Neoatal thrombocytopeia


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  • Bone or skeleton defects. FA can cause missing, oddly shaped, or three or more thumbs. Arm bones, hips, legs, hands, and toes may not form fully or normally. The spine may be curved—a condition called scoliosis Eye and ear defects. The eyes, eyelids, and ears may not be normally shaped. A child also may be born deaf. Skin discoloration. This includes coffee-colored areas or odd-looking patches of lighter skin. Kidney problems. A child might be born with a missing kidney or kidneys that aren't shaped normally. Congenital heart defects . The most common congenital heart defect linked to FA is a ventricular septal defect (VSD). VSD is when the wall that separates the left and right chambers of the heart (the ventricles) is deformed or has a hole in it.
  • Kasabach–Merritt syndrome ( KMS , also known as "Hemangioma with thrombocytopenia" [1] :597 ) is a rare disease , usually of infants , in which a vascular tumor leads to decreased platelet counts and sometimes other bleeding problems , [2] which can be life-threatening. [3] It is also known as hemangioma thrombocytopenia syndrome . It carries the names of Dr Haig Haigouni Kasabach and Dr Katharine Krom Merritt, the two pediatricians who first described the condition in 1940. [4] [5]
  • Bernard-Soulier syndrome (BSS), also called hemorrhagiparous thrombocytic dystrophy , [1] , is a rare autosomal recessive coagulopathy (bleeding disorder) that causes a deficiency of glycoprotein Ib (GpIb), the receptor for von Willebrand factor , which is important in clot formation. It is a Giant Platelet Syndrome that is characterized by abnormally large platelets. Characterized by prolonged bleeding time, thrombocytopenia , giant platelets, and decreased platelet survival, Bernard–Soulier syndrome (BSS) is associated with quantitative or qualitative defects of the platelet glycopotein complex GPIb/V/IX Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema , thrombocytopenia (low platelet count), immune deficiency , and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczema-thrombocytopenia-immunodeficiency syndrome in keeping with Aldrich's original description in 1954. [1] The diagnosis is made on the basis of clinical parameters, the blood film and low immunoglobulin levels. Typically, immunoglobulin M (IgM) levels are low, IgA levels are elevated, and IgE levels may be elevated; paraproteins are occasionally observed. [4 Chediak–Higashi syndrome is a rare autosomal recessive disorder that affects multiple systems of the body, and arises from a mutation in the lysosomal trafficking regulator gene, LYST . It occurs in humans, cattle , white tigers , blue Persian cats and the only known captive albino orca [1] . Contents [hide] Quebec Platelet Disorder (QPD) is a rare, autosomal dominant bleeding disorder described in a family from the province of Quebec in Canada [1] [2] . The disorder is characterized by large amounts of the fibrinolytic enzyme urokinase -type plasminogen activator (u-PA) in platelets [3] . Consequently, stored platelet plasminogen is converted to plasmin , which is thought to play a role in degrading a number of proteins stored in platelet α- granules [4] . These proteins include platelet factor V, Von Willebrand factor, fibrinogen, thrombospondin-1, and osteonectin [3] . There is also a quantitative deficiency in the platelet protein multimerin 1 ( MMRN1 ). Furthermore, upon QPD platelet activation, u-PA can be released into forming clots and accelerate clot lysis, resulting in delayed-onset bleeding (12-24hrs after injury) [5] . Individuals with QPD are at risk for experiencing a number of bleeding symptoms, including joint bleeds, hematuria, and large brusing [6
  • Oe randomised trial showed no difference inincedence of ICH if plt kept >50,000 and >150000
  • Neoatal thrombocytopeia

    1. 1. Dr Varsha Atul Shah
    2. 2. Objectives Definitions Epidemiology Etiological classifications History and physical exam findings Laboratory investigations Neonatal alloimmune thrombocytopenia (NAIT) Neonatal autoimmune thrombocytopenia General treatment issues
    3. 3. Definitions Normal platelet count 150,000 - 450,000/mcL MILD 100,000-150, 000 MODERATE 50,000-100,0 00 SEVERE <50,000
