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Neonatal Thrombocytopenia: Causes and Management I Roberts, N a Murray

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Neonatal Thrombocytopenia: Causes and Management I Roberts, N a Murray F359 Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.88.5.F359 on 1 September 2003. Downloaded from REVIEW Neonatal thrombocytopenia: causes and management I Roberts, N A Murray ............................................................................................................................. Arch Dis Child Fetal Neonatal Ed 2003;88:F359–F364 Neonatal thrombocytopenia is a common clinical A common clinical problem? problem. Thrombocytopenia presenting in the first 72 Twenty six weeks gestation, day 4, respiratory hours of life is usually secondary to placental distress syndrome, stable on mechanical ventila- insufficiency and caused by reduced platelet tion; platelet count 85 × 109/l and falling. production; fortunately most episodes are mild or Platelet count normal or abnormal? Abnormal. Common or uncommon clinical problem? Com- moderate and resolve spontaneously. mon. Thrombocytopenia presenting after 72 hours of age is Thrombocytopenia requires specific treatment? Depends on the concurrent circumstances. usually secondary to sepsis or necrotising enterocolitis Reason for thrombocytopenia? Simple clinical and is usually more severe and prolonged. Platelet and laboratory evaluation provides the answer in most newborns. transfusion remains the only treatment. There is a need for trials to define the safe lower limit for platelet count and which neonates will benefit from treatment. platelet count of all healthy newborn infants, regardless of gestational age, should be 150 × 109/l .......................................................................... and above, and counts below this represent thrombocytopenia, just as in older children and very neonatal paediatrician will be familiar adults. with the clinical situation described in the Ebox. Iatrogenic (phlebotomy induced) anae- INCIDENCE mia excepted, thrombocytopenia is the most At birth copyright. common haematological abnormality encoun- Thrombocytopenia is present in 1–5% of new- tered in the neonatal period. In fact, it is so com- borns at birth,7–9 and severe thrombocytopenia mon in neonatal intensive care unit (NICU) (platelets < 50 × 109/l) occurs in 0.1–0.5%.9–13 patients that it may be tempting to disregard it as a clinical problem and simply resort to platelet In NICU patients transfusion when the count gets “too low for Thrombocytopenia develops in 22–35% of all comfort”. However, there are several reasons why babies admitted to NICUs14–16 and in up to 50% of this approach now needs to be re-evaluated. those admitted to NICUs who require intensive Platelets for transfusion are associated with 15 16 1 care. A considerable proportion (20%) of these risks and are likely to be in short supply because episodes of thrombocytopenia are severe.14 17 of both increased demand and measures to This means that 8% of preterm and 6% of all reduce the risk of possible variant Creutzfeldt- 2 neonates admitted to an NICU have severe http://fn.bmj.com/ Jakob disease and should therefore only be given thrombocytopenia17 and are at increased risk of when clearly clinically indicated. haemorrhage, presenting a common manage- The main causes of neonatal thrombocytopenia ment problem. are now becoming clearer and many traditionally held beliefs have recently been shown to have little or no evidence to support them. Further CAUSES AND MECHANISMS defining the causes and mechanisms behind the It is well recognised that many fetomaternal and on September 25, 2021 by guest. Protected common forms is the only way to develop more neonatal conditions are associated with 18–20 appropriate treatment, including novel ap- thrombocytopenia. Previous detailed studies proaches. We owe it to our vulnerable patients and have attempted to define the mechanisms juniors to stop saying “we simply don’t know the by which these conditions cause 14 15 right answer here”. thrombocytopenia, but, until recently, the See end of article for This paper will first briefly review the definition mechanism underlying many neonatal thrombo- authors’ affiliations and incidence of neonatal thrombocytopenia, cytopenias remained unknown. As a result, ....................... then describe current ideas about the causes of classifications based on mechanism have proved Correspondence to: the common and clinically important forms and of little practical help to neonatal paediatricians Dr Roberts, Department of its clinical impact, and finally present contempo- because of overemphasis of rare conditions of Haematology, rary management plans for each. Hammersmith Campus, Hammersmith Hospital, Du ................................................. Cane Road, London Abbreviations: NICU, neonatal