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Year : 2019  |  Volume : 8  |  Issue : 3  |  Page : 186-188

Neonatal thrombosis after antenatal treatment of neonatal alloimmune thrombocytopenia with intravenous immunoglobulin

1 Division of Pediatric Cancer and Blood Disorders; Department of Pediatrics, Atrium Health, Levine Children's Hospital, Charlotte, NC, USA
2 Department of Pediatrics; Division of Neonatology, Atrium Health, Levine Children's Hospital, Charlotte, NC, USA

Date of Web Publication6-Aug-2019

Correspondence Address:
Dr. Ashley R. P Hinson
1001 Blythe Blvd., MCP Suite 601, Charlotte, NC 28203
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_44_19

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Neonatal alloimmune thrombocytopenia (NAIT) may lead to serious complications, including perinatal intracranial hemorrhage and death. Mothers with a history of previously affected pregnancies should receive antenatal treatment with intravenous immunoglobulin (IVIG), which can be associated with toxicities including thrombosis. An infant born to a mother treated with IVIG and steroids was diagnosed with an inferior vena cava thrombus shortly after birth, was anticoagulated and recovered. Thus, this side effect can be seen, and should be considered, in infants of NAIT-affected pregnancies treated with IVIG.

Keywords: Intravenous immunoglobulin, neonatal alloimmune thrombocytopenia, neonatal thrombosis

How to cite this article:
Hinson AR, Saxonhouse M. Neonatal thrombosis after antenatal treatment of neonatal alloimmune thrombocytopenia with intravenous immunoglobulin. J Clin Neonatol 2019;8:186-8

How to cite this URL:
Hinson AR, Saxonhouse M. Neonatal thrombosis after antenatal treatment of neonatal alloimmune thrombocytopenia with intravenous immunoglobulin. J Clin Neonatol [serial online] 2019 [cited 2020 Feb 26];8:186-8. Available from: http://www.jcnonweb.com/text.asp?2019/8/3/186/264040

  Introduction Top

Neonatal alloimmune thrombocytopenia (NAIT) is a common cause of neonatal thrombocytopenia. Incompatibilities between maternal and fetal platelet antigens cause destruction of fetal platelets, which can lead to intracranial hemorrhage (ICH).[1],[2] To prevent this complication, antenatal treatment of affected mothers is recommended with intravenous immunoglobulin (IVIG), which has been associated with thrombosis. We present an infant diagnosed with an inferior vena cava (IVC) thrombus after his mother received IVIG during pregnancy. To our knowledge, this represents the first reported case of this complication.

  Case Report Top

The infant was born at 33- and 6/7-week gestation by elective cesarean section to a G3, serology-negative mother. A prior pregnancy was affected by NAIT, resulting in ICH and neonatal death. Thus, during this pregnancy, the mother received IVIG 2 g/kg twice weekly beginning at 12-week gestation, with prednisone per obstetrician discretion. She also received packed red blood cells 2 weeks before delivery for anemia. Prenatal ultrasound of the infant was abnormal for ascites and possible right hydronephrosis. At birth, the baby was vigorous, with Appearance, Pulse, Grimace, Activity, and Respirations of seven and eight at 1 and 5 min, respectively. On examination, the infant had a palpable right-sided abdominal mass. The infant's initial complete blood count demonstrated a platelet count of 48 × 103/μL and a hemoglobin of 17.4 g/dL with negative coombs. The infant had no bleeding, bruising, or petechiae on examination. Cranial ultrasound showed no hemorrhage. Due to the infant's prenatal ultrasound and examination findings, an abdominal ultrasound was performed that identified a nonocclusive thrombus within the IVC, extending into the right renal vein, with increased size and parenchymal echogenicity of the right kidney. The infant was given IVIG 1 g/kg for the treatment of NAIT, and the platelet count improved. The infant was then started on enoxaparin anticoagulation for the extension of thrombus. A therapeutic anti-xa level of 0.5–1 was reached, and the infant was treated for 2 months until complete thrombus resolution. The infant experienced no adverse bleeding and his kidney function was normal. Family history was negative for both thromboses and thrombophilia. The infant's thrombophilia evaluation was completed by 2 years of age and was negative for anti-thrombin III, protein C, and protein S deficiencies; homocystinuria; factor V leiden; and prothrombin 20210A mutations. The child is now healthy and active, with normal platelet counts and no evidence of thrombus recurrence.

  Discussion Top

Although infection accounts for most cases, NAIT is one of the most common causes of severe neonatal thrombocytopenia, occurring in 1/800–2000 live births.[3] NAIT results from maternal–fetal platelet antigen incompatibility, most commonly human platelet antigen (HPA)-1a, resulting in formation of maternal alloantibodies.[1] These antibodies cross the placenta through FcRn binding, causing destruction of fetal platelets and damage to endothelial cells.[4] Affected infants have varying severities of thrombocytopenia and are at risk for minor to severe/fatal bleeding (ICH).

