Thrombocytopenia in Small for Gestational Age (SGA) Neonates

Thrombocytopenia in SGA Neonates Israel Neonatology Association Robert Christensen, MD

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Meberg A, Halvorsen S, Orstavik I. Transitory thrombocytopenia in small for dates infants, possibly related to maternal smoking. Lancet 1977:11;303-304 23 neonates weighing <10th % who, with no other explanation, had one or more platelet count <100,000/ L in the first days after birth. Counts typically increased to >150,000/ L by DOL 15. None had pathological bleeding. Authors speculated that this variety of thrombocytopenia was the result of placental insufficiency-induced chronic hypoxia in utero.

Shuper A, Mimouni F, Merlob P, Zaizov R, Reisner SH. Thrombocytopenia in small for gestational age infants. Acta Paediatr Scand1983:72;139-140 14 SGA with one or more platelet count <100,000/ L in first week, and no other explanation for the thrombocytopenia. Bone marrow aspirates on two where thrombocytopenia persisted more than 2 weeks. Erythroid hyperplasia and few megakaryocytes in both. Elevated NRBCs at birth were common. Postulated (as had Meberg et al.) that the condition was due to reduced platelet production associated with chronic intrauterine hypoxia.

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Martha C. Sola-Visner and Matthew A. Saxonhouse Chapter 11: Placental Insufficiency and Chronic Intrauterine Hypoxia Thrombocytopenia is common in SGA (? Incidence). Mild to moderate thrombocytopenia (50 - 100K). Nadir (low point) not defined. Duration 2 weeks, sometimes longer (?). Pathogenesis ? involves chronic intrauterine hypoxia. (Lower circulating megakarycytopoietic progenitors. Lower marrow megakaryocytes progenitors, n=3). Best treatment and Outcome ?

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

O R I G I N A L A R T I C L E Thrombocytopenia in late preterm and term neonates after perinatal asphyxia Robert D. Christensen, Vickie L. Baer and Hassan M. Yaish Transfusion. January 2015;55:187-196.

Thrombocytopenia Among Small for Gestational Age Infants RD Christensen, VL Baer, E Henry, GL Snow, A Butler, and MC Sola-Visner Aims: 1) Identify a group of thrombocytopenic SGA neonates where the thrombocytopenia was not a readily apparent variety (Sepsis, ECMO, DIC, NAIT). 2) In that group (termed the thrombocytopenia of SGA ) to identify the incidence, nadir, severity, and duration of the thrombocytopenia, to determine whether it was more closely associated with preeclampsia vs. SGA status, to assess the responsible mechanisms, and to describe the outcomes.

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

NICU admissions during the 9-year period studied (n = 24,036) Not SGA (birth weight >10th %) (n = 20,072) SGA (birth weight <10th %) (n = 3,964) Not SGA, matched 1:1 with SGA infants (n=2,891) Had 2 platelet counts obtained during the first week (n = 2,891) Thrombocytopenic ( 2 counts <150,000/ L) (n = 287) 10.0% Thrombocytopenic ( 2 counts <150,000/ L) (n = 905) 31.5% Excluded from further analysis (n=102) ECMO (n=28)* Aneuploidy (n=30)* Early onset bacterial sepsis (n=6) Congenital marrow failure syndrome (n=4) CMV (n=6) Alloimmune (n=2) DIC (n=8) Multiple malformation syndromes (n=18) *Three had ECMO and also trisomy 21 Included as Thrombocytopenia of SGA (n = 803)

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Only moderate severity, nadir 4 days, have a count >150,000 by 13-15 days

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Thrombocytopenia does not appear to be associated with PIH, but with SGA status.

Thrombocytopenia may be more severe with more severe growth (weight) restriction.

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

MVP is similar to thrombocytopenias due to reduced platelet production (high MVP with accelerated platelet destruction).

Similar to thrombocytopenia of perinatal asphyxia, may be associated with intrauterine hypoxia.

Response to transfusion is similar to thrombocytopenia from reduced platelet production (poor response with accelerated platelet destruction).

