- Email: [email protected]
Neonatal thrombocytopenia
Early Human Development (2005) 81, 35 — 41
www.elsevier.com/locate/earlhumdev
Neonatal thrombocytopenia Subarna Chakravortya, Neil Murrayb,1, Irene Robertsc,* a
Department of Haematology, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK Department of Neonatal Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK c Department of Haematology, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK b
KEYWORDS Neonatal thrombocytopenia; Platelets; Platelet transfusion; Alloimmune thrombocytopenia
Abstract Thrombocytopenia occurs in up to a third of preterm neonates admitted to intensive care units. In these babies, thrombocytopenia typically presents in one of two patterns: early-onset thrombocytopenia occurring within 72 h of birth and lateonset thrombocytopenia which develops after 72 h. Early-onset thrombocytopenia is most commonly caused by disorders associated with placental insufficiency (e.g. maternal hypertension), is mild-moderate, self-limiting and requires no treatment; it is caused by reduced platelet production. Late-onset thrombocytopenia is usually due to bacterial sepsis or necrotising enterocolitis; it is often severe (platelets b50109/l), prolonged and requires treatment with platelet transfusions. In term babies, neonatal thrombocytopenia is usually severe and most commonly caused by bacterial sepsis, perinatal asphyxia or neonatal alloimmune thrombocytopenia. There is a lack of evidence-based guidelines for treatment of neonatal thrombocytopenia. The most important future developments will depend upon studies aimed at determining optimal platelet transfusion schedules for term and preterm neonates. D 2004 Elsevier Ireland Ltd. All rights reserved.
1. Introduction With the exception of phlebotomy-induced anaemia, thrombocytopenia is the commonest haematological abnormality encountered in the neonatal period [1]. Although there is a vast number of causes of neonatal thrombocytopenia, including * Corresponding author. Tel.: +44 208 383 2163; fax: +44 208 742 9335. E-mail addresses: [email protected] (N. Murray)8 [email protected] (I. Roberts). 1 Tel.: +44 208 383 2476; fax: +44 208 740 8281.
rare inherited causes [1—3], only a few are commonly encountered in neonatal practice and are therefore most clinically relevant. The spectrum of thrombocytopenia includes, on the one hand, the extremely sick premature neonate with profound thrombocytopenia secondary to sepsis in whom the impact of a major haemorrhage may be catastrophic but whose survival will depend mainly on successful treatment of infection, and, on the other hand, severe isolated thrombocytopenia in a term neonate who is otherwise well and for whom the clinical outcome may solely depend on the impact of the thrombocytopenia. It is therefore
0378-3782/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2004.10.013
36 important to recognise the common causes of thrombocytopenia and identify appropriate investigation and management of individual cases. Our understanding of the pathogenesis and natural history of neonatal thrombocytopenia has improved considerably in recent years. This helps us provide appropriately tailored management in individual cases and paves the way for new therapeutic approaches. In this review, we will discuss our current knowledge of the incidence, pathogenesis and management of neonatal thrombocytopenia.
S. Chakravorty et al. sented neonates of low birth weight, the high risk population for neonatal thrombocytopenia [10].
4. Causes of neonatal thrombocytopenia 4.1. Natural history of thrombocytopenia as a guide to diagnosis Recent studies show that most cases of neonatal thrombocytopenia fall into two main groups depending upon the age of the neonate when the
2. Definition of thrombocytopenia By the end of the first trimester of pregnancy, the fetal platelet count has already reached 150109/l [4] and rises further to 175—250109/l by the middle of the second trimester [5]. Thus, platelet counts of b150109/l define thrombocytopenia in any neonate regardless of gestational age. Although the healthy fetus or neonate can generate and maintain a circulating platelet count similar to that of adults, several studies indicate that sick neonates often have reduced platelet producing capacity compared to that of adults and this may become increasingly evident during times of increased platelet demand [1,6,7].
3. Incidence of neonatal thrombocytopenia The incidence of neonatal thrombocytopenia varies greatly, depending upon the population studied, from b1% in healthy term babies to around one third of neonates admitted to neonatal intensive care units (NICU). In a recent, population-based prospective study in Helsinki of 4489 term infants, they found that the incidence of thrombocytopenia (platelet counts of b150109/l) on cord blood testing was 2% (95% CI 1.5—2.3) with severe thrombocytopenia (platelet counts b50109/l) occurring in 0.24% of cases (95% CI 0.10—0.38) [8]. In another large study of 8388 newborns, thrombocytopenia (b150109/l) was found in 0.5% of cases (95% CI 0.3— 0.6), of which 0.12% were severe (platelet count b50109/l) (95% CI 0.05—0.20) [9]. However, the incidence of thrombocytopenia in preterm neonates in NICU is much higher, consistently reaching 22—35% in our unit, with severe thrombocytopenia (platelets b50109/l) in 6% of all admissions (these babies) [8,9]. Data from other recent studies are more difficult to interpret since they include only neonates with platelet counts b100109/l or, because of methodological difficulties, have under-repre-
Table 1 Causes of fetal and early neonatal thrombocytopenia Placental insufficiency Maternal hypertension Intrauterine growth restriction (IUGR) Maternal diabetes Immune Alloimmune Autoimmune (maternal ITP) Neonatal lupus Infection Congenital: CMV, toxoplasma, rubella, HIV, coxsackie Perinatal: Group B streptococcus, Haemophilus influenzae, E. coli Congenital/inherited Aneuploidy: trisomies 13, 18 and 21; triploidy Bone marrow failure affecting megakaryocytes (e.g. congenital amegakaryocytic thrombocytopenia, thrombocytopenia absent radii syndrome) Bone marrow failure syndromes with pancytopenia (e.g. Fanconi anaemia) Myelodysplasia (e.g. Monosomy 7) Immunodeficiencies (e.g. Wiskott Aldrich, Haemophagocytic Lymphohistiocytosis) Platelet function disorders with thrombocytopenia (e.g. Bernard Soulier syndrome) Disseminated intravascular coagulation Perinatal asphyxia Bacterial infection Whole body cooling Congenital thrombotic thrombocytopenic purpura (ADAMTS-13 deficiency) Other (rare in most NICU) Thrombosis-aortic, renal Kasabach Merritt Hepatic haemangioendothelioma Metabolic-propionic acidaemia, methylmalonic acidaemia Congenital leukaemia Heparin-induced thrombocytopenia (HIT) Subcutaneous fat necrosis of the newborn (SCFN) Exchange transfusion Rhesus haemolytic disease of the newborn Commonest causes shown in italics.
