Disclosure Statement. Thrombocytopenia in the NICU: Simple and Complex Cases OUTLINE OUTLINE 7/11/2018

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1 Thrombocytopenia in the NICU: Simple and Complex Cases Disclosure Statement financial relationship with any entity producing, marketing, re-selling, or distributing health care goods or services discussed in the presentation. off-label use of any product will be advocated. Robert D. Christensen MD Neonatology/Hematology/Oncology Learning Objectives 1. Participants will be able to describe reference intervals for platelet counts, mean platelet volume measurements, and immature platelet fractions. 2. Participants will differentiate hyporegenerative from consumptive varieties of neonatal thrombocytopenia, and evaluate risks and benefits of transfusions. OUTLINE OUTLINE Platelet Reference Intervals for Neonates >47,000 neonates from Intermountain Healthcare, Utah All run on the same model of platelet counter Data excluded if diagnosis of SGA, PIH, sepsis. 1

2 500,000 Platelet Count At Birth First Platelet Count By Gestational Age 3 Days of Age or Less Platelet Count By Age in Days Platelet Count, First 90 days After Birth 900, , ,000 Feb , ,000 Platelet Count 300, ,000 Platelet Count 500, , ,000 Feb , , , Gestational Age (weeks) 5 th %, mean, 95 th % Age in Days Mean 5th %ile 95th %ile 900,000 First Platelet Count By Age in Days Platelet Count, First 90 days After Birth Mean Platelet Volume 800, , , Platelet size varies. Platelet Count 500, , , , , TPO SURGE Age in Days Mean 5th %ile 95th %ile The MPV is an electronic estimate of the average size (volume) of platelets in femtoliters (fl) 14 Immature Platelet Fraction MPV Age in Days Mean 5th %ile 95th %ile Cremer Charitė-Universitätsmedzin July 2017 Macqueen Univ of Utah The immature platelet fraction (IPF) is a laboratory quantification of immature platelets in the circulation The IPF can be expressed either as a percent (IPF%) or as an absolute number of immature platelets per microliter of blood (IPC/µL) 2

3 Forward Scatter (Cell Size) Fluorescent Platelet Channel IPF Platelets Side Fluorescence (Nucleic Acid Content) Immature Platelet Fraction The IPF reflects the state of thrombopoiesis. Typically, thrombocytopenia due to production failure results in a normal IPF, while thrombocytopenia due to platelet destruction results in a high IPF (from a compensatory increase in platelet production). August 2013 July 2017 Among neonates with NEC or sepsis the most severe cases (deaths) had a lower IPF than did the survivors, suggesting marrow failure. IPF Values in Thrombocytopenic Neonates Hypoproliferative (Syndromes/SGA/Asphyxia) Consumptive (Immune/Sepsis/NEC/DIC) IPF% July 2017 IPC x 10 3 /µl 10.4 ± ± ± ± Pvalue < < OUTLINE What is the incidence of thrombocytopenia? Nine years of Intermountain Healthcare records 2891 SGA neonates

4 What causes this variety of thrombocytopenia? What is the typical nadir platelet count? What is the typical nadir platelet count? 50 75K What is the typical nadir platelet count? 50 75K What is the typical duration of thrombocytopenia? 4

5 What is the typical nadir platelet count? 50 75K What is the typical duration 14 days of thrombocytopenia? What is the typical nadir platelet count? 50 75K What is the typical duration 14 days of thrombocytopenia? Is thrombocytopenia related to maternal blood pressure or fetal growth retardation? What is the typical nadir platelet count? 50 75K What is the typical duration 14 days of thrombocytopenia? Is thrombocytopenia related to maternal blood Relationship is with SGA. independent pressure or fetal growth retardation? relationship with PIH What is the typical nadir platelet count? 50 75K What is the typical duration 14 days of thrombocytopenia? Is thrombocytopenia related to maternal blood Relationship is with SGA. independent pressure or fetal growth retardation? relationship with PIH Is thrombocytopenia in SGA neonates associated with a higher likelihood of adverse outcomes? What is the typical nadir platelet count? 50 75K What is the typical duration 14 days of thrombocytopenia? Is thrombocytopenia related to maternal blood Relationship is with SGA. independent pressure or fetal growth retardation? relationship with PIH Is thrombocytopenia in SGA neonates associated with Thrombocytopenia a higher likelihood of SGA of adverse 2% mortality. outcomes? Consumptive thrombocytopenia 65% mortality Generalizations about the Thrombocytopenia of SGA 2015 Among SGA neonates, the more severe the growth restriction (1 st percentile vs. 10 th percentile): 1. The more likely they will have thrombocytopenia. 2. The lower the nadir count will be. 3. The longer the thrombocytopenia will persist. 5

