Revisiting the Role of the Stat Laboratory: Is It Safe to Perform Activated Clotting Time Determinations (ACTs) Out of the Operating Room

Abstract Abstract 4256 Background: Activated clotting time (ACT) is determined during cardiac procedures in order to assess the level of anti-coagulation. There are three main anticoagulants used during cardiac procedures:heparin, angiomax and Plavix. Heparin is often used in the cardiac OR for major procedures and is neutralized, over time, by platelet factor 4(PF4). Angiomax, bivalirudin, has a quick onset of action, but a much shorter half-life when compared to Heparin. Plavix, clopidogrel, irreversibly inhibits platelets from clotting and is used on patients in need of anticoagulation for an extended period of time. The purpose of this study was to evaluate the stability of ACT results over time utilizing different coagulation regimens. If the ACT value remains stable over time, this would enable us to remove the device from the OR and place it in a stat laboratory. Methods: ACTs were determined by the ISTAT (Abbott), a hand held point of care device, using kaolin activated cartridges. A single blood sample was obtained and was evaluated at intervals of 0, 5, 10, 15, and 20 minutes. In addition, temperature, age, body surface area and platelet count of patient were recorded. The time 0 specimen was used to determine the patients ACT and interval testing was performed on the remnant. Results: 36 samples representing 22 patients had ACT tests performed using the ISTAT. There was no significant change from 0 to 20 minutes over the entire dada set. However, when divided into different anti-clotting agents there were significant changes. Patients who had only taken Angiomax had a significant difference within the first 5 minutes (p value=.0094). Patients taking Angiomax and Plavix together had no change in ACT values at 20 minutes. Patients on Heparin alone demonstrated a loss of ACT stability at 10 minutes with values both increasing and decreasing. Conclusions: Patients on Angiomax alone demonstrated a significant difference in ACT value within the first 5 minutes and all intervals thereafter. Based on Angiomax short half-life the ACT should be performed as soon as possible. The ACT values in patients taking both Angiomax and Plavix achieved steady state throughout the 20 minutes and had little if any decrease in value. The results for the Heparin group were unreliable at 10 minutes. As a result of these findings, performing an ACT outside the OR is feasible assuming the test can be performed by 10 minutes. Disclosures: No relevant conflicts of interest to declare.

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Longitudinal Analysis of Hydroxyurea and Fetal Hemoglobin in Adult Patients with Sickle Cell Anemia

Blood ◽

10.1182/blood-2021-153890 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2054-2054

Author(s):

Aryeh Pelcovits ◽

Giancarlo Riotto ◽

Katie Cherenzia ◽

Patrick T. McGann ◽

John L Reagan

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Surrogate Marker ◽

Fetal Hemoglobin ◽

P Value ◽

Significant Difference ◽

Dosing Strategies ◽

Over Time ◽

Painful Crisis

Abstract Introduction: Hydroxyurea (HU) was the first FDA-approved therapy for sickle cell anemia (SCA) and remains the most well-established disease-modifying therapy, reducing painful crisis and improving morbidity and mortality. HU improves outcomes through the upregulation of fetal hemoglobin (HbF). Dosing is highly variable with doses ranging from <10-35 mg/kg/day. Most dosing strategies escalate with a goal of mild myelosuppression, commonly defined using an absolute neutrophil count (ANC) between 2,000-4,000 and platelets >80,000. Macrocytosis is often used as a surrogate marker for compliance and effect. Despite its well-established effectiveness, clinical use remains limited with only 12% of adults with SCA taking HU. The reasons for this are multifactorial but include skepticism by both providers and patients regarding its effectiveness in the adult population. Some experts suggest up to 30% of adults are non-responders with no significant HbF change, and many believe that the effect of HU fades with time. Dosing strategies are usually quite conservative to prevent excessive myelosuppression, though dose is highly correlated with clinical effect and ultimate %HbF. There is very limited real-world data regarding long term effectiveness of HU in adults with SCA over time. Methods: We retrospectively analyzed the records of the 109 adults with SCA currently treated in our multidisciplinary sickle cell clinic. Data from 1/1/2011-6/30/2021 was collected, including genotype, HU prescription status, current and maximum laboratory values (HbF, MCV, ANC), and number of admissions for painful crisis. We performed Wilcoxon rank sum testing between pts prescribed and not prescribed HU and measures of HbF (peak, average and current) and number of admissions for painful crisis over the study period. Results: Among 106 pts (3 excluded from analysis, 2 for lack of data and 1 for post-transplant status), 79 are currently prescribed HU (75%). Among our 63 pts with HbSS genotype 58 are prescribed HU (92%). Average HbF over time for all pts prescribed HU was 11.9%. Average peak HbF was 18.1% and average current HbF is 12.4%. In the pts not prescribed HU HbF average, peak and current levels were 5.5%, 6.7%, and 5.0% respectively. HU prescription was significantly associated with increased HbF at peak, average, and current levels (p-value <0.001, Figure A). HU prescription was also significantly associated with decreased number of admissions for painful crisis (p-value 0.001). Among pts prescribed HU, MCV levels >100 at time of peak HbF were associated with higher peak levels than pts with MCV <100 (p-value <0.001, Figure B). Larger peak HU doses were also correlated with higher MCVs at the time of peak HbF levels (Figure C). Larger current HU doses were also significantly associated with higher current HbF levels (Figure, D). Doses >9.9m/kg were associated with significantly higher HbF levels however there was no significant difference between dose levels 10-19.9mg/kg and 20-29.9 or 20-29.9 and 30-39.9mg/kg (p-values 0.02, 0.68 and 0.84 respectively). Among pts prescribed HU, 34 obtained ANC levels <4000 at the times of peak HbF and 24 at the current dosing level (43% and 30% respectively). 24 pts obtained both MCV>100 and ANC <4000 at time of peak HbF and only 11 achieved both at current dosing levels (30% and 14% respectively). Conclusion: In our adult multidisciplinary sickle cell clinic prescribing rates are well above current HU usage for adults with SCA. Our data notes that elevated HbF levels can be maintained over long periods of time. HU prescription was significantly associated with increased HbF levels and reduced admissions for painful crisis. This was despite a majority of pts not meeting target prescribing levels of ANC <4000 and MCV >100. While higher peak HbF levels were significantly associated with higher HU doses, this was only true for doses above 9.9 mg/kg. Further investigation is needed to explore the factors contributing to suboptimal HbF and MCV response, including careful assessment with medication adherence and dose selection. Overall, these data illustrate the importance of dosing and suggest that one size dosing of HU for adults with SCA does not fit all. We hypothesize that there may be a role individualized dosing strategies in adults with SCA, incorporating factors such as pharmacokinetics and renal function to achieve the optimal dose for each patient. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Toward a predictive theoretical model for osmolality rise with non-humidified incubation: a randomized, multivariate response-surface study

