A guide to the management of unexplained bleeding, anaemia (including haemolysis), thrombosis and neutropenia in the neonate, and the immediate management of inherited haematological disorders.
This document is applicable to all medical, nursing and midwifery staff caring for the newborn in hospital or community. It is intended as a guide to common haematological problems in the newborn, and the immediate postnatal investigation and management of babies who are at risk of an inherited haematological disorder
The guideline should be used with reference to the relevant pharmacy monographs.
The majority of haemorrhagic problems in the neonatal period are due to acquired haemostatic defects, either thrombocytopenia or coagulation disorders. These are most often observed in the context of underlying illness or in sick preterm neonates, although neonatal alloimmune thrombocytopenia (NAIT) may present in otherwise clinically well babies at any gestation.
Inherited coagulopathies may present as abnormal bleeding in an apparently healthy baby; in the presence of a positive family history the diagnosis is usually straightforward, but there will often be no such family history and so a high index of clinical suspicion is required.
Whom to investigate
Presentation
Investigation
|
Acquired |
Congenital |
||||
|
DIC |
vitamin K deficiency |
liver disease |
heparin contamination |
haemophilia A/B |
Von Willebrand’s |
PT |
↑ |
↑↑ |
↑ |
N |
N |
N |
APTT |
↑ |
↑ or N |
↑ |
↑ |
↑ |
↑ or N |
TCT |
↑↑ |
N |
↑ or N |
↑↑ |
N |
N |
Fibrinogen |
↓ |
N |
↓ |
N |
N |
N |
d-dimers |
↑ |
N |
↑ |
N |
N |
N |
Platelets |
↓ or N |
N |
↓ or N |
N |
N |
N |
Management |
treat cause If bleeding also add |
vitamin K If bleeding also add FFP or 4 factor concentrate (Beriplex) |
vitamin K If bleeding also add |
repeat |
appropriate factor replacement discuss with haematology |
Haemate-P discuss with haematology |
N.B. Reference ranges are dependent on the gestational and postnatal age of the infant and may vary between laboratories.
Be aware that severe FXIII deficiency can result in major haemorrhage and normal baseline coagulation.
Treatment options
For DIC, treatment of the underlying cause (including management of sepsis, correction of acidosis etc.) is paramount. Correction of coagulation using appropriate blood products should occur if the patient is bleeding or at very high risk of significant bleeding (e.g. ICH) and/or prior to surgical interventions. There is limited evidence to support the use of FFP to correct abnormalities of the coagulation screen alone, and FFP should not be used for simple volume replacement.
Fresh Frozen Plasma (FFP)
Platelets
Cryoprecipitate (virally inactivated)
Vitamin K
Specific factor concentrates
1.2 Inherited bleeding disorders
Note: At risk infants born to mothers who are known carriers of an inherited bleeding disorder will have a neonatal delivery plan in the obstetric notes which should be consulted and followed.
Haemophilia A and B
Usually presents in male infants of known haemophilia carriers but up to one-third of cases may arise due to a new mutation and therefore a high-index of suspicion is needed. Coagulation testing and consideration of factor assays should be undertaken in the context of a neonate presenting with:
This is a condition which results from a quantitative or qualitative defect of von Willebrand factor (vWF) resulting in an increased tendency to bleeding. Up to 1% of the population have vWD as defined by reduced levels of vWF but not all have a clinically significant bleeding disorder. There are a number of subtypes, of which type 1 is the most common.
|
inheritance |
Description |
Severity |
neonatal diagnosis |
Type 1 |
AD |
quantitative partial deficiency of vWF |
mild to moderate, usually asymptomatic in neonatal period |
delay until 10-12 months |
Type 2A |
AD/AR |
qualitative functional deficiency of vWF |
bleeding may occur and can be severe |
sometimes possible - d/w haematology (and consult delivery plan) |
Type 2B |
AD |
|||
Type 2M |
AD/AR |
|||
Type 2N |
AR |
|||
Type 3 |
AR |
quantitative complete deficiency of vWF |
Severe |
Yes |
Management of neonates with suspected inherited bleeding disorder
Cord sampling
A cord blood sample should be sent for relevant factor assays where the neonate:
These samples should be discussed with haematology; it is important that the cord sample is not contaminated with maternal blood.
Note: female neonates who are or may be carriers of haemophilia do not require cord blood sampling as they rarely have low factor levels.