    4. 4. Types of classificationEtiological classification based on clinical features PATHOLOGICA CLINICAL L MECHANISMS FEATURES TIMING OF THROMBOCYT OPEIA
    5. 5. Epidemiology General neonatal population: Incidence of thrombocytopenia 1% Severe thrombocytopenia (< 50,000 ) 8% of preterm & 6 0.12% ( Hamilton data) % all neonates 0.24% ( Finnish data) admitted to ICU have severe NICU population: thrombocytopenia Incidence of thrombocytopenia 22 –35 % < 100,000 > 50% of affected newborns <50, 000 20% of affected newborns Premature newborns Incidence of severe thrombocytopenia 8%
    6. 6. Etiology classification according topathological mechanismsImpaired production Increased consumption  Immune mediated (15-20%): autoimmune, alloimmune, drug Placental insufficiency(eg.IUGR, induced Maternal PIH)  Peripheral consumption: Infections: bacterial, viral, hypersplenism ( eg. congenital fungal infections); Kassabach- Merritt Infiltrative disorders (eg. syndrome; DIC; infection; congenital leukemia) NEC; drug toxicity, thrombus Congenital thrombocytopenia  Procedure related : eg. eg. TAR, hereditary postexchange transfusion macrothrombocytopenias)  Miscellaneous: neonatal cold Drug toxicity injury
    7. 7. Combined mechanisms Some neonates develop thrombocytopenia secondary to combined mechanisms: i.e. a premature infant born to a mother with PIH who develops sepsis or an IUGR infant who develops NEC Also some etiologies like sepsis can cause thrombocytopenia due to impaired production in the marrow as well as increased destruction from DIC, endothelial damage and platelet aggregation due to bacterial products adhering to platelet membranes
    8. 8. Impaired procuction Accounts for 75 % of cases Have impaired megakaryoctyopoiesis and platelet production Megakaryocytes and their precursor and progenitor cells are considerably reduced at birth Levels of the megakaryocytopoietic cytokine thrombopoietin (Tpo) are therefore elevated.
    9. 9. Consumption and sequestration 25–35% of episodes of neonatal thrombocytopenia 15–20% of neonatal thrombocytopenias present at birth result from transplacental passage of maternal platelet alloantibodies and autoantibodies disseminated intravascular coagulation is responsible for a further 10–15% of cases, nearly always in babies who are very ill, particularly in association with perinatal asphyxia and infection
    10. 10. Etiological classification basedon clinical features Sick neonates, Normal appearing preterm and those neonates with other medical conditions Neonates with physical abnormalities and dimorphic features
    11. 11. Healthy neonates Maternal autoimmune thrombocytopenia ( eg. ITP or SLE), maternal drug Neonatal alloimmune thrombocytopenia (NAIT) Occult infection Amegakaryocytic thrombocytopenia Hereditary macrothrombocytopenias Wiskott- Aldrich syndrome
    12. 12. Neonates preterm/assoc medicalconditions Hypoxia +/- acidosis after  RDS birth trauma  PPHN Chronic hypoxia from  NEC placental insufficiency  Thrombosis ( indwelling Cold injury vascular catheters,ECMO) Maternal pre-eclampsia  Exchange transfusions Bacterial infection/sepsis  Bone marrow disorders Congenital viral infection (leukeumia, (CMV, rubella) neuroblastoma, other DIC solid tumours)
    13. 13. Neonates who have physicalabnormalities or dysmorphic features Thrombocytopenia with absent radius (TAR) syndrome Fanconi anemia( can present with mild thrombocytopenia alone) Chromosomal abnormalities due to trisomy 21, 13, 18 or Turner’s syndrome Kasabach- Merritt syndrome
    14. 14. Thrombocytopenia with absentradius (TAR) syndrome
    16. 16. Fetal Early Neonatal <72 hrs Late Neonatal >72 hrs
    17. 17. Fetal onset Alloimmune Autoimmune (maternal ITP, SLE) Congenital infections (CMV, toxoplasma, rubella, HIV) Aneuploidy ( trisomy 21, 13, 18), or triploidy Severe Rh hemolytic disease Congenital/ inherited ( eg Wiskott- Aldrich syndrome)
    18. 18. Early onset Late onset-usually secondary to -usually secondary toplacental insufficiency sepsis or necrotisingand caused by enterocolitisreduced plateletproduction; -usually more severe and prolonged.-fortunately mostepisodes are mild or -Plateletmoderate transfusion remains- resolve the only treatment.spontaneously.