Human Reproduction ◽

10.1093/humrep/deab015 ◽

2021 ◽

Author(s):

Steven F Mullen

Keyword(s):

Mathematical Model ◽

Response Surface ◽

Surface Area ◽

Embryo Culture ◽

Culture Medium ◽

Conflicts Of Interest ◽

Volume Ratio ◽

P Value ◽

Cook Medical ◽

Over Time

Abstract STUDY QUESTION What factors associated with embryo culture techniques contribute to the rate of medium osmolality change over time in an embryo culture incubator without added humidity? SUMMARY ANSWER The surface area-to-volume ratio of culture medium (surface area of the medium exposed to an oil overlay), as well as the density and height of the overlaying oil, all interact in a quantitative way to affect the osmolality rise over time. WHAT IS KNOWN ALREADY Factors such as medium volume, different oil types, and associated properties, individually, can affect osmolality change during non-humidified incubation. STUDY DESIGN, SIZE, DURATION Several experimental designs were used, including simple single-factor completely randomized designs, as well as a multi-factor response surface design. Randomization was performed at one or more levels for each experiment. Osmolality measurements were performed over 7 days, with up to 8 independent osmolality measurements performed per treatment group over that time. For the multi-factor study, 107 independent combinations of factor levels were assessed to develop the mathematical model. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was conducted in a research laboratory setting. Commercially available embryo culture medium and oil was used. A MINC incubator without water for humidification was used for the incubation. Osmolality was measured with a vapor pressure osmometer after calibration. Viscometry and density were conducted using a rheometer, and volumetric flasks with an analytical balance, respectively. Data analyses were conducted with several commercially available software programs. MAIN RESULTS AND THE ROLE OF CHANCE Preliminary experiments showed that the surface area-to-volume ratio of the culture medium, oil density, and oil thickness above the medium all contributed significantly (P < 0.05) to the rise in osmolality. A multi-factor experiment showed that a combination of these variables, in the form of a truncated cubic polynomial, was able to predict the rise in osmolality, with these three variables interacting in the model (P < 0.05). Repeatability, as measured by the response of identical treatments performed independently, was high, with osmolality values being ± 2 of the average in most instances. In the final mathematical model, the terms of the equation were significant predictors of the outcome, with all P-values being significant, and only one P-value > 0.0001. LIMITATIONS, REASONS FOR CAUTION Although the range of values for the variables were selected to encompass values that are expected to be encountered in usual embryo culture conditions, variables outside of the range used may not result in accurate model predictions. Although the use of a single incubator type and medium type is not expected to affect the conclusions, that remains an uncertainty. WIDER IMPLICATIONS OF THE FINDINGS Using this predictive model will help to determine if one should be cautious in using a specific system and will provide guidance on how a system may be modified to provide improved stability during embryo culture. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Cook Medical. The author is a Team Lead and Senior Scientist at Cook Medical. The author has no other conflicts of interest to declare TRIAL REGISTRATION NUMBER N/A.