Neonatal thrombocytopenia thrombocytopenia first develops [1]. Early-onset thrombocytopenia develops either in utero or within the first 72 h of birth; the main causes are listed in Table 1. Late-onset thrombocytopenia presents after the first 72 h of age; the main causes are listed in Table 2. This simple classification is a useful starting point for working out the cause (and therefore the most useful diagnostic tests) of the majority of episodes of neonatal thrombocytopenia.
4.2. Early-onset neonatal thrombocytopenia Thrombocytopenia associated with placental insufficiency is the commonest pattern of early-onset thrombocytopenia in neonates. In the absence of conditions causing platelet consumption (e.g. infection), precipitous falls in platelet count in such neonates are uncommon, the platelet count rarely falls below 50109/l and platelet recovery is spontaneous [6,7]. This form of thrombocytopenia is therefore usually a benign condition with little evidence of clinically important haemorrhage and treatment is rarely required unless additional complications, such as sepsis, develop. By contrast, early neonatal thrombocytopenia, which does not conform to the above pattern, is likely to be a marker of significant pathology, which requires further investigation. Severe thrombocytopenia (platelet count b50 109/l) within 72 h of birth is uncommon [11]. This may be due to perinatal asphyxia or perinatally acquired bacterial infection (e.g. Group B streptococcus) in which case further investigation is unnecessary. However, an early presentation of severe neonatal thrombocytopenia usually has its origin in fetal life and further investigations need to be organised, often urgently; the most likely causes are [1,2,3,11]: ! ! ! !
allo- or autoimmune thrombocytopenia congenital infections (particularly with cytomegalovirus) aneuploidy (particularly trisomies 18, 13 and 21 or triploidy) congenital/inherited thrombocytopenias.
Table 2
Causes of late neonatal thrombocytopenia
Bacterial sepsis Necrotising enterocolitis Congenital infection Congenital/inherited bone marrow failure syndromes Disseminated intravascular coagulation Other: late diagnosis of immune thrombocytopenia, rarities (see Table 1) Commonest causes shown in italics.
37 Early-onset neonatal thrombocytopenia which persists for more than 7—10 days is also unusual and warrants further investigation. As most other forms of thrombocytopenia will have resolved by this time, the likely causes of prolonged thrombocytopenia are: immune thrombocytopenias, congenital infections and congenital/inherited thrombocytopenias.
4.3. Late-onset thrombocytopenia (N72 h after birth) In the setting of NICU, late-onset thrombocytopenia is almost always caused by bacterial sepsis or necrotising enterocolitis (NEC) [11]. This type of thrombocytopenia has a distinctly different pattern to that seen in early-onset thrombocytopenia associated with placental insufficiency. It occurs usually as an isolated thrombocytopenia and develops concurrently with, or sometimes precedes by up to 24 h, other evidence of sepsis or NEC. In this situation, thrombocytopenia progresses rapidly with a platelet nadir reached within 24—48 h; it is often severe (plateletsb50109/l) and prolonged, persisting until sepsis or NEC is controlled, followed by a slow recovery over 1—2 weeks [11]. In a recent retrospective survey of severe thrombocytopenia in admissions to our NICU, this pattern of late-onset thrombocytopenia developed in 6% of all admissions [11].
5. Mechanisms of thrombocytopenia Neonatal thrombocytopenia may develop either as a result of reduced platelet production secondary to reduced megakaryopoiesis (the process by which megakaryocytes are produced from their progenitor cells in the bone marrow or, in fetal life, in the liver); or alternatively the thrombocytopenia may be due to increased platelet destruction or sequestration. Examples of thrombocytopenia due to reduced platelet production are those which occur secondary to placental insufficiency [6,7] and those which occur as part of inherited bone marrow failure syndromes. The most common reasons for thrombocytopenia due to increased destruction/sequestration are neonatal alloimmune thrombocytopenia (NAIT) [2,12] and disseminated intravascular coagulation (DIC) in association with perinatal asphyxia or NEC [11]. In many instances, an individual neonate will have a combination of both mechanisms, e.g. impaired platelet production as a result of placental insufficiency combined with increased
38
S. Chakravorty et al.
Figure 1 Diagnostic approach to thrombocytopenia in preterm neonates. Abbreviations: Plts—platelets, Hrs—hours, NAIT: neonatal alloimmune thrombocytopenia, NEC: necrotising enterocolitis.
platelet consumption during an episode of lateonset sepsis or NEC.
6. Diagnostic approach to neonatal thrombocytopenia We use a diagnostic approach based on the gestational age, the age at presentation and the severity of the thrombocytopenia. A diagnostic algorithm for preterm babies is shown in Fig. 1 and for term babies in Fig. 2.
In preterm babies with early-onset thrombocytopenia, where there is good evidence of placental insufficiency and thrombocytopenia is mild and recovers within 10—14 days, there is no need for further investigations. In the remaining cases screening for bacterial and congenital infections should be carried out and immune causes sought only where these are negative or the thrombocytopenia is severe (b50109/l). Investigation for NAIT is described below. For preterm babies with late-onset thrombocytopenia, NAIT is an unlikely cause but should be excluded if the thrombocytopenia remains unexplained. Persistent thrombocy-
Figure 2 Diagnostic approach to thrombocytopenia in term neonates. Abbreviations: Plts—platelets, NAIT: neonatal alloimmune thrombocytopenia, DIC: disseminated intravascular coagulation.
