5/1/2017 DISCUSSION POINTS. Clinical Utility of Immature Cell Indices Beyond the Routine CBC John E. Donnelly BSN, RN

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1 DISCUSSION POINTS Importance of hematological immature cell indices Clinical Utility of Immature Cell Indices Beyond the Routine CBC John E. Donnelly BSN, RN Investigate the evidence for clinical utility: Reticulocyte indices in management of ID and IDA IPF in understanding causes of thrombocytopenia IG as part of expanded WBC differential Understand how new information can be applied to patient care Completed November 5, Sysmex America, Inc. All rights reserved. For Clinical Support Team Use Only. Not for Sales Use. HEMATOPOIESIS: FORMATION OF BLOOD CELLS IN THE BONE MARROW Immature cell count data can be used with mature cell counts to assess pathophysiological mechanisms Leukopoiesis (IG) White Blood Cells Erythropoiesis (RET-He) Red Cell Hemoglobinization Thrombopoiesis (IPF) Platelets HEMATOLOGICAL CHALLENGES Infection/Inflammation Management Iron Deficiency/Anemia Management Thrombocytopenia Management SIGNIFICANCE OF LEFT SHIFT WBC PARAMETERS IG (Immature Granulocytes) Peripheral Blood WBC (White Blood Cell Count) 1

2 WDF CHANNEL SCATTERGRAM - NORMAL PATTERN MANUAL DIFFERENTIAL IMPRECISION # of True Cells N = 100 N = 200 N = 500 N = 10, Mono Lymph IG Neut + Baso Manual is imprecise with counts less than 5% 1 The 400-cell diff may be acceptable to relatively high counts, it is not suitable for counts of less than 5% 2 EO Debris 1. Rumke, C.L., The statistically expected variability in differential leukocyte counting. p. 39. In Koepke JA (ed): Differential Leukocyte Counting. College of American Pathologists, Skokie, IL 1978, with permission. 2.Fernandes, B., et al. Automated enumeration of immature granulocytes. Am J Clin Pathol : Y. Hamaguchi. (2007) AJCP 128: Automated enumeration of Immature Granulocytes. IMMATURE GRANULOCYTES ELEVATED WHEN OTHER MARKERS ARE NOT Sample Rate Number of Samples Positive Positive Negative Total Criteria CRP 5.0 mg/dl 42 (84.0%) 8 (16.0%) 50 ESR 20 mm/hr 19 (95.0%) 1(5.0%) 20 The IG count can highlight a potential acute infection or inflammatory response at a relatively early stage of the development clinical features when other blood count parameters are in the overall normal range and are generally nonspecific as indicators. CD (80.3%) 15 (19.7%) 76 IL pg/ml 37 (57.8%) 27 (42.2%) 64 Positive samples with high IG counts ( 2.0%) and normal neutrophil levels (N=84) Briggs, C., et al. Evaluation of immature granulocyte counts by the XE-IG master: Upgraded software for the XE-2100 automated hematology analyzer. Lab. Hematology Briggs, C., et al. Evaluation of immature granulocyte counts by the XE-IG master: Upgraded software for the XE-2100 automated hematology analyzer. Lab. Hematology IG: Better than WBC SUMMARY: AUTOMATED IG COUNT IMMATURE GRANULOCYTES Direct cellular measure of leukopoiesis Excellent correlation with flow cytometry and more precise than manual cell differential 1 Early indicator to distinguish infected and non-infected patients 2 Complimentary test for infection surveillance protocols Figure 1. ROC curves comparing ability of IG (blue), ANC (grey), and WBC count (green) to predict infection. IG and ANC curves are superimposable. 92% PPV in patients with positive blood cultures and IG>3%. Ansari-Lari, M., et al. Immature granulocyte measurement using the Sysmex XE-2100: Relationship to infection and sepsis. Am J Clin Pathol : Fernandes, B., et al. Automated enumeration of immature granulocytes. Am J Clin Pathol : Briggs, C., et al. Evaluation of immature granulocyte counts by the XE-IG master: Upgraded software for the XE-2100 automated hematology analyzer. Lab. Hematology Sysmex 2015 America, Sysmex Inc. America, All rights Inc. reserved. All rights For Clinical reserved. Support Team Use Only. Not for Sales Use. 2