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Hodgkin Lymphoma Outcomes: Can We Expect Ethnic Parity in a Hispanic Prevalent Population?

Blood ◽

10.1182/blood-2019-129058 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4056-4056

Author(s):

Michelle Janania Martinez ◽

Prathibha Surapaneni ◽

Juan F Garza ◽

Tyler W Snedden ◽

Snegha Ananth ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Conflicts Of Interest ◽

Relative Survival ◽

Complete Response ◽

Statistical Testing ◽

P Value ◽

Hispanic Population ◽

Significant Difference ◽

The Mean

BACKGROUND It is estimated that 8110 persons will be diagnosed with Hodgkin Lymphoma (HL) in the US during 2019, but the advent of new treatment options has increased the cure rate to at least 80%. It has been reported that the rates of HL are lower in the adolescent and young adult (AYA) Hispanic population but significantly higher in the Hispanic population older than 65. The relative survival estimates are stated to be similar between AYA Hispanics (HI) and non-Hispanics (NH) but for ages 65-84, HI have a significantly higher mortality rate. Pediatric studies have suggested that ethnicity plays a role in outcomes in patients with HL but there is limited data in the adult population. There is an unmet need in the field, where dossiers on underrepresented ethnic minorities need to be carefully considered and compared to existing data. Therefore, our study aims to compare survival outcomes in Hispanics vs Non-Hispanics with HL, who were treated at the only NCI designated cancer center of South Texas. To our knowledge this is the largest cohort of HL patients from a single academic institution that serves primarily Hispanics. METHODS We located and retrospectively analyzed a total of 616 patients with diagnosis of Lymphoma (HL and NHL) by International Classification of Diseases (ICD) codes and identified 116 cases of HL; all the patients received care at UT Health San Antonio, between 2008-2018. Key variables for each patient included age, gender, race/ethnicity, comorbidities, insurance status, stage, BM and extranodal involvement, treatment received, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with the mean and standard deviation and categorical outcomes were summarized with frequencies and percentages. The significance of variation in the mean with disease category was assessed with one way ANOVA and the significance of associations between categorical outcomes was assessed with Pearson's Chi Square or Fisher's Exact test as appropriate. Multivariate logistic regression was used to model binary outcomes in terms of covariates and indicators of disease. All statistical testing was two-sided with a significance level of 5%. R1 was used throughout. The study was approved by the local Institutional Review Board. The findings will be available to patients, funders and medical community through traditional publishing and social media. RESULTS We identified 116 patients with HL, of which 73 were HI (63%), 43 NH (36%) and 1 not specified (1%). In regard to race, 92% identified as Caucasian, 4% as African American, 3% other and 1% Asian. The median age at diagnosis was 37.4, (SD 15.13). There were 49 females (42%) and 67 males (58%). The most common funding source was commercial insurance N=54 (47%), followed by a hospital payment plan N=30 (26%), Medicare N=16 (14%), unfunded N=13 (11%) and Medicaid N=3 (2%). Most prevalent co-morbidities were HTN N=28 (24%) and diabetes mellitus N= 23(20%); 50% of patients had no co-morbidities (N=63).At diagnosis ECOG of 0-1 was seen in 108 patients (93%); 8 were Stage I (7%), 39 stage II (33%), 32 stage III (28%), and 37 stage IV (32%). EBV was positive in 26 patients (22%). There were 15 patients that were HIV positive (13%), 54% with CD4 count <200, and 12 (75%) on antiretroviral therapy at diagnosis. Median PFS was 853.85 days (SD 912.92). We excluded patients who were lost to follow up or had not reached 3/5 years. At 3 year follow up there was: complete response in 37 HI (74%) vs 22 NH (92%); disease progression in 8 (16%) vs 0 (0%); death in 5 (10%) vs 2 (8%), respectively (p-value= 0.094). At 5 year follow up there was: complete response in 30 HI (77%) vs 17 NH (90%); progressive disease in 2 (5%) vs 0 (0); death 7 (18%) vs 2 (11%), respectively (p-value = 0.619). At the end of 2018, 41 HI (84%) were alive compared to 22 NH (88%) [p-value 0.74]. CONCLUSION Within the limitations of sample size, our study demonstrates that in the prevalently Hispanic population of our institution, HI patients with HL have no statistically significant difference in outcome when compared to NH patients. Disclosures No relevant conflicts of interest to declare.