Neonatal thrombocytopenia topenia in the absence of infective, immune or placental problems should prompt a search for the rare disorders listed in Table 1. Further investigations should be discussed with the haematologist as a bone marrow examination is usually necessary. In term babies, the clinical presentation with thrombocytopenia is either with a significant haemorrhage or as an incidental finding, sometimes after minor haemorrhagic signs (e.g. petechiae), have been noted. If the baby is otherwise well, the most likely explanation is NAIT and, in the term baby, this is the most important diagnosis to identify, particularly where the platelet count is b50109/l [12]. To diagnose NAIT, blood should be sent from the mother, baby and if possible the father. This will allow the identification of the human platelet antigen (HPA) genotype of the mother, baby and father and determine whether the mother has anti-HPA antibodies against paternally derived platelet antigens expressed by the baby. In the majority of cases (80%) the mother is HPA-1a-negative with anti-HPA-1a antibodies directed against the baby’s platelets which are HPA-1apositive. A further 10—15% of cases are due to antiHPA-5b. In some cases, a presumptive diagnosis has to be made on the basis of HPA-incompatibility between the mother and baby as the antibodies have a low titre in vitro despite their strong activity in vivo [1,12].
7. Management of neonatal thrombocytopenia 7.1. General principles While a number of studies highlight the association between thrombocytopenia and poor outcome in neonates [1,11,13], the direct contribution of thrombocytopenia to the clinical course of these neonates is difficult to assess. Most studies suggest that neonatal thrombocytopenia in general, as well as in the specific situation of NAIT, is a risk factor for significant haemorrhage (particularly intracranial haemorrhage), for mortality and for adverse neurodevelopmental outcome [1,11—13]. Apart from NAIT, most studies do not make it clear whether neonatal thrombocytopenia directly contributes to adverse outcome or is simply a marker of the severity of concurrent neonatal complications (e.g. birth asphyxia or severe sepsis). This is partly because there have been no trials in neonates with severe thrombocytopenia (platelets b50109/l) to address whether prophylactic platelet transfusion reduces haemorrhage and improves
39 outcome. The only trial of prophylactic platelet transfusion in neonates was limited to those with platelet counts between 50 and 150109/l and this failed to show any benefit [14]. Despite a paucity of evidence-based studies, the overall conclusion that can be drawn from the data available is that neonatal thrombocytopenia is linked both to an increased risk of haemorrhage and to a poorer outcome [13,15]. The aim in management of this complication is therefore to reduce these risks. To achieve this, we suggest the following approach: ! ! !
identification of the likely cause of the thrombocytopenia specific management tailored to the cause (e.g. for NAIT) appropriate administration of platelet transfusions.
Identification of the cause of the thrombocytopenia helps to predict its likely pattern and enable appropriate monitoring of the platelet count, which is particularly important in conditions where precipitous falls in platelet count are common, e.g. sepsis and NAIT. This allows the planned use of prophylactic platelet transfusion. In addition, deviations from the expected pattern of thrombocytopenia alert the clinician to possible alternative reasons for thrombocytopenia that may require more specific investigations or management, e.g. congenital bone marrow failure syndromes.
7.2. Management of NAIT NAIT should be suspected in any neonate with unexplained thrombocytopenia. Babies who present with very severe thrombocytopenia (platelets b30109/l) and/or those with evidence of intracranial or other major bleeding, should be promptly transfused with HPA-compatible platelets. In 95% of cases, HPA-1a negative/HPA-5b negative platelets are suitable. In the UK, there is a pool of suitable donors and these platelets are available at short notice from the National Blood Service; washed maternal platelets are no longer recommended except in rare emergencies [1,12,15]. In severely affected babies with suspected NAIT, it is not necessary to wait for the results of serological investigations before giving HPA-compatible platelets because of the risks of haemorrhage associated with delay. By contrast, babies with NAIT who have platelet counts above 30109/l do not require platelet transfusion except in the unusual situation of severe haemorrhage [12,15]. It is, however, important to monitor
40 the platelet count in every baby with NAIT as it will fall over the first 4—5 days of life and may reach the severely affected range; similarly, all babies with NAIT should have intracranial haemorrhage excluded (cranial ultrasound is sufficient in most cases). If severe thrombocytopenia and/or haemorrhage persist despite HPA-compatible platelets, intravenous IgG (total dose 2 g/kg over 2—5 days) is often useful in ameliorating the thrombocytopenia until spontaneous recovery occurs 1—6 weeks after birth [1,12]. The risk of recurrence of NAIT in subsequent pregnancies is high. Management of such dat riskT pregnancies is controversial and beyond the scope of this review (reviewed in Ref. [12]).
7.3. Platelet transfusion Platelet transfusion is the only available immediate and specific therapy for the remaining causes of thrombocytopenia since there are no available haemopoietic growth factors of clinical benefit in neonatal thrombocytopenia. Platelet transfusion confers one of the highest risks of transfusionrelated infections and reactions of all blood products. However, there is no clear evidencebased practice to guide clinicians in the appropriate use of platelet transfusions in neonates. Instead, a number of consensus-based guidelines have been devised [1,15]. Current US guidelines suggest that in stable neonates prophylactic platelet transfusion is probably justified at platelet counts below 50109/l, or in the case of very sick or preterm neonates when counts fall below 100109/l. In contrast, UK guidelines suggest lower thresholds of 30 and 50109/l, respectively [15]. In the retrospective review of severe thrombocytopenia, we carried out recently in our unit, 53 (6%) of the 901 admissions to the NICU over a 3-year period developed at least 1 episode of severe thrombocytopenia and 27/53 (51%) received at least 1 platelet transfusion; nearly all of these neonates had late-onset sepsis or NEC [11]. Nevertheless, 5 of the 44 preterm neonates developing severe thrombocytopenia died prior to discharge. All five had a platelet nadir b30109/l and all had received platelet transfusions. Significant haemorrhage (intraventricular haemorrhage grades 3—4) was common, occurring in 7/44 (16%) of the group as a whole. However, the initial bleeding episode had almost invariably occurred prior to the development of severe thrombocytopenia. Conversely, of the severely thrombocytopenic preterm neonates who were otherwise clinically stable and who were therefore not treated by platelet transfusion
S. Chakravorty et al. (19/44 patients), none suffered significant haemorrhage or died prior to discharge. Thus, in our preterm patients with late-onset sepsis and NEC, poor outcome was more closely related to the overall clinical condition than to the degree of thrombocytopenia or response to platelet transfusion. This suggests that prophylactic platelet transfusions should be considered in otherwise stable preterm neonates only when the platelet count falls below 30109/l. This now forms part of our own NICU guidelines as well as those recommended in the recent British Committee for Standards in Haematology guidelines [15]. The principal indications for platelet transfusion in neonates are summarised in Table 3. These guidelines are based on the principles discussed above and take into account the clinical condition of the neonate and the rate of fall of the platelet count as well as the absolute count. Precise definitions of clinical instability are difficult and reflect the predicted risk of bleeding. Studies to more precisely measure the impact of platelet transfusion in the management of thrombocytopenic neonates are currently in progress. A further uncertainty is the optimal volume and frequency of platelet transfusion for thrombocytopenic neonates. It is useful to measure the 1 h posttransfusion platelet count following each platelet transfusion in NICU patients, as this provides an assessment of the effectiveness of the transfusion (by documenting the platelet increment) and helps to predict the need for and timing of further platelet transfusions. It is also worth noting that a good platelet increment suggests platelet underproduction and predicts a good response to platelet transfusion therapy, whereas a poor platelet increment suggests that there is significant platelet
Table 3 Guidelines for platelet transfusion in term and preterm neonates ! Platelet count b30109/l In otherwise well infants, including NAIT, if no bleeding and no family history of ICH ! Platelet count b50109/l In infants with: clinical instability concurrent coagulopathy birth weight b1000 g and age b1 week previous major bleeding (e.g. Grade 3/4 IVH) current minor bleeding (e.g. petechiae) planned surgery or exchange transfusion platelet count falling and likely to fall b30 NAIT if previous affected sib with ICH Modified from: Gibson et al. [15]. Abbreviations: NAIT: Neonatal alloimmune thrombocytopenia, ICH: Intracranial haemorrhage, IVH: Intraventricular haemorrhage.
