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NEONATAL THROMBOCYTOPAENIA

NEONATAL THROMBOCYTOPAENIA. History. Baby DP, white male B orn 30 March 2011 (now 5 weeks old) Normal vaginal delivery Birth weight 2830g Length 45cm Head circumference 33cm APGARS 8/10, 9/10, 10/10 Given oxygen via face mask at delivery, but no need for resuscitation. Mother.

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NEONATAL THROMBOCYTOPAENIA

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  1. NEONATAL THROMBOCYTOPAENIA

  2. History • Baby DP, white male • Born 30 March 2011 (now 5 weeks old) • Normal vaginal delivery • Birth weight 2830g • Length 45cm • Head circumference 33cm • APGARS 8/10, 9/10, 10/10 • Given oxygen via face mask at delivery, but no need for resuscitation

  3. Mother • 21 years old • Apparently 32 weeks pregnant by dates, but unsure of dates, birthweight suggests closer to term • Primigravida • Rhesus positive, RPR negative, HIV negative • Had a ?pustular rash throughout pregnancy, otherwise well during pregnancy • No medications taken other than routine vitamins, folate

  4. Intern called to see baby on Day 1 of life for a ‘rash’ on the body • On examination • Baby looked like a term neonate by Ballard score • Pink in room air • No distress • Not obviously dysmorphic • Petechial rash over trunk, arms, legs • Bruising on trunk (right upper quadrant), palms and soles • Rest of examination noted to be normal • Assessment • Term male neonate with a suspected clotting abnormality/ bleeding tendency presenting on Day 1 of life • Mother not known to be hypertensive or diabetic, no history of perinatal asphyxia

  5. Investigations • FBC • White cell count 22.35 • Haemoglobin 18.2 • Platelet count 10(not clumped) • MCV 112.4 • Platelet volume normal • INR, PTT • 1.26, 39.9 (normal)

  6. Mother’s results • FBC (31/03/2011) • WCC 20.8 • Hb 12.0 • Plts 293 (normal)

  7. Management and course • Admitted to neonatal ward • Antibiotics, Vitamin K • Platelet (random donor) infusion ordered immediately • Cranial sonar (1 April 2011) showed possible intracerebral haemorrhage • CT brain confirmed a haemorrhage in right frontal lobe (suspected to be about a week old already)

  8. Baby developed jaundice on day 3, phototherapy started, resolved quickly • No seizures in ward • Blood cultures remained negative • CRP, U&E day 3 unremarkable • Fed well • Gained weight (latest 3.36kg) • Much later noted to have abnormal ‘webbed’ toes on left foot – Xrays taken – showed polydactyly of middle and terminal phalanx 5th and 6th toes

  9. Platelet count trend

  10. Expert advice sought • Oncologists(08/04) • Considered alloimmune thrombocytopenia • Suggested testing mother for HPA-1a antibodies • Advised IVIG (intravenous immunoglobulin) if platelets not improving • Plasma serum screen for antibodies to platelet glycoproteins GPIIb/IIIa, GPIa/IIa and GPIb/IX and platelet antigens HPA 1a, -Ib, -3a, -3b, -4a, -5a and -5b: • NEGATIVE • Plasma serum screen for HLA Class I antibodies: • NEGATIVE

  11. Oncologist (21/04) • May be false negative results • Advised to test father’s blood also • Give normal platelets again, but would need specific platelets in near future • Consider steroids • lood • Head of SA National Blood Transfusion Service • Unusual to have no antibodies on screen performed if alloimmune thrombocytopenia • AIT unlikely • Not for HPA-1a negative platelets as diagnosis not confirmed • Head of Neonatal ICU • Try steroids • HPA-1a negative platelets/ mother’s platelets

  12. Other results • Urine CMV Shell vial culture – negative • HIV negative • Rubella serology – IgG positive, IgM negative – suggestive of maternal antibodies • Xrays long bones – no periosteal reactions or features of congenital infections (rubella, syphilis) • Xray skull – no calcifications noted suggestive of CMV, Toxoplasmosis

  13. Platelet production • Process similar in neonates and adults • Important developmental differences • Tpo concentrations higher in neonate • But neonates with thrombocytopenia have lower Tpoconcentrations than adults with similar degrees of thrombocytopenia • Megakaryocyte progenitors have higher proliferative potential, more sensitive to Tpo, and are present in BM and blood • Each megakaryocyte produces fewer platelets (smaller) • Can increase number of megakaryocytes

  14. Neonatal Thrombocytopenia (NT) • Relatively common haematological problem in neonates • Defined as count < 150 x 10⁹/L • Occurs in 1-5% of all newborns • Depends on population – sick prems, ICU – more common (22-35% of all admissions) • Most have mild-moderate thrombocytopenia • 5-10% - severe (<30 x10⁹/L) • urgent investigation and management needed • List of causes • Until recently many called “idiopathic” • Reduced platelet production main underlying mechanism • Newer classifications based on timing of onset