3 ANEMIA MANAGEMENT ANEMIA OVERVIEW Indication of underlying disorders Underrecognized and undertreated Increased morbidity and mortality Contributes to overutilization of blood transfusions AABB TRANSFUSION RECOMMENDATIONS DIAGNOSIS OF IRON DEFICIENCY Biochemical Parameters Hematological Parameters AABB. Five Things Physicians and Patients Should Question. Should-Question.PDF (Accessed 30 December 2014). Transferrin, Transferrin saturation (TSAT) Ferritin Serum iron Hepcidin Based on RBC: Hgb, MCV, RDW Based on Reticulocytes Retic # and % IRF RET-He CONDITIONS AFFECTING TEST RESULTS Test Falsely Increased Results Falsely Decreased Results RET CHANNEL SCATTERGRAM ON NORMAL PATTERN RET RET Serum Iron Transferrin Saturation Infection/Inflammation Sample late in the day Meal iron intake Supplement iron intake Hemolysis Oral contraceptive Diurnal variation Infection/Inflammation RBC LFR MFR HFR Serum Ferritin Infection/Inflammation Hyperthyroidism Aging Liver disease (HCV) Malignancy Alcohol consumption Oral contraceptives Vitamin C deficiency Hypothyroidism Exercise PLT IRF 3

4 RETICULOCYTE PARAMETERS RETICULOCYTE HEMOGLOBIN Reticulocytes # and % Immature Reticulocyte Fraction (IRF) Measure of erythropoiesis Reticulocyte Hemoglobin (RET-He) Measure of hemoglobin content Snapshot of iron availability Ret-He/CHr Measured at cellular level Monitors acute changes in reticulocyte hemoglobin More sensitive than indirect chemical measurements Detects non-responders to ESA/functional iron deficiency CASE STUDY : ANEMIA IN PREGNANCY CASE STUDY : ANEMIA IN PREGNANCY Lab Range WBC g/dl RBC x 10 6 /µl HgB ng/ml HCT % MCV mcg/dl MCH pg MCHC g/dl RDW mcg/dl Lab Range MCV mcg/dl HCT % HgB ng/ml Reticuloytes (%) 1.54 H % Reticulocytes (#) 64.8 H x10 6 /µl IRF % RET-He 20.6L pg/cell Reticulocyte panel provides additional insight regarding diagnosis Patient History/Presentation: Pregnant female presents to physician for a scheduled evaluation; routine CBC is within normal limits Diagnosis: Iron deficiency anemia secondary to pregnancy (based upon reticulocyte panel data) SMEAR REVIEW & FERRITIN RESULTS IRON DEFICIENCY PREVALENCE IN CHILDREN Smear Review No evidence of IDA Ferritin Results Low level confirms IDA diagnosis % Patients with IDA 10% Patients with ID Adverse consequences in pediatric patients: Increased lead absorption Impaired immunity Anemia Impaired neurocognitive development Ferritin 6.8 L g/dl % children ages12-36 months in the US have iron deficiency anemia; 10% have iron deficiency without anemia 1,2 1. Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. 2. Baker, R et al. The committee on nutrition. diagnosis and prevention of iron deficiency and iron-deficiency anemia in and infants and young children (0-3 years of age). Pediatrics :