Neonatal thrombocytopenia consumption, which is unlikely to respond to platelet transfusion alone.
41 needed in order to properly assess the indications for platelet transfusion, the optimum dose and schedule of administration and its therapeutic effects in the short- and long-term.
8. Research directions There have been several advances in our understanding of the pathogenesis both of acquired and inherited causes of neonatal thrombocytopenia in recent years [1,3]. These have revealed the importance of thrombopoietin [7] and its receptor [3] to fetal and neonatal platelet production. However, despite the availability of thrombopoietin, both in recombinant form and as a mimetic peptide, its therapeutic potential has still not been realised either in adults or in neonates. It seems unlikely that thrombopoietin will play a major role in therapy of neonatal thrombocytopenia as an alternative to platelet transfusion mainly because in vivo studies in animal models and in adults indicate that it takes more than a week to increase the platelet count [1]. Interleukin-11 (IL-11) is another cytokine, which stimulates megakaryopoiesis and platelet production in vivo and in vitro and is available in recombinant form for administration to humans. There are no data about recombinant IL-11 in neonatal thrombocytopenia but in view of its beneficial effects in animal models of NEC and sepsis it remains a potential therapeutic prospect for the future [1].
9. Key guidelines ! !
!
!
Around one third of preterm neonates cared for in NICU develop thrombocytopenia Early-onset thrombocytopenia in preterm neonates is most commonly due to disorders associated with placental insufficiency, particularly IUGR and maternal hypertension; this is usually mild-moderate, self-limiting and does not require treatment Late-onset thrombocytopenia in preterm neonates is most commonly due sepsis and NEC; this is often severe (platelets b50 10 9 /l) and requires treatment by platelet transfusion Evidence-based guidelines for platelet transfusion for neonatal thrombocytopenia are
References [1] Roberts IAG, Murray NA. Thrombocytopenia in the newborn. Curr Opin Pediatr 2003;15:17 — 23. [2] Blanchette VS, Rand ML. Platelet disorders in newborn infants: diagnosis and management. Semin Perinatol 1997; 21:53 — 62. [3] Geddis AE, Kaushansky K. Inherited thrombocytopaenis: toward a molecular understanding of disorders of platelet production. Curr Opin Pediatr 2004;16:15 — 22. [4] Pahal G, Jauniaux E, Kinnon C, Thrasher AJ, Rodeck CH. Normal development of human fetal haemopoiesis between eight and seventeen weeks’ gestation. Am. J. Obstet.Gynecol. 2000;183:1029—34. [5] Forestier F, Daffos F, Galactaros F. Haematological values of 163 normal fetuses between 18 and 30 weeks of gestation. Pediatr Res 1986;30:342 — 6. [6] Murray NA, Roberts IAG. Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates. Pediatr Res 1996;40:112 — 9. [7] Murray NA, Watts TL, Roberts IAG. Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res 1998;43:148 — 51. [8] Sainio S, Jarvenpaa AL, Renlund M, Riikonen S, Teramo K, Kekomaki R. Thrombocytopenia in term infants: a population-based study. Obstet Gynecol 2000;95:441 — 6. [9] de Moerloose P, Boehlen F, Extermann P, Hohfeld P. Neonatal thrombocytopenia: incidence and characterization of maternal antiplatelet antibodies by MAIPA assay. Br J Haematol 1998;100:735 — 40. [10] Uhrynowska M, Niznikowska-Marks M, Zupanska B. Neonatal and maternal thrombocytopenia: incidence and immune background. Eur J Haematol 2000;64:42 — 6. [11] Murray NA, Howarth LJ, McCloy MP, Letsky EA, Roberts IAG. Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfus Med 2002;12:35 — 41. [12] Bussel JB. Alloimmune thrombocytopenia in the fetus and newborn. Semin Thromb Hemost 2001;27:245 — 52. [13] Jhawar BS, Ranger A, Steven D, Del Maestro RF. Risk factors for intracranial hemorrhage among full-term infants: a case-control study. Neurosurgery 2003;52:581 — 90. [14] Andrew M, Castle V, Saigal S, Carter C, Kelton JG. Clinical impact of neonatal thrombocytopenia. J Pediatr 1987; 110:457 — 64. [15] Gibson BE, Todd A, Roberts I, Pamphilon D, Rodeck C, Bolton-Maggs P, et al. British Committee for Standards in Haematology Transfusion Task Force: Writing Group. Transfusion guidelines for neonates and older children. Br J Haematol 2004;124:433 — 53.
www.elsevier.com/locate/earlhumdev
Neonatal thrombocytopenia Subarna Chakravortya, Neil Murrayb,1, Irene Robertsc,* a
Department of Haematology, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK Department of Neonatal Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK c Department of Haematology, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK b
KEYWORDS Neonatal thrombocytopenia; Platelets; Platelet transfusion; Alloimmune thrombocytopenia
Abstract Thrombocytopenia occurs in up to a third of preterm neonates admitted to intensive care units. In these babies, thrombocytopenia typically presents in one of two patterns: early-onset thrombocytopenia occurring within 72 h of birth and lateonset thrombocytopenia which develops after 72 h. Early-onset thrombocytopenia is most commonly caused by disorders associated with placental insufficiency (e.g. maternal hypertension), is mild-moderate, self-limiting and requires no treatment; it is caused by reduced platelet production. Late-onset thrombocytopenia is usually due to bacterial sepsis or necrotising enterocolitis; it is often severe (platelets b50109/l), prolonged and requires treatment with platelet transfusions. In term babies, neonatal thrombocytopenia is usually severe and most commonly caused by bacterial sepsis, perinatal asphyxia or neonatal alloimmune thrombocytopenia. There is a lack of evidence-based guidelines for treatment of neonatal thrombocytopenia. The most important future developments will depend upon studies aimed at determining optimal platelet transfusion schedules for term and preterm neonates. D 2004 Elsevier Ireland Ltd. All rights reserved.
1. Introduction With the exception of phlebotomy-induced anaemia, thrombocytopenia is the commonest haematological abnormality encountered in the neonatal period [1]. Although there is a vast number of causes of neonatal thrombocytopenia, including * Corresponding author. Tel.: +44 208 383 2163; fax: +44 208 742 9335. E-mail addresses: [email protected] (N. Murray)8 [email protected] (I. Roberts). 1 Tel.: +44 208 383 2476; fax: +44 208 740 8281.
rare inherited causes [1—3], only a few are commonly encountered in neonatal practice and are therefore most clinically relevant. The spectrum of thrombocytopenia includes, on the one hand, the extremely sick premature neonate with profound thrombocytopenia secondary to sepsis in whom the impact of a major haemorrhage may be catastrophic but whose survival will depend mainly on successful treatment of infection, and, on the other hand, severe isolated thrombocytopenia in a term neonate who is otherwise well and for whom the clinical outcome may solely depend on the impact of the thrombocytopenia. It is therefore
0378-3782/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2004.10.013
36 important to recognise the common causes of thrombocytopenia and identify appropriate investigation and management of individual cases. Our understanding of the pathogenesis and natural history of neonatal thrombocytopenia has improved considerably in recent years. This helps us provide appropriately tailored management in individual cases and paves the way for new therapeutic approaches. In this review, we will discuss our current knowledge of the incidence, pathogenesis and management of neonatal thrombocytopenia.
S. Chakravorty et al. sented neonates of low birth weight, the high risk population for neonatal thrombocytopenia [10].
4. Causes of neonatal thrombocytopenia 4.1. Natural history of thrombocytopenia as a guide to diagnosis Recent studies show that most cases of neonatal thrombocytopenia fall into two main groups depending upon the age of the neonate when the
2. Definition of thrombocytopenia By the end of the first trimester of pregnancy, the fetal platelet count has already reached 150109/l [4] and rises further to 175—250109/l by the middle of the second trimester [5]. Thus, platelet counts of b150109/l define thrombocytopenia in any neonate regardless of gestational age. Although the healthy fetus or neonate can generate and maintain a circulating platelet count similar to that of adults, several studies indicate that sick neonates often have reduced platelet producing capacity compared to that of adults and this may become increasingly evident during times of increased platelet demand [1,6,7].
3. Incidence of neonatal thrombocytopenia The incidence of neonatal thrombocytopenia varies greatly, depending upon the population studied, from b1% in healthy term babies to around one third of neonates admitted to neonatal intensive care units (NICU). In a recent, population-based prospective study in Helsinki of 4489 term infants, they found that the incidence of thrombocytopenia (platelet counts of b150109/l) on cord blood testing was 2% (95% CI 1.5—2.3) with severe thrombocytopenia (platelet counts b50109/l) occurring in 0.24% of cases (95% CI 0.10—0.38) [8]. In another large study of 8388 newborns, thrombocytopenia (b150109/l) was found in 0.5% of cases (95% CI 0.3— 0.6), of which 0.12% were severe (platelet count b50109/l) (95% CI 0.05—0.20) [9]. However, the incidence of thrombocytopenia in preterm neonates in NICU is much higher, consistently reaching 22—35% in our unit, with severe thrombocytopenia (platelets b50109/l) in 6% of all admissions (these babies) [8,9]. Data from other recent studies are more difficult to interpret since they include only neonates with platelet counts b100109/l or, because of methodological difficulties, have under-repre-
Table 1 Causes of fetal and early neonatal thrombocytopenia Placental insufficiency Maternal hypertension Intrauterine growth restriction (IUGR) Maternal diabetes Immune Alloimmune Autoimmune (maternal ITP) Neonatal lupus Infection Congenital: CMV, toxoplasma, rubella, HIV, coxsackie Perinatal: Group B streptococcus, Haemophilus influenzae, E. coli Congenital/inherited Aneuploidy: trisomies 13, 18 and 21; triploidy Bone marrow failure affecting megakaryocytes (e.g. congenital amegakaryocytic thrombocytopenia, thrombocytopenia absent radii syndrome) Bone marrow failure syndromes with pancytopenia (e.g. Fanconi anaemia) Myelodysplasia (e.g. Monosomy 7) Immunodeficiencies (e.g. Wiskott Aldrich, Haemophagocytic Lymphohistiocytosis) Platelet function disorders with thrombocytopenia (e.g. Bernard Soulier syndrome) Disseminated intravascular coagulation Perinatal asphyxia Bacterial infection Whole body cooling Congenital thrombotic thrombocytopenic purpura (ADAMTS-13 deficiency) Other (rare in most NICU) Thrombosis-aortic, renal Kasabach Merritt Hepatic haemangioendothelioma Metabolic-propionic acidaemia, methylmalonic acidaemia Congenital leukaemia Heparin-induced thrombocytopenia (HIT) Subcutaneous fat necrosis of the newborn (SCFN) Exchange transfusion Rhesus haemolytic disease of the newborn Commonest causes shown in italics.
