Isoimmune Hemolytic Anemia and Thrombocytopenia

Catherine M. Bendel, MD
Assistant Professor, Department of Pediatrics, Division of Neonatology

I. Rh Hemolytic Anemia

• Pathogenesis: Preceding lecture
• Clinical Presentation:
  • Hydrops fetalis
  • Jaundice (<24o)
  • Pallor
  • Hepatospenomegaly
  • Petechiae/purpura
  • Early vs Late
    
• Laboratory Findings:
  • Decreased hemoglobin (<13gm/dl)
  • Increased recticulocyte (>6%)
  • Increased nucleated RBC on peripheral smear
  • Spherocytes not present
  • Positive direct Coombs' test
  • Indirect hyperbilirubinemia
    
• Treatment: PREVENTION!!!!!
  • Immediate assessment of the severity of the disease
  • Cord- hemoglobin<10.5gm/dl, bilirubin>4.5mg/dl
  • Exchange transfusion
  • Phototherapy
  • Close follow-up of possible ongoing anemia

II. ABO Hemolytic Disease

• Pathogenesis:
  • Hemolysis secondary to the presence of maternal anti-A or anti-B antibodies.
  • Incidence = 20% of all pregnancies associated with ABO incompatability, but very few infants symtomatic.
  • Fewer A or B antigenic sites are present on neonatal erythrocytes, resulting in: weakly reactive Coombs' less hemolysis
    
• Clinical Presentation: Jaundice (<24h)
  
• Laboratory Findings:
  • Indirect hyperbilirubinemia
  • An A or B baby of an O mother
  • Increased reticulocyte count
  • Spherocytes present
  • ± anemia
  • ± Coombs' test
    
• Treatment:
  • Phototherapy
  • Hydration
  • Exchange transfusion

NEONATAL ALLOIMMUNE/ISOIMMUNE THROMBOCYTOPENIA

• 3100 g, 37 GA, white male infant born by repeat C/S
• Noted in the DR to have "bruises and petechiae over his entire body".

• Maternal History:
  • 28 year old, O positive, G4, P2-0-1-2, married caucasian female.
  • Consanguinity, she and her husband are "second cousins".
  • 1985 - First pregnancy - C/S delivery (secondary to FTP) of a full term 7 pound male who is alive and well.
  • 1986 - Second pregnancy - Repeat C/S delivery of a full term 7 pound, 5 ounce male infant. Transported to the University of MN for DIC and thrombocytopenia at birth. He also had hydrocephalus secondary to a large porencephalic cyst which required placement of a VP shunt. He was given the diagnosis of congenital CMV. He is alive and living at home with significant developmental delays and a chronic seizure disorder.
  • 1990 - Third pregnancy - spontaneous abortion at 10 wks GA.
  • 1991 - Fourth pregnancy - case presentation.
    
• Prenatal History:
  • Unremarkable by report.
  • Rubella immune, serology negative, antibody screen negative.
  • No alcohol, tobacco, illicit or prescription drug use (PNV only).
  • Fetal ultrasound at 10-11 weeks gestation revealed no abnormalities.
    
• Labor and Delivery:
  • SROM five hours prior to delivery with clear amniotic fluid.
  • Repeat C/S, maternal platelet count 180,000.
  • Apgar scores of 5 and 7 at one and five minutes, respectively.
  • He was noted to be cyanotic with petechiae and purpura covering his entire body - UMHC called for transport.
    
• Transport:
  • On arrival of the transport team he was noted to have diffuse petechiae and purpura, as well as macrocephaly and respiratory distress requiring 60% FiO2 for saturations > 90%.
  • CXR showed a possibly enlarged heart with pulmonary congestion.
  • ABG = 6.92/ 44/ 27/ 9.
  • Sodium bicarbonate administered and he was intubated.
  • ABG = 7.37/ 19/ 76/ 11.
  • Dopamine and Dobutamine drips started.
  • Hgb = 11.9, WBC = 14.8 K (37%N, 5%B, 8%E, 1%Bas, 38%L,1%M).
  • Plt = 12, 000.
  • PT = 14.7 and PTT = 29.5.
  • Transfusions of platelets and PRBCs given prior to transport.
  • Plt = 160,000
  • Serum glucose = 120 mg%.
  • Blood cultures obtained; ampicillin and gentamicin given.
  • Transported without incident.
    