6 The Thrombocytopenia of Perinatal Asphyxia DEFINITION: Cord ph <6.99 and/or Cord base deficit >16 mmol/l Two or more platelet counts in the first week after birth <150,000/µL 1. Incidence: Thrombocytopenia in 31% of 375 neonates with perinatal asphyxia vs. 5% of matched nonasphyxiated controls (p<0.0001). 2. Nadir and Severity: Day 3 (75,000/µL). Asphyxia and thrombocytopenia 14.5 % died. Asphyxia and no thrombocytopenia 5% died (p<0.002) Duration of Thrombocytopenia: 2½ to 3 weeks. 4. Cause: Reduced pl production. Associated with NRBC count at birth (related to hypoxia in utero). NOT worse with hypothermia. 5. Treatment: t likely to need TPO agonists. Platelet transfusion should not be needed unless DIC or ECMO. Platelet counts of 375 neonates born after perinatal asphyxia Grey = reference range Hyporegenerative Congenital Thrombocytopenia Hyporegenerative Congenital Thrombocytopenia Small Platelets rmal Size Platelets Large Platelets Hyporegenerative Congenital Thrombocytopenia Hyporegenerative Congenital Thrombocytopenia Small Platelets rmal Size Platelets Large Platelets Small Platelets rmal Size Platelets Large Platelets MPV <6 fl MPV 8 to 12 fl MPV >15 fl MPV <6 fl MPV 8 to 12 fl MPV >14 fl X-linked or Wiscott Aldrich syndrome Mutation in WAS at Xp

7 Hyporegenerative Congenital Thrombocytopenia Small Platelets rmal Size Platelets Large Platelets MPV <6 fl MPV 8 to 12 fl MPV >15 fl Bernard Soulier [3q21.3, 17p13.2 or 22q11.21] MYH9-related disorder[22q12.3] von Willebrand disease type IIB VWF [12p13.31] Congenital Thrombocytopenia with rmal Size Platelets Are Specific Orthopedic Forearm Anomalies Present? YES or NO Orthopedic anomalies YES TAR = Thrombocytopenia and Absent Radii A microdeletion on 1q21.1 is necessary (haploinsufficient). This deletion plus a point mutation on the allele (RBM8A gene) Autosomal Recessive Orthopedic anomalies YES Inability to pronate/supinate forearm ATRUS = Amegakaryocytic Thrombocytopenia with RadioUlnar Synostosis Orthopedic anomalies NO Previously all lumped into the category CAMT = Congenital Amegakaryocytic Thrombocytopenia A mutation in the HOXA11 7p15.2 (haploinsufficient) - Autosomal Dominant or de novo mutation) 7

8 Severe Hyporegenerative Congenital Thrombocytopenia and rmal Size Platelets Forearm Defect? Severe Hyporegenerative Congenital Thrombocytopenia and rmal Size Platelets Forearm Defect? ATRUS TAR SGA and other anomalies? ATRUS TAR SGA or other anomalies? Jacobsen RUNX1 PTPN11 CAMT Jacobsen RUNX1 PTPN11 CAMT Symmetrical SGA, hyperteloric, developmental delay, Microdeletion 11q23 (Genomic Microarray) Severe Hyporegenerative Congenital Thrombocytopenia and rmal Size Platelets ATRUS Jacobsen TAR Forearm Defect? RUNX1 SGA or other anomalies? PTPN11 Symmetrical SGA, developmental delay, Microdeletion 21q22.11 (Genomic Microarray) CAMT RUNX1 on Chromosome 21 Encodes a Runt-Related Transcription Factor Katzaki et al. Siena. Microdeletions of 21q22.11 Am J Med Genet 2010 Christensen et al. Utah. Microdeletions of 21q22.11 J Perinatology 2012 Click et al. Seattle. Microdeletions of 21q22.11 Am J Med Genet 2011 Severe Hyporegenerative Congenital Thrombocytopenia and rmal Size Platelets ATRUS Jacobsen TAR Forearm Defect? RUNX1 SGA or other anomalies? PTPN11 CAMT onan phenotype, SGA, developmental delay, Mutation in PTPN11 12q24.13 [c.218 C>T] Severe Hyporegenerative Congenital Thrombocytopenia and rmal Size Platelets ATRUS TAR Forearm Defect? SGA or other anomalies? Kratz C, Niemeyer CM et al. Germany. BLOOD 2005 Nunes Jacobson et al. Portugal. RUNX1 BMJ Case PTPN11 Reports 2012 CAMT Christensen et al. USA. NEONATOLOGY 2013 onan phenotype, SGA, developmental delay, Mutation in PTPN11 12q24.13 [c.218 C>T] 8