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A Better Mobilization Regimen for Newly Diagnosed Multiple Myeloma Patients,

Blood ◽

10.1182/blood.v118.21.4051.4051 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4051-4051

Author(s):

Ahmed Y Abuabdou ◽

Eric R Rosenbaum ◽

Saad Usmani ◽

Bart Barlogie ◽

Michele Cottler-Fox

Keyword(s):

Multiple Myeloma ◽

Conflicts Of Interest ◽

Optimal Number ◽

P Value ◽

Newly Diagnosed ◽

The Poor ◽

Cd34 Cells ◽

Significant Difference ◽

Minimum Number ◽

Poor Mobilizer

Abstract Abstract 4051 Introduction: What constitutes an acceptable mobilization regimen for collecting CD34+ cells depends on whether the goal of collection is to obtain a minimum number versus optimal number of cells. When treating patients with high-risk myeloma it may be important to obtain an optimal number. Here we compare retrospectively our earlier mobilization regimen, VTD-PACE, with MVTD-PACE in newly diagnosed, previously untreated multiple myeloma patients. Materials and Methods : We reviewed data for all patients who collected hematopoietic progenitor cells on Total Therapy protocols TT3a/TT3b with VTD-PACE (n=394) from February 2004 to September 2008 (138 females and 256 males, median age 59y; range 31–75), and on TT4/TT5 with MVTD-PACE (n=188) from August 2008 to May 2011 (78 females and 110 males, median age 61y, range 30–76). Based on their predicted first day collection with a large volume leukapheresis (30L processed), using our center's predictive formula (Blood 2010; 116(21):1182a), patients were stratified into 4 mobilizer types: poor (<2×106 CD34+ cells/kg), intermediate (≥2 to 10×106), good (>10 to 20×106) and excellent (>20×106). Variables examined included number of CD34+ cells/μl blood on day 1 and day 2 of collection (we have a minimum 2 day collection requirement), number of collection days to reach our minimum goal of 20×106 CD34+ cells/kg, and total CD34+ cells/kg collected for both chemotherapy groups. Variables for both groups stratified by mobilizer type were compared using two-tailed student's t-tests, except for the poor mobilizer group, where population size was too small for formal statistical analyses (VTD-PACE n=7, MVTD-PACE n=4), although averages were calculated. Results : There was no significant difference between VTD-PACE and MVTD-PACE for CD34+ cells/μl blood on day 1 of collection among the excellent [mean 368.9 (n=184) vs. 434.6 x106 (n=92); p-value 0.07], good [mean 138.6 (n=102) vs. 128.6 x106 (n=40); p-value 0.19], and intermediate [mean 60.1 (n=100) vs. 55.9 x106 (n=52); p-value 0.39] groups. A statistically significant difference between VTD-PACE and MVTD-PACE was found for CD34+ cells/μl blood on day 2 of collection for excellent mobilizers [mean 333.8 (n=184) vs. 460 ×106 (n=92); p-value <0.001], but not for the good [mean 165.7 (n=102) vs. 189.5×106 (n=40); p-value 0.21] and intermediate [mean 80.1 (n=101) vs. 102.3 ×106 (n=52); p-value 0.07] groups. When CD34+ cell/kg collection totals with VTD-PACE and MVTD-PACE were compared, a significant difference was seen for the intermediate mobilizer group only [mean 23.6 (n=101) vs. 26.3 ×106 (n=52); p-value 0.03]. For the poor mobilizer group, VTD-PACE had an average CD34+ cells/μl blood of 13.5×106 for day 1 of collection and 17.0 ×106 for day 2, with a total of 14.5×106 CD34+cells/kg collected; while MVTD-PACE had an average of 13.2×106 CD34+ cells/μl blood for day 1 of collection, 24.9×106 for day 2, with a total of 24.2×106CD34+ cells/kg collected. The number of collection days was similar between VTD-PACE and MVTD-PACE in the excellent mobilization group (2 days), but was slightly more for VTD-PACE compared to MVTD-PACE for the good (2.1 vs. 2 days), intermediate (3.2 vs. 2.9 days), and poor (6.1 vs. 5.8 days) groups. Conclusion : Both regimens allow more than minimum collections, but MVTD-PACE provides a higher peak number of CD34+ cells/μl blood, resulting in a slightly lower mean number of days of collection than VTD-PACE to reach an optimal collection. Disclosures: No relevant conflicts of interest to declare.

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Abstract 107: RNA Seq Transcriptome Analysis Reveals Genes and Pathways Involved in the Cardiac Protection of VCP Against Pressure Overload

Circulation Research ◽

10.1161/res.121.suppl_1.107 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Christiana Leimena ◽

Xin Chen ◽

Ning Zhou ◽

Shaunrick Stoll ◽

Charles Wang ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Transcriptome Analysis ◽