• Physical Exam:
  • PE consistent with a 37 week GA , male.
  • 3270 grams (50-75 %tile), OFC = 38.5 cm (> 2 S.D.)
  • Diffuse petechiae and purpura.
  • HEENT: AF and PF both large and tense; Coronal and sagittal sutures widely split;bilateral scleral hemorrhages; PERRL
  • Chest: Clear and equal breath sounds without rales
  • CV: Grade 2-3/6 systolic murmur at LSB, pulses palpable in all extremities, but weak; perfusion and BP good on inotropes
  • Abdomen: Soft and nontender without masses, liver 3cm below the RCM and the spleen tip was palpable
  • GU: Normal male, both testes descended
  • Neuro: Alert, responsive, MAE, increased tone, palmar and plantar grasp present with symmetric Moro; lusty cry by report prior to intubation. However, he demonstrated abnormal jerky movements of his UE suspected to be seizures.
    
• Laboratory Studies:
  • Plt = 55,000
  • Pt = 19.3, PTT = 48.7, TT = 29.4, fibrinogen = 0.08
    
• Diagnostic Studies:
  • Cranial ultrasound on admission revealed massive bilateral ventriculomegaly ( R>L) with a large posterior porencephalic cyst on the right, multiple small cysts on the left and an intraparenchymal hemorrhage on the right. Very little normal brain tissue was present.
  • EEG revealed multifocal seizures with a marked abnormal background pattern.
  • Echocardiogram revealed severe left ventricular hypoplasia with aortic and mitral atresia, hypoplasia of the aorta and partial anomalous pulmonary venous return.
  • Maternal blood tests revealed that she was PlA1 negative with circulating PlA1 antibodies. Paternal platelets were PlA1 positive.
  • Chromosomes were normal, 46 XY.
  • All bacterial and viral cultures were negative, as well as all viral titers obtained.
    
• Management:
  • PlA1 negative platelet transfusions.
  • FFP and cryoprecipitate to correct the coagulopathy.
  • Consultations with Pediatric cardiology, neurology and genetics.
  • Given the severity of the multiple anomalies present, the parents elected to discontinue support of this infant and he died shortly after extubation.

• History:
  • Maternal platelet count normal
  • Previous child with thrombocytopenia at birth and antenatal intracranial hemorrhage resulting in hydrocephalus
    
• Physical Exam:
  • AGA
  • Hydrocephalus (porencephalic cysts)
  • Petechiae and purpura
  • HSM
  • Active bleeding
    
• Laboratory DATA:
  • Severe thrombocytopenia
  • Anemia
  • Prolonged coags
  • Decreased fibrinogen
  • Increased FDP
  • Peripheral smear
    
• Additional Studies:
  • TORCH evaluation
  • Blood cultures
  • Parental anti-platelet antibody studies
  • ?? Bone marrow ??
    
• Pathophysiology:
  • Maternal antibodies directed against paternal platelet antigens cross the placenta and destroy fetal platelets expressing the paternal antigen. (Platelet equivalent of Rh disease)
  • PlA1 antigen incompatibility responsible for at least 50% of cases. (Maternal platelets PLA1- and paternal platelets PlA1+
  • 1-3% of the population PlA1-
  • Polymorphism affecting the PLA (HPA-1) antigen resulting from a change from cytosine196 to thymine196 in the platelet glycoprotein IIIA gene. This results in a substitution of proline for leucine33.
  • Other antigen systems that may result in this disease include Bak, Br, and Pen/Yuk.
    
• Clinical Presentation:
  • Incidence = 1/1000 births
  • Bleeding
    • Most commonly petechiae and purpura
    • Intracranial hemorrhage in 10-20% cases (As many as 50% occurring antenatally)
  • Thrombocytopenia
    • Often severe; Documented prenatally as early as 18-20 weeks
    • No sustained rise in platelet count following a random donor transfusion.
  • ± DIC
  • >75% recurrence with subsequent pregnancies
  • Overall 85-95% for PlA1- mothers. However, the specific risk for any individual is based upon the paternal phenotype. For a heterozygous father (PlA1/PlA2) the recurrence rate is 50%, while it is 100% if the father is homozygous for PlA1.
  • The degree of thrombocytopenia and severity of complications in subsequent infants is usually as severe as in the preceding affected sibling, or worse.
• Management:
  • Neonate:
    • Treatment indicated for infants with plt < 30-50,000 or evidence of bleeding.
    • Definitive therapy = transfusion of platelets lacking the target antigen. (i.e. washed maternal platelets or banked PlA1 negative platelets)
    • Intravenous gamma globulin.
    • Corticosteroids not proven to be effective.
    • Address coagulopathy, neurologic status and other complications as indicated per case.
  • Fetus:
    • Classical = Cesarean section delivery
    • Experimental =
      • Intrauterine transfusion of washed maternal platelets.
      • Prenatal maternal treatment with intravenous gamma globulin.
  • Subsequent Pregnancies:
    • Paternal platelet phenotyping (homozygous vs heterozygous).
    • Good genetic counseling (including notification of mother's sisters).
    • Careful prenatal monitoring.
    • Atraumatic delivery.
    • Availability of PlA1 negative platelets for neonate.

REVISED 3/96

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REVISED 8/97