10/15/2015. Clinical Utility of Immature Cell Indices DISCUSSION POINTS HEALTHCARE REFORM PAYMENT MODEL EXPERIMENTS

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1 Clinical Utility of Immature Cell Indices Leveraging Technology to Help Manage Anemia and Blood Utilization 2015 Sysmex America, Inc. All rights reserved. For Clinical Support Team Use Only. Not for Sales Use. DISCUSSION POINTS The significance of hematological immature cell indices Clinical applications of the parameters for wellness, prevention, and chronic disease management Cost of care implications for parameter utilization HEALTHCARE REFORM PAYMENT MODEL EXPERIMENTS Quality-based Payment Models Care Processes Error Penalties Readmission Penalties Patient Satisfaction Shared Savings Clinical Outcomes Bonus pay for Reduced higher compliance payment for with SCIP protocols hospitals with and other care high rates of processes. SSI s, blood clots, retained objects, etc. Reduced payment for hospitals with high 30-day readmission rates, by diagnosis. Hospital score on HCAHPS survey; a component of many qualitybased pay programs. Providers share savings from lower complications and readmissions, greater efficiency. Payment linked to patient outcomes, achievement of quality and utilization goals. Source: Surgical Directions 1

2 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 ANEMIA MANAGEMENT ANEMIA PREVALENCE 3.4 million people in US; 2 billion people globally (1/3 of population) Iron deficiency (ID) is the most common cause of anemia (> 600 million people). Leading causes: Gastrointestinal blood loss Dietary iron deficiency (poor nutrition, malabsorption) Infectious disease, cancer treatment Rapid diagnosis and treatment of iron deficiency can prevent anemia. National Anemia Action Council,

3 ANEMIA OVERVIEW Indication of underlying disorders Underrecognized and undertreated Increased morbidity and mortality Contributes to overutilization of blood transfusions DIAGNOSIS OF IRON DEFICIENCY Biochemical Parameters Hematological Parameters 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 Serum Iron Transferrin Saturation Infection/Inflammation Sample late in the day Meal iron intake Supplement iron intake Hemolysis Oral contraceptive Diurnal variation Infection/Inflammation Serum Ferritin Infection/Inflammation Hyperthyroidism Aging Liver disease (HCV) Malignancy Alcohol consumption Oral contraceptives Vitamin C deficiency Hypothyroidism Exercise 3

4 RET CHANNEL SCATTERGRAM ON NORMAL PATTERN RET RET RBC LFR MFR HFR IRF PLT RETICULOCYTE PARAMETERS Reticulocytes # and % Immature Reticulocyte Fraction (IRF) Measure of erythropoiesis Reticulocyte Hemoglobin (RET-He) Measure of hemoglobin content Snapshot of iron availability RETICULOCYTE HEMOGLOBIN 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 4

5 CLINICAL APPLICATIONS OF RET-He INPATIENT & OUTPATIENT SETTINGS Wellness: Pediatrics Prevention: Surgical patients Chronic Disease Management: End-stage renal disease Congestive heart failure Cancer IRON DEFICIENCY PREVALENCE IN CHILDREN % Patients with IDA 10% Patients with ID Adverse consequences in pediatric patients: Increased lead absorption Impaired immunity Anemia Impaired neurocognitive development % 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 : INITIAL SCREENING OF INFANTS FOR IRON DEFICIENCY Non-Iron Deficient (N=179) Iron-Deficient (N=23) At CHr cutoff of 27.5 pg 83% sensitivity, 72% specificity Hgb is poor predictor 26% sensitivity, 95% specificity Ulrich, C., et al. Screening healthy infants for iron deficiency using reticulocyte hemoglobin content. JAMA. 2005, 294:

6 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. 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 : WELLNESS MANAGEMENT: SCREENING AND PREVENTION 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 6

