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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,

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Presentation on theme: "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,"— Presentation transcript:

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2 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 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 FBC White cell count Haemoglobin 18.2 Platelet count 10 (not clumped) MCV Platelet volume normal INR, PTT 1.26, 39.9 (normal)

6 FBC (31/03/2011) WCC 20.8 Hb 12.0 Plts 293 (normal)

7 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)

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9 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 5 th and 6 th toes

10 21/0424/0425/0426/0428/0404/ Platelets givenPlatelets + IVIGPlatelets + steroids

11 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

12 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

13 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

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19 Process similar in neonates and adults Important developmental differences Tpo concentrations higher in neonate But neonates with thrombocytopenia have lower Tpo concentrations 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

20 Relatively common haematological problem in neonates Defined as count < 150 x 10 ⁹ /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 x10 ⁹ /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

21 Early (< 72 hours) Placental insufficiency (IUGR, PIH) Perinatal asphyxia Perinatal infection (GBS, E coli) DIC Alloimmune (severe NT) Autoimmune (ITP, SLE) Late (> 72 hours) Late-onset sepsis NEC Account for >80% cases

22 Early Congenital infection (TORCH) Kasabach-Merritt syndrome Metabolic disease Congenital/ inherited (TAR, CAMT) Thrombosis Bone marrow replacement Late Congenital infection Kasabach-Merritt syndrome Metabolic disease Congenital/ inherited Autoimmune

23 Alloimmune Autoimmune Congenital infection Aneuploidy Severe Rhesus disease Congenital/ inherited

24 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

25 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

26 Thrombocytopenia develops very rapidly over 1-2 days Often very severe (< 30 x 10 ⁹ /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

27 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

28 Infant of mother with AI disease Platelet count checked at birth (cord/peripheral blood – NOT heel-prick) If >150 x 10 ⁹ /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

29 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

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

31 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

32 Blood film showing giant platelets

33 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

34 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

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36 Bilateral absence of radii Thrombocytopenia – present at birth/ within first 4 months Both thumbs present and normal Platelets usually < 50 x 10 ⁹ /L WCC elevated (sometimes > 100 x 10 ⁹ /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

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38 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 10 ⁹ /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

39 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

40 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

41 Previously thought to be haemangioma, actually histological features of kaposiform haemangioendothelioma 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

42 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

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44 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

45 Thrombocytopenia common presenting feature in certain inborn errors of metabolism Methylmalonic acidaemia, propionic acidaemia, Gaucher disease Can also complicate induced hypothermia used to treat HIE

46 Trisomy 18, 13, 21, Turner syndrome and triploidy can 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)

47 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 Antibodies cross placenta Destroy fetal platelets Cause severe thrombocytopenia, bleeding, ICH

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49 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 < 20x10 ⁹ /L)

50 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

51 . Fig 1. Pyramid model of NAT. Each tier shows the number of affected pregnancies and infants expected out of a sample of white women. Each tier represents a proportion of the tier below, shown in parentheses along the right side of the pyramid

52 3 major platelet antigen systems on surface of platelets HLA class 1 uncertain role in NAIT ABH blood group antigens Specific platelet antigens (HPA’s) HPA system assigns a name to platelet antigens based on recognition by specific antisera, in chronological order in which they were identified; high- and low-frequency alleles designated a and b respectively 16 unique polymorphisms been described Human platelet antigens are epitopes on platelet glycoproteins Most polymorphisms expressed on GPIIIa Polymorphisms readily detected by PCR techniques

53 Major platelet antigens (high frequency of NAIT) HPA-1a HPA-5a HPA-5b HPA-15a HPA-15b Platelet antigens accounting for up to 2% of NAT collectively HPA-3a HPA-2a HPA-2b Platelet antigens implicated in NAT but found on very few individuals in the general population HPA-6b HPA-7b HPA-8b HPA-9b HPA-10b HPA-11b HPA-12b HPA-13b HPA-14b HPA-16b Platelet antigens rarely associated with NAT HPA-1b HPA-3b Platelet antigens commonly implicated in NAT in the Asian population HPA-4a

54 HPA-1a implicated in +/- 80% of serologically confirmed NAIT – white population Japanese – HPA-4a alloimmunization far more common HPA-5b, HPA-15a implicated in up to 20% of cases of NAIT All other specificities account for remaining 2% Because of relatively high expression of both alleles in population, genetic incompatibilities are common However not sufficient for NAIT – observed syndrome far less common than would be expected Other factors involved (HLA haplotypes)

