An Introduction to the Complete Blood Count for Clinical Chemists: Red Blood Cells.

BACKGROUND: The most frequently ordered laboratory test worldwide is the complete blood count (CBC). CONTENT: In this primer, the red blood cell test components of the CBC are introduced, followed by a discussion of the laboratory evaluation of anemia and polycythemia. SUMMARY: As clinical chemists are increasingly tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This review article is a dedication to that effort.

An Introduction to the Complete Blood Count for Clinical Chemists: Platelets.

BACKGROUND: The most ordered laboratory test worldwide is the complete blood count (CBC). CONTENT: In this primer, an introduction to platelet testing in the context of the CBC is provided with a discussion of the laboratory evaluation of platelet abnormalities including thrombocytopenia and thrombocytosis. SUMMARY: As clinical chemists continue to be tasked to direct laboratories outside of the traditional clinical chemistry sections such as hematology, expertise must be developed. This primer is dedicated to that effort.

Advances in sepsis biomarkers.

Sepsis, a dysregulated host immune response to an infectious agent, significantly increases morbidity and mortality for hospitalized patients worldwide. This chapter reviews (1) the basic principles of infectious diseases, pathophysiology and current definition of sepsis, (2) established sepsis biomarkers such lactate, procalcitonin and C-reactive protein, (3) novel, newly regulatory-cleared/approved biomarkers, such as assays that evaluate white blood cell properties and immune response molecules, and (4) emerging biomarkers and biomarker panels to highlight future directions and opportunities in the diagnosis and management of sepsis.

The stability of blood gases and CO-oximetry under slushed ice and room temperature conditions.

OBJECTIVES: Human blood gas stability data is limited to small sample sizes and questionable statistical techniques. We sought to determine the stability of blood gases under room temperature and slushed iced conditions in patients using survival analyses. METHODS: Whole blood samples from ∼200 patients were stored in plastic syringes and kept at room temperature (22-24 °C) or in slushed ice (0.1-0.2 °C) before analysis. Arterial and venous pO2 (15-150 mmHg), pCO2 (16-72 mmHg), pH (6.73-7.52), and the CO-oximetry panel [total hemoglobin (5.4-19.3 g/dL), percentages of oxyhemoglobin (O2Hb%, 20-99%), carboxyhemoglobin (COHb, 0.1-5.4%) and methemoglobin (MetHb, 0.2-4.6%)], were measured over 5-time points. The Royal College of Pathologists of Australasia's (RCPA's) criteria determined analyte instability. Survival analyses identified storage times at which 5% of the samples for various analytes became unstable. RESULTS: COHb and MetHb were stable up to 3 h in slushed ice and at room temperature; pCO2, pH was stable at room temperature for about 60 min and 3 h in slushed ice. Slushed ice shortened the storage time before pO2 became unstable (from 40 to 20 min), and the instability increased when baseline pO2 was ≥60 mmHg. The storage time for pO2, pCO2, pH, and CO-oximetry, when measured together, were limited by the pO2. CONCLUSIONS: When assessing pO2 in plastic syringes, samples kept in slushed ice harm their stability. For simplicity's sake, the data support storage times for blood gas and CO-oximetry panels of up to 40 min at room temperature if following RCPA guidelines.

Implementation of pharmacogenomics into inpatient general medicine.