    19. 19. Early onset neonatal Placental insufficiency  Congenital infection eg PIH, IUGR, diabetes)  Thrombosis ( eg. aortic, Perinatal asphyxia renal vein) Perinatal infection  Bone marrow replacement ( eg. E. coli, GBS) (eg. Congenital leukemia) DIC  Kasabach- Merritt Allommune syndrome Autoimmune(eg ITP, SLE)  Metabolic disease ( eg. Congenital / inherited Propionic or ( eg. methylmalonic acidemia) TAR, congenital amegakaryocytic thrombocytopenia)
    20. 20. Late onset neonatal Late onset sepsis NEC Congenital infection Autoimmune Kasabach- Merritt syndrome Metabolic disease Congenital/ inherited
    21. 21. Congenital and inherited thrombocytopeniasthat may present in the fetus or neonateWith thrombocytopathy Without thrombocytopathy Bernard-Soulier syndrome  Fanconi’s anaemia Wiskott-Aldrich syndrome  TAR syndrome X-linked thrombocytopenia  Amegakaryocytic Chediak-Higashi syndrome thrombocytopenia Quebec platelet disorder  Giant platelet syndromes Some giant platelet (e.g. syndromes (e.g. Montreal May-Hegglin anomaly, syndrome) Sebastian syndrome, Fechtner syndrome)  Autosomal dominant thrombocytopenia
    22. 22. Kasabach - Merrittsyndrome
    23. 23. Approach to neonate withthrombocytopenia: Maternal history History or ITP,SLE or splenectomy Previous infant with thrombocytopenia or family history of neonate with thrombocytopenia Pre or perinatal infections Drug use ( eg.quinine, thiazides, hydralazine) PIH Abnormal placenta ( infarction, congenital infection, chorioamnionitis) Maternal platelet count: decreased suggests autoimmune; normal may be autoimmune or alloimmune in well appearing neonate Prior pregnancy : ? Same partner
    24. 24. Approach to neonate withthrombocytopenia: neonatal history History of perinatal asphyxia Meconium aspiration or RDS Infection NEC DIC IUGR Thrombus or indwelling catheters Intracranial hemorrhage or other severe bleeding
    25. 25. Approach to neonate with thrombocytopenia: neonatalphysical exam Head circumference and weight percentile Signs of thrombocytopenia: bruising , oozing from puncture sites, petechiae Sick vs. well : signs of sepsis, RDS, asphyxia Hepatosplenomegaly, blueberry muffin rash ( congenital infections) Dysmorphic features: trisomy 13, 18, 21 or certain syndromes: eg TAR , Fanconi Large hemangioma
    26. 26. Approach to neonate with thrombocytopenia:laboratory investigations Confirm that thrombocytopenia is not factitious Abnormalities in WBCs ( sepsis, congenital leukemia), hemoglobin ( bleeding, aplasia) Evidence of co-existing coagulopathy ( INR, PTT, d-dimers, FDP, fibrinogen) LFTs MPV: large platelets often indicate increased production in response to increased consumption ( though can rarely see giant platelets related to congenital platelet disorders) Other investigations tailored to the cause: ie platelet antibodies and antigen typing in NAIT, septic workup, viral studies looking for congenital viral infections, chromosomal studies Bone marrow in persistent or unusual cases