7 CLINICAL CHALLENGES IN ANEMIA MANAGEMENT Which tests provide the best assessment of iron deficiency anemia? Assessing iron stores before treatment? Assessing efficacy of ESA and Iron therapy? EARLY IDENTIFICATION FOR APPROPRIATE INTERVENTION Clear difference between responders and non-responders to EPO RET-He is an early detector of Functional Iron Deficiency 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). PATIENT BLOOD MANAGEMENT Retrospective, risk-adjusted, clinical outcome study Bloodless inpatients, n=294,control group of transfusion inpatients, n=1157 Iron Protocol Oral, IV iron, and/or EPO Clinical outcomes of bloodless inpatients were similar or better than those who had transfusion Similar discharge hemoglobin levels Mortality in bloodless group (0.7%) vs control group (2.7%) Reduced direct hospital costs by 18% in bloodless group Frank, S.M., et al. Risk-adjusted clinical outcomes in patients enrolled in a bloodless program. Transfusion. Oct :10,

8 LABORATORY TESTING ALGORITHM FOR ANEMIA SABM WEBSITE (IRWIN GROSS, MD) Hgb is less than 13 gm/dl MCV less than or equal to 105 If TSAT greater than 20% and ferritin greater than 100 ng/ml and MCV less than 80 consider thalassemia or hemoglobinopathy Reticulocyte count, RET-He, iron, iron binding capacity, ferritin, creatinine Add testing for vitamin B12 if MCV greater than or equal to 90 Ferritin less than 100 ng/ml? Flow Diagram: Inclusion of RET-He in algorithm CLINICAL UTILITY OF RET-He BANNER HEALTH, ARIZONA Iron assessment with RET-He ED screening using RET-He Post discharge anemia management Joint Commission Certification Re-admission rate dropped from 13 to 10% (23%) Courtesy of Larry Spratling, MD, Chief Medical Officer, Banner Health, Arizona CLINICAL UTILITY OF RET-He CORE SURGICAL GROUP, BANNER HEALTH, ARIZONA Blood Management Clinic for elective orthopedic surgeries Pre-surgical anemia assessment by nurses and pharmacist Anemia criteria based upon Hgb and RET-He Hgb 10-13g/dL erythropoietin and iron Ret-He<30.6pg - IV iron sucrose Hgb and RETIC- pre-discharge Reduced transfusion rates from 60% to10% Courtesy of Banner Health, Arizona 8

9 RET-He IN CLINICAL PROTOCOL FOR ANEMIA LAS PALMAS & DEL SOL MEDICAL CENTERS, TEXAS Use of RET-He has made degree of anemia easier to ascertain/treat Courtesy of Las Palmas and Del Sol Medical Centers, El Paso, TX AABB TRANSFUSION RECOMMENDATIONS AABB. Five Things Physicians and Patients Should Question. Should-Question.PDF (Accessed 30 December 2014). CHRONIC DISEASE MANAGEMENT : FOR IRON DEFICIENCY AND ANEMIA 9

10 CHRONIC DISEASE MANAGEMENT OF ANEMIA Chronic Kidney Disease Anemia - Hgb < g/dl Result of insufficient production of erythropoietin Iron deficiency anemia due to ESA treatment and dialysis-related blood loss Serum iron studies unreliable Challenges with ESA and iron therapy VARIATIONS IN IRON TESTS Source and Magnitude of Variation Variation RET-He Hgb Hct TSAT Ferritin Total 7.2% 6.0% 6.2% 40.9% 22.0% (N=30) RET-He, Hgb, and Hct, but not TSAT or Ferritin are useful to guide ESA and iron therapy Van Wyck, D., et al.. Analytical and biological variation in measures of anemia and iron status in patients treated with maintenance hemodialysis. Am J Kidney Dis. Sept :3, RET-He IN THE DIAGNOSIS OF IDA Cut off Sensitivity Specificity 27.2 pg 93.3% 83.2% Iron Deficiency Anemia Diagnostic Criteria Fe TSAT Ferritin Hgb * <40 <20 <100 <11 (N=126) Brugnara, C. et al. Reticulocyte hemoglobin equivalent (Ret He) and assessment of iron-deficient states. Clin. Lab. Hem. Oct :5,

