but none died. Among inpatients receiving warfarin, 35% had bleeding and 17% died. Factors associated with bleeding were older age, renal failure, and alcohol use. Withholding warfarin or giving vitamin K treatment was ineffective at reducing the INR within 24 hours, whereas plasma infusion immediately dropped the INR to 2.4 ± 0.9. Because of underlying disease, comorbidities, and medications, hospitalized patients with INR higher than 9 may not respond quickly to withholding warfarin or vitamin K treatment, and plasma infusion may be needed to reduce INR and the risk of bleeding within 24 hours. [ABSTRACT FROM AUTHOR]

We compared 2 commercial plasma procoagulant phospholipid activity (PPA) assays, chromogenic, using bound annexin V to capture phosphatidylserine-containing microparticles, and clot-based. In both, anionic phospholipids accelerated activation of prothrombin by factor Xa. PPA levels were lower in the chromogenic vs the clot-based assay, with poor correlation between methods: normal samples, mean ± SD, 27 ± 17 vs 590 ± 414 nmol/L (n = 24; r⊃2 = 0.29) and patient samples, mean ± SD, 45 ± 44 vs 401 ± 330 nmol/L (n = 51; r⊃2 = 0.26). Recovery of phosphatidylserine added to normal, heparinized, and warfarin plasma samples averaged 109% ± 39% using the chromogenic assay but was higher and more varied (mean ± SD, 176% ± 59%) in the clot-based assay. Lupus anticoagulants caused low recovery in both assays. Removal of microparticles by 0.22-µm filtration reduced PPA by 91% in the clot-based and 65% in the chromogenic assay. The clot-based assay showed higher correlation (r⊃2 = 0.82 vs 0.23) with flow cytometric platelet microparticle counts. The 2 assays measure different aspects of PPA in plasma, with the chromogenic assay primarily measuring smaller microparticles. [ABSTRACT FROM AUTHOR]

We evaluated the accuracy and precision of von Willebrand disease (vWD) testing performed by up to 50 North American Specialty Coagulation Laboratories from 2004 through 2009, using proficiency samples from healthy subjects (n = 7) and patients with type 1 vWD (n = 7) or type 2 vWD (n = 3). We analyzed 2,212 submitted results. Precision was highest for von Willebrand factor (vWF) antigen assays (coefficient of variation, 14%), which were performed predominantly by latex immunoassays, and lowest for ristocetin cofactor assays (coefficient of variation, 28%), which were increasingly replaced by collagen binding and immunofunctional methods during the 6-year evaluation period. Overall interpretation error rates ranged from 3% for normal samples, 28% for type 1 vWD, and 60% for type 2 vWD. Type 2 vWD samples were correctly identified by all laboratories using collagen binding/antigen ratios but by only one third of laboratories using ristocetin cofactor/antigen or immunofunctional/antigen ratios. In 2009, only 27% (12/45) of laboratories performed vWF multimer analysis, with error rates ranging from 7% to 22%. [ABSTRACT FROM AUTHOR]

Evaluation of hemostasis in bleeding patients requires both accuracy and speed. As an alternative to point-of-care testing, we developed an emergency hemorrhage panel (EHP: prothrombin time [PT], fibrinogen, platelet count, hematocrit) for use in making transfusion decisions on bleeding patients with a goal of less than 20-minute turnaround time (TAT) when performed in the clinical laboratory on automated instruments. Because point-of-care samples are not checked for clotting or hemolysis, we evaluated their effect on automated testing. TAT was reduced by moving the sample immediately to testing and shortening centrifugation times. Clotting in samples was rare (1.1%) and shortened the PT by only 0.7 seconds. It lowered fibrinogen on average 18%, but resulted in only one of 2300 samples changing from normal to low fibrinogen. Hemolysis had no clinically significant effect on the PT or fibrinogen. Therefore, hemolysis checks were eliminated and clot checks minimized. Initially TAT averaged 15 ± 4 minutes (range, 8-30 min), but 9% of samples exceeded the 20-minute goal due to low fibrinogens that slowed testing. A revised fibrinogen assay with expanded calibration range resulted in a TAT of 14 ± 3 minutes (range, 6-28 min) with only 2% of samples exceeding the 20-minute goal. By limiting EHPs to patients that were actively bleeding, EHPs accounted for only 8 of 243 coagulation samples per day. Limiting EHPs to bleeding patients and modifications to the process and assays used for hemostasis testing lead to TATs of less than 20 minutes for critical testing in the clinical laboratory. [ABSTRACT FROM AUTHOR]