5 RECOMMENDATIONS FOR WELLNESS SCREENING A low CHr concentration has been shown to be the strongest predictor of ID in children. For infants with Hgb <11.0 mg/dl or with significant risk of ID or IDA, SF and CRP or CHr levels should also be measured to increase the sensitivity and specificity of the diagnosis. CASE STUDY : INFANT WITH LETHARGY Lab Range RBC x 10 6 /µl HgB 7.0 L ng/ml HCT 23.7 L % MCV 59.1 L mcg/dL MCH 17.5 L pg MCHC 295 L g/dl RDW 19.3 H % Patient History/Presentation: 5 month old presents to ER with lethargy and decreased appetite Baker, R et al. The committee on nutrition. diagnosis and prevention of iron deficiency and iron-deficiency anemia in and infants and young children (0-3 years of age). Pediatrics : CASE STUDY : INFANT WITH LETHARGY CASE STUDY : INFANT WITH LETHARGY Lab Range MCH 17.5 L pg HgB 7.0 L ng/ml HCT 23.7 L % Reticulocyte (%) 0.68 L % Reticulocyte (#) 27.3 L x 10 6 /µl IRF 4.8L % RET-He 11.9 L pg/cell Reticulocyte panel provided additional data that enhanced plan of care Diagnosis: Severe iron deficiency anemia secondary to poor intake and nutrition Treatment Plan: Started on oral iron therapy and instructed to see pediatrician in 7 day for repeat labs and evaluation Lab Day 7 Range RBC x 10 6 /µl HgB 7.0 L 7.20 L ng/ml HCT 23.7 L 24.1 L % MCV 59.1 L 60.9 L mcg/dl MCH 17.5 L 18.2 L pg MCHC 295 L 299 L g/dl RDW 19.3 H 23.3 H mcg/dl Reticulocyte (%) 0.68 L % Is therapy working? Caregiver noncompliance vs non-responder to therapy What is the next step? Admit to hospital for intravenous iron therapy Recommend gastrointestinal consult to rule out an malabsorption issue CASE STUDY : INFANT WITH LETHARGY Is therapy working? Yes - RET-He shows an appropriate increase Lab Day 7 Range MCH 17.5 L 18.2 L pg HgB 7.0 L 7.20 L ng/ml HCT 23.7 L 24.1 L % Reticulocyte (%) 0.68 L % Reticulocyte (#) 27.3 L x 10 6 /µl IRF 4.8 L 45.5 H % RET-He 11.9 L 24.6 L pg/cell Reticulocyte panel provided clinically significant data that enhanced care What is the next step? Continue on oral iron therapy with routine follow up ANEMIA MANAGEMENT IN PRE-SURGICAL PATIENTS Increased morbidity and mortality Anemia screening 4 6 weeks prior to surgery Determine etiology/type of anemia Therapy to correct anemia before surgery. 5

6 EARLY IDENTIFICATION FOR APPROPRIATE INTERVENTION Clear difference between responders and non-responders to EPO RET-He is an early detector of Functional Iron Deficiency GUIDELINES FOR ANEMIA EVALUATION KDOQI Initial Anemia Evaluation Cellular Assessment Hgb < 12g/dL RBC indices Absolute Retic WBC & Diff Iron Assessment Serum Serum TSAT or CHr Iron Assessment Indices Ferritin > 200 ng/ml and TSAT > 20% or CHr > 29 pg Other tests of iron status, such as percentage of hypochromic red blood cells and reticulocyte Hgb content may be used instead of, or in addition to, TSAT and ferritin levels if available. Muusze, R.G., et al. Protocol for transfusion free major orthopaedic operations using RET-He. Sysmex Journal International :1, 1-8 (adapted from Dutch publication). National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis :S1-S146, (suppl 3) contents & 2012 KDIGO. Aug :4 PERFORMANCE OF RET-He IN CANCER SUMMARY: RETICULOCYTE HEMOGLOBIN (RET-He) Patient Screening With RET-He N=200 Reduced Iron Studies by 80% RET-He <32 pg And Hgb <11 g/dl NPV 98.5% Rapid rule out of iron deficiency anemia Reduced unnecessary testing Cost savings for laboratory and health care system Measured at cellular level Estimates real-time bone marrow iron Monitors acute hemoglobinization changes Provides less variation than acute phase reactants Sensitive for early detection of ID May improve care of patients in wellness, prevention and chronic disease settings May contribute to cost effectiveness of complex anemia care Peerschke, E., et al. Using the hemoglobin content of reticulocytes (RET-He) to evaluate anemia in patients with cancer. AJCP : THROMBOPOIESIS Clinical Challenge in Thrombocytopenia What is the cause of the thrombocytopenia? Is this a disorder of decreased production? Aplastic Anemia, Leukemia, BM suppression, drugs Is platelet destruction increased? ITP, TTP, DIC, drugs Is patient s bone marrow recovering without intervention? 6