Thrombocytopenia of SGA is likely the kinetic result of reduced platelet production, resulting from intrauterine hypoxia. Tpo deficiency? (3 of 3 cases)

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

OUTCOME - DEATHS Group Number Mortality Rate SGA No Thrombocytopenia SGA Thrombocytopenia 1986 905 2% 9% (p<0.0001 vs no thrombocytopenia) 65% (p<0.0001 vs all other groups) 102 Thrombocytopenia with known cause (ECMO, DIC, EOS) The Thrombocytopenia of SGA 803 2% Footnotes: All thrombocytopenic SGA neonates with DIC who died had bleeding problems at the time of death, predominantly pulmonary hemorrhage. None of those with trisomy 18 or 13 who died had bleeding problems.

OUTCOME SEVERE PERSISTENT THROMBOCYTOPENIA Ten SGA neonates had severe (<50K) thrombocytopenia that persisted for at least four weeks for which platelet transfusions were being administered. These 10 received 4 to 33 platelet transfusions. All but three transfusions were prophylactic for platelet counts in the range of 50,000 to 75,000/ L but with no signs of bleeding. Nine of these 10 were severely SGA (<1st % at birth).

Birth weight (g) SGA (%) Gestational age @ birth (wks/days) Maternal preeclampsia/ Lowest platelet count between four and six weeks (/ L) Number platelet transfusion s received Outcome eclampsia/ HELLP <1st 350 24/0 No 48,000 21 Died at 6 months in NICU Died at home at 7 months Died at home at 17 months Lived Lived Lived Lived <1st 406 22/6 HELLP 30,000 33 <1st 420 24/5 HELLP 23,000 31 <1st <1st <1st <1st 470 480 510 565 26/5 23/6 26/4 27/0 Eclampsia Preeclampsia Preeclampsia HELLP 40,000 38,000 36,000 47,000 8 11 8 10 <1st 580 27/1 No 10,000 16 Lived <1st 663 29/2 No 37,000 4 Lived

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Romiplostim Analog of thrombopoietin Developed by Amgen under the trade name Nplate FDA approved 2008 for long-term treatment for chronic ITP in adults who have not responded to other treatments. The wholesale cost of romiplostim if administered weekly (adults) is about $55,000 per year. IV or sub Q use only

Eltrombopag Small molecule agonist of the Thrombopoietin receptor Discovered as a result of research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals. FDA approved in 2008 for adults with ITP refractory to other treatments Oral preparation only File:Eltrombopag.svg

TPO-RECEPTOR AGONISTS 1)Not rapid-acting (10 days) 2)If severe persistent thrombocytopenia could be predicted in the first days after birth, would TPO-receptor agonists have advantages over platelet transfusion? 3)Cost of one apheresis pl transfusion $1300

Calculate the odds that severe thrombo- cytopenia will persist beyond 2 wks Predicted probability of platelet count < 50 @ 2 weeks 30% Male Gender . Gestation Age (weeks rounded down) Lowest Platelet Count in First 7 Days . 23 40

Outline 1.Early reports 2.What we DON T know 3.Nine-years of SGA neonates in the Intermountain Healthcare NICUs 4.Sorting out those with a recognized cause of thrombocytopenia from those with the Thrombocytopenia of SGA 5.Incidence, Nadir, Duration 6.Association with preeclampsia? 7.Kinetic cause & Value of platelet transfusions 8.Outcomes 9.Are any candidates for Romiplostim?

Take-Home Messages 1. 1/3 of SGA neonates will have early thrombocytopenia. 2. 10% of these will have a readily apparent cause (ECMO, DIC, EOS; high mortality rate 65%). 3. 90% will have the thrombocytopenia of SGA . 4. Low point = day 4. 5. Typically increase to >150,000 by 2 weeks. 6. Should not need platelet transfusions. 7. Most severe (<1%) are likely to have lower counts and longer durations. 8. Can t predict which will be severe and prolonged. 9. If still <50K, and receiving pl transfusions at 1 week, should we measure serum TPO and talk about studying Romiplostim?

Thrombocytopenia in SGA Neonates Thanks for your Kind Attention