9 Severe Hyporegenerative Congenital Thrombocytopenia and rmal Size Platelets ATRUS Jacobsen TAR Forearm Defect? RUNX1 SGA or other anomalies? PTPN11 CAMT Mutation in TPO receptor 1p34.2 OUTLINE Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Goel R, Ness PM et al (Hopkins) 2015 While platelets are primary mediators of hemostasis, there is emerging evidence to show that they may also mediate pathologic thrombogenesis. Study utilized the nationwide inpatient date to evaluate 100,000 hospitalizations of adults with platelet consumptive disorders (ITP, Hep-induced thromb, and TTP). Pl transfusions (adjusting for clinical severity/acuity) were associated with higher odds of acute MI (OR 2.0; 95% CI ), mortality (PR 2.0; , and arterial thrombosis (OR 5.8; ). Platelet transfusions for adults with consumptive platelet disorders are associated with higher odds of arterial thrombosis, MI, and death. What are the risks vs benefits of platelet transfusions for neonates who have CONSUMPTIVE thrombocytopenia? CONSUMPTIVE thrombocytopenias in NICU: DIC IMMUNE (NAIT, maternal ITP) SEPSIS (end-stage may have element of production failure). NEC (end-stage may have element of production failure). Very high users of platelet transfusions in the neonatal intensive care unit Intermountain Healthcare neonates received >20 platelet transfusions (29, range 20-79). Top four diagnoses were consumptive varieties: 1. ECMO 2. Fungal sepsis 3. NEC 4. Bacterial sepsis WHY WERE PL TRANSFUSIONS ORDERED? 19% oozing, bruising, or bleeding; 81% not bleeding (prophylaxis). 50% of high users died (none from hemorrhage). All survivors developed BPD. All survivors weighing <1250 g developed ROP. Severe Thrombocytopenia in the NICU Intermountain Healthcare 2009 Severe 2 platelet counts <50,000/µL Among admissions, severe thrombocytopenia in 273 (2.4%). Most common, CONSUMPTIVE varieties onset days/weeks 30% present at birth (or in first 3 days) 50% present by day 10 75% present by day 28 95% present by day 100 correlation between platelet count & pulmonary, GI, or IVH. Cutaneous bleeding more common with counts <20K. The lowest platelet count did not predict mortality rate, but the number of platelet transfusions received did. 9

10 OUTLINE Platelet Transfusion in Todays NICU 2% = Treatment of thrombocytopenic bleeding. 98% = Prophylaxis. Hope to prevent bleeding when platelets fall below arbitrary blood level. Sola-Visner. Acquired thrombocytopenia. In Neonatal Hematology, Eds. De Alarcon, Werner, Christensen, 2012 RISKS vs. BENEFITS In non-bleeding, thrombocytopenic neonates, what are the RISKS of prophylactic platelet transfusions? What are the BENEFITS? Correlation: More NICU platelet transfusions = Higher mortality rate Baer & Christensen 2009 Multiple platelet transfusions to NICU patients are, themselves, a risk factor for adverse outcome. Dec 2007 BENEFITS: Do prophylactic platelet transfusions prevent intraventricular hemorrhage? 1. Andrew - pl 50,000 vs. 150,000/µL. J Pediatr Del Vecchio - pl in the range 100, ,000/µL do not increase bleeding time J Perinatol Von Lindern - Platelet transfusion and IVH. Comparison of a liberal vs. restrictive guidelines. Arch Dis Child

11 Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants Sparger, Christensen, Widness, Sola-Visner et al 2016 Sparger, Christensen, Widness, Sola-Visner et al 2016 BACKGROUND: Survey results suggest that US neonatologists frequently administer prophylactic platelet transfusions to VLBW infants with mild to moderate thrombocytopenia to prevent IVH. BACKGROUND: Survey results suggest that US neonatologists frequently administer prophylactic platelet transfusions to VLBW infants with mild to moderate thrombocytopenia to prevent IVH. AIM: Examine the association between platelet count, platelet transfusion, and the risk for IVH in the first 7 days of life. Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants Platelet Transfusion Practices Among Very-Low-Birth-Weight Infants Sparger, Christensen, Widness, Sola-Visner et al 2016 Sparger, Christensen, Widness, Sola-Visner et al 2016 BACKGROUND: Survey results suggest that US neonatologists frequently administer prophylactic platelet transfusions to VLBW infants with mild to moderate thrombocytopenia to prevent IVH. AIM: Examine the association between platelet count, platelet transfusion, and the risk for IVH in the first 7 days of life. METHODS: Multicenter, retrospective cohort study; 972 VLBW infants treated in 6 US NICUs, BACKGROUND: Survey results suggest that US neonatologists frequently administer prophylactic platelet transfusions to VLBW infants with mild to moderate thrombocytopenia to prevent IVH. AIM: Examine the association between platelet count, platelet transfusion, and the risk for IVH in the first 7 days of life. METHODS: Multicenter, retrospective cohort study; 972 VLBW infants treated in 6 US NICUs, FINDINGS: After controlling for significant clinical factors prophylactic platelet transfusions did not reduce the incidence of IVH (hazard ratio, 0.92; 95% CI, ; P =.80). Platelet transfusion practices among neonatologists in the United States and Canada: results of a survey. PEDIATRICS 2009 Platelet transfusions in neonates: practices in the United States vary significantly from those in Austria, Germany, and Switzerland. TRANSFUSION 2011 Web based surveys of neonatologists Significant diversity of practice in platelet transfusions. CD Josephson & MC Sola-Visner In USA, but not in Central Europe, platelet transfusions are commonly ordered for nonbleeding neonates with counts 50-75K Central Europe 167 PLT transf/1000 NICU patients, compared to 299/1000 in the USA Platelets for Neonatal Transfusion Study 2 (PlaNet-2 study) Dr. Simon Stanworth, Consultant Haematologist John Radcliffe Hospital, Oxford Study Aim: platelet transfusion threshold at 50K vs 25K to establish if the lower threshold is as good as the higher. Eligibility: <34 week at birth, platelet count <50, cranial ultrasound within 6 hours before randomization (to examine for IVH). Intended randomization 655 thrombocytopenic neonates; 15 ml/kg platelets when platelet count falls below the threshold. Two year neuro-developmental follow-up. 11