Interpretation of results
Factor VIII and VWF are increased in the healthy neonate at delivery and therefore most boys with haemophilia A can be diagnosed at birth. Very mild forms of haemophilia A/VWD may however not be able to be confirmed or excluded without a further blood sample at 6 months of age.
Factor IX levels are decreased in the healthy neonate at delivery and therefore mild forms of haemophilia B may not be able to be confirmed or excluded without a further blood sample at 6 months of age.
Neonatal Vitamin K
As a rule, if cord blood has been taken a standard dose of oral vitamin K should be given as soon as possible after delivery. If cord blood excludes the diagnosis of a bleeding disorder either one dose of IM vitamin K can then be given or the full course of oral regimen completed.
In all cases, neonatal blood spot samples can and should still be taken (normal technique; ensure pressure applied to the heel for 5 minutes post sampling).
Neonatal Factor testing
Abnormal or suspicious factor results from a cord specimen should be repeated on a neonatal blood sample
Cranial Ultrasound
Cranial ultrasound should be undertaken prior to discharge in all male neonates suspected of having a moderate or severe bleeding disorder e.g. moderate/severe VIII or IX deficiency, severe Type I (baseline RiCof <20%), Type II or Type III VWD.
Cranial ultrasound should also be considered in those with:
If a neonate has neurological signs suggestive of an intracranial bleed, cranial ultrasound +/- subsequent MRI should be performed.
Factor therapy for neonates
Prophylactic factor therapy is indicated for neonates with low factor levels and:
Two or three treatment doses (aiming for target level of 100%) should be given over the first 3 days of life. DDAVP is contraindicated under the age of 2 years.
Note: primary prophylaxis is not at present recommended for all severe haemophiliacs but is appropriate in some of the rare coagulation disorders (e.g. severe deficiencies of FVII, X and XIII due to the high risk of ICH). Children with Type III vWD require intermediate purity factor VIII (Haemate P) rather than recombinant products. Discuss with Haemophilia Unit, RHSC.
Referral to Paediatric Haematology
The following neonates should be referred to Dr Chalmers, Haemophilia Unit at RHC:
Neonates whose levels have been assessed and are clearly normal do not need referral to RHC, unless from families with borderline deficiencies (e.g. mild Type 1 VWD) where there may be overlap with what is physiologically normal at birth.
Childhood vaccinations
All children in whom a bleeding disorder is diagnosed at or shortly after birth should have their routine vaccinations by subcutaneous injection (many of the severe patients come to the haemophilia centre, at least for the first dose).
Infants with possible mild vWD or possible carriers (i.e. those who are due to be assessed at RHC at 6-12 months of age) usually have their vaccinations as normal, although this should be reviewed in symptomatic neonates or carriers with particularly low levels.
1.3 Rarer coagulation disorders
Factor XIII deficiency
This is an autosomal recessive condition. Homozygous deficiency (activity <10%) classically causes umbilical stump bleeding with a high rate of ICH, haematomas and impaired wound healing. Heterozygous deficiency (activity 50-60) is not associated with bleeding. Neonatal diagnosis of severe deficiency is possible. Note that the coagulation screen is normal – diagnosis is made by measuring Factor XIII (assay performed at Glasgow Royal Infirmary). Due to the very significant risk of ICH, prophylactic administration of high purity Factor XIII concentrate is recommended for homozygous deficiency. Dose - 30 units/kg/month intravenously to maintain Factor XIII levels >3%
Others e.g. Dysfibrinogenaemia, Factor V/VII/X deficiencies.
For babies with a known family history there should be a neonatal bleeding disorders delivery plan in the maternal notes – this should be consulted and followed. All other babies should be discussed with a consultant haematologist on a case by case basis
Thrombocytopenia is frequently encountered in neonatal intensive care units, particularly among very low birth weight or sick neonates.
Early-onset thrombocytopenia (<72 hours old)
This is the commonest time to present with thrombocytopenia and most cases are seen in preterm neonates born to pregnancies complicated by placental insufficiency (e.g. maternal pre-eclampsia, hypertension or diabetes) and/or chronic fetal hypoxia / idiopathic intrauterine growth restriction. Affected neonates often have a low normal or modestly reduced platelet count at birth (120-200x109/L), which falls to a nadir of 80-100 at day 4 -5 of life before recovering to >150x109/L by 7 -10 days of age.
In contrast to the mild-moderate thrombocytopenia seen in most cases of placental insufficiency, severe early onset severe thrombocytopenia (<50x109/L) requires urgent investigation. The two most important causes are neonatal alloimmune thrombocytopenia (NAIT), which is discussed in detail below, and hypoxic ischaemic encephalopathy (HIE) due to acute perinatal asphyxia. Up to 30% of all neonates with HIE develop thrombocytopenia which is often severe and prolonged and principally appears to be precipitated by disseminated intravascular coagulation. Treatment is supportive.
Late-onset thrombocytopenia (>72 hours old)
This is often severe, develops acutely and may be prolonged. Most cases are secondary to sepsis or necrotising enterocolitis (NEC), often associated with DIC (check coagulation screen). Thrombocytopenia may be prolonged for several weeks beyond the onset of sepsis/NEC.
Neonatal alloimmune thrombocytopenia (NAIT)
NAIT is the commonest cause of severe thrombocytopenia in well, term infants and is caused by maternal sensitisation to paternally derived fetal platelet antigens. It has a prevalence of 0.7 per 1000 pregnancies. In Caucasian populations, human platelet antigen HPA1a is implicated in 80% cases of NAIT, and HPA5b in 10-15%. The laboratory diagnosis of NAIT involves assays to detect maternal anti-HPA antibodies; both parents as well as the infant should be genotyped for the most common HPA alloantigens (HPA-1a, -2, -3, -5b, and -15). This testing is performed by the National Blood Service Platelet Immunology Laboratory Bristol; samples will be sent via the local blood bank (discuss with the Blood Transfusion service (telephone 0141 451 9104) regarding which samples are required, and ask the obstetric team to arrange for a sample of blood from mum).
Most neonates with NAIT present with severe thrombocytopenia, often <20x109/L. The most feared complication is intracranial haemorrhage (ICH) which occurs in ~20% of neonates with HPA1a- associated NAIT and is associated with a very high risk of severe neurodevelopmental problems, including cerebral palsy. A high proportion of ICH (~80%) occurs in utero and NAIT has been reported as early as 20 weeks gestation. Since NAIT can affect first pregnancies, the diagnosis at birth is often unsuspected; the clinical presentation varies from asymptomatic thrombocytopenia or petechiae to seizures secondary to ICH.
Management of NAIT
All cases of suspected NAIT should undergo cranial ultrasound scans to exclude ICH. Most cases of NAIT resolve within a week without long-term sequelae. Since the platelet count usually falls over the first 4-7 days of life, all thrombocytopenic neonates with NAIT should be monitored until there is a sustained rise in their platelet count into the normal range. In well neonates with documented or suspected NAIT who have no evidence of haemorrhage, transfusion of HPA-compatible platelets is recommended only when the platelet count is <20-30x109/L. Consult the MCN neonatal transfusion guideline for further information on management of NAIT
Usually HPA-1a, 5b-negative platelets are given pending an accurate diagnosis. In the event of major haemorrhage, including ICH, the platelet count should be maintained >50x109/L using appropriate HPA-negative platelets. If appropriate HPA-negative platelets are unobtainable, random donor platelet transfusions or intravenous immunoglobulin (IVIG) can be used in an emergency. In all cases, such platelets should be CMV antigen-negative and single-donor apheresis units; neonates who have received intrauterine platelet transfusions should be given irradiated platelets. In some cases, thrombocytopenia may persist for up to 8 -12 weeks; in these babies IVIG is usually a better option than repeated platelet transfusions.
Parents should be counselled about the potential risk of NAIT in future pregnancies, which should be managed in conjunction with a fetal medicine unit.
Neonatal Autoimmune Thrombocytopenia
Transplacental passage of maternal platelet autoantibodies due to maternal immune thrombocytopenia (ITP) or systemic lupus erythematosus (SLE) can cause neonatal thrombocytopenia. Severe thrombocytopenia (<50x109/L) occurs in about 10% neonates with maternal platelet autoantibodies of whom about half have platelet counts of <20x109/L. However, studies have shown that risk of severe haemorrhage, including ICH, is low in these babies.
All neonates with history of maternal thrombocytopenia should have their platelet count checked at birth; if found to be >150x109/L, no further action is necessary. Thrombocytopenic neonates should have their platelet count rechecked after 2-3 days, as the platelet count often drops to its lowest levels at this age, after which it tends to resolve spontaneously by 7 days of age in the majority. More rarely, thrombocytopenia may persist up to the age of 12 weeks. When the thrombocytopenia is severe (platelet count <30 x 109/L in the first week of life and <20x109/L thereafter), treatment with IVIG (1 gram/kg/day for 2 days) may be useful.
Other causes of thrombocytopenia
In the case of unexplained thrombocytopenia always consider rarer causes such as:
Congenital infections: most commonly CMV and rubella but enteroviruses (Coxsackie A and B and echovirus), HIV and parvovirus B19 can also cause severe, acute neonatal thrombocytopenia. In most cases, thrombocytopenia will be present in combination with other clinical features suggestive of congenital infections, e.g., intracranial calcification, hepatosplenomegaly, jaundice, or “viral” lymphocytes on the blood film. Severe thrombocytopenia (platelet count <50x109/L) that is present in the first days of life and persists for more than the first week is a common feature in congenital infections and may suggest the diagnosis even in the absence of other more common clinical features.
Perinatal bacterial infection: especially Group B strep and E. coli, are often associated with DIC.
Chromosomal abnormalities: fetal thrombocytopenia is seen in up to 86% of cases of trisomy 18, 31% of trisomy 13, 75% of triploidy and 31% of Turner syndrome babies at the time of fetal diagnosis.
Thrombocytopenia is also common in trisomy 21. The latter may be part of a transient abnormal myelopoiesis (Transient Leukaemia of Down Syndrome (TL-DS)) seen in 10-20% of neonates with Down syndrome and characterised by increased peripheral blood myeloblasts, abnormal megakaryocytes and variable thrombocytopenia. Screening for TL-DS should occur in all infants with trisomy 21 as per the MCN trisomy 21 pathway. FBC and film (0.5ml in EDTA bottle) should be sent and can be carried out via cord bloods (same sample type and volume) if antenatal diagnosis has been carried out.
In most cases TL-DS resolves spontaneously, but ~30% of neonates with TL-DS develop acute megakaryocytic leukaemia within the first 5 years of life. Clinically, TL-DS has a variable neonatal presentation from asymptomatic mild thrombocytopenia to fulminant hepatic fibrosis due to hepatic infiltration with abnormal megakaryocytes and blasts. TL-DS is due to acquired somatic mutations in the key megakaryocytic transcription factor GATA-1. GATA-1 mutations can be tested for at birth – liaise with the Paediatric Haematology unit to arrange testing.
Inherited thrombocytopenia: thrombocytopenia generally presents at birth and persists in the absence of any other symptoms such sepsis or NEC. Examples include Bernard Soulier syndrome, congenital amegakaryocytic thrombocytopenia (CAMT) or thrombocytopenia with absent radii (TAR) syndrome. If any of these is suspected the baby should be discussed with the paediatric haematology department.
Indications for platelet transfusion
Thrombocytopenia usually occurs as a response to a systemic disorder, and in most cases, resolves spontaneously or following resolution of the underlying pathology. However, the risk of significant or serious haemorrhage in thrombocytopenic neonates is high, particularly in those who are very preterm or of low birth weight. The treatment of thrombocytopenia, particularly in the context of platelet transfusion thresholds, remains controversial and lacks consensus among neonatologists. Consult the MCN neonatal transfusion guideline for local policy and platelet thresholds.
Presentation
History and clinical assessment
Investigation
Diagnosing non-immune haemolysis and identifying the cause can be very difficult in the neonatal period. Treatment may have to be with supportive care (phototherapy +/- exchange transfusion) pending further investigations in later childhood.
Identifying haemolysis
Immune-mediated haemolysis
ABO incompatibility
Effect of routine antenatal anti-D prophylaxis (RAADP)
Anti-D prophylaxis is being increasingly used antenatally. This can cross the placenta and bind to fetal cells; consequently, up to 3-6% of D positive cord or infant samples will have a positive DCT in the absence of significant haemolysis.
Isolating a cause for haemolysis
Samples required (pre-transfusion!)
(don’t forget blood spot screening card if baby < 5days old)
If haemolysis has been confirmed and the cause is uncertain
2.3 Inherited conditions; Enzyme Disorders
Hereditary spherocytosis
Inheritance |
|
Ethnicity |
northern European |
Clinical features |
|
Is neonatal diagnosis possible? |
|
Investigations |
Investigations are generally deferred until 3-6 months of age:
babies considered to require investigation in the neonatal period should be discussed with the neonatal consultant on call, and with haematology. |
Treatment |
|
Referral |
|
Glucose-6-phosphate dehydrogenase deficiency
Inheritance |
|
Ethnicity |
|
Clinical features |
|
Is neonatal diagnosis possible? |
|
Investigations
|
|
Treatment |
|
Miscellaneous information |
|
Referral |
|
These comprise a large group of inherited blood disorders which result in abnormalities of the haemoglobin molecule. There are two main groups: the haemoglobin variants (e.g. sickle cell disease (SCD)), which are associated with the production of abnormal forms of haemoglobin, and the thalassaemias in which there is an abnormality in the amount of haemoglobin produced.
Antenatal Haemoglobinopathy Screening
Newborn Haemoglobinopathy Testing
Neonatal Screening
Sickle cell disease
Conditions |
homozygote |
- HbSS (Sickle cell disease) |
heterozygote |
- HbAS (Sickle cell trait) |
|
compound heterozygotes |
- HbSC, HbS/ßthalassaemia (will sickle) - HbSD (unlikely to sickle) |
|
Ethnicity |
|
|
Clinical features |
|
|
Neonatal diagnosis possible? |
|
|
Investigations |
|
|
Treatment
|
|
β thalassaemia
Conditions |
|
Ethnicity |
|
Clinical features
|
|
Is neonatal diagnosis possible? |
|
Whom to test? |
|
Investigations
|
|
Treatment |
|
Miscellaneous information |
symptoms generally appear at 3-6 months as the switch is made from fetal to adult haemoglobin, but may be apparent from 6-8 weeks |
a thalassaemia
Conditions |
|
Ethnicity
|
|
Clinical features |
|
Is neonatal diagnosis possible? |
|
Investigations |
|
Treatment |
|
Referral |
|
Neonatal thrombosis may be either arterial or venous and is usually associated with indwelling catheters. Spontaneous thrombosis is very rare and mostly involves the renal vein (although it can extend to the SVC).
Predisposing Factors
Inherited |
Acquired |
protein S deficiency |
asphyxia |
antithrombin deficiency |
septicaemia |
protein C deficiency |
cardiac disease |
factor V leiden mutation |
dehydration |
prothrombin gene mutation |
maternal diabetes |
maternal inherited antiphospholipid syndrome |
|
Investigations
Thrombophilia screening is not generally indicated in neonates presenting with thrombosis in the setting of known risk factors (indwelling lines, sepsis, dehydration etc). Consider measuring protein C, protein S and antithrombin levels if there are spontaneous or unusual thrombotic events, including purpura fulminans.
Family history of thrombophilia:
Protein C, protein S and antithrombin. Babies born to mothers who are heterozygous for a thrombophilia, do not need to be tested for that thrombophilia at birth, unless they have severe symptoms to suggest they are homozygotes, when expert input from haematology should be sought regarding testing and management.
In the case of a family history of factor V leiden mutation or prothrombin gene mutation the risk of thrombosis low and no investigation is necessary in the neonatal period.
Treatment of thrombosis
Acquired |
Congenital |
infection |
severe congenital neutropenia (Kostmann syndrome) |
drugs |
|
immune (see below) |
|
nutritional deficiency eg. B12/folate/copper |
|
complement activation with ECMO |
|
|
Neonatal alloimmune neutropenia
Clinical features |
|
Mechanism |
|
Investigations |
|
Treatment |
|
Referral |
|
British Committee for Standards in Haematology (BCSH) – Website
UK Haemophilia Centre Doctors' Organisation (UKHCDO) - Website
Chakravorty et al, Br J Haematol. 2012 Jan;156(2):155-62
Literature review & References
See national guidelines on BCSH and UKHCDO Websites (above)
Last reviewed: 01 January 2023
Next review: 01 January 2026
Author(s): Dr Christina Halsey – Consultant Paediatric Haematologist; Dr Helen Mactier – Neonatal Consultant; Dr Elizabeth Chalmers – Consultant Paediatric Haematologist
Co-Author(s): Other specialists consulted: Haematology GRI – Dr Catherine Bagot – Consultant Haematologist
Approved By: West of Scotland Neonatology Managed Clinical Network