Neonatal thrombocytopenia thrombocytopenia first develops [1]. Early-onset thrombocytopenia develops either in utero or within the first 72 h of birth; the main causes are listed in Table 1. Late-onset thrombocytopenia presents after the first 72 h of age; the main causes are listed in Table 2. This simple classification is a useful starting point for working out the cause (and therefore the most useful diagnostic tests) of the majority of episodes of neonatal thrombocytopenia.
4.2. Early-onset neonatal thrombocytopenia Thrombocytopenia associated with placental insufficiency is the commonest pattern of early-onset thrombocytopenia in neonates. In the absence of conditions causing platelet consumption (e.g. infection), precipitous falls in platelet count in such neonates are uncommon, the platelet count rarely falls below 50109/l and platelet recovery is spontaneous [6,7]. This form of thrombocytopenia is therefore usually a benign condition with little evidence of clinically important haemorrhage and treatment is rarely required unless additional complications, such as sepsis, develop. By contrast, early neonatal thrombocytopenia, which does not conform to the above pattern, is likely to be a marker of significant pathology, which requires further investigation. Severe thrombocytopenia (platelet count b50 109/l) within 72 h of birth is uncommon [11]. This may be due to perinatal asphyxia or perinatally acquired bacterial infection (e.g. Group B streptococcus) in which case further investigation is unnecessary. However, an early presentation of severe neonatal thrombocytopenia usually has its origin in fetal life and further investigations need to be organised, often urgently; the most likely causes are [1,2,3,11]: ! ! ! !
allo- or autoimmune thrombocytopenia congenital infections (particularly with cytomegalovirus) aneuploidy (particularly trisomies 18, 13 and 21 or triploidy) congenital/inherited thrombocytopenias.
Table 2
Causes of late neonatal thrombocytopenia
Bacterial sepsis Necrotising enterocolitis Congenital infection Congenital/inherited bone marrow failure syndromes Disseminated intravascular coagulation Other: late diagnosis of immune thrombocytopenia, rarities (see Table 1) Commonest causes shown in italics.
37 Early-onset neonatal thrombocytopenia which persists for more than 7—10 days is also unusual and warrants further investigation. As most other forms of thrombocytopenia will have resolved by this time, the likely causes of prolonged thrombocytopenia are: immune thrombocytopenias, congenital infections and congenital/inherited thrombocytopenias.
4.3. Late-onset thrombocytopenia (N72 h after birth) In the setting of NICU, late-onset thrombocytopenia is almost always caused by bacterial sepsis or necrotising enterocolitis (NEC) [11]. This type of thrombocytopenia has a distinctly different pattern to that seen in early-onset thrombocytopenia associated with placental insufficiency. It occurs usually as an isolated thrombocytopenia and develops concurrently with, or sometimes precedes by up to 24 h, other evidence of sepsis or NEC. In this situation, thrombocytopenia progresses rapidly with a platelet nadir reached within 24—48 h; it is often severe (plateletsb50109/l) and prolonged, persisting until sepsis or NEC is controlled, followed by a slow recovery over 1—2 weeks [11]. In a recent retrospective survey of severe thrombocytopenia in admissions to our NICU, this pattern of late-onset thrombocytopenia developed in 6% of all admissions [11].
5. Mechanisms of thrombocytopenia Neonatal thrombocytopenia may develop either as a result of reduced platelet production secondary to reduced megakaryopoiesis (the process by which megakaryocytes are produced from their progenitor cells in the bone marrow or, in fetal life, in the liver); or alternatively the thrombocytopenia may be due to increased platelet destruction or sequestration. Examples of thrombocytopenia due to reduced platelet production are those which occur secondary to placental insufficiency [6,7] and those which occur as part of inherited bone marrow failure syndromes. The most common reasons for thrombocytopenia due to increased destruction/sequestration are neonatal alloimmune thrombocytopenia (NAIT) [2,12] and disseminated intravascular coagulation (DIC) in association with perinatal asphyxia or NEC [11]. In many instances, an individual neonate will have a combination of both mechanisms, e.g. impaired platelet production as a result of placental insufficiency combined with increased
38
S. Chakravorty et al.
Figure 1 Diagnostic approach to thrombocytopenia in preterm neonates. Abbreviations: Plts—platelets, Hrs—hours, NAIT: neonatal alloimmune thrombocytopenia, NEC: necrotising enterocolitis.
platelet consumption during an episode of lateonset sepsis or NEC.
6. Diagnostic approach to neonatal thrombocytopenia We use a diagnostic approach based on the gestational age, the age at presentation and the severity of the thrombocytopenia. A diagnostic algorithm for preterm babies is shown in Fig. 1 and for term babies in Fig. 2.
In preterm babies with early-onset thrombocytopenia, where there is good evidence of placental insufficiency and thrombocytopenia is mild and recovers within 10—14 days, there is no need for further investigations. In the remaining cases screening for bacterial and congenital infections should be carried out and immune causes sought only where these are negative or the thrombocytopenia is severe (b50109/l). Investigation for NAIT is described below. For preterm babies with late-onset thrombocytopenia, NAIT is an unlikely cause but should be excluded if the thrombocytopenia remains unexplained. Persistent thrombocy-
Figure 2 Diagnostic approach to thrombocytopenia in term neonates. Abbreviations: Plts—platelets, NAIT: neonatal alloimmune thrombocytopenia, DIC: disseminated intravascular coagulation.
Neonatal thrombocytopenia topenia in the absence of infective, immune or placental problems should prompt a search for the rare disorders listed in Table 1. Further investigations should be discussed with the haematologist as a bone marrow examination is usually necessary. In term babies, the clinical presentation with thrombocytopenia is either with a significant haemorrhage or as an incidental finding, sometimes after minor haemorrhagic signs (e.g. petechiae), have been noted. If the baby is otherwise well, the most likely explanation is NAIT and, in the term baby, this is the most important diagnosis to identify, particularly where the platelet count is b50109/l [12]. To diagnose NAIT, blood should be sent from the mother, baby and if possible the father. This will allow the identification of the human platelet antigen (HPA) genotype of the mother, baby and father and determine whether the mother has anti-HPA antibodies against paternally derived platelet antigens expressed by the baby. In the majority of cases (80%) the mother is HPA-1a-negative with anti-HPA-1a antibodies directed against the baby’s platelets which are HPA-1apositive. A further 10—15% of cases are due to antiHPA-5b. In some cases, a presumptive diagnosis has to be made on the basis of HPA-incompatibility between the mother and baby as the antibodies have a low titre in vitro despite their strong activity in vivo [1,12].
7. Management of neonatal thrombocytopenia 7.1. General principles While a number of studies highlight the association between thrombocytopenia and poor outcome in neonates [1,11,13], the direct contribution of thrombocytopenia to the clinical course of these neonates is difficult to assess. Most studies suggest that neonatal thrombocytopenia in general, as well as in the specific situation of NAIT, is a risk factor for significant haemorrhage (particularly intracranial haemorrhage), for mortality and for adverse neurodevelopmental outcome [1,11—13]. Apart from NAIT, most studies do not make it clear whether neonatal thrombocytopenia directly contributes to adverse outcome or is simply a marker of the severity of concurrent neonatal complications (e.g. birth asphyxia or severe sepsis). This is partly because there have been no trials in neonates with severe thrombocytopenia (platelets b50109/l) to address whether prophylactic platelet transfusion reduces haemorrhage and improves
39 outcome. The only trial of prophylactic platelet transfusion in neonates was limited to those with platelet counts between 50 and 150109/l and this failed to show any benefit [14]. Despite a paucity of evidence-based studies, the overall conclusion that can be drawn from the data available is that neonatal thrombocytopenia is linked both to an increased risk of haemorrhage and to a poorer outcome [13,15]. The aim in management of this complication is therefore to reduce these risks. To achieve this, we suggest the following approach: ! ! !
identification of the likely cause of the thrombocytopenia specific management tailored to the cause (e.g. for NAIT) appropriate administration of platelet transfusions.
Identification of the cause of the thrombocytopenia helps to predict its likely pattern and enable appropriate monitoring of the platelet count, which is particularly important in conditions where precipitous falls in platelet count are common, e.g. sepsis and NAIT. This allows the planned use of prophylactic platelet transfusion. In addition, deviations from the expected pattern of thrombocytopenia alert the clinician to possible alternative reasons for thrombocytopenia that may require more specific investigations or management, e.g. congenital bone marrow failure syndromes.
7.2. Management of NAIT NAIT should be suspected in any neonate with unexplained thrombocytopenia. Babies who present with very severe thrombocytopenia (platelets b30109/l) and/or those with evidence of intracranial or other major bleeding, should be promptly transfused with HPA-compatible platelets. In 95% of cases, HPA-1a negative/HPA-5b negative platelets are suitable. In the UK, there is a pool of suitable donors and these platelets are available at short notice from the National Blood Service; washed maternal platelets are no longer recommended except in rare emergencies [1,12,15]. In severely affected babies with suspected NAIT, it is not necessary to wait for the results of serological investigations before giving HPA-compatible platelets because of the risks of haemorrhage associated with delay. By contrast, babies with NAIT who have platelet counts above 30109/l do not require platelet transfusion except in the unusual situation of severe haemorrhage [12,15]. It is, however, important to monitor
40 the platelet count in every baby with NAIT as it will fall over the first 4—5 days of life and may reach the severely affected range; similarly, all babies with NAIT should have intracranial haemorrhage excluded (cranial ultrasound is sufficient in most cases). If severe thrombocytopenia and/or haemorrhage persist despite HPA-compatible platelets, intravenous IgG (total dose 2 g/kg over 2—5 days) is often useful in ameliorating the thrombocytopenia until spontaneous recovery occurs 1—6 weeks after birth [1,12]. The risk of recurrence of NAIT in subsequent pregnancies is high. Management of such dat riskT pregnancies is controversial and beyond the scope of this review (reviewed in Ref. [12]).
7.3. Platelet transfusion Platelet transfusion is the only available immediate and specific therapy for the remaining causes of thrombocytopenia since there are no available haemopoietic growth factors of clinical benefit in neonatal thrombocytopenia. Platelet transfusion confers one of the highest risks of transfusionrelated infections and reactions of all blood products. However, there is no clear evidencebased practice to guide clinicians in the appropriate use of platelet transfusions in neonates. Instead, a number of consensus-based guidelines have been devised [1,15]. Current US guidelines suggest that in stable neonates prophylactic platelet transfusion is probably justified at platelet counts below 50109/l, or in the case of very sick or preterm neonates when counts fall below 100109/l. In contrast, UK guidelines suggest lower thresholds of 30 and 50109/l, respectively [15]. In the retrospective review of severe thrombocytopenia, we carried out recently in our unit, 53 (6%) of the 901 admissions to the NICU over a 3-year period developed at least 1 episode of severe thrombocytopenia and 27/53 (51%) received at least 1 platelet transfusion; nearly all of these neonates had late-onset sepsis or NEC [11]. Nevertheless, 5 of the 44 preterm neonates developing severe thrombocytopenia died prior to discharge. All five had a platelet nadir b30109/l and all had received platelet transfusions. Significant haemorrhage (intraventricular haemorrhage grades 3—4) was common, occurring in 7/44 (16%) of the group as a whole. However, the initial bleeding episode had almost invariably occurred prior to the development of severe thrombocytopenia. Conversely, of the severely thrombocytopenic preterm neonates who were otherwise clinically stable and who were therefore not treated by platelet transfusion
S. Chakravorty et al. (19/44 patients), none suffered significant haemorrhage or died prior to discharge. Thus, in our preterm patients with late-onset sepsis and NEC, poor outcome was more closely related to the overall clinical condition than to the degree of thrombocytopenia or response to platelet transfusion. This suggests that prophylactic platelet transfusions should be considered in otherwise stable preterm neonates only when the platelet count falls below 30109/l. This now forms part of our own NICU guidelines as well as those recommended in the recent British Committee for Standards in Haematology guidelines [15]. The principal indications for platelet transfusion in neonates are summarised in Table 3. These guidelines are based on the principles discussed above and take into account the clinical condition of the neonate and the rate of fall of the platelet count as well as the absolute count. Precise definitions of clinical instability are difficult and reflect the predicted risk of bleeding. Studies to more precisely measure the impact of platelet transfusion in the management of thrombocytopenic neonates are currently in progress. A further uncertainty is the optimal volume and frequency of platelet transfusion for thrombocytopenic neonates. It is useful to measure the 1 h posttransfusion platelet count following each platelet transfusion in NICU patients, as this provides an assessment of the effectiveness of the transfusion (by documenting the platelet increment) and helps to predict the need for and timing of further platelet transfusions. It is also worth noting that a good platelet increment suggests platelet underproduction and predicts a good response to platelet transfusion therapy, whereas a poor platelet increment suggests that there is significant platelet
Table 3 Guidelines for platelet transfusion in term and preterm neonates ! Platelet count b30109/l In otherwise well infants, including NAIT, if no bleeding and no family history of ICH ! Platelet count b50109/l In infants with: clinical instability concurrent coagulopathy birth weight b1000 g and age b1 week previous major bleeding (e.g. Grade 3/4 IVH) current minor bleeding (e.g. petechiae) planned surgery or exchange transfusion platelet count falling and likely to fall b30 NAIT if previous affected sib with ICH Modified from: Gibson et al. [15]. Abbreviations: NAIT: Neonatal alloimmune thrombocytopenia, ICH: Intracranial haemorrhage, IVH: Intraventricular haemorrhage.