BACKGROUND: Trauma patients are at risk of developing an acute coagulopathy of trauma (ACT) related to tissue injury, shock, and hemodilution. ACT is incompletely understood, but is similar to disseminated intravascular coagulation (DIC) and is associated with poor outcome. STUDY DESIGN AND METHODS: Thrombin generation assays were used to evaluate plasma hemostasis in 42 trauma patients, 25 normal subjects, and 45 patients on warfarin and in laboratory-prepared factor reduced plasma. RESULTS: Prolonged prothrombin time (PT), more than 18 seconds, or an international normalized ratio of greater than 1.5 was present in 15 trauma patients indicating possible ACT. Native thrombin generation (no activator added, contact activation blocked) showed that Trauma with ACT patients had lag times 68% shorter and peak thrombin generation threefold higher than normal patients indicating the presence of circulating procoagulants capable of initiating coagulation systemically. Trauma patients had lower platelet counts and fibrinogen and Factor (F)II levels putting them at increased risk of bleeding. In laboratory-prepared isolated factor-reduced samples and in patients with vitamin K–dependent factor deficiency due to warfarin, thrombin generation decreased in direct proportion to FII levels. In contrast, in diluted plasma and in trauma patients with reduced factor levels, thrombin generation was increased and associated with slower inhibition of thrombin generation (prolonged termination time) and decreased antithrombin levels (43% of normal in Trauma with ACT). CONCLUSIONS: Thrombin generation studies indicate that Trauma with ACT patients show dysregulated hemostasis characterized by excessive non–wound-related thrombin generation due to a combination of circulating procoagulants capable of activating coagulation systemically and reduced inhibitor levels allowing systemic thrombin generation to continue once started. [ABSTRACT FROM AUTHOR]

Background: Clinical studies conducted to elucidate the systemic response to cardiopulmonary bypass (CPB) did not differentiate possible effect of different types of cardiac surgical pathologies and operations on outcomes and have typically combined different procedures. We hypothesized that valve surgery induces more prominent systemic reaction compared to isolated on-pump CABG. Methods: Twenty-seven patients undergoing primary on-pump CABG (Group 1, n = 14) or valve surgery with or without CABG (Group 2, n = 13) were prospectively enrolled. Heparin-bonded circuits were used in all patients. Cardiotomy suction was only used in Group 2. Clinical and laboratory markers were evaluated. Results: Clinical measurements, including chest tube output, blood transfusion requirement, inotropic support requirement, and duration of ICU stay were not significantly different. Thrombin generation (PF-1.2) was significantly higher in Group 2 (p = 0.001). tPA was also significantly higher in Group 2 at 15 and 60 minutes on CPB (p < 0.01). Group 2 had significantly higher inflammatory response shown by elevation of IL6 (p = 0.005). Neuronal injury markers, S100β and NSE, were significantly higher at the termination of CPB in Group 2 (p < 0.01). At no point of time course for any marker, Group 1 had significantly higher response compared to Group 2. Conclusions: Valve surgery induced more prominent systemic response than CABG. The possible explanations include the difference in baseline disease pathophysiology, and/or difference associated with the procedures such as open systems and use of cardiotomy suction. Future clinical studies assessing systemic response to CPB and therapies to blunt these need consider and account for these observed differences. [ABSTRACT FROM AUTHOR]