Pressure Overload ◽

Left Ventricular ◽

P Value ◽

Type I ◽

Rna Seq ◽

Cardiac Protection ◽

Platelet Factor ◽

Significant Difference

Aims: We previously showed that the valosin containing protein (VCP), a member of ATPases associated protein, protects the heart against pressure overload induced cardiac hypertrophy and dysfunction in transgenic (TG) mice. The mechanisms remain unknown. We hypothesize that VCP regulated alteration in transcriptome contributes to its cardio-protection by targeting cardiac cell growth and survival. Methods and results: Cardiac-specific VCPTG mice and their litter-matched wild type (WT) mice were subjected to transverse aortic constriction (TAC) for 2 and 5 weeks and compared to the sham mice. By using echocardiography and hemodynamic analysis, cardiac hypertrophy and dysfunction were confirmed in 2 weeks- and 5 weeks- TAC models respectively in WT but not in VCPTG mice. Total RNA was extracted from left ventricular tissues and gene expression was determined by RNA-Seq transcriptome analysis. Upon 2 weeks TAC, 690 differentially expressed genes were identified between VCPTG and WT (Fold Change ≥ 1.5, P value ≤ 0.05). Among these genes, VCPTG TAC mice, compared to WT TAC mice, showed significant activation of the genes linked to transcriptional factors, Protein Kinase CGMP-Dependent Type I ( Prkg1 ) and Kruppel Like factor 15 ( Klf15 ), the known repressors of cardiac hypertrophy under stress. On the contrary, there is significant increase in cardiac hypertrophy associated genes in WT TAC mice, such as myosin light chain 7 ( Myl7 ), periostin ( Postn ) and tropomyosin beta chain ( Tpm2) , and in fetal gene natriuretic peptide A ( Nppa) , but these alterations were not observed in VCPTG TAC mice, which may contribute to repression of cardiac hypertrophy in VCPTG mice. In addition, pro-apoptosis genes, such as platelet factor 4 ( Pf4), Pleckstrin homology like domain A1 ( Phlda1 ) and Radical S-Adenosyl Methionine Domain Containing 2 ( Rsad2 ), are significantly downregulated continually in 2 weeks through 5 weeks TAC in VCPTG mice, but not in WT TAC, which may contribute to the protection of cell survival in VCPTG mice. Conclusion: Significant difference of gene regulation exists between VCPTG and WT in the heart under the pressure overload which may be the mechanism of VCP mediated cardiac protection.

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A 15 Hour Dosing-Collection Interval for Plerixafor Is at Least as Effective as the Standard 10 Hour Interval.

Blood ◽

10.1182/blood.v114.22.2152.2152 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2152-2152 ◽

Cited By ~ 1

Author(s):

Eric R Rosenbaum ◽

Mayumi Nakagawa ◽

Gina Pesek ◽

John Theus ◽

Bart Barlogie ◽

...

Keyword(s):

Phase I ◽

Conflicts Of Interest ◽

P Value ◽

Number Of Patients ◽

Cd34 Cells ◽

Significant Difference ◽

The Difference ◽

Student’S T ◽

Age Range ◽

Total Average

Abstract Abstract 2152 Poster Board II-129 Introduction: Plerixafor (formerly AMD3100) is a reversible CXCR4 inhibitor used to mobilize CD34+ cells for collection and use in hematopoietic transplant. Since beginning phase I trials, the drug has been given at 10 pm and collection initiated 10h later at 8 am. After recent FDA approval, we examined use of a dosing-collection interval of 15h (5 pm administration/8 am collection) for patient (pt) convenience. Here we compare results retrospectively from phase I and II trials at our institution using the 10h interval with post-approval collections using the 15h interval. We also evaluated prechemotherapy platelet (plt) count as a predictor of response to plerixafor+G-CSF. Materials and Methods: We reviewed data for all pts (n=107) at our institution who received plerixafor using the 10h (n=79) and 15h (n=34) intervals. This group was reduced to only those who received 4 consecutive days of plerixafor (n=76), of which 67 had the 10h interval and 21 had the 15h interval. The age range of the 10h group was 30-79y (median 62) and the range of the 15h group was 45-78y (median 57). The primary disease in both groups was multiple myeloma, but included 2 NHL in the 10h group, and 5 NHL in the 15h group. Chemotherapy given prior to mobilization for both the 10h and 15h interval groups were similar and plerixafor was administered with G-CSF in all pts. CD34+ cells collected on days 1-4 were quantified by flow cytometry. Finally, some patients (n=9) underwent mobilization with plerixafor two or more times, of which 4 did so on both the 10h and 15h intervals. These instances were recorded as separate events. Prechemotherapy plt counts were also reviewed for each patient and subcategorized into 3 groups: <100, 100-150, and >150,000/uL. Mean CD34+ cells collected were compared between the plt subcategories for both the 10h and 15h groups. Results: The mean number of CD34+ cells collected for the 10h group on days 1-4 of plerixafor administration was 1.26, 1.04, 0.71, and 0.55 ×10e6 CD34+ cells/kg, respectively, with total average collection of 3.56 × 10e6 CD34+ cells/kg. For the 15h group, the average number of CD34+ cells collected on days 1-4 were 2.20, 1.61, 1.44, and 1.01 × 10e6 CD34+ cells/kg, respectively, with total average collection of 6.26 × 10e6 CD34+ cells/kg. The two groups were compared using two-tailed student's t-tests. There was no statistically significant difference between the quantity of CD34+ cells collected on days 1 or 2 for the 10h and 15h groups, however there was a statistically significant difference on days 3 and 4. On these latter two days, the 15h group collected a significantly higher number of CD34+ cells compared to the 10h group. The difference in average total collection for the two groups over all 4 days was statistically significant at an alpha level of 0.05 (p-value: 0.03). The different prechemotherapy plt groups were compared using one-way ANOVA statistical analysis. Within the 10h group the <100 group had the least amount collected (mean 2.46×10e6 CD34+/kg), the 100-150 had an intermediate amount (mean 3.30×10e6CD34+/kg), and the >150 group the most (4.30×10e6CD34+/kg; p-value 0.02). The same comparison within the 15h group showed similar findings but the number of patients in each subcategory was too small to be statistically significant. Conclusion: Administration of plerixafor with the 15h interval (5 pm dosing/8 am collection) appears to be equivalent to the standard 10h interval with regard to quantity of CD34+ cells collected over the first 2 days, and is superior to the 10 h schedule if the collection continues for 4 days. Further, prechemotherapy plt count is predictive of ability to mobilize CD34+ cells with perixafor+G-CSF for the 10h interval, as has been previously shown by our group for G-CSF alone in a similar population. Additional pts are needed to demonstrate conclusively the same finding for the 15h dosing/collection interval. Disclosures: No relevant conflicts of interest to declare.