Pharmacogenomics is a crucial piece of personalized medicine. Preemptive pharmacogenomic testing is only used sparsely in the inpatient setting and there are few models to date for fostering the adoption of pharmacogenomic treatment in the inpatient setting. We created a multi-institutional project in Chicago to enable the translation of pharmacogenomics into inpatient practice. We are reporting our implementation process and barriers we encountered with solutions. This study, 'Implementation of Point-of-Care Pharmacogenomic Decision Support Accounting for Minority Disparities', sought to implement pharmacogenomics into inpatient practice at three sites: The University of Chicago, Northwestern Memorial Hospital, and the University of Illinois at Chicago. This study involved enrolling African American adult patients for preemptive genotyping across a panel of actionable germline variants predicting drug response or toxicity risk. We report our approach to implementation and the barriers we encountered engaging hospitalists and general medical providers in the inpatient pharmacogenomic intervention. Our strategies included: a streamlined delivery system for pharmacogenomic information, attendance at hospital medicine section meetings, use of physician and pharmacist champions, focus on hospitalists' care and optimizing system function to fit their workflow, hand-offs, and dealing with hospitalists turnover. Our work provides insights into strategies for the initial engagement of inpatient general medicine providers that we hope will benefit other institutions seeking to implement pharmacogenomics in the inpatient setting.

Reducing Specimen Rejection Rates Using Concentration-Dependent Hemolysis Rejection Thresholds.

BACKGROUND: Using middleware solutions, it is possible to implement concentration-dependent analyte-specific hemolysis rejection limits. This makes day-to-day reporting of clinical specimens more efficient and potentially lowers sample rejection rates compared to a "one-size-fits-all" approach (i.e., solely based on a single cutoff provided in the package insert). METHODS: Hemolysis interference studies were performed at multiple analyte concentrations for three frequently ordered tests. For each assay, concentration-dependent hemolysis rejection limits were designed based on the total allowable error (TAE) for the analyte as well as the clinical significance of such incurred inaccuracy at the respective concentrations. In general, the following rationale was used: if the interference exceeds 10% (or package insert cutoffs), a comment is placed on the result. If the interference exceeds the TAE, the result will not be reported. Reduction in specimen rejection rates were estimated by comparing the incurred specimen rejection rates when package inserts' vs concentration-dependent hemolysis interference limits were applied to a data set in our institute during a three-month period. RESULTS: Concentration-dependent analyte-specific hemolysis rejection thresholds were designed for three commonly ordered assays that are especially susceptible to hemolysis interference. It is estimated that these novel thresholds for aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and direct bilirubin (DBIL) reduced specimen rejection rates from 9.3% to 1.3%, 31.4% to 4.8%, and 19.9% to 7.1%, respectively. CONCLUSIONS: Concentration-dependent analyte-specific hemolysis rejection thresholds for three commonly ordered assays can reduce rejection rates without significantly compromising the quality of test results.

Pilot Findings of Pharmacogenomics in Perioperative Care: Initial Results From the First Phase of the ImPreSS Trial.

BACKGROUND: Pharmacogenomics, which offers a potential means by which to inform prescribing and avoid adverse drug reactions, has gained increasing consideration in other medical settings but has not been broadly evaluated during perioperative care. METHODS: The Implementation of Pharmacogenomic Decision Support in Surgery (ImPreSS) Trial is a prospective, single-center study consisting of a prerandomization pilot and a subsequent randomized phase. We describe findings from the pilot period. Patients planning elective surgeries were genotyped with pharmacogenomic results, and decision support was made available to anesthesia providers in advance of surgery. Pharmacogenomic result access and prescribing records were analyzed. Surveys (Likert-scale) were administered to providers to understand utilization barriers. RESULTS: Of eligible anesthesiology providers, 166 of 211 (79%) enrolled. A total of 71 patients underwent genotyping and surgery (median, 62 years; 55% female; average American Society of Anesthesiologists (ASA) score, 2.6; 58 inpatients and 13 ambulatories). No patients required postoperative intensive care or pain consultations. At least 1 provider accessed pharmacogenomic results before or during 41 of 71 surgeries (58%). Faculty were more likely to access results (78%) compared to house staff (41%; P = .003) and midlevel practitioners (15%) ( P < .0001). Notably, all administered intraoperative medications had favorable genomic results with the exception of succinylcholine administration to 1 patient with genomically increased risk for prolonged apnea (without adverse outcome). Considering composite prescribing in preoperative, recovery, throughout hospitalization, and at discharge, each patient was prescribed a median of 35 (range 15-83) total medications, 7 (range 1-22) of which had annotated pharmacogenomic results. Of 2371 prescribing events, 5 genomically high-risk medications were administered (all tramadol or omeprazole; with 2 of 5 pharmacogenomic results accessed), and 100 genomically cautionary mediations were administered (hydralazine, oxycodone, and pantoprazole; 61% rate of accessing results). Providers reported that although results were generally easy to access and understand, the most common reason for not considering results was because remembering to access pharmacogenomic information was not yet a part of their normal clinical workflow. CONCLUSIONS: Our pilot data for result access rates suggest interest in pharmacogenomics by anesthesia providers, even if opportunities to alter prescribing in response to high-risk genotypes were infrequent. This pilot phase has also uncovered unique considerations for implementing pharmacogenomic information in the perioperative care setting, and new strategies including adding the involvement of surgery teams, targeting patients likely to need intensive care and dedicated pain care, and embedding pharmacists within rounding models will be incorporated in the follow-on randomized phase to increase engagement and likelihood of affecting prescribing decisions and clinical outcomes.

Clinically actionable genotypes for anticancer prescribing among >1500 patients with pharmacogenomic testing.

BACKGROUND: In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care. METHODS: Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5-fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab-govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high-risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies. RESULTS: Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high-risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one-third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype. CONCLUSIONS: These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling. LAY SUMMARY: Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others. Pharmacogenomics is the study of how genetic variations affect an individual's response to medications. In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy. By analyzing the genetic results of >1500 patients, it was found that nearly one-third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given. Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care.

Stability of Whole Blood Electrolyte Specimens at Room Temperature vs. Slushed Ice Conditions.

BACKGROUND: Data on the stability of whole blood electrolytes is limited to small sample sizes. We sought to determine the stability of whole blood electrolytes under room temperature and slushed iced conditions in human patients at a major hospital center. METHODS: Whole blood samples were obtained from 203 patients hospitalized for various pathophysiological conditions. Electrolyte concentrations of sodium, potassium [K+], ionized calcium, and chloride were measured at 5 different timepoints spanning 3 h. Samples were stored at room temperature (22-24 °C) or under slushed ice conditions (0.1-0.2 °C) before analysis. RESULTS: Under both conditions, sodium, ionized calcium, and chloride did not show a measurable change up to 109 min compared to baseline; however, the mean increase in [K+] over 138 min of storage in slushed ice was 0.0032 (0.0021 [5th percentile] to 0.0047 [95th percentile]) mmol/L/min (adjusted R2 = 0.62, P < 0.001). Five percent of the specimens demonstrated a ≥0.3 mmol/L change in [K+] from baseline after 67 min of storage in slushed ice. In contrast, 1% of the specimens stored at room temperature showed the same change at the same timepoint. CONCLUSIONS: Whole blood sodium, [K+], ionized calcium, and chloride concentrations remain stable for at least 109 min at room temperature. However, whole blood specimens stored in slushed ice for not more than 67 min exhibit a 5% probability that the [K+] concentration will increase by at least 0.3 mmol/L compared to baseline. The other analytes do not destabilize for up to 178 min of slushed ice storage.

Development of an LC-MS/MS Method for Measurement of Irinotecan and Its Major Metabolites in Plasma: Technical Considerations.