    28. 28. NormalPlatelets
    29. 29. Thrombocytopenia
    30. 30. Large platelets
    31. 31. Wiskott Aldrich syndrome: smallplatelets
    32. 32. Caused by maternalplatelet specificantibodies against paternallyinherited plateletantigens
    33. 33. Neonatal alloimmune thrombocytopenia(NAIT) Incidence 1/1000-1/3000 pregnancies Anti – HPA-1a accounts for 80-90% of cases in Caucasians; 10 - 15% of cases are associated with anti - HPA- 5b In the Caucasian population 2% of women are HPA-1a negative and about 10% of these women develop anti- HPA-1a ( influenced by certain HLA classes) In Asians NAIT occurs secondary to anti-HPA-4
    34. 34. NAIT: morbidity 10 – 20% of affected newborns develop an intracranial hemorrhage (ICH) with about a 7% mortality 20% of survivors of ICH develop long term neurodevelopmental sequelae ¼- ½ of ICH occur in utero severe NAIT occurs during the first pregnancy in 40-50% of cases The recurrence rate of NAIT is greater than 75% for subsequent pregnancies and generally follows a more severe course: therefore need referral to high risk obstetrics for subsequent pregnancies
    35. 35. NAIT: diagnostic workup Presumptive diagnosis in otherwise well infant with severe thrombocytopenia +/- unexplained ICH and no history of maternal ITP, SLE or drugs that can cause thrombocytopenia In suspected cases need to send maternal blood for HPA antibody and genotyping and paternal blood for genotyping, can also send sample on subsequent fetuses for genotyping when the father is heterozygous for HPA 1a/1b ( can be done by amnio or CVS) At present there is no routine prenatal screening
    36. 36. Affected neonate Confirm thrombocytopenia on a repeat blood sample If Plt count <100000 Neonatal studies Maternal studies Suspect alloimmune CarefulCareful history & exam antenatal thrombocytopenia Test for DIC history for PIH if cause uncertain Consider Kassabach Maternal FBCmerritt syndrome, TAR, Urgent studies TORCH Maternal & paternalPerform head USG to r/ blood samples for o ICH rapid HPA1a alloantibodies
    37. 37. Plt count <30000 Plt count >30000 with and/or clinically no evidence ofsignificant bleeding bleedingTransfuse platelet10-20ml/kg Observe, follow theObtain post platlet count dailytransfusion plt count Await results of initial serological studies and do not transfuse >30000 <30000 Follow plt daily Consider 2nd dose random donor plt, Transfuse irradiated, single dose of IVIG(1gm/kg/d) washed or plasma If Plt <10000 and/or clinical bleeding, depleted maternal transfuse irradiated, washed or plasma platelets or antigen neg depleted maternal platelets or platelets if clinically compatible antigen negative donor indicated platlets asap.
