1. Neonatal Thrombocytopenia
Suzanne Reuter MD
SDPA 2014
Deadwood, SD

2. Financial Disclosure
I have no relevant financial relationships to disclose.

3. Objectives Definition of thrombocytopenia
Understand the pathophysiology of neonatal alloimmune thrombocytopenia
Review bone marrow function as it relates to platelet production and release
Differential Diagnosis in a well, term infant
Differential Diagnosis in a sick, term infant

4. Neonatal Alloimmune Thrombocytopenia (NAIT)* * * * *

5. Neonatal Alloimmune Thrombocytopenia (NAIT)
Mom
Fetus * * *
Placenta * *

6. Neonatal Alloimmune Thrombocytopenia (NAIT)
Mom
Fetus * * *
Placenta * *

7. Would you treat the severe thrombocytopenia in NAIT?
a. Yes, the risk of bleeding is really high b. No, this condition will spontaneously resolve and the risk of bleeding is only a threat in premature infants. c. Depends on what the doctor wants to do

8. Would you treat the severe thrombocytopenia in NAIT?
a. Yes, the risk of bleeding is really high b. No, this condition will spontaneously resolve and the risk of bleeding is only a threat in the fetus and premature infants. c. Depends on what the doctor wants to do

9. Baby Lydia – 37 weeks Delivered with spontaneous cry. Apgars 8/9
Dried, suctioned, admitted to NBN
Initial platelet count of 177,000
Nadir 120,000 at 36 hr of age
Bili 48 hr of age

10. Baby ‘Lila’ – 37 weeks (No Tx)
Delivered with spontaneous cry. Apgars 8/9
Dried, suctioned, admitted to NICU
Initial platelet count of 8,000
PE: diffuse petechiae, bruising over lower extremities
Platelet transfusion 15 ml/kg
Administered intravenous immunoglobulin 1 gm/kg
Repeat platelet count 4 hours later 94,000
Platelet f/u 31,000
IVIG repeated x2 – normalization of platelet counts

11. Head Ultrasound – Day 1

12. Neonatal Alloimmune Thrombocytopenia (NAIT)
Develops in first pregnancy (unlike Rh sensitization)
Fetal platelet antigens form early in gestation
Maternal antibodies cross early 2nd trimester
Thrombopoietin level is normal
Megakaryocytes and platelets produced bind to it
Severely low platelet counts in the newborn
< 20,000 /microL
Normal maternal platelet count

13. Neonatal Alloimmune Thrombocytopenia (NAIT)
Most severe complication is intraventricular hemorrhage
Occurs in 10-20% of affected newborns
¼ - ½ occurs in utero

14. Neonatal Alloimmune Thrombocytopenia
Rate of recurrence in future pregnancies
75%-90%
As severe or more severe than previous
Fetal therapies
In utero platelet transfusions
Maternal therapies
IVIG
Corticosteroids

15. Which is the best treatment for thrombocytopenia in NAIT in the first 48 hr of life in an infant with a platelet count of 6,000 /microL?
a. Random donor platelet transfusion b. Washed maternal platelets c. Intravenous Immunoglobulin d. Methylprednisolone
**Remember 98% of Caucasians have HPA-1a on their platelets.
Washing maternal platelets takes hours to collect and process.

16. Which is the best treatment for thrombocytopenia in NAIT in the first 48 hr of life in an infant with a platelet count of 6,000 /microL?
a. Random donor platelet transfusion b. Washed maternal platelets c. Intravenous Immunoglobulin d. Methylprednisolone
**Remember 98% of Caucasians have HPA-1a on their platelets.
Washing maternal platelets takes hours to collect and process.

17. What is the definition of neonatal thrombocytopenia?
a. Platelet count < 100, 000/microL b. Platelet count < 50,000/microL c. Platelet count < 25, 000/microL d. Platelet count < 150, 000/microL

18. What is the definition of neonatal thrombocytopenia?
Platelet count < 150,000 /microL
Actually, platelet count < 5th percentile
5th percentile decreases with decreasing gestational age
34-36 weeks – 123, 100 /microL
32 weeks – 104, 200 /microL
J Perinatol. 2009;29(2):130

19. Definition Platelet count < 150,000/microL Ensure a central sample
Clumping with capillary specimens

20. Mechanisms of Thrombocytopenia
Increased destruction
Decreased production

23. The most likely physical symptom of neonatal thrombocytopenia is:
a. Petechiae
b. Bruising
c. Oozing from the umbilical cord
d. No symptoms

24. The most likely physical symptom of neonatal thrombocytopenia is:
No physical sign or symptom is the most likely presentation of isolated thrombocytopenia.
Petechiae, bruising, bleeding can be appreciated on physical exam

26. Treatment with which of the following medications increases the risk of thrombocytopenia in premature infants:
a. Quinidine
b. Digoxin
c. Indomethacin
d. Heparin
e. All of the above
Quinidine – antiarrythmic, blocks Na channels
Digoxin – cardiac medication used to slow the HR in CHF

27. Treatment with which of the following medications increases the risk of thrombocytopenia in premature infants:
a. Quinidine
b. Digoxin
c. Indomethacin
d. Heparin
e. All of the above
Quinidine – antiarrythmic, blocks Na channels
Heparin – immune and non immune mediated (nonimmune due to direct effect on plt activation) abnormal ab that activate platelets to clots and low plts
Digoxin – immune mediated

28. If maternal thrombocytopenia follows drug exposure and is mediated by IgG antibody, the Ab may cross the placenta and affect fetal platelets.
Indomethacin and Heparin have been implicated in neonatal thrombocytopenia.
Indomethacin – platelet dysfunction
Heparin – development of platelet antibodies

29. Thrombocytopenia in a Well, Term Newborn

30. Well, Term Newborn Maternal history
History of immune thrombocytopenic purpura (ITP) or systemic lupus erythematosus (SLE)?
Previous infant with thrombocytopenia or family history?
Any infections during pregnancy?
Drug/medication use during pregnancy?
History of HELLP, preeclampsia
What is mom’s platelet count?
Decreased -- may be autoimmune
Normal – may be autoimmune of alloimmune

31. (Auto)Immune Thrombocytopenia (1st and early 2nd trimester)
Antibodies coat platelets
When traversing the spleen, the platelets are “eaten” by splenic macrophages
At birth, infants have minimal splenic function
After birth, splenic function increases and risk of severe thrombocytopenia .