intensive care unit; NEC, W12 0NN, UK; DEFINITION [email protected] A number of large studies have shown that the necrotising enterocolitis; NAITP, neonatal alloimmune; thrombocytopenia; HPA, human platelet antigen; ICH, × 9 fetal platelet count is above 150 10 /l by the sec- intracranial haemorrhage; IVIG, intravenous Accepted 3–6 4 October 2002 ond trimester of pregnancy, and then remains immunoglobulin; Tpo, thrombopoietin; IL, interleukin; rh, ....................... fairly constant until term.7 Therefore the normal recombinant human www.archdischild.com F360 Roberts, Murray Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.88.5.F359 on 1 September 2003. Downloaded from reduced at birth,16 21 22 and levels of the megakaryocytopoietic Table 1 Classification of fetal and neonatal cytokine thrombopoietin (Tpo) are therefore elevated.23 thrombocytopenias Condition Consumption and sequestration Increased platelet consumption and/or sequestration are the Fetal Alloimmune major mechanisms in about 25–35% of episodes of neonatal Congenital infection (e.g. CMV, toxoplasma, rubella, HIV) thrombocytopenia. Overall, 15–20% of neonatal thrombocyto- Aneuploidy (e.g. trisomies 18, 13, 21, or penias present at birth result from transplacental passage of triploidy) maternal platelet alloantibodies and autoantibodies,912 and Autoimmune (e.g. ITP, SLE) disseminated intravascular coagulation is responsible for a Severe Rh haemolytic disease Congenital/inherited (e.g. Wiskott-Aldrich further 10–15% of cases, nearly always in babies who are very syndrome) ill, particularly in association with perinatal asphyxia and infection.14 15 17 Thrombosis or platelet activation/ Early onset neonatal Placental insufficiency (e.g. PET, IUGR, immobilisation at sites of inflammation—for example, in the (<72 hours) diabetes) Perinatal asphyxia gut during necrotising enterocolitis (NEC) or in Perinatal infection (e.g. Ecoli, GBS, haemangiomas—are further examples of neonatal thrombo- Haemophilus influenzae) cytopenias principally caused by platelet consumption. In DIC addition, there is evidence that limited splenic sequestration Alloimmune of platelets occurs in sick newborns.24 Autoimmune (e.g. ITP, SLE) Congenital infection (e.g. CMV, toxoplasma, rubella, HIV) Combined mechanisms Thrombosis (e.g. aortic, renal vein) Many neonates develop thrombocytopenia as a result of mul- Bone marrow replacement (e.g. congenital tiple mechanisms. A preterm neonate from a mother with leukaemia) pre-eclampsia who develops early bacterial sepsis and a baby Kasabach-Merritt syndrome Metabolic disease (e.g. proprionic and with intrauterine growth restriction who develops NEC may methylmalonic acidaemia) both become thrombocytopenic as a result of underlying Congenital/inherited (e.g. TAR, CAMT) impaired platelet production (after pre-eclampsia or intra- uterine growth restriction) combined with platelet consump- Late onset neonatal Late onset sepsis (>72 hours) NEC tion (during sepsis or NEC). Indeed it is likely that most Congenital infection (e.g. CMV, neonates who develop thrombocytopenia do so because their toxoplasma, rubella, HIV) adverse fetal environment causes impaired megakaryo- Autoimmune cytopoiesis at birth, with a predisposition for thrombocyto- Kasabach-Merritt syndrome penia to worsen when the baby is exposed to concurrent neo- Metabolic disease (e.g. proprionic and copyright. methylmalonic acidaemia) natal platelet consumptive “stress”. In addition, during sepsis Congenital/nherited (e.g. TAR, CAMT) and NEC, the natural history of thrombocytopenia (rapid onset and progression followed by slow recovery over five to The most common conditions are highlighted. seven days) suggests that it probably results from a combina- CMV, Cytomegalovirus; ITP, idiopathic thrombocytopenic purpura; SLE, systemic lupus erythematosus; PET, pre-eclampsia; IUGR, tion of mechanisms—that is, platelet consumption (rapid intrauterine growth restriction; E coli Escherichia coli; GBS, group B onset phase) followed by impaired platelet production (slow streptococcus; DIC, disseminated intravascular coagulation; TAR, recovery phase). thrombocytopenia with absent radii; CAMT, congenital amegakaryocytic thrombocytopenia; NEC, necrotising enterocolitis. COMMON PRESENTATIONS OF THROMBOCYTOPENIA IN THE PERINATAL PERIOD known mechanism—for example, thrombocytopenia with Fetal thrombocytopenia absent radii (TAR syndrome; see table 1 for “practical” classi- Fetal thrombocytopenia is now identified more often, as a fication). They have also tended to perpetuate widely held consequence of primary diagnostic investigations for inher- http://fn.bmj.com/ beliefs that common neonatal conditions—for example, ited thrombocytopenia (such as Wiskott-Aldrich syndrome sepsis—cause thrombocytopenia because of platelet con- (table 2)6 or alloimmune thrombocytopenia in fetuses with
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