OBJECTIVE: Irinotecan (CPT-11) is an important drug used in the treatment of several solid tumor types. To minimize its toxicity, therapeutic drug monitoring of CPT-11 and its major metabolites (SN-38, SN-38-glucuronide [SN-38G], and APC) has been proposed. We aimed to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of CPT-11 and its major metabolites in plasma. METHODS: Specimen preparation consisted of protein precipitation, evaporation, and reconstitution. Analyses were performed on a C18 column using reverse-phase gradient elution. Electrospray ionization and multiple reaction monitoring in positive mode were used for MS. The following heavy isotope-labeled internal standards were used: CPT-11 D10, SN-38 D3, SN-38G D3, and APC D3. RESULTS: We found that CPT-11, SN-38G, and APC eluted at ~4.6 to 4.7 minutes, and SN-38 eluted at ~5.1 to 5.2 minutes. A second peak for SN-38 was detected at ~4.6 to 4.7 minutes. Given that the structure of SN-38 is found in CPT-11, SN-38G, and APC, and in the CPT-11 D10 used here, in-source fragmentation was the likely cause. In addition, we found that a low-level SN-38 impurity was present in CPT-11 D10 and to a lesser extent in SN-38 D3. CONCLUSION: When developing methods for CPT-11 and its metabolites, it is important to consider the effects of in-source fragmentation and the choice of internal standards.

Large inter-assay difference of serum creatinine in pediatric population: a threat to accurate staging of chronic kidney disease.

BACKGROUND: Serum creatinine concentration is a primary component of Bedside Schwartz equation for estimated glomerular filtration rate (eGFR) in children. To standardize creatinine measurement, most manufacturers have adopted calibration procedures traceable to isotope dilution mass spectrometry (IDMS) using National Institute of Standards and Technology reference material. However, reference material representing much lower creatinine concentrations seen in children is not available and it is unclear how well commercial assays perform at pediatric levels. METHODS: One thousand nine hundred seventy-one specimens from consecutive children <19 years, with creatinine ≤0.8 mg/dL by Abbott Jaffe method were included. Creatinine measurements were compared between Abbott-Jaffe and Abbott-enzymatic methods. Furthermore, we evaluated performance of six commercial creatinine assays at concentrations seen in pediatric patients utilizing IDMS traceable serum samples. RESULTS: Median difference (enzymatic-Jaffe) for prepubertal females was -0.18 mg/dL (2.5%tile, 97.5%tile: -0.30, -0.06), -0.12 mg/dL (-0.25, -0.00) for pubertal females, -0.17  mg/dL (-0.30, -0.04) for prepubertal males, -0.11 mg/dL (-0.24, 0.01) for pubertal males. Bias appeared proportional for each subgroup and decreased as creatinine concentrations increased. Using IDMS traceable samples, the greatest inter-assay variability was seen with the lowest creatinine levels (target 0.273 mg/dL), where 67% (4/6) of methods failed to reach minimal bias specification of 8% (range -7.5 to 86%). For samples with higher creatinine targets (0.440-0.634 mg/dL), two methods failed to meet minimal bias specification, whereas four showed bias <8%. CONCLUSION: Many commonly used creatinine assays remain inaccurate for pediatric populations after over a decade of nationwide efforts to standardize measurements. When creatinine-based eGFR is used for chronic kidney disease (CKD) staging in children, large inter-assay variability can lead to disease misclassification, inappropriate diagnostic and therapeutic interventions. A higher resolution version of the Graphical abstract is available as Supplementary information.

Applicability of Pharmacogenomically Guided Medication Treatment during Hospitalization of At-Risk Minority Patients.

Known disparities exist in the availability of pharmacogenomic information for minority populations, amplifying uncertainty around clinical utility for these groups. We conducted a multi-site inpatient pharmacogenomic implementation program among self-identified African-Americans (AA; n = 135) with numerous rehospitalizations (n = 341) from 2017 to 2020 (NIH-funded ACCOuNT project/clinicaltrials.gov#NCT03225820). We evaluated the point-of-care availability of patient pharmacogenomic results to healthcare providers via an electronic clinical decision support tool. Among newly added medications during hospitalizations and at discharge, we examined the most frequently utilized medications with associated pharmacogenomic results. The population was predominantly female (61%) with a mean age of 53 years (range 19-86). On average, six medications were newly prescribed during each individual hospital admission. For 48% of all hospitalizations, clinical pharmacogenomic information was applicable to at least one newly prescribed medication. Most results indicated genomic favorability, although nearly 29% of newly prescribed medications indicated increased genomic caution (increase in toxicity risk/suboptimal response). More than one of every five medications prescribed to AA patients at hospital discharge were associated with cautionary pharmacogenomic results (most commonly pantoprazole/suboptimal antacid effect). Notably, high-risk pharmacogenomic results (genomic contraindication) were exceedingly rare. We conclude that the applicability of pharmacogenomic information during hospitalizations for vulnerable populations at-risk for experiencing health disparities is substantial and warrants continued prospective investigation.

Impact of CYP2D6 Pharmacogenomic Status on Pain Control Among Opioid-Treated Oncology Patients.

BACKGROUND: Several opioids have pharmacogenomic associations impacting analgesic efficacy. However, germline pharmacogenomic testing is not routinely incorporated into supportive oncology. We hypothesized that CYP2D6 profiling would correlate with opioid prescribing and hospitalizations. MATERIALS AND METHODS: We analyzed 61,572 adult oncology patients from 2012 to 2018 for opioid exposures. CYP2D6 metabolizer phenotype (ultra-rapid [UM], normal metabolizer [NM], intermediate [IM], or poor [PM]), the latter two of which may cause inefficacy of codeine, tramadol, and standard-dose hydrocodone, was determined for patients genotyped for reasons unrelated to pain. The primary endpoint was number of opioid medications received during longitudinal care (IM/PMs vs. NMs). Secondary endpoint was likelihood of pain-related hospital encounters. RESULTS: Most patients with cancer (n = 34,675, 56%) received multiple opioids (average 2.8 ± 1.6/patient). Hydrocodone was most commonly prescribed (62%), followed by tramadol, oxycodone, and codeine. In the CYP2D6 genotyped cohort (n = 105), IM/PMs received a similar number of opioids (3.4 ± 1.4) as NMs (3.3 ± 1.9). However, IM/PMs were significantly more likely to experience pain-related hospital encounters compared with NMs, independent of other variables (odds ratio [OR] = 5.4; 95% confidence interval [CI], 1.2-23.6; p = .03). IM/PMs were also more likely to be treated with later-line opioids that do not require CYP2D6 metabolism, such as morphine and hydromorphone (OR = 3.3; 95% CI, 1.1-9.8; p = .03). CONCLUSION: CYP2D6 genotype may identify patients with cancer at increased risk for inadequate analgesia when treated with typical first-line opioids like codeine, tramadol, or standard-dose hydrocodone. Palliative care considerations are an integral part of optimal oncology care, and these findings justify prospective evaluation of preemptive genotyping as a strategy to improve oncology pain management. IMPLICATIONS FOR PRACTICE: Genomic variation in metabolic enzymes can predispose individuals to inefficacy when receiving opioid pain medications. Patients with intermediate and/or poor CYP2D6 metabolizer status do not adequately convert codeine, tramadol, and hydrocodone into active compounds, with resulting increased risk of inadequate analgesia. This study showed that patients with cancer frequently receive CYP2D6-dependent opioids. However, patients with CYP2D6 intermediate and poor metabolizer status had increased numbers of pain-related hospitalizations and more frequently required the potent non-CYP2D6 opioids morphine and hydromorphone. This may reflect inadequate initial analgesia with the common "first-line" CYP2D6-metabolized opioids. Preemptive genotyping to guide opioid prescribing during cancer care may improve pain-related patient outcomes.

Validation of a Large Custom-Designed Pharmacogenomics Panel on an Array Genotyping Platform.

BACKGROUND: Pharmacogenomics has the potential to improve patient outcomes through predicting drug response. We designed and evaluated the analytical performance of a custom OpenArray® pharmacogenomics panel targeting 478 single-nucleotide variants (SNVs). METHODS: Forty Coriell Institute cell line (CCL) DNA samples and DNA isolated from 28 whole-blood samples were used for accuracy evaluation. Genotyping calls were compared to at least 1 reference method: next-generation sequencing, Sequenom MassARRAY®, or Sanger sequencing. For precision evaluation, 23 CCL samples were analyzed 3 times and reproducibility of the assays was assessed. For sensitivity evaluation, 6 CCL samples and 5 whole-blood DNA samples were analyzed at DNA concentrations of 10 ng/µL and 50 ng/µL, and their reproducibility and genotyping call rates were compared. RESULTS: For 443 variants, all samples assayed had concordant calls with at least 1 reference genotype and also demonstrated reproducibility. However, 6 of these 443 variants showed an unsatisfactory performance, such as low PCR amplification or insufficient separation of genotypes in scatter plots. Call rates were comparable between 50 ng/µL DNA (99.6%) and 10 ng/µL (99.2%). Use of 10 ng/µL DNA resulted in an incorrect call for a single sample for a single variant. Thus, as recommended by the manufacturer, 50 ng/µL is the preferred concentration for patient genotyping. CONCLUSIONS: We evaluated a custom-designed pharmacogenomics panel and found that it reliably interrogated 437 variants. Clinically actionable results from selected variants on this panel are currently used in clinical studies employing pharmacogenomics for clinical decision-making.

A retrospective analysis of high sensitivity cardiac troponin-T ranges in non-myocardial infarction emergency department visits.

INTRODUCTION: Current evidence suggests that high sensitivity cardiac troponin-T (hs-cTnT) values differ based on sex, race, age, and kidney function. However, most studies examining the relationship of hs-cTnT and these individual factors are in healthy participants, leading to difficulty in interpreting hs-cTnT values in the Emergency Department (ED) setting. We seek to examine the relationship between hs-cTnT values and sex, race, age, and kidney function in a contemporary, urban academic setting. METHODS: ED visits from June 2018 through April 2019 with at least 1 hs-cTnT and no diagnosis of acute myocardial infarction (AMI) at an academic medical center in the south side of Chicago were retrospectively analyzed. Median hs-cTnT values were stratified by sex (male or female), race (African American or Caucasian), age, estimated glomerular filtration rate (eGFR), and stage of chronic kidney disease. RESULTS: 9679 encounters, representing 7989 distinct patients, were included for analysis (age 58 ± 18 years, 59% female, 85% black). Males had significantly higher median hs-cTnT values than females (16 [8-34] vs. 9 [6-22] ng/L, p < 0.001), African Americans had a significantly lower median value than Caucasians (10 [6-24] vs. 15 [6-29] ng/L, p < 0.001), and those with atrial fibrillation (27 [16-48] vs. 9 [6-19] ng/L, p < 0.001) and heart failure (28 [14-48] vs. 8 [6-15] ng/L, p < 0.001) had higher median values than those without. Median hs-cTnT values increased significantly with increased age and decreased eGFR. All relationships continued to be significant even after multivariable regression of sex, age, race, eGFR, presence of atrial fibrillation, and presence of heart failure (p < 0.01). CONCLUSIONS: Analysis of hs-cTnT in non-AMI patients during ED encounters showed that males have higher values than females, African Americans have lower values than Caucasians, those with atrial fibrillation and heart failure have higher values than those without, and that older age and lower eGFR were associated with higher median values.

Role of von Willebrand Factor in COVID-19 Associated Coagulopathy.

BACKGROUND: COVID-19, the disease caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) can present with symptoms ranging from none to severe. Thrombotic events occur in a significant number of patients with COVID-19, especially in critically ill patients. This apparent novel form of coagulopathy is termed COVID-19-associated coagulopathy (CAC), and endothelial derived von Willebrand factor (vWF) may play an important role in its pathogenesis. CONTENT: vWF is a multimeric glycoprotein molecule that is involved in inflammation, primary and secondary hemostasis. Studies have shown that patients with COVID-19 have significantly elevated levels of vWF antigen and activity, likely contributing to an increased risk of thrombosis seen in CAC. The high levels of both vWF antigen and activity have been clinically correlated with worse outcomes. Furthermore, the severity of a COVID-19 infection appears to reduce molecules that regulate vWF level and activity such as ADAMTS-13 and high-density lipoproteins (HDL). Finally, studies have suggested that patients with group O blood (a blood group with lower baseline levels of vWF) have a lower risk of infection and disease severity compared to other ABO blood groups; however, more studies are needed to elucidate the role of vWF. SUMMARY: CAC is a significant contributor to morbidity and mortality. Endothelial dysfunction with the release of prothrombotic factors, such as vWF, needs further examination as a possible important component in the pathogenesis of CAC.