55 Many antibodies exist to low-frequency antigens (6b- 14b, 16b) – antigen expressed in very few individuals Antibodies to these will recognize the GP target on paternal platelets, but not on most random donor target platelets Implication – diagnostic testing – platelets from FATHER optimal platelet targets for detection of NAIT antibodies Fetal platelets/ platelet antigens enter maternal circulation early in pregnancy (unknown mechanism) First pregnancy usually affected

56 High risk of bleeding ?not only due to low platelet numbers but also defect in platelet function, antibodies to endothelial cells > loss of vessel integrity Generalised petechiae, mucocutaneous purpura common ICH most feared complication 20% of those with anti HPA-1a antibodies Risk not same for all antigen incompatilities 1/3 of ICH events fatal

57 Non-fatal often associated with serious neurological sequelae, mental retardation, cerebral palsy, seizures Up to 80% occur in utero, as early as 16 weeks Lead to migrational disorders, porencephalic cysts, hydrocephalus Bleeding elsewhere unusual Thrombocytopenia may last weeks – antibody- mediated destruction of megakaryocytes also

58 Most NB predictor history of NAIT in sibling Severity worsens with each subsequent pregnancy and increasing gestational age Depends on antigen incompatibility – HPA-1a severe, but HPA-5a/5b and HPA-15a/15b rarely cause severe disease Maternal antibody titre not consistently reliable as predictor of severity NAIT CAN OCCUR IN ABSENCE OF DETECTABLE ANTIBODIES

59 Glycoprotein assays – monoclonal antibody immobilisation of platelet antigen (MAIPA) More sensitive than previous tests Enzyme immunoassay Uses GP-specific monoclonal antibodies to identify antigenic target of maternal alloantibodies Goals of investigations Determine if maternal-fetal platelet antigen incompatibilty exists Detect platelet alloantibodies in maternal serum Risk to fetus then determined

60 Whole blood samples from mother and father Genotyping and platelet phenotyping Genotyping by PCR techniques Use known ‘anti-sera’ for all relevant alloantigens ELISA kits for common platelet antigens – BUT limited in ability to detect new antigen targets, and high cost Maternal serum For antibody investigations (MAIPA, RIP) Carried out with paternal platelets as ‘target platelets’ where possible, to allow for detection of antibodies against rare / new antigens

61 Multidisciplinary – haematologists, obstetricians, neonatologists, fetal medicine specialists, transfusion services, specialised platelet testing lab Antenatal Previously affected infant Start treatment by as early as 12 weeks’ gestation – if previous intrauterine ICH Serial fetal sonars – ICH, signs of distress – need for treatment escalation IVIG weekly 2g/kg/week if previous fetus had ICH in 2 nd trimester 1-2g/kg/week if previous fetus had ICH in 3 rd trimester/perinatally Start at weeks if no history of ICH

62 Side effects Headaches, fever most common Steroids Not dexamethasone Used in combination with IVIG in high-risk mothers/ when treatment escalation required Side effects Mood alterations, diabetes, fluid retention Fetal blood sampling, intrauterine platelet transfusion Complicated by exsanguination, worsening of alloimmunisation, induction of labour Risks outweigh benefits Not advised

63 Mode of delivery Caesarian section often used, but evidence to support this lacking Use of fetal platelet count impractical Advantage is planning ahead – have platelets ready, personnel Summary Weekly IVIG 1g/kg/week from 24 weeks Benefit of steroids not proven, but considered FBS, intrauterine procedures too risky Screening Shown to be cost effective Lack of well-defined pre-clinical phase, insufficient specificity of diagnostic tests, high risk and cost of treatment

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65 Once suspected, treat before having results of workup Need to prevent ICH – ‘safe’ platelet count not really defined IVIG (2g/kg over 2-5 days) effective in 75% Platelet transfusions - for severe thrombocytopenia and/or bleeding Random donor platelets if antigen-negative (HPA-1a and 5b negative) or maternal platelets not available Latter platelets ideal Platelet count response higher, lasts longer Maternal platelets must be washed to get rid of antibodies Generally threshold to transfuse platelets – 30 x 10 ⁹ /L (some say 50 x 10 ⁹ /L), higher if ICH or other bleeding No proven role for steroids

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67 TERM OTHERWISE WELL SEVERE THROMBOCYTOPENIA DAY 1 OF LIFE (EARLY) 1 ST BABY HIGHLY SUGGESTIVE OF NAIT BUT NO RESPONSE TO IVIG NOT IMPROVING AFTER 5 WEEKS MATERNAL ANTIBODY TESTS NEG ?THUMB/ TOE ABNORMALITIES > ?INHERITED THROMBOCYTOPENIA - but plt count should rise after transfusion

68 BMAT today Finally to receive HPA-1a neg plts (?will they help) Mother’s platelets ideal


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