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Influence of Protein Tyrosine Phosphatase Polymorphisms on the Development of Antibodies to Platelet Factor 4 and the Risk of Heparin-Induced Thrombocytopenia.

Blood ◽

10.1182/blood.v116.21.3683.3683 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3683-3683

Author(s):

Jerôme Rollin ◽

Claire Pouplard ◽

Dorothee Leroux ◽

Marc-Antoine May ◽

Yves Gruel

Keyword(s):

Immune Response ◽

Platelet Activation ◽

Conflicts Of Interest ◽

Critical Role ◽

Platelet Factor 4 ◽

Control Group ◽

Platelet Factor ◽

Heparin Induced Thrombocytopenia ◽

Protein Tyrosine ◽

Significant Difference

Abstract Abstract 3683 Introduction. Heparin-induced thrombocytopenia (HIT) results from an atypical immune response to platelet factor 4/heparin complexes (PF4/H), with rapid synthesis of platelet-activating IgG antibodies that activate platelets via FcgRIIa receptors. The reasons explaining why only a subset of patients treated with heparin develop IgG to PF4/H complexes, and why most patients who synthesize these antibodies do not develop HIT, have not been fully defined. The immune response in HIT involves both B and T cells, and protein tyrosine kinases (PTKs) and phosphatases (PTPs) are crucial for regulating antigen receptor-induced lymphocyte activation. Moreover, some PTPs such as CD148 and low-molecular-weight PTP (LMW-PTP) could also have a critical role in platelet activation. Dysregulation of the equilibrium between PTK and PTP function could therefore have pathologic consequences and influence the pathogenesis of HIT. Aim of the study. To investigate an association between polymorphisms affecting genes encoding 4 different PTPs i.e. CD45 (PTPRC), CD148 (PTPRJ), LYP (PTPN22) and LMW-PTP (ACP1) and the development of heparin-dependent antibodies to PF4 and HIT. Patients and methods. A cohort of 89 patients with definite HIT (positive PF4-specific ELISA and positive serotonin release assay) and two control groups were studied. The first control group (Abneg) consisted of 179 patients who had undergone cardiopulmonary bypass (CBP) with high doses of heparin and who did not develop Abs to PF4 post-operatively. The second control group (Abpos) consisted of 160 patients who had also undergone cardiac surgery with CPB and heparin, who had all developed significant levels of PF4-specific antibodies but without HIT. Genotypes of PTPRC 77C/G (rs17612648), PTPN22 1858C/T (rs2476601), PTPRJ 2965 C/G (rs4752904) and PTPRJ 1176 A/C (rs1566734) were studied by a PCR-HRM method using the LightCycler 480 (Roche). In addition, the ACP1 A, B, C alleles were defined by combining the analysis of T/C transition at codon 43 of exon 3 (rs11553742) and T/C transition at codon 41 of exon 4 (rs11553746). Results. The frequency of PTPRC 77G and PTPN22 1858T alleles was not different in HIT patients and controls, whether they had developed antibodies to PF4 or not. The third PTP gene analyzed was ACP1, in which three alleles (A, B and C) were previously associated with the synthesis of distinct active LMW-PTP isoforms exhibiting different catalytic properties. The percentage of subjects in our study carrying the AC, BB and BC genotypes was significantly higher in the HIT and the Abpos groups than in patients without antibodies to PF4 after CPB (Abneg). In addition, the ACP1 A allele was less frequent in patients with antibodies to PF4, whether they had developed HIT (25%) or not (27.5% in Abpos controls), than in Abneg subjects (37%). The AC, BB and BC genotypes (associated in Caucasians with the highest LMW-PTP enzyme activity) therefore appeared to increase the risk of antibody formation in heparin-treated patients (OR 1.8; 95% CI 1.2–2.6, p=0.004 after comparing Abpos + HIT vs. Abneg). We also evaluated 2 SNPs affecting PTPRJ encoding CD148. No significant difference was found concerning the 2965 C/G polymorphism, but the frequency of PTPRJ 1176 AC and CC genotypes was significantly lower in the HIT (17%) than in the Abneg and Abpos groups (35%, p=0.003 and 29.5%, p=0.041, respectively). The C allele therefore appeared to provide a significant protection from the risk of HIT (OR 0.52; 95%CI 0.29–0.94, p=0.041) in patients with antibodies to PF4. Discussion-Conclusion. Recent studies have demonstrated that CD148 is a positive regulator of platelet activation by maintaining a pool of active SFKs in platelets. This non-synonym PTPRJ 1176 A/C SNP is associated with a Q276P substitution inducing a torsional stress of a fibronectin domain that is critical for the activity of CD148 and may influence the pathogenic effects of HIT Abs. This study supports the hypothesis that PTPs such as LMW-PTP and CD148 influence the immune response to heparin and the risk of HIT in patients with antibodies to PF4. Disclosures: No relevant conflicts of interest to declare.