Cardiac Troponin Composition Characterization after Non ST-Elevation Myocardial Infarction: Relation with Culprit Artery, Ischemic Time Window, and Severity of Injury.

BACKGROUND: Troponin composition characterization has been implicated as a next step to differentiate among non-ST elevation myocardial infarction (NSTEMI) patients and improve distinction from other conditions with troponin release. We therefore studied coronary and peripheral troponin compositions in relation to clinical variables of NSTEMI patients. METHODS: Samples were obtained from the great cardiac vein (GCV), coronary sinus (CS), and peripheral circulation of 45 patients with NSTEMI. We measured total cTnI concentrations, and assessed both complex cTnI (binary cTnIC + all ternary cTnTIC forms), and large-size cTnTIC (full-size and partially truncated cTnTIC). Troponin compositions were studied in relation to culprit vessel localization (left anterior descending artery [LAD] or non-LAD), ischemic time window, and peak CK-MB value. RESULTS: Sampling occurred at a median of 25 hours after symptom onset. Of total peripheral cTnI, a median of 87[78-100]% consisted of complex cTnI; and 9[6-15]% was large-size cTnTIC. All concentrations (total, complex cTnI, and large-size cTnTIC) were significantly higher in the CS than in peripheral samples (P < 0.001). For LAD culprit patients, GCV concentrations were all significantly higher; in non-LAD culprit patients, CS concentrations were higher. Proportionally, more large-size cTnTIC was present in the earliest sampled patients and in those with the highest CK-MB peaks. CONCLUSIONS: In coronary veins draining the infarct area, concentrations of both full-size and degraded troponin were higher than in the peripheral circulation. This finding, and the observed associations of troponin composition with the ischemic time window and the extent of sustained injury may contribute to future characterization of different disease states among NSTEMI patients.

Evaluation of Biomarkers in Sepsis: High Dimethylarginine (ADMA and SDMA) Concentrations Are Associated with Mortality.

BACKGROUND: As modulators of nitric oxide generation, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) may play important roles in sepsis. Current data on dimethylarginines are conflicting, and direct comparison data with other biomarkers are limited. METHODS: Fifty-five patients were included in the final analysis and were divided into 4 groups: infection without sepsis, sepsis, severe sepsis, and septic shock. The first available samples on hospital admission were analyzed for ADMA, SDMA, procalcitonin (PCT), C-reactive protein, heparin binding protein (HBP), zonulin, soluble CD25 (sCD25), and soluble CD163 (sCD163). White blood cell (WBC) counts and lactate results were obtained from the medical record. RESULTS: There were no statistically significant differences in ADMA and SDMA concentrations among the 4 groups; however, PCT, WBC, HBP, and sCD25 showed statistically significant differences. Lactate only trended toward statistical significance, likely because of limited availability in the medical record. Differences between survivors of sepsis and nonsurvivors at 30 days were highly statistically significant for ADMA and SDMA. Areas under the curve (AUCs) for ROC analysis were 0.88 and 0.95, respectively. There was also a statistically significant difference between survivors of sepsis and nonsurvivors for HBP, lactate, sCD25, and sCD163; however, AUCs for ROC curves were not statistically significantly different from 0.5. CONCLUSIONS: Analysis of biomarkers other than dimethylarginines were in general agreement with expectations from the literature. ADMA and SDMA may not be specific markers for diagnosis of sepsis; however, they may be useful in short-term mortality risk assessment.