11 KDOQI GUIDELINES FOR ANEMIA EVALUATION Initial Anemia Evaluation Cellular Assessment Hgb < 12g/dL RBC indices Absolute Retic WBC & Diff PLC Iron Assessment Serum Serum TSAT or CHr Iron Assessment Indices HD-CKD Target Ferritin > 200 ng/ml and TSAT > 20% or CHr > 29 pg 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) KDIGO CLINICAL PRACTICE GUIDELINE FOR ANEMIA IN CHRONIC KIDNEY DISEASE 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. contents & 2012 KDIGO. Aug :4 ANEMIA IN PATIENTS WITH CANCER Complex etiology Chronic disease/inflammation Treatment side effects Nutritional deficiencies Conventional biochemical markers inaccurate Management RBC transfusions, ESA, Iron 2012 recommendations Investigate patients with Hgb < 11g/dl 11

12 PERFORMANCE OF RET-He IN CANCER 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 Peerschke, E., et al. Using the hemoglobin content of reticulocytes (RET-He) to evaluate anemia in patients with cancer. AJCP : SUMMARY: RETICULOCYTE HEMOGLOBIN (RET-He) 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 THROMBOPOIESIS 12

13 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? POSSIBLE CAUSES OF THROMBOCYTOPENIA Production Disorders Destruction Disorders Myeloablative Therapy Bone Marrow Transplant Acute Myeloid Leukemia Neoplasia ITP/TTP Hepatitis C DIC Splenomegaly Autoimmune Disease Bacteremia/Sepsis HIT/DIT Pregnancy There is no single hematologic or biochemical test that is conclusive for a given mechanism of thrombocytopenia 2015 Sysmex 2015 America, Sysmex Inc. America, All rights Inc. reserved. All rights For reserved. Clinical Support Team Use Only. Not for Sales Use. 13

14 PLT-F CHANNEL SCATTERGRAM - NORMAL PATTERN RBC IPF PLT-F IMMATURE PLATELET FRACTION Fluorescent technology Immature platelet staining Cellular measurement of thrombopoiesis Reference Range % Briggs, C, et al. Assessment of an immature platelet fraction (IPF) in peripheral thrombocytopenia. BJH :93 99 DIFFERENTIATE PHYSIOLOGICAL MECHANISMS Low PLT + Normal/Low IPF (Consistent with production disorder) Normal Low PLT+ High IPF (Consistent with destruction disorders) 14

15 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 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 IMMATURE PLATELET FRACTION TO ASSESS BONE MARROW RECOVERY Study Objective How well can IPF help the clinician predict bone marrow recovery following peripheral blood HPC transplantation? (N=50) A persistently low IPF in this setting would suggest failure of thrombopoietic recovery. Zucker, M., et al. Immature Platelet Fraction as a predictor of platelet recovery following hematopoietic progenitor cell transplantation. Laboratory Hematology : IPF TO ASSESS BONE MARROW RECOVERY Bone marrow recovery after stem cell transplant (SCT, N=16) IPF# preceded PLT recovery by 3 days IPF% preceded PLT recovery by 4 days At IPF cutoff 5.3% after SCT, PLT recovery in 2 days, PPV 0.93 Van der Linden, N., et al. Immature platelet fraction measured on the Sysmex XN hemocytometer predicts thrombopoietic recovery after autologous stem cell transplantation. Eur J Haematol. Aug :2,

16 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) Have, L.W., et al. Absolute immature platelet count may predict imminent platelet recovery in thrombocytopenic children following chemotherapy. Pediatr Blood Cancer : IPF MEASURES MARROW PRODUCTION AIPF validated as a reflection of PLT production in marrow Platelet transfusion did not change AIPN IPF% decreased after transfusion due to increase in circulating PLT AIPN Absolute Immature Platelet Number IPF% - Percent of Immature Platelets Batt, T., et al. Measurement of the absolute immature platelet number reflects marrow production and is not impacted by platelet transfusion. Transfusion :6, SUMMARY: IMMATURE PLATELET FRACTION (IPF) Cellular measurement of thrombopoiesis May assist in differential diagnosis of thrombocytopenia Platelet production vs platelet destruction Earlier indicator of bone marrow recovery 16

17 THANK YOU! 2015 Sysmex America, Inc. All rights reserved. For Clinical Support Team Use Only. Not for Sales Use. 17