Haematological Disorders in Neonates

 

Reviewed by Clinical Practice Committee
September 2016
Clinical Guidelines Back Newborn Services Home Page
Introduction Thrombocytopenia Haemophilia and Comments von Willebrand Disease
Factor V Leiden Mutation Protein C/S/Antithrombin Deficiency Thalassaemia Intravascular Haemolysis
Glucose-6-Phosphate Dehydrogenase Deficiency Vitamin K Deficiency Bleeding References

Introduction

"Bleeding problems" or a tendency to bruise or bleed are common problems. There may be a family history of specific haematological diagnoses, or there may be more general notes about bleeding tendencies in the maternal history. Bleeding in an otherwise well infant may be a marker of deficiency in a component of the haemostatic system.

Thrombocytopenia

See the Thrombocytopenia guideline.

Haemophilia A and B (Factor VIII Deficiency and IX Deficiency)

There are a number of coagulation factor defects that fall under the general heading of haemophilia. The two most common are Factor VIII Deficiency  and  Factor IX Deficiency which are X-linked recessive gene disorders (affecting males)

The clinical presentation of a severe factor deficiency is spontaneous bleeding or excessive bleeding following minor trauma or procedures in otherwise healthy infants (including bleeding post intramuscular vitamin K injection, cord stump oozing). Intracranial haemorrhage (ICH) or significant extracranial bleeding may be the only presenting symptom. ICH occurs in 3-4% of newborns with haemophilia in the first 28 days of life.1,2,3

Factor VIII Deficiency (Haemophilia A) is the "classical" haemophilia, and causes approximately 75% of all significant inborn coagulopathies. The incidence is approximately 1:5000 male births.4 The underlying abnormality is a defect in factor VIII. Around one-third are sporadic cases diagnosed following bleeding events.3,5 Seventy percent of those diagnosed within 1 month of birth have a known carrier mother or family history.

Factor IX Deficiency (Haemophilia B Christmas Disease) accounts for about 15% of all patients with haemophilia, and is clinically indistinguishable from Factor VIII Deficiency.

Investigations

  • If male infant with known carrier mother, urgent (<3 hours) Factor VIII / IX assay from cord blood or the baby (avoid heel prick samples).
  • Normal neonatal ranges are the same as adult ranges for factor VIII, so low values are pathologic for Haemophillia A. The normal neonatal ranges for factor IX are decreased compared with adults, so diagnosis of a mild deficiency can be difficult.
  • If urgent factor VIII / IX assay is not available, do a coagulation screen the APTT will be prolonged, upper limit of normal APTT in a newborn is 36 (avoid heel prick samples).

Newborn Management

  • Avoid intramuscular injections. Vaccinations may be given subcutaneously.
  • Vitamin K should be given orally until the results of the factor assays are available.
  • Closely monitor for signs of ICH.
  • Arrange a screening Head Ultrasound prior to discharge.
  • Discuss with a paediatric haematologist.
  • Prophylactic factor replacement should not be given due to the risk of inhibitor development.6

Other comments about Haemophilia A and B

If factor assay indicates a severe (<1%) or moderate (1-4%) factor VIII or IX deficiency;

von Willebrand Disease (VWD)

Von Willebrand Disease is also classified as a haemophilia although it is clinically less severe than Factor VIII and IX Deficiencies and is not usually diagnosed in the newborn period. The basic defect in vWD is an abnormality of von Willebrand factor (vWF) which promotes platelet adhesion and transports factor VIII by the factor VIII-vWF complex. It is most commonly inherited as an autosomal dominant trait with a mild to moderate bleeding tendency. There is variable clinical and laboratory expression of platelet dysfunction and factor VIII deficiency. There are 3 different recognised types of vWD, depending on qualitative or quantitative abnormalities of vWF.

There are very few reports of newborn infants with bleeding secondary to vWD. The most common manifestations in children and adults are nosebleeds and easy bruising. Diagnosis is made by platelet function analysis (PFA) and specific tests for vW antigen and activity. Bleeding times are rarely performed.

Investigations

  • No investigations are necessary unless unexplained significant bleeding (discuss with haematology).
  • Levels of vWF are physiologically increased in the neonatal period.

Newborn Management

  • Prophylactic vitamin K at birth
  • Referral to paediatric haematology

Vitamin K Deficiency Bleeding (VKDB, Haemorrhagic Disease of the Newborn)

See the Vitamin K guideline and Vitamin K drug protocol.

This diagnosis should be considered in infants who appear to bleed excessively easily, particularly if there is major evidence of haemorrