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Neonatal thrombocytopenia
Current Paediatrics (1998) 8, 212-214 © 1998 Harcourt Brace & Co. Ltd
Symposium: Haematology
Neonatal thrombocytopenia
R.O. Garr, A.M. Weindling second most common mechanism is pooling of platelets. This occurs when there is hypersplenism, often associated with serious infection, e.g. gram-negative sepsis or fungaemia. Decreased platelet production is very rare, and occurs when there is bone marrow aplasia or replacement as in, for example, histiocytosis, congenital leukaemia, osteopetrosis or neuroblastoma.
INTRODUCTION The normal platelet count is between 150x109/1 and 450x109/1. The incidence of thrombocytopenia during the neonatal period, irrespective of aetiology, has been reported as being between 0.12% and 22%. The essence of the management of thrombocytopenia is treatment of the underlying cause. The problem that concerns clinicians most is when to give a platelet transfusion, particularly since the most serious consequence of thrombocytopenia is intracranial haemorrhage, although this is thankfully rare. Although there are no randomized clinical trials to guide practice, there have been a number of case reports. The general view is that the risk of bleeding increases when the platelet count drops to below 20 x 109/1. Bleeding is also more common if thrombocytopenia is associated with defective platelet function. Our own clinical practice is not to treat thrombocytopenia with platelet transfusion unless there is bleeding from mucous membranes or puncture sites, or the platelet count is below 10 ×109/1.
Table i
Diseases associated with neonatal thrombocytopenia (Adapted from Nathan & Oski 'The Hemostatic System in the Infant' in Nathan Oski 'Haematology of Infancy and Childhood' 4e, 1993 Reproduced with kind permission from the publisher (a) Increased destruction/consumption (1) Immune-mediated Maternal Idiopathic thrombocytopenic purpura Systemic lupus erythematosus Hypothyroidism Drugs (Thiazides, Quinine, Hydrallazine, Tolbutamide, Heparin) Pre-eclampsia Neonatal Allo-immune (2) Non-immune (probably DIC-related) Neonatal asphyxia Necrotizing enterocolitis Neonatal thrombosis (3) Other Polycythaemia Rhesus haemolytic disease Congenital thrombotic thrombocytopenic purpura Wiskott-Aldrich syndrome (b) Sequestration Giant haemangiomas Hypersplenism Hypothermia (c) Decreased platelet production (1) Bone marrow replacement Congenital leukaemia and leukaemoid reactions Neuroblastoma Histiocytosis Osteopetrosis (2) Bone marrow aplasia Thrombocytopenia with absent radius Megakaryocytic thrombocytopenia Fanconi's anaemia
AETIOLOGY The causes of thrombocytopenia are varied, as shown in Table 1. Broadly, there are three possible mechanisms: decreased platelet production, increased platelet destruction, or platelet pooling. Increased platelet destruction is the most common and usually occurs when there is disseminated intravascular coagulation (DIC) or because of an immune mediated disorder like allo-immune thrombocytopenia. The Dr R.O. Garr, Research fellow, Professor A.M. Weindling,
Consultant Neouatologist The Regional Neonatal Intensive Care Unit, Department of Child Health, Liverpool Women's Hospital, Crown Street, Liverpool L8 7SS, UK. Correspondence and requests for offprints to ROG. 212
Neonatal thrombocytopenia The average life span of platelets is 7-10 days in normal subjects but can be considerably shorter in thrombocytopenic patients. Treatment
It is axiomatic that treatment should be aimed at the underlying cause. Platelet concentrates may be used if the baby is actively bleeding or if surgical intervention is planned including any invasive procedures such as arterial sampling, lumbar puncture or ventricular taps. Platelet concentrate at 15-20 ml/kg is used. It is important to irradiate platelet concentrates to prevent graft versus host disease.
ALLO-IMMUNE THROMBOCYTOPENIA Antiplatelet antibodies were identified in 1951. Since then a number of syndromes have been described. The most common is neonatal allo-immune thrombocytopenia, which has an incidence of 1 in 2-5000 livebirths. This serious disorder is associated with profound thrombocytopenia in the fetus and neonate. Consumption of platelets is caused by maternal antibody directed against a fetal platelet antigen inherited from the father and lacking in the mother's platelets, usually the platelet-specific alloantigen P1A1. Most mothers with thrombocytopenia irrespective of aetiology have babies with normal platelet counts. This was demonstrated by a large prospective study which compared the platelet counts of mothers and babies. Six percent of the mothers had platelet counts <150,000 x109/1 while a platelet count of <50,000 x 109/1 was found in 0.12% of the cord samples. The majority of mothers with thrombocytopenia had babies with normal platelet counts. The same study found that the highest incidence of neonatal thrombocytopenia was 33% in babies of mothers with alloimmune thrombocytopenia, 8.6% in babies of mothers with idiopathic thrombocytopenic purpura, and 0.35% in babies of mothers with hypertension. The diagnosis of allo-immune thrombocytopenia is often based on a history of an affected child, parental phenotyping and fetal/neonatal platelet counts. Intracranial haemorrhage may occur in utero. The clinical presentation of allo-immune thrombocytopenia during the neonatal period is of a baby with petechiae and low platelet count who is otherwise healthy. The platelet count usually drops in the first 2 days and then stabilizes. Treatment of allo-immune thrombocytopenia has been controversial. Various therapeutic approaches have been used, but there have been no controlled trials. In 1991, Morgan, using an isolated perfused lobule of human placenta in studies in vitro, showed that intravenous immunoglobulin inhibited antiplatelet antibody transfer. There have been a number of other case series and studies, all small and none randomized,
213
reporting an increase in the fetal platelet count in mothers given weekly intravenous immunoglobulin. All reported no intracranial haemorrhage in the fetus. In utero, platelet transfusions have been reported as effective although none of the studies were randomized. Two approaches have been used: (a) Platelet transfusion at 21 and 38 weeks', and (b) weekly platelet transfusions from 26 weeks' to term. The first approach was used by Kaplan who described a series of nine patients where accurate diagnosis was only possible by repeated fetal blood sampling (FBS) under ultrasound guidance. The first FBS was started at 21 weeks' gestation if fetal thrombocytopenia was detected, washed platelets preferably from the mother were infused. This was repeated at 38 weeks' before delivery. In the intervening period, monthly ultrasound scans were carried out paying particular attention to intracranial haemorrhage. In this study the fetus was selectively immobilized by the administration of vecuronium into the umbilical vein. Washed, irradiated maternal platelets were used. The volume of platelets infused was calculated by the formula V=VSF (C3-C1)/C2, where VSF= estimated fetal blood volume (according to fetal weight estimation), C1 = platelet concentration before transfusion, C2= platelet concentration in the product to be transfused (maternal platelet concentrate), and C3= platelet concentration desired at the end of transfusion. This works out to 58 ml for a fetus with an estimated weight of 500 g and a platelet count of 20 x 109/1, if the intention is to raise the platelet count to 100 x 109/1. No abnormal side-effects were noted. A pragmatic approach is used at the Liverpool Women's Hospital. Intravenous immnnoglobulin is given to the mother until 28 weeks' gestation and then intrauterine transfusions of platelets if thrombocytopenia is found in the fetal blood samples between 28 weeks' gestation and term. If an intrauterine transfusion is required, delivery is by caesarean section. In the last 2 years, four fetuses have been treated by weekly intrauterine transfusions of platelets. The initial median fetal platelet count was 33 x 109/1, and the range was between 5 and 220 x109/1. The median volume of platelets infused was 55 ml (range 20-100 ml). No adverse effects have been recorded in this small series. Nevertheless, there are risks associated with the procedure, in particular, cord haemorrhage and sudden death possibly due to rapid infusion of non-oxygen carrying material into the blood stream. When the procedure is carried out, preparations for emergency delivery should be in place. Postnatal management
The consensus guidelines published by the Maternal and Neonatal Haemostasis Working Party of the British Society for Haematology 1997, recommended the administration of intravenous IgG 1 g/kg to the infant for the treatment of neonatal allo-immune
214
Current Paediatrics
thrombocytopenia if the platelet count falls below 20 x 10~/1 or if clinical haemorrhage is apparent. An alternative therapy, also unsupported by clinical trial, is intravenous hydrocortisone, although the Working Party considered that the theoretical risk of infection was a drawback. Platelet transfusion, they suggested, should be reserved for life threatening haemorrhage, and combined with steroid and immunoglobulin therapy. The sequelae of untreated allo-immune thrombocytopenia, when intracranial haemorrhage occurs are 20% neurological damage and 10% death. The condition is said to recur in up to 90% of subsequent pregnancies, although the severity in each case is not predictable.
MATERNAL IDIOPATHIC T H R O M B O C Y T O P E N I C PURPURA Maternal idiopathic thrombocytopenic purpura (ITP) is an important cause of thrombocytopenia in the newborn as transport of maternal antibodies occurs across the placenta. Thrombocytopenia below 50 xl0e/1 occurs in 30% of the babies born to affected mothers. Antenatal diagnosis can be made from umbilical cord samples. A randomized trial has been conducted to assess the effect of antenatal steroids on neonatal platelet count and showed no significant effect. No specific postnatal therapy has been formally evaluated.
MATERNAL I N F E C T I O N Intrauterine infections like rubella, cytomegalic inclusion disease and other viral illness as well as protozoan infections like toxoplasmosis may cause neonatal thrombocytopenia. These are usually associated with other features, such as growth retardation, petechiae, hepatosplenomegaly and microcephaly.
NEONATAL I N F E C T I O N AND N E C R O T I Z I N G ENTEROCOLITIS A low platelet count is one of the earliest haematological findings in necrotizing enterocolitis (NEC). The mechanism is thought to be platelet destruction.
HYPOTHERMIA There have been several case reports associating hypothermia (<34°C) and thrombocytopenia (<50 x 109/1), with platelet counts recovering on rewarming the patient. It is likely to be due to sequestration of the platelets in the liver and spleen.
O T H E R NEONATAL CAUSES Other neonatal causes of thrombocytopenia include systemic bacterial infections, drugs (heparin), and spurious causes like a clot in the blood sample.
MATERNAL HYPERTENSION Severe maternal hypertension, especially associated with maternal haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is associated with neonatal thrombocytopenia. H E L L P syndrome is a variant of severe pre-eclampsia affecting 4-12% of patients with pre-eclampsia/eclampsia. This complication of pregnancy occurs more commonly in older Caucasian multiparous women with a preterm gestation. The decline in platelets is believed to be due to increased platelet destruction in the peripheral circulation. Between 11% and 34% of these neonates become thrombocytopenic with platelet counts below 150x109/1. The main morbidity in these infants is due to the consequences of prematurity, premature delivery often being induced because of the mother's condition.
FURTHER READING Andrew M. The HemostaticSystemin the Infant in Nathan and Oski Haematologyof infancy and childhood4'~'1993 115-153. Eeltink C M, van-LingenR A, Aarnoudse J Get al. Maternal haemolysis,elevatedliverenzymesand low platelets syndrome: Specificproblemsin the newborn. Eur J Pediatr 1993; 152 (2): 160-163. Kaplan C, Daffos F, ForestierF et al. Managementof Alloimmune Thrombocytopenia:Antenatal Diagnosis and in utero Transfusionof Maternal Platelets. Blood 1988;72 (1): 340-343. Greaves M. LetskyE A. Guidelineson the investigationand management of thrombocytopeniain pregnancyand neonatal alloimmune thrombocytopenia.BritishJournal of Obstetrics and Gynaecology1997; 104:1108. Burrows R F. Kelton J G. Fetal thrombocytopeniaand its relation to maternal thrombocytopenia.New Engl J. Med 1993; 329/20: 1463-i466. Cohen I J Amir J, Gedaliah A et al. Thrombocytopeniaof neonatal cold injury.J. Pediatr 1984; 104 (4): 620-622.
Symposium: Haematology
Neonatal thrombocytopenia
R.O. Garr, A.M. Weindling second most common mechanism is pooling of platelets. This occurs when there is hypersplenism, often associated with serious infection, e.g. gram-negative sepsis or fungaemia. Decreased platelet production is very rare, and occurs when there is bone marrow aplasia or replacement as in, for example, histiocytosis, congenital leukaemia, osteopetrosis or neuroblastoma.
INTRODUCTION The normal platelet count is between 150x109/1 and 450x109/1. The incidence of thrombocytopenia during the neonatal period, irrespective of aetiology, has been reported as being between 0.12% and 22%. The essence of the management of thrombocytopenia is treatment of the underlying cause. The problem that concerns clinicians most is when to give a platelet transfusion, particularly since the most serious consequence of thrombocytopenia is intracranial haemorrhage, although this is thankfully rare. Although there are no randomized clinical trials to guide practice, there have been a number of case reports. The general view is that the risk of bleeding increases when the platelet count drops to below 20 x 109/1. Bleeding is also more common if thrombocytopenia is associated with defective platelet function. Our own clinical practice is not to treat thrombocytopenia with platelet transfusion unless there is bleeding from mucous membranes or puncture sites, or the platelet count is below 10 ×109/1.
Table i
Diseases associated with neonatal thrombocytopenia (Adapted from Nathan & Oski 'The Hemostatic System in the Infant' in Nathan Oski 'Haematology of Infancy and Childhood' 4e, 1993 Reproduced with kind permission from the publisher (a) Increased destruction/consumption (1) Immune-mediated Maternal Idiopathic thrombocytopenic purpura Systemic lupus erythematosus Hypothyroidism Drugs (Thiazides, Quinine, Hydrallazine, Tolbutamide, Heparin) Pre-eclampsia Neonatal Allo-immune (2) Non-immune (probably DIC-related) Neonatal asphyxia Necrotizing enterocolitis Neonatal thrombosis (3) Other Polycythaemia Rhesus haemolytic disease Congenital thrombotic thrombocytopenic purpura Wiskott-Aldrich syndrome (b) Sequestration Giant haemangiomas Hypersplenism Hypothermia (c) Decreased platelet production (1) Bone marrow replacement Congenital leukaemia and leukaemoid reactions Neuroblastoma Histiocytosis Osteopetrosis (2) Bone marrow aplasia Thrombocytopenia with absent radius Megakaryocytic thrombocytopenia Fanconi's anaemia
AETIOLOGY The causes of thrombocytopenia are varied, as shown in Table 1. Broadly, there are three possible mechanisms: decreased platelet production, increased platelet destruction, or platelet pooling. Increased platelet destruction is the most common and usually occurs when there is disseminated intravascular coagulation (DIC) or because of an immune mediated disorder like allo-immune thrombocytopenia. The Dr R.O. Garr, Research fellow, Professor A.M. Weindling,
Consultant Neouatologist The Regional Neonatal Intensive Care Unit, Department of Child Health, Liverpool Women's Hospital, Crown Street, Liverpool L8 7SS, UK. Correspondence and requests for offprints to ROG. 212
Neonatal thrombocytopenia The average life span of platelets is 7-10 days in normal subjects but can be considerably shorter in thrombocytopenic patients. Treatment
It is axiomatic that treatment should be aimed at the underlying cause. Platelet concentrates may be used if the baby is actively bleeding or if surgical intervention is planned including any invasive procedures such as arterial sampling, lumbar puncture or ventricular taps. Platelet concentrate at 15-20 ml/kg is used. It is important to irradiate platelet concentrates to prevent graft versus host disease.
ALLO-IMMUNE THROMBOCYTOPENIA Antiplatelet antibodies were identified in 1951. Since then a number of syndromes have been described. The most common is neonatal allo-immune thrombocytopenia, which has an incidence of 1 in 2-5000 livebirths. This serious disorder is associated with profound thrombocytopenia in the fetus and neonate. Consumption of platelets is caused by maternal antibody directed against a fetal platelet antigen inherited from the father and lacking in the mother's platelets, usually the platelet-specific alloantigen P1A1. Most mothers with thrombocytopenia irrespective of aetiology have babies with normal platelet counts. This was demonstrated by a large prospective study which compared the platelet counts of mothers and babies. Six percent of the mothers had platelet counts <150,000 x109/1 while a platelet count of <50,000 x 109/1 was found in 0.12% of the cord samples. The majority of mothers with thrombocytopenia had babies with normal platelet counts. The same study found that the highest incidence of neonatal thrombocytopenia was 33% in babies of mothers with alloimmune thrombocytopenia, 8.6% in babies of mothers with idiopathic thrombocytopenic purpura, and 0.35% in babies of mothers with hypertension. The diagnosis of allo-immune thrombocytopenia is often based on a history of an affected child, parental phenotyping and fetal/neonatal platelet counts. Intracranial haemorrhage may occur in utero. The clinical presentation of allo-immune thrombocytopenia during the neonatal period is of a baby with petechiae and low platelet count who is otherwise healthy. The platelet count usually drops in the first 2 days and then stabilizes. Treatment of allo-immune thrombocytopenia has been controversial. Various therapeutic approaches have been used, but there have been no controlled trials. In 1991, Morgan, using an isolated perfused lobule of human placenta in studies in vitro, showed that intravenous immunoglobulin inhibited antiplatelet antibody transfer. There have been a number of other case series and studies, all small and none randomized,
213
reporting an increase in the fetal platelet count in mothers given weekly intravenous immunoglobulin. All reported no intracranial haemorrhage in the fetus. In utero, platelet transfusions have been reported as effective although none of the studies were randomized. Two approaches have been used: (a) Platelet transfusion at 21 and 38 weeks', and (b) weekly platelet transfusions from 26 weeks' to term. The first approach was used by Kaplan who described a series of nine patients where accurate diagnosis was only possible by repeated fetal blood sampling (FBS) under ultrasound guidance. The first FBS was started at 21 weeks' gestation if fetal thrombocytopenia was detected, washed platelets preferably from the mother were infused. This was repeated at 38 weeks' before delivery. In the intervening period, monthly ultrasound scans were carried out paying particular attention to intracranial haemorrhage. In this study the fetus was selectively immobilized by the administration of vecuronium into the umbilical vein. Washed, irradiated maternal platelets were used. The volume of platelets infused was calculated by the formula V=VSF (C3-C1)/C2, where VSF= estimated fetal blood volume (according to fetal weight estimation), C1 = platelet concentration before transfusion, C2= platelet concentration in the product to be transfused (maternal platelet concentrate), and C3= platelet concentration desired at the end of transfusion. This works out to 58 ml for a fetus with an estimated weight of 500 g and a platelet count of 20 x 109/1, if the intention is to raise the platelet count to 100 x 109/1. No abnormal side-effects were noted. A pragmatic approach is used at the Liverpool Women's Hospital. Intravenous immnnoglobulin is given to the mother until 28 weeks' gestation and then intrauterine transfusions of platelets if thrombocytopenia is found in the fetal blood samples between 28 weeks' gestation and term. If an intrauterine transfusion is required, delivery is by caesarean section. In the last 2 years, four fetuses have been treated by weekly intrauterine transfusions of platelets. The initial median fetal platelet count was 33 x 109/1, and the range was between 5 and 220 x109/1. The median volume of platelets infused was 55 ml (range 20-100 ml). No adverse effects have been recorded in this small series. Nevertheless, there are risks associated with the procedure, in particular, cord haemorrhage and sudden death possibly due to rapid infusion of non-oxygen carrying material into the blood stream. When the procedure is carried out, preparations for emergency delivery should be in place. Postnatal management
The consensus guidelines published by the Maternal and Neonatal Haemostasis Working Party of the British Society for Haematology 1997, recommended the administration of intravenous IgG 1 g/kg to the infant for the treatment of neonatal allo-immune
214
Current Paediatrics
thrombocytopenia if the platelet count falls below 20 x 10~/1 or if clinical haemorrhage is apparent. An alternative therapy, also unsupported by clinical trial, is intravenous hydrocortisone, although the Working Party considered that the theoretical risk of infection was a drawback. Platelet transfusion, they suggested, should be reserved for life threatening haemorrhage, and combined with steroid and immunoglobulin therapy. The sequelae of untreated allo-immune thrombocytopenia, when intracranial haemorrhage occurs are 20% neurological damage and 10% death. The condition is said to recur in up to 90% of subsequent pregnancies, although the severity in each case is not predictable.
MATERNAL IDIOPATHIC T H R O M B O C Y T O P E N I C PURPURA Maternal idiopathic thrombocytopenic purpura (ITP) is an important cause of thrombocytopenia in the newborn as transport of maternal antibodies occurs across the placenta. Thrombocytopenia below 50 xl0e/1 occurs in 30% of the babies born to affected mothers. Antenatal diagnosis can be made from umbilical cord samples. A randomized trial has been conducted to assess the effect of antenatal steroids on neonatal platelet count and showed no significant effect. No specific postnatal therapy has been formally evaluated.
MATERNAL I N F E C T I O N Intrauterine infections like rubella, cytomegalic inclusion disease and other viral illness as well as protozoan infections like toxoplasmosis may cause neonatal thrombocytopenia. These are usually associated with other features, such as growth retardation, petechiae, hepatosplenomegaly and microcephaly.
NEONATAL I N F E C T I O N AND N E C R O T I Z I N G ENTEROCOLITIS A low platelet count is one of the earliest haematological findings in necrotizing enterocolitis (NEC). The mechanism is thought to be platelet destruction.
HYPOTHERMIA There have been several case reports associating hypothermia (<34°C) and thrombocytopenia (<50 x 109/1), with platelet counts recovering on rewarming the patient. It is likely to be due to sequestration of the platelets in the liver and spleen.
O T H E R NEONATAL CAUSES Other neonatal causes of thrombocytopenia include systemic bacterial infections, drugs (heparin), and spurious causes like a clot in the blood sample.
MATERNAL HYPERTENSION Severe maternal hypertension, especially associated with maternal haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is associated with neonatal thrombocytopenia. H E L L P syndrome is a variant of severe pre-eclampsia affecting 4-12% of patients with pre-eclampsia/eclampsia. This complication of pregnancy occurs more commonly in older Caucasian multiparous women with a preterm gestation. The decline in platelets is believed to be due to increased platelet destruction in the peripheral circulation. Between 11% and 34% of these neonates become thrombocytopenic with platelet counts below 150x109/1. The main morbidity in these infants is due to the consequences of prematurity, premature delivery often being induced because of the mother's condition.
FURTHER READING Andrew M. The HemostaticSystemin the Infant in Nathan and Oski Haematologyof infancy and childhood4'~'1993 115-153. Eeltink C M, van-LingenR A, Aarnoudse J Get al. Maternal haemolysis,elevatedliverenzymesand low platelets syndrome: Specificproblemsin the newborn. Eur J Pediatr 1993; 152 (2): 160-163. Kaplan C, Daffos F, ForestierF et al. Managementof Alloimmune Thrombocytopenia:Antenatal Diagnosis and in utero Transfusionof Maternal Platelets. Blood 1988;72 (1): 340-343. Greaves M. LetskyE A. Guidelineson the investigationand management of thrombocytopeniain pregnancyand neonatal alloimmune thrombocytopenia.BritishJournal of Obstetrics and Gynaecology1997; 104:1108. Burrows R F. Kelton J G. Fetal thrombocytopeniaand its relation to maternal thrombocytopenia.New Engl J. Med 1993; 329/20: 1463-i466. Cohen I J Amir J, Gedaliah A et al. Thrombocytopeniaof neonatal cold injury.J. Pediatr 1984; 104 (4): 620-622.