Workup for suspected NAIT includes HPA genotyping of the mother and father and evaluating for anti-HPA antibodies in maternal serum.[4] If confirmed or suspected, neonatal treatment in severely thrombocytopenic babies includes close monitoring with cranial ultrasound and treatment with platelet transfusions and IVIG.[5] In mothers with a previous affected pregnancy and/or infant, antenatal management of all future pregnancies is recommended. It is difficult to predict severity of NAIT in subsequent pregnancies. High anti-HPA-1a titers are associated with severe disease, but severely affected neonates with very low antibody levels also exist.[6] The most reliable predictor for disease severity is ICH in previous pregnancies. Thus, antenatal treatment with IVIG and/or steroids is generally recommended. According to a Cochrane analysis, 97%–98% of ICH can be prevented with antenatal use of IVIG alone.[7],[8] Standard risk pregnancies should begin IVIG at 0.5 g/kg/week at 24 weeks of gestation; those deemed high risk (by history of previous infant/fetus with ICH) receive IVIG at an earlier and higher dose, 1 g/kg/week beginning at 12–16 weeks, as platelet antigens are first expressed in the fetus at 16 weeks' gestation.[4] Some centers add prednisone to IVIG therapies; this improved platelet counts in one study but has shown no significant differences to IVIG alone in others.[7]

IVIG is a blood product of pooled human plasma, used for numerous clinical entities including immunodeficiencies and autoimmune conditions. Its use in immune-mediated diseases, such as NAIT, relies on IVIG's effect on antibodies, complement activation, cytokines, and macrophage receptors.[9] The infusion is generally well tolerated, but has potential toxicities. These range from mild fever to more serious acute renal failure and thrombosis.[9] The risk of IVIG-associated thrombosis is estimated to be 1%–16% depending on patient population, with the majority of data from adults. IVIG-related thrombus in pediatric patients with immune thrombocytopenia is rare with only six reported cases, with the youngest reported at 3 years old.[10] Thus, thrombosis after IVIG is rare in pediatrics. Patient characteristics which increase thrombotic risk include prior thrombus, immobilization, hereditary thrombophilia, presence of central lines, and certain medications. Higher doses of IVIG at 1–2 g/kg/day and faster infusion times also seem to increase thrombotic risk. Concomitant steroid administration may further increase thrombotic risk through platelet activation and fibrinolysis inhibition.[9] Proposals for mechanism of IVIG-induced thrombosis include: High protein load leading to increased blood viscosity, increase in platelet count and/or platelet aggregation, cytokine changes which activate complement, and increase in vasoconstrictive cytokines.[9] In this patient, we believe thrombosis resulted from repeat exposure to high-dose IVIG and concomitant steroids in utero.

In summary, we present an infant with prenatal ultrasound abnormalities, followed by an IVC thrombus at birth, believed to be secondary to recurrent doses of high-dose IVIG with combination steroids given prenatally to the mother. NAIT is a common cause of severe neonatal thrombocytopenia, which can result in potentially fatal ICH. Repeated doses of maternal IVIG decrease the risk of neonatal ICH, but can be given in a risk-stratified fashion (low-dose IVIG [0.5 g/kg/week] starting later in pregnancy in low-risk mothers and high-dose IVIG [1 g/kg/week] starting at 12–16 weeks gestation in high-risk mothers). As prednisone has not shown clear additional benefit and may contribute to thrombotic risk, clinicians should consider carefully before concomitant use. Further, as pregnant women have additional thrombotic risk factors due to the inherent high estrogen state of pregnancy, clinicians should remain vigilant about the possibility of thrombus formation in the mother or infant while using IVIG.

IRB approval for consent waiver has been obtained at our institution.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Brojer E, Husebekk A, Dębska M, Uhrynowska M, Guz K, Orzińska A, et al. Fetal/Neonatal alloimmune thrombocytopenia: Pathogenesis, diagnostics and prevention. Arch Immunol Ther Exp (Warsz) 2016;64:279-90.  Back to cited text no. 1
Kamphuis MM, Paridaans NP, Porcelijn L, Lopriore E, Oepkes D. Incidence and consequences of neonatal alloimmune thrombocytopenia: A systematic review. Pediatrics 2014;133:715-21.  Back to cited text no. 2
Kjeldsen-Kragh J, Killie MK, Tomter G, Golebiowska E, Randen I, Hauge R, et al. Ascreening and intervention program aimed to reduce mortality and serious morbidity associated with severe neonatal alloimmune thrombocytopenia. Blood 2007;110:833-9.  Back to cited text no. 3
Winkelhorst D, Oepkes D, Lopriore E. Fetal and neonatal alloimmune thrombocytopenia: Evidence based antenatal and postnatal management strategies. Expert Rev Hematol 2017;10:729-37.  Back to cited text no. 4
Winkelhorst D, Oostweegel M, Porcelijn L, Middelburg RA, Zwaginga JJ, Oepkes D, et al. Treatment and outcomes of fetal/neonatal alloimmune thrombocytopenia: A nationwide cohort study in newly detected cases. Br J Haematol 2019;184:1026-9.  Back to cited text no. 5
Ghevaert C, Campbell K, Stafford P, Metcalfe P, Casbard A, Smith GA, et al. HPA-1a antibody potency and bioactivity do not predict severity of fetomaternal alloimmune thrombocytopenia. Transfusion 2007;47:1296-305.  Back to cited text no. 6
Winkelhorst D, Murphy MF, Greinacher A, Shehata N, Bakchoul T, Massey E, et al. Antenatal management in fetal and neonatal alloimmune thrombocytopenia: A systematic review. Blood 2017;129:1538-47.  Back to cited text no. 7
Rayment R, Brunskill SJ, Stanworth S, Soothill PW, Roberts DJ, Murphy MF. Antenatal interventions for fetomaternal alloimmune thrombocytopenia. Cochrane Database Syst Rev 2005. p. CD004226.  Back to cited text no. 8
Dalakas MC, Clark WM. Strokes, thromboembolic events, and IVIg: Rare incidents blemish an excellent safety record. Neurology 2003;60:1736-7.  Back to cited text no. 9
Park KM, Yang EJ, Lim YT. Dural venous sinus thrombosis and pulmonary embolism following immunoglobulin treatment in pediatric patient with immune thrombocytopenic purpura. J Pediatr Hematol Oncol 2017;39:e508-11.  Back to cited text no. 10

This article has been cited by
1 Immune-globulin/prednisone
Reactions Weekly. 2019; 1770(1): 208
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