  15. Classification based on timing of onset(more common causes) Early (< 72 hours) Late (> 72 hours) Late-onset sepsis NEC Account for >80% cases • Placental insufficiency (IUGR, PIH) • Perinatal asphyxia • Perinatal infection (GBS, E coli) • DIC • Alloimmune(severe NT) • Autoimmune (ITP, SLE)

  16. Less common causes Early Late Congenital infection Kasabach-Merritt syndrome Metabolic disease Congenital/ inherited Autoimmune • Congenital infection (TORCH) • Kasabach-Merritt syndrome • Metabolic disease • Congenital/ inherited (TAR, CAMT) • Thrombosis • Bone marrow replacement

  17. Fetal causes • Alloimmune • Autoimmune • Congenital infection • Aneuploidy • Severe Rhesus disease • Congenital/ inherited

  18. Classifying causes helps guide towards investigations and management • Often a dilemma – when to transfuse platelets? • Variation in platelet transfusion practice between centres • No study has yet shown benefit of platelet transfusion in NT • Possibly even adverse effects – increased mortality, increased risk of short-bowel syndrome in transfused neonates surviving NEC

  19. Chronic fetal hypoxia • Occurs in infants of mothers with PIH (pregnancy-induced hypertension), diabetes • Manifest in fetus by IUGR • Mild-moderate thrombocytopenia • Self-limiting, usually resolves within 10 days • Mechanism • Reduced megakaryopoeisis • Associated neutropenia, increased circulating nucleated red cells, +/- polycythaemia • Tpo normal/ only minimally elevated – inadequate up-regulation of Tpo production • If severe/ not resolving after 2 weeks, look for other causes of thrombocytopenia

  20. Sepsis, NEC • Thrombocytopenia develops very rapidly over 1-2 days • Often very severe (< 30 x 10⁹/L) • May recover over weeks • Uncommon causes of NT in first few days of life • Mechanism – peripheral consumption • Elevated levels of Tpo • Increased numbers of circulating megakaryocyte progenitors • Actually up-regulation of thrombopoiesis

  21. Neonatal Autoimmune Thrombocytopenia • Transplacental passage maternal platelet auto-antibodies • Maternal platelets low • Immune thrombocytopenic purpura, SLE • 1-2:1000 pregnancies • Much less clinically problematic than NAIT • thrombocytopenia only occurs in 10% of those with auto-antibodies • Incidence of ICH only 1% • Caesarean section not indicated • Maternal disease severity, thrombocytopenia, previous severe NT most useful indicators of likelihood of significant NT in current pregnancy

  22. Infant of mother with AI disease • Platelet count checked at birth (cord/peripheral blood – NOT heel-prick) • If >150 x 10⁹/L – no further action • If platelet count low – repeat after 2-3 days – drop to lowest at this time, then rise spontaneously by day 7 • Thrombocytopenia may persist for several weeks in few cases – if severe (< 30)/ prolonged, treat with IVIG – most respond promptly

  23. Congenital infections • HIV, CMV, enterovirus, Rubella can cause NT • HIV • Immune-mediated destruction • Sequestration • Suppression of production, though increased megakaryocytes (ineffective thrombopoiesis) • CMV • Quite common • Thrombocytopenia 50-75% of cases • Massive splenomegaly causes sequestration • Decreased production

  24. Inherited thrombocytopenia • Numerous, rare • Present in fetus/neonate • Unexplained, persistent thrombocytopenia • due to reduced platelet production • Due to abnormal haemopoeiticstem cell development • Often associated congenital abnormalities > guide investigations, diagnosis • Advances in molecular techniques aid in diagnosis and management

  25. Bernard-Soulier Syndrome • May present in neonatal period though bleeding not usually severe • Mild-moderate thrombocytopenia • Giant platelets • AR pattern of inheritance • Defect in glycoprotein Ib-IX-V complex • Platelet transfusion effective, but reserve for life-threatening haemorrhage • Transfused patients may form allo-antibodies to GPIb, GPIX, GPV • Offspring of mothers with BSS may present as NAIT with severe fetal ICH • due to formation of such allo-antibodies

  26. Blood film showing giant platelets

  27. Wiskott-Aldrich Syndrome • WAS, X-linked thrombocytopenia spectrum of disorders • Mutation in WAS protein gene, short arm X chromosome • Over 100 different mutations • Microthrombocytopenia, eczema, recurrent bacterial, viral infections, propensity to autoimmune conditions • Present in first year, rarely neonatal period unless known family history • Bleeding due to abnormal platelet function and reduced platelet survival, number • X-linked thrombocytopenia – other clinical features absent, thrombocytopenia milder

  28. Fanconi Anaemia • Usually presents after infancy, but thrombocytopenia reported in neonates • Result of a genetic defect in a cluster of proteins responsible for DNA repair • Consider diagnosis • Unexplained thrombocytopenia • Especially if typical dysmorphic features – malformations of skin, thumb, face, eyes • If parental consanguinity • Diepioxybutane test diagnostic • Treatment rarely necessary in neonatal period