Neonatal thrombocytopenia consumption, which is unlikely to respond to platelet transfusion alone.
41 needed in order to properly assess the indications for platelet transfusion, the optimum dose and schedule of administration and its therapeutic effects in the short- and long-term.
8. Research directions There have been several advances in our understanding of the pathogenesis both of acquired and inherited causes of neonatal thrombocytopenia in recent years [1,3]. These have revealed the importance of thrombopoietin [7] and its receptor [3] to fetal and neonatal platelet production. However, despite the availability of thrombopoietin, both in recombinant form and as a mimetic peptide, its therapeutic potential has still not been realised either in adults or in neonates. It seems unlikely that thrombopoietin will play a major role in therapy of neonatal thrombocytopenia as an alternative to platelet transfusion mainly because in vivo studies in animal models and in adults indicate that it takes more than a week to increase the platelet count [1]. Interleukin-11 (IL-11) is another cytokine, which stimulates megakaryopoiesis and platelet production in vivo and in vitro and is available in recombinant form for administration to humans. There are no data about recombinant IL-11 in neonatal thrombocytopenia but in view of its beneficial effects in animal models of NEC and sepsis it remains a potential therapeutic prospect for the future [1].
9. Key guidelines ! !
!
!
Around one third of preterm neonates cared for in NICU develop thrombocytopenia Early-onset thrombocytopenia in preterm neonates is most commonly due to disorders associated with placental insufficiency, particularly IUGR and maternal hypertension; this is usually mild-moderate, self-limiting and does not require treatment Late-onset thrombocytopenia in preterm neonates is most commonly due sepsis and NEC; this is often severe (platelets b50 10 9 /l) and requires treatment by platelet transfusion Evidence-based guidelines for platelet transfusion for neonatal thrombocytopenia are
References [1] Roberts IAG, Murray NA. Thrombocytopenia in the newborn. Curr Opin Pediatr 2003;15:17 — 23. [2] Blanchette VS, Rand ML. Platelet disorders in newborn infants: diagnosis and management. Semin Perinatol 1997; 21:53 — 62. [3] Geddis AE, Kaushansky K. Inherited thrombocytopaenis: toward a molecular understanding of disorders of platelet production. Curr Opin Pediatr 2004;16:15 — 22. [4] Pahal G, Jauniaux E, Kinnon C, Thrasher AJ, Rodeck CH. Normal development of human fetal haemopoiesis between eight and seventeen weeks’ gestation. Am. J. Obstet.Gynecol. 2000;183:1029—34. [5] Forestier F, Daffos F, Galactaros F. Haematological values of 163 normal fetuses between 18 and 30 weeks of gestation. Pediatr Res 1986;30:342 — 6. [6] Murray NA, Roberts IAG. Circulating megakaryocytes and their progenitors in early thrombocytopenia in preterm neonates. Pediatr Res 1996;40:112 — 9. [7] Murray NA, Watts TL, Roberts IAG. Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res 1998;43:148 — 51. [8] Sainio S, Jarvenpaa AL, Renlund M, Riikonen S, Teramo K, Kekomaki R. Thrombocytopenia in term infants: a population-based study. Obstet Gynecol 2000;95:441 — 6. [9] de Moerloose P, Boehlen F, Extermann P, Hohfeld P. Neonatal thrombocytopenia: incidence and characterization of maternal antiplatelet antibodies by MAIPA assay. Br J Haematol 1998;100:735 — 40. [10] Uhrynowska M, Niznikowska-Marks M, Zupanska B. Neonatal and maternal thrombocytopenia: incidence and immune background. Eur J Haematol 2000;64:42 — 6. [11] Murray NA, Howarth LJ, McCloy MP, Letsky EA, Roberts IAG. Platelet transfusion in the management of severe thrombocytopenia in neonatal intensive care unit patients. Transfus Med 2002;12:35 — 41. [12] Bussel JB. Alloimmune thrombocytopenia in the fetus and newborn. Semin Thromb Hemost 2001;27:245 — 52. [13] Jhawar BS, Ranger A, Steven D, Del Maestro RF. Risk factors for intracranial hemorrhage among full-term infants: a case-control study. Neurosurgery 2003;52:581 — 90. [14] Andrew M, Castle V, Saigal S, Carter C, Kelton JG. Clinical impact of neonatal thrombocytopenia. J Pediatr 1987; 110:457 — 64. [15] Gibson BE, Todd A, Roberts I, Pamphilon D, Rodeck C, Bolton-Maggs P, et al. British Committee for Standards in Haematology Transfusion Task Force: Writing Group. Transfusion guidelines for neonates and older children. Br J Haematol 2004;124:433 — 53.