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Pharmacokinetics and Tolerability of Etoposide in Newly Diagnosed Lymphoma Patients with Hepatic Impairment

Blood ◽

10.1182/blood.v124.21.4445.4445 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4445-4445

Author(s):

Catherine Lai ◽

Diane Cole ◽

Nicole Lucas ◽

Seth M. Steinberg ◽

Brigitte C Widemann ◽

...

Keyword(s):

Febrile Neutropenia ◽

Dose Reduction ◽

Hepatic Impairment ◽

Conflicts Of Interest ◽

Aggressive Lymphoma ◽

P Value ◽

Newly Diagnosed ◽

Aggressive Lymphomas ◽

Significant Difference ◽

Elevated Bilirubin

Abstract Background: The addition of etoposide to chemotherapy regimens (e.g.- CHOEP and EPOCH) may be beneficial for the treatment of aggressive lymphomas. Previous studies have shown decreased clearance of etoposide in hepatic impairment leading to a dose reduction or removal of drug. Total clearance of etoposide does not change significantly in patients with elevated bilirubin. However, free (or unbound) etoposide levels are a more accurate measurement of drug clearance (Stewart el al. Changes in the Clearance of Total and Unbound Etoposide in Patients with Liver Dysfunction. J Clin Oncol. 1990 Nov;8(11):1874-9.). No studies have analyzed etoposide pharmacokinetics and clinical toxicity in lymphoma patients with hepatic impairment. Methods: Patients with newly diagnosed aggressive lymphoma received 1 to 8 cycles of DA-EPOCH +/-R at the NCI. Of 56 pts studied, 48 had normal and 8 had elevated bilirubin (median 3.4mg/dL, range 1.4-22.5mg/dL). All patients received full dose etoposide at 200mg/m2 over 96-hours on cycle 1. Blood samples were collected at 0, 22 and 96 hours after infusion began. Results: There was no significant difference between free etoposide clearance (Cl) and the free etoposide concentration (Css) in patients with elevated versus normal bilirubin (see table below). In all patients, irrespective of bilirubin, there was no significant correlation between free etoposide Cl, free etoposide Css and creatinine clearance (CrCl) or age. Neutropenia and thrombocytopenia was higher in patients with elevated bilirubin. Complete response (CR) was achieved in 75% (6/8) versus 85% (41/48) and PR in 0% (0/8) vs 4% (2/48) of patients with elevated vs normal bilirubin. Conclusions: Etoposide pharmacokinetics were not altered in patients with abnormal versus normal hepatic function. Although there was an increase in hematologic toxicities, there was no difference in Css or Cl of etoposide. Importantly, there were no significant differences in febrile neutropenia or grade 3/4 toxicities. The toxicity difference is likely attributed to other drugs. Response rates were similar between the 2 groups. Our results do not support the empiric dose reduction of etoposide in patients with aggressive lymphomas receiving potentially curative treatment. Table Results Elevated Bilirubin Normal Bilirubin p-value Median age (yrs) 39 (17-59) 54 (20-75) 0.15 IPI (int hi/hi risk) 75% (6/8) 23% (11/48) 0.0070 ANC nadir < 500/mm3 (C1) 100% (8/8) 54% (26/48) 0.017 PLT nadir < 25x103/mm3 (C1) 38% (3/8) 4% (2/48) 0.017 Febrile Neutropenia (C1) 13% (1/8) 13% (6/48) 1.00 G3/4 GI and neuro tox (C1) 38% (3/8) 13% (6/48) 0.11 Median free etoposide clearance on C1 (ml/min/m2) 724 (438-1413) 663 (199-1148) 0.40 Median free etoposide concentration on C1 (μM) 0.082 (0.044-0.135) 0.089 (0.052-0.298) 0.44 Disclosures No relevant conflicts of interest to declare.