32. Splenic Function at Birth
Not functional at birth
Howell-Jolly bodies on smear – DNA remnants left over in RBC
Usually Howell-Jolly bodies removed on passage of RBC thru spleen

33. Immune Thrombocytopenia
Must follow neonate’s platelet levels closely after birth
Especially as splenic function improves
Monitoring the fetus during pregnancy and labor is no longer recommended

34. Which immunoglobulin does not cross the placenta?
a. IgA b. IgE c. IgM d. IgG

35. Which immunoglobulin does not cross the placenta?
a. IgA (300,000 D) b. IgE (190,000 D) c. IgM (900,000 D) d. IgG (150,000 D)
Which immunoglobulin will not cross the placenta due to size? IgM
IgE 190,000 MW
IgA 300,000
IgM 900,000
IgG 150,000

36. Gestational Thrombocytopenia
Mild and asymptomatic thrombocytopenia
No past history of thrombocytopenia (except possibly during a previous pregnancy)
Occurrence during late gestation
No association with fetal thrombocytopenia
Spontaneous resolution after delivery

37. Gestational Thrombocytopenia
Considered benign
Mild and transient ITP?
Less antibodies compared to ITP
No thrombocytopenia in neonate
To make the diagnosis:
Thrombocytopenia not severe
Occurs during last part of pregnancy/term
Platelet count returns to normal after pregnancy
Infant’s platelet count is normal

38. The Placenta May reveal: Congenital infection (CMV, syphilis)
Vasculopathy (Preeclampsia)
Hemorrhage
Infarcts
Thrombi
Vascular malformations
Placenta with syphilis – acute/chronic villitis, spirochetes noted on stain
CMV, Herpes – viral inclusions noted with special stains

39. Maternal Pre Eclampsia
Estimated 1 in 100 births
Thrombocytopenia, neutropenia in newborns
Decreased production
Neutrophil, platelet inhibitor
Present at birth
Nadir is 2-4 days of age

40. Thrombosis If you cannot explain thrombocytopenia, evaluate for clot
Infants with RVT , more likely to have inherited prothrombotic condition like: factor V Leiden mutation, protein C and S deficiency, methylenetetrahydrofolate reductase (MTHFR) mutation, and elevation of lipoprotein

41. Thrombocytopenia in a Sick, Term Newborn

42. Birth Asphyxia
True mechanism is unknown
May relate to hypoxia

43. Bacterial Infection Mechanism Disseminated intravascular coagulation
Platelet aggregation caused by bacterial products on platelet membranes
Injury to megakaryocytes too
Megakaryocyte – giant cell in bone marrow which produces plt

44. Congenital Infection Most common: Others: Cytomegalovirus (CMV)
Toxoplasmosis
Herpes
Rubella

46. Disseminated Intravascular Coagulation
Systemic process producing:
Thrombosis
Hemorrhage
Characterized by:
Prolonged protime (PT)
Prolonged activated partial thromboplastin time (PTT)
Decrease in fibrinogen
Increase in fibrin split products or D-Dimers
Decreased platelets
Prolonged PT and this INR
Fibrinogen – Factor 1 (fibrinogen to fibrin which is a clot)
FSP/Ddimer : a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis
Preterm infants have hyporeactive plat compared to term infants.

47. Disseminated Intravascular Coagulation
Due to
Sepsis
Asphyxia (acidosis)
Meconium aspiration
Severe respiratory distress syndrome

48. Syndromes with Thrombocytopenia

49. Thrombocytopenia, Absent Radii (TAR)

51. Kasabach-Merritt Syndrome
Capillary Hemangiomas
DIC
Thrombocytopenia
Shortened platelet survival
Sequestration in vascular malformation
Tx is pred, vincristine, cyclophosphamide
**abnormal endothelium and convoluted architecture of the tumor vasculature promote platelet adhesion and trapping [12]. Platelet aggregation and activation result in thrombocytopenia, consumption of fibrinogen, and ongoing fibrinolysis, leading to intralesional bleeding and tumor enlargement

52. Wiskott-Aldrich Syndrome
X-linked
MPV (mean platelet volume) 3-5 fL (nl 7-10)
Immunodeficiency
Thrombocytopenia
Eczema
Thrombocytopenia with small platelets
This condition primarily affects males.
WBC are nonfunctional
fL =metric unit of volume equal to 10−15 (femtoliter)

53. Summary Points Neonatal Thrombocytopenia
Platelet levels < 150,000
Neonatal Alloimmune Thrombocytopenia
Severely low fetal platelet levels
Maternal platelet value – normal
Obtain a good accurate specimen
Central specimen

55. References NeoReviews Vol. 14 No. 2 February 1, 2013, pp. e74 -e82
Incidence and Consequences of Neonatal Alloimmune Thrombocytopenia: A Systematic Review. Pediatrics Mar 3.
Neonatal Thrombocytopenia, Up to Date 2014.
Wiedmeier SE, Henry E, Sola-Visner MC, Christensen RD, SO. J Perinatol. 2009;29(2):130