Background: The mechanism behind the triggering effect of fine particulate matter (PM) air pollution on cardiovascular events remains elusive. We postulated that elevated levels of PM would be associated with increased blood levels of inflammatory and thrombotic markers in elderly individuals. We also hypothesized that elevated PM would increase levels of cytokines in individuals with heart disease. Methods: We measured these blood markers in 47 elderly individuals with (23) and without (16 COPD and 8 healthy) cardiovascular disease (CVD) on 2 or 3 mornings over a 5 or 10-day period between February 2000 and March 2002. Blood measures were paired with residence level outdoor PM measured by nephelometry. Analyses determined the within-individual effect of 24- hour averaged outdoor PM on blood measures. Results: Analyses found no statistically significant effect of a same day 10 ug/m3 increase in fine PM on log transformed levels of CRP 1.21 fold-rise [95% CI: 0.86, 1.70], fibrinogen 1.02 fold-rise [95% CI: 0.98, 1.06], or D-dimer 1.02 fold-rise [95% CI: 0.88, 1.17] in individuals with CVD. One-day lagged analyses in the CVD subgroup found similar null results. These same models found no change in these blood markers at the same-day or 1-day lag in the group without CVD. In 21 individuals with CVD, a 10 μg/m³ increase in same-day PM was associated with a 1.3 fold-rise [95% CI: 1.1, 1.7] in the level of monocyte chemoattractant protein-1. Conclusion: We did not find consistent effects of low ambient levels of PM on blood measures of inflammation or thrombosis in elderly individuals. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients undergoing cardiac surgery requiring cardiopulmonary bypass develop a systemic inflammatory reaction. Antithrombin III (AT) has anticoagulant effects but also shows evidence of anti-inflammatory activity. The aim of this study was to examine whether exogenous AT could reduce white blood cell activation (CD11b up regulation or elastase release), in addition to inhibiting platelet (PLT) activation and fibrin generation, during simulated cardiopulmonary bypass (sCPB), undertaken in the absence of endothelium. STUDY DESIGN AND METHODS: sCPB was carried out with minimally heparinized (2 U/mL) human blood for 90 minutes in controls and with supplementation by low-dose (1 U/mL) and high-dose (5 U/mL) AT. RESULTS: High-dose AT blunted thrombin generation during sCPB (prothrombin fragment 1.2); both doses significantly inhibited thrombin activity (fibrinopeptide A). Complement activation (C3a and C5b-9) was unaffected by AT. High-dose AT inhibited PLT activation (P-selectin expression and P-selectin–dependent monocyte-PLT conjugate formation). AT supplementation at the higher dose significantly abrogated monocyte and neutrophil CD11b up regulation and neutrophil elastase release. CONCLUSION: In addition to anticoagulant and anti-PLT effects, pharmacologic AT doses significantly blunted monocyte and neutrophil CD11b up regulation and neutrophil elastase release during sCPB, independent of endothelial effects. These data provide evidence for the direct anti-inflammatory activity of AT that has clinical relevance for CPB complications. [ABSTRACT FROM AUTHOR]

Introduction: Hypocretin-1 is a hypothalamic neuropeptide that may help regulate arousal and feeding behavior and is quantifiable in cerebrospinal fluid (CSF). In this retrospective pilot study, hypocretin-1 levels obtained from ventricular CSF of neurologically injured patients were correlated with clinical and laboratory results to test whether arousal or metabolic factors might be related to the level of hypocretin-1.Methods: CSF samples from a heterogeneous group of neurosurgical patients with externally draining intraventricular catheters were assayed in a standard manner for hypocretin-1 and other routine laboratories. Associations were sought between hypocretin-1 and clinical data such as body mass index (BMI), temperature, and Glasgow Coma Scale (GCS) score and between hypocretin-1 and laboratory data such as serum and CSF glucose, protein, and cell counts.Results: Lower levels of ventricular CSF hypocretin-1 were correlated with higher levels of serum (p = 0.020) and ventricular CSF glucose (p = 0.001). Clinical findings such as BMI, temperature, and GCS failed to correlate with hypocretin-1.Conclusions: In a group of neurologically injured patients, hypocretin-1 and glucose levels are inversely correlated. More studies are needed to investigate these associations, particularly in a homogenous patient sample. [ABSTRACT FROM AUTHOR]

A rapidly growing body of evidence demonstrates important associations between the metabolic syndrome, characterized by a cluster of risk factors or phenotypes that include dyslipidemia, central obesity, hypertension, and hyperinsulinemia, and both cardiovascular disease and type 2 diabetes. The purpose of the present study was to characterize the metabolic syndrome in a sample of 432 individuals from 68 Japanese-American families, using factor analysis of quantitative phenotypes, and to estimate the heritability of these independent factors. Using nine characteristic phenotypes that included LDL particle size and C-reactive protein (CRP), factor analysis identified three multivariate factors interpreted as lipids, body fat/insulin/glucose/CRP, and blood pressure, explaining 65% of the variance. Heritability analysis revealed significant genetic effects on all of the factors: lipids (h&sup2 = 0.52, P < 0.001), body fat/insulin/glucose/CRP (h² = 0.27, P = 0.016), and blood pressure (h² = 0.25, P = 0.026). This analysis shows that independent, multivariate factors of the metabolic syndrome are heritable, demonstrating genetic influences on the underlying pathophysiological mechanisms of the syndrome. [ABSTRACT FROM AUTHOR]