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Abstract 16805: Assessing Correlation and Agreement in Activated Clotting Time (ACT) Measurement Using Hemochron Signature Elite

Circulation ◽

10.1161/circ.142.suppl_3.16805 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ankita Aggarwal ◽

Anubhav Jain ◽

Arjun Bhardwaj ◽

Nishit Choksi

Keyword(s):

Clinical Decision Making ◽

Clinical Decision ◽

P Value ◽

Clotting Time ◽

Paired Samples ◽

Activated Clotting Time ◽

Cardiac Procedures ◽

Heparin Administration ◽

Device Reliability ◽

Before And After

Introduction & Hypothesis: ACT is the preferred mode of assessing degree of anti-coagulation during cardiac catheterization. Studies have shown significant variability in ACT measurement with different company analysers. We aimed to assess correlation and agreement between two instruments of the same company, Hemochron Signature Elite. Method: Paired samples were collected before and after heparin administration for each patient. Each paired sample was collected and entered into the two instruments tagged A & B using the same syringe and at the same time. Results: A total of 46 samples were included in the study. There was a significant correlation between the two instruments (r= 0.92, p- value 0.02). However, the two devices had significant discordance with a mean bias of 11.1 , 95% CI 0.77 to 24.9 and limits of agreement -35.8 to 58.1. Mean ACT between the two devices was significantly different (231 vs 248, p-value 0.01). Inter-device reliability was 30%. There was a more than 10% difference in about 30% of the paired samples and more than 20% difference in 9% of the samples. Conclusion: Significant correlation but discordance exists in ACT measurement even between the same type of device. This may affect clinical decision making during cardiac procedures and need further investigation.

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Heparin-Induced Thrombocytopenia Antibody Is More Common in Patients with Active Bacterial Infections

Blood ◽

10.1182/blood.v118.21.4678.4678 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4678-4678

Author(s):

Melody Smith ◽

Prapti A. Patel ◽

Jonathan E Dowell ◽

Eugene P. Frenkel ◽

Ravindra Sarode ◽

...

Keyword(s):

Bacterial Infection ◽

Subgroup Analysis ◽

Bacterial Infections ◽

Conflicts Of Interest ◽

Igg Antibodies ◽

Platelet Factor ◽

Platelet Surface ◽

Heparin Induced Thrombocytopenia ◽

E Coli ◽

Significant Difference

Abstract Abstract 4678 Heparin mobilizes and binds to platelet factor 4 (PF4), forming a heparin-PF4 complex on the platelet surface. Rarely, IgG antibodies recognize and bind to the immune complex, causing platelet activation and thrombin generation, resulting in heparin induced thrombocytopenia (HIT). There is evidence that PF4 has a role in antibacterial host defense and can concurrently prime the immune system with IgG antibodies that can cross-react with the heparin-PF4 complex (Krauel et al, Blood 2011). In the setting of a bacterial infection, the PF4 molecules interact with the bacterial cell wall and induce antibody production. These antibodies are able to recognize any bacteria coated in PF4, resulting in phagocytosis. In the setting of heparin, this antibody can cross react with the heparin-PF4 complex and result in HIT. In vitro studies suggest that E. coli, S. pneumo, and S. aureus coated in PF4 cross-react with human heparin induced anti-PF4/heparin antibodies. We have collected a database of patients being tested for HIT at our institution and performed a retrospective analysis of the incidence of bacterial infections. We hypothesize that patients who have a bacterial infection will be more likely to develop HIT due to anti-bacterial antibodies that cross-react with the heparin-PF4 complex. We collected culture data from 54 patients with positive HIT antibody by ELISA and 178 patients with negative HIT antibody. The incidence of positive cultures and active infections in described in table 1. In the HIT negative patients, 61/178 (34.3%) had positive cultures, compared to 28/54 (51.9%) in the HIT positive patients (p=0.0198). Given that there is data to support E. coli, S. pneumo, and S. aureus-induced antibody cross-reactivity, we performed a subgroup analysis of the incidence of these specific bacterial infection in HIT positive and negative patients (33.3% versus 19.7%, p=0.0357). There is a statistically significant difference noted in the active infections, subgroup analysis, as well presence of any positive cultures in the HIT positive patients as compared to the HIT negative patients.Table 1Colonized Infections (%)Active Infections (%)E. coli, S. pneumo, S. aureus (%)Any + culture (%)HIT negative (n=178)15 (8.4)61 (34.3)35 (19.7)66 (37.1)HIT positive (n=54)2 (3.7)28 (51.9)18 (33.3)29 (53.7)p value0.2420.01980.03570.0293 This data supports that in the setting of active infection, particularly with E. coli, S. pneumo, and S. aureus, HIT antibody results should be carefully evaluated. Patients with positive cultures are likely to have thrombocytopenia from infection or sepsis, regardless of the presence of a HIT antibody. Thus, additional factors, such as the patient's 4T score and the presence of thrombosis should be considered prior to initiating treatment for HIT. Disclosures: No relevant conflicts of interest to declare.

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