Thrombocytopenia in SGA Neonates Israel Neonatology AssociationRobert Christensen, MD.

Thrombocytopenia in SGA Neonates Israel Neonatology AssociationRobert 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?

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 <10 th % who, with no other explanation, had one or more platelet count <100,000/µL in the first days after birth. Counts typically increased to >150,000/µL 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 Scand 1983:72;139-140 14 SGA with one or more platelet count <100,000/µL 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.

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 ?

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.

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. Thrombocytopenia Among Small for Gestational Age Infants RD Christensen, VL Baer, E Henry, GL Snow, A Butler, and MC Sola-Visner

NICU admissions during the 9-year period studied (n = 24,036) SGA (birth weight <10 th %) (n = 3,964) Thrombocytopenic (≥ 2 counts <150,000/µL) (n = 905) 31.5% Had ≥2 platelet counts obtained during the first week (n = 2,891) Not SGA (birth weight >10 th %) (n = 20,072) Thrombocytopenic (≥ 2 counts <150,000/µL) (n = 287) 10.0% Not SGA, matched 1:1 with SGA infants (n=2,891) Included as “Thrombocytopenia of SGA” (n = 803) 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

Only moderate severity, nadir 4 days, ½ have a count >150,000 by 13-15 days

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

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

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)

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 - DEATHS GroupNumberMortality Rate SGA No Thrombocytopenia19862% SGA Thrombocytopenia9059% (p<0.0001 vs no thrombocytopenia) Thrombocytopenia with known cause (ECMO, DIC, EOS) 10265% ( p<0.0001 vs all other groups) The “Thrombocytopenia of SGA” 8032%

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/µL but with no signs of bleeding. Nine of these 10 were severely SGA (<1 st % at birth). OUTCOME – SEVERE PERSISTENT THROMBOCYTOPENIA

Birth weight (g) SGA (%) Gestational age @ birth (wks/days) Maternal preeclampsia/ eclampsia/ HELLP Lowest platelet count between four and six weeks (/µL) Number platelet transfusion s received Outcome 350<1 st 24/0No48,00021Died at 6 months in NICU 406<1 st 22/6HELLP30,00033Died at home at 7 months 420<1 st 24/5HELLP23,00031Died at home at 17 months 470<1 st 26/5Eclampsia40,0008Lived 480<1 st 23/6Preeclampsia38,00011Lived 510<1 st 26/4Preeclampsia36,0008Lived 565<1 st 27/0HELLP47,00010Lived 580<1 st 27/1No10,00016Lived 663<1 st 29/2No37,0004Lived

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

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

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

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

Thrombocytopenia in SGA Neonates Israel Neonatology AssociationRobert Christensen, MD.

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