12 Enhance Platelet Production Rather than Administer Repeated Platelet Transfusions Which (if any) Thrombocytopenic Neonates Might be Good Candidates for TPO Mimitics as an Alternative to Repeated Platelet Transfusions? Good Candidates? 1. Neonates who are very likely to have significant bleeding problems with no treatment. 2. Neonates who are very likely to need multiple (? >10) platelet transfusions. Two TPO receptor agonists; Eltrombopag (PO) and Romiplostim (IV/SQ). Long-term Use of the Thrombopoietin- Mimetic Romiplostim in Children with Severe Chronic ITP. Bussel JB et al Children with chronic ITP, mean pl count 13K 2015 Weekly SQ romiplostim to maintain platelet counts K (maximum dose 10 µg/kg). Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Romiplostim in children with immune thrombocytopenia: a phase 3, randomized, double-blind, placebo-controlled study. Tarantino MD, Bussel JB, et al Patients 1 to 17 years, mean platelet counts 30K were recruited from 27 sites in the USA, Canada, Australia. Randomly assigned (2:1) to weekly romiplostim or placebo for 24 weeks, adjusting the dose weekly to target platelet counts of K Durable platelet response in 52% (OR 9.1; 95% CI, ). new safety signals. Developmental Differences Between Newborn and Adult Mice in Response to Romiplostim Sparger, Sola-Visner et al 2017 Newborn and adult mice treated, single SQ dose (escalating doses), with murine TPO or Romiplostim, platelet counts and IPF followed for 14 days. Max response: Platelet counts increased 4.2 fold in adults 2.1 fold in neonates. Newborn mice are less responsive to ROM than adult mice, due to a combination of pharmacokinetic differences and developmental differences in the response of MKs to thrombopoietic stimulation, evidenced by neonatal MKs increasing in numbers but not in size. Eltrombopag, a TPO Mimetic, Crosses the Blood-brain Barrier and Impairs Irondependent Hippocampal Neuron Dendrite Development. Bastian Sola-Visner and Georgieff 2017 Thrombopoietin mimetics (eltrombopag [ELT]) might provide an alternative therapy for selected neonates who have severe and prolonged thrombocytopenia. Findings in newborn mice: ELT crosses the BBB in a timedependent manner and chelates intracellular iron. This is associated with impaired neuronal development and synaptic function. 12

13 Will Pharmacological Stimulators of Platelet Production have an Important Role in the NICU? are throwing some cold water on the idea of Tpo Mimetics as an alternative to pl transfusion In thrombocytopenic older children and adults Romiplostim and Eltrombopag can be very useful In neonatal animal models, Poorer response and Unwanted CNS side-effects. Possible Exception X-linked Micro- Thrombocytopenia with WAS mutation. Eltrompag can reduce/eliminate pl transf RECAP WAS gene mutations that cause absent protein expression result in classic WAS. Mutations that reduce WASp protein expression result in X-linked thrombocytopenia. WAS gain-of-function mutations result in X-linked neutropenia. RECAP RECAP Term, lower limit 120 K Preterm, lower limit 100 K IPF, like a retic count for platelets SGA Perinatal Asphyxia 13

14 RECAP RECAP Concern about thrombotic complications when pl transfusion given to adults with consumptive thrombocytopenia. Likely too many prophylactic platelet transfusions given in NICU Moving toward Evidence based NICU pl transfusion. Less enthusiasm about TPO mimetics, except in selectec dx. Thanks for your kind attention! Thrombocytopenia in the NICU: Simple and Complex Cases Robert D. Christensen MD Neonatology/Hematology/Oncology 14