    38. 38. NAIT: antenatal treatment Subsequent pregnancies should be managed by maternal-fetal medicine Risk stratification can be based on presence and timing ( prenatal vs postnatal) ICH in a previous infant +/- platelet count obtained from fetal blood sampling of index pregnancy(increased risk if platelets <20,000)
    39. 39. NAIT : antenatal treatment Treatments include IVIG to mum, po steroids for mum and fetal platelet transfusions Fetal blood sampling (FBS) entails risk with as much as an 8% fetal loss/pregnancy in cases of NAIT: in utero transfusion of HPA-1a and 5b negative platelets should be given at time of sampling if the fetal platelet count is <50,000
    40. 40. NAIT: antenatal treatment: riskstratification approach Standard risk : no ICH in previously affected child: IVIG 1g/kg/wk OR prednisone 0.5 mg/kg/ day starting at 20 wks gestation High risk : peripartum ICH in previously affected child: IVIG 1g/kg/wk AND prednisone 1 mg/kg/d starting at 20 wks; response monitored by FBS Very high risk : antenatal ICH in previously affected child: IVIG 2g/kg/wk starting at 12 wks with FBS at 20 wks and the addition of prednisone 1 mg/kg/d for poor responders If persistent poor response can give weekly in utero platelet transfusion C/section if fetal platelet count is <50,000
    41. 41. NAIT : neonatal management Need to monitor platelets closely particularly in the first 72- 96 hrs of life since the risk of ICH is highest during that time Need baseline cranial US to detect ICH Should transfuse with platelets for all infants with platelets < 30,000 and for premature, sick or infants with ICH at < 50,000 Traditionally initial treatment was washed maternal platelets or HPA –1a and 5b negative platelets More recent studies ( Kiefel et al, 2006, Bussel et al, 2005) show that random donor platelets can be effective( may adsorb circulating alloantibodies): this depends on availability of maternal platelets or Ag negative platelets IVIG can be used as additional therapy in cases of suboptimal response
    42. 42. NAIT : natural history Thrombocytopenia usually resolves by 2 weeks although can last for up to 6 weeks
    43. 43. Neonatal autoimmunethrombocytopenia Due to antibody directed against maternal and fetal platelets ( eg. Maternal ITP or lupus) Antenatally may be difficult to distinguish between this and gestational thrombocytopenia which has an extremely low risk of neonatal thrombocytopenia Mothers may have a normal platelet count if they have had a splenectomy or if there is enough compensatory thrombocytosis
    44. 44. Infants of mothers with ITP : risk forthrombocytopenia 10% risk overall of developing severe thrombocytopenia ( platelets <50,000) in infants of mums with ITP May be increased if the mother has had a splenectomy, if her platelet count has been < 50,000 at some point during her pregnancy or if there has been a previously affected sibling Risk of ICH is 1% or less Subsequent pregnancies do not have a risk of a more severely affected infant
    45. 45. Neonatal Autoimmune thrombocytopenia: antenatalmanagement IVIG can be used for severely affected women Prednisone has also been used early in pregnancy in selected patients C/section should only be performed for obstetrical indications
    46. 46. Neonatal autoimmunethrombocytopenia: neonatal management Cord platelets should be obtained and serial platelet counts should be monitored every 8- 24 hrs for the first few days of life since the nadir typically occurs at 2 – 5 days of age Should perform cranial US if significant thrombocytopenia ( platelets< 100,000) Treat with IVIG 1g/kg/d X 2 days if platelets < 30,000 May give IVIG at higher threshold +/- platelets if significant bleeding Antibodies may persist for a while and may need a second course of IVIG even a 2-3 weeks later
    47. 47. Treatment of other causes ofneonatal thrombocytopenia Treat underlying cause if possible: ie sepsis,RDS Platelet transfusions as indicated
    48. 48. Transfusion thresholds(Murray, NA, 2002) <30,000 Consider transfusion for all30,000-49,000 Do not transfuse if clinically stable Consider transfusion if: < 1000 g and < 1 wk of age Clinically unstable Previous major bleeding (GR 3-4 IVH or pulmonary hemorrhage) Current minor bleeding Concurrent coagulopathy Requires surgery or exchange transfusion 50,000-99,000 Do not transfuse >99,000 Transfuse if bleeding
    49. 49. Summary Neonatal thrombocytopenia is a relatively common problem especially in the NICU setting Etiologies are diverse and differ in sick and well infants clinical features and timing of presentation can help sort out the causes Immune mediated thrombocytopenia requires specific investigations and management strategies NAIT conveys a greater risk for significant bleeding ( including antenatal ICH) compared to autoimmune thrombocytopenia Random donor platelets have been shown to be effective in many cases of NAIT contrary to previously held beliefs