Increased thrombin generation and impaired fibrinolysis during Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS) plausibly diminish myocardial blood flow, but the frequency of cardiac ischemia during HUS is unknown. We identified a 9-year-old boy with HUS in whom myocardial diastolic dysfunction was demonstrated by echocardiography, who also had elevated serum troponin-I and creatine kinase MB mass. However, eight additional patients with HUS did not have elevated markers of cardiac injury. When present, elevated troponin-I should be considered to represent myocardial injury, and not attributed simply to renal insufficiency. It is possible that myocardial ischemia and secondary arrhythmias account for some sudden deaths that occur during acute HUS. [ABSTRACT FROM AUTHOR]

Examines the role of plasminogen activator inhibitor type 1 (PA-1) in blood in peripheral arterial thrombolysis failure. Risk factors for major bleeding associated with thrombolytic therapy; Results of tissue plasminogen activator (t-PA) infusion into subjects with low versus high levels of baseline PA-1 activity; Hypothesis on the effect of t-PA on patients with normal PA-1.

Background: The brain is rich in creatine kinase–BB isoenzyme activity (CK-BB), which is not normally present in cerebrospinal fluid (CSF). Results of previous studies have shown that CK-BB can be detected in the CSF of patients with aneurysmal subarachnoid hemorrhage (SAH), but whether CK-BB levels correlate with patients' neurologic outcomes is unknown. Objective: To evaluate the relationship between CSF CK-BB level and outcome after SAH. Design: Prospective observational cohort. Setting: University-affiliated tertiary care center. Patients: Convenience sample of 30 patients seen for cerebral aneurysm clipping. Interventions: We sampled and assayed CSF for CK isoenzymes a median of 3 days after SAH in 27 patients, and at the time of unruptured aneurysm clipping in 3 patients. Main Outcome Measures: Without knowledge of CK results, we assigned the Glasgow Outcome Scale score early (&ap;1 week) and late (&ap;2 months) after surgery. Results: Higher CSF CK-BB levels were associated with higher Hunt and Hess grades at hospital admission (Spearman rank correlation, ρ=0.69; P<.001), lower Glasgow Coma Scale scores at hospital admission (ρ=-0.72; P<.001), and worse early outcomes on the Glasgow Outcome Scale (ρ=-0.64; P<.001). For patients with a favorable early outcome (Glasgow Outcome Scale score, 3-5), all CK-BB levels were less than 40 U/L. With a cutoff value of 40 U/L, CK-BB had a sensitivity of 70% and a specificity of 100% for predicting unfavorable early outcome (Glasgow Outcome Scale score, 1-2). Having a CK-BB level greater than 40 U/L increased the chance of an unfavorable early outcome, from 33% (previous probability) to 100%, whereas a CK-BB level of 40 U/L or less decreased it to 13%. Similar findings were obtained when considering late outcomes. Conclusion: The level of CSF CK-BB may help predict neurologic outcome after SAH. [ABSTRACT FROM AUTHOR]

New anticoagulants, like the orally available direct thrombin inhibitor (DTI) dabigatran etexilate, have recently been introduced into the market for venous thromboembolic prophylaxis and for stroke prevention in atrial fibrillation. While dabigatran has been approved for use without the need for routine therapeutic monitoring, there are clinical scenarios in which monitoring can help guide clinical management. We report herein the application of a recently described plasma-diluted thrombin time (DTI assay) used to monitor intravenous DTI as a useful and easily implemented method to monitor oral DTIs. [ABSTRACT FROM AUTHOR]

We report a case where a phenotypic test (an activity assay for activated protein C resistance) correctly indicated that the patient had an abnormality, whereas the initial genetic test (a PCR-based DNA assay used to detect the mutation in the FV gene) incorrectly indicated that the patient did not. The apparent false negative result of the DNA-based test was due to the use of peripheral blood leucocytes for DNA analysis. The patient had undergone a stem cell transplant several months before, and the leucocytes in her blood were derived from the stem cell donor, which lacked the FV defect. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses various reports within the issue on topics including the roles of pathologists and clinical laboratories regarding anticoagulants, the different factor X-related assays and their use for monitoring anticoagulants, and treatment options for patients taking direct thrombin inhibitors.