  29. Thrombocytopenia absent radii (TAR) syndrome • Bilateral absence of radii • Thrombocytopenia – present at birth/ within first 4 months • Both thumbs present and normal • Platelets usually < 50 x 10⁹/L • WCC elevated (sometimes > 100 x 10⁹/L) in > 90% of patients, may mimic congenital leukaemia • Associated abnormalities • Cow’s milk protein intolerance • Lower limb abnormalities • Renal, cardiac abnormalities • Platelet count seems to improve spontaneously • AR inheritance • Tpo increased, megakaryocytes decreased > presumed defect in Tpo signalling pathway

  30. Some other rare inherited conditions • Amegakaryocytic thrombocytopenia with radio-ulnar synostosis • Severe thrombocytopenia at birth, absent megakaryocytes in BM • Congenital amegakaryocytic thrombocytopenia (CAMT) • Nearly always in neonatal period • Platelet count < 20 x 10⁹/L • Evidence of bleeding • Physical anomalies present in 50% • 50% later develop aplastic anaemia, leukaemia, myelodysplasia • AR inheritance – mutations in Tpo receptor (c-mpl) • Stem cell transplant curative

  31. Giant platelet syndromes • Many, rare • Present in neonatal period/fetus • May-Hegglin anomaly • Giant platelets, thrombocytopenia, leucocyte Dohle-like inclusion bodies • Rare cause of fetal/neonatal intracerebral haemorrhage

  32. Kasabach-Merritt Syndrome • Neonatal period • 50% vascular tumour diagnosed at birth, 90% diagnosed by 1 year of age • Life-threatening consumptive coagulopathy • Profound thrombocytopenia PLUS microangiopathic anaemia, disseminated intravascular coagulation • Due to enlarging vascular lesion – usually obvious – cutaneous, involving face, neck, trunk or extremities • 20% visceral/retroperitoneal involvement (liver) without cutaneous signs; abdominal distension, organ dysfunction, high-output cardiac failure

  33. Previously thought to be haemangioma, actually histological features of kaposiformhaemangioendothelioma or tufted angioma • Locally aggressive vascular tumours • Trapping of platelets on endothelium, exacerbated occasionally by DIC • Diagnosis – MRI most frequently used modality • Diffusely enhancing • Significant morbidity and mortality • Haemorrhage • Invasion/compression of vital structures • 10-30% mortality

  34. Maintain haemostasis • Platelets for active bleeding/ prior to surgery only, as can increase size of tumour or even exacerbate KMP • Aminocaproic acid • Antiplatelet agents (Aspirin, diprridamole) may reduce platelet aggregation • Fresh frozen plasma if clinically indicated • Curative therapy – treat underlying tumour • No treatment uniformly effective • Surgery not usually possible • Tumour embolization with medical/ surgical therapy • Corticosteroids, alpha interferon, vincristine – alone/in combination

  35. Thrombotic disorders • Seen in adults, older children, but reported in neonates • TTP, HUS, Heparin-induced thrombocytopenia • Inherited deficiency of von Willebrand factor cleaving protease • Thrombocytopenia, hyperbilirubinaemia, anaemia • Diagnosis delayed as condition rare, signs common in sick neonates • HUS reported due to B pertussis • NT may occur after thrombosis of major vessel (renal vein thrombosis) • Consider in neonate with thrombocytopenia and renal failure

  36. Metabolic disorders • Thrombocytopenia common presenting feature in certain inborn errors of metabolism • Methylmalonicacidaemia, propionic acidaemia, Gaucher disease • Can also complicate induced hypothermia used to treat HIE

  37. Aneuploidies • Trisomy 18, 13, 21, Turner syndrome and triploidycan be associated with thrombocytopenia • Down syndrome frequently associated with mild thrombocytopenia • Mechanisms • Similar to that seen in IUGR infants – chronic fetal hypoxia • 10% neonates develop a pre-leukaemic disorder (Transient Abnormal Myelopoiesis); increased myeloblasts, variable degrees of thrombocytopenia • Usually resolves spontaneously but 20-30% develop AMKL (acute megakaryoblastic leukaemia)

  38. Neonatal Alloimmune Thrombocytopenia (NAIT) • Also referred to as AIT, FM(fetomaternal)AIT • Life-threatening bleeding disorder • Represents <5% cases of early NT, most common cause of severe thrombocytopenia in well, term neonates • Due to maternal platelet antibodies produced in response to fetal platelet antigens inherited from the father

  39. Incompatibility between maternal and fetal platelets for HPA 1a accounts for most cases of NAIT

  40. Clinical presentation • Clinical picture varies from mild thrombocytopenia at birth to intracerebral haemorrhage (ICH) in utero/ at delivery/ in first days life • Characterised by low platelets and bleeding in an otherwise healthy neonate • Severe thrombocytopenia (often < 20x10⁹/L)

  41. Incidence • NAIT affects approximately 1:2000 newborns • Approximately 2% of women are at risk (HPA-1a negative) • 10% of these have detectable antibodies • 30% of these have affected fetus • 20% of these have intracerebral haemorrhage

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