7 PLT-F CHANNEL SCATTERGRAM - NORMAL PATTERN There is no single hematologic or biochemical test that is conclusive for a given mechanism of thrombocytopenia RBC IPF PLT-F 2015 Sysmex 2015 America, Sysmex Inc. America, All rights Inc. reserved. All rights For Clinical reserved. Support Team Use Only. Not for Sales Use. DIFFERENTIATE PHYSIOLOGICAL MECHANISMS IPF IN DIFFERENTIAL DIAGNOSIS IPF% is a supportive diagnostic test for ITP IPF% and RP% highly correlated Significantly increased in ITP patients Low values in AA+CIT Low PLT + /Low IPF (Consistent with production disorder) Low PLT+ High IPF (Consistent with destruction disorders) ITP Immune Thrombocytopenia (N=47) AA + CIT - Aplastic Anemia (AA, N=18) or chemotherapy-induced thrombocytopenia (CIT, N=10) Sakuragi, M., et al. Clinical significance of IPF% and RP% measurement in distinguishing primary immune thrombocytopenia from aplastic thrombocytopenic disorders. Int J Hematology. Jan epub IPF AFTER CHEMOTHERAPY (PEDIATRIC PATIENTS) IPF# (AIPC) increased significantly 24 to 48 hours prior to platelet recovery AIPC was not influenced by PLT transfusion AIPC increased >0.6 x 10 9 /L, PLT increased within 24 hours (77% PPV) IPF CASE STUDY 48 YEAR OLD MALE WITH PANCREATIC CANCER CBC Cycle 1 Day 8 Units Range WBC Low X10^3µl 4-11 RBC Low 3.97 Low X10^6µl HgB 13.1 Low 12.1 Low 10.9 Low g/dl HCT 36.3 Low 30.6 Low % PLT Low 42 Low X10^3µl IPF 0.0 Low % Have, L.W., et al. Absolute immature platelet count may predict imminent platelet recovery in thrombocytopenic children following chemotherapy. Pediatr Blood Cancer : The views expressed in the following slide are those of the author and their healthcare facility. Results of case studies are not predictive of other cases and results may vary. With permission from Cancer and Hematology of Western Michigan. 7

8 IPF CASE STUDY 48 YEAR OLD MALE WITH PANCREATIC CANCER IPF CASE STUDY 59 YEAR OLD FEMALE WITH BREAST CANCER CBC Cycle 1 Day 8 Next Day Units Range WBC Low X10^3µl 4-11 RBC Low 3.97 Low X10^6µl HgB 13.1 Low 12.1 Low 10.9 Low g/dl HCT 36.3 Low 30.6 Low % PLT Low 42 Low 6 Low X10^3µl IPF 0.0 Low 0.0 Low % Value of IPF Relevant data that may contribute to treatment decisions Part of CBC, using the same lavender tube Results can be obtained quickly without additional drain on resources Minimal cost and no discomfort compared to invasive diagnostic testing Cycle 1 CBC Units Day 8 Range WBC Low 2.1 Low X10^3µl 4-11 RBC Low 2.99 Low X10^6µl HgB Low 10.6 Low g/dl HCT Low 31.1 Low % PLT Low 17 Low X10^3µl IPF High % The views expressed in the following slide are those of the author and their healthcare facility. Results of case studies are not predictive of other cases and results may vary. With permission from Cancer and Hematology of Western Michigan. The views expressed in the following slide are those of the author and their healthcare facility. Results of case studies are not predictive of other cases and results may vary. With permission from Cancer and Hematology of Western Michigan. IPF CASE STUDY 59 YEAR OLD FEMALE WITH BREAST CANCER SUMMARY: IMMATURE PLATELET FRACTION (IPF) CBC Cycle 1 Day 8 Cycle 4 Units Range WBC Low 2.1 Low 2.6 Low X10^3µl 4-11 RBC Low 2.99 Low 3.41 Low X10^6µl HgB Low 10.6 Low 10.0 Low g/dl HCT Low 31.1 Low 30.0 Low % PLT Low 17 Low 119 Low X10^3µl IPF High % Value of IPF Relevant data that may contribute to treatment decisions Part of CBC, using the same lavender tube Results can be obtained quickly without additional drain on resources Minimal cost and no discomfort compared to invasive diagnostic testing Cellular measurement of thrombopoiesis May assist in differential diagnosis of thrombocytopenia Platelet production vs platelet destruction Earlier indicator of bone marrow recovery The views expressed in the following slide are those of the author and their healthcare facility. Results of case studies are not predictive of other cases and results may vary. With permission from Cancer and Hematology of Western Michigan. THANK YOU! donnellyj@sysmex.com Completed November 5, Sysmex America, Inc. All rights reserved. For Clinical Support Team Use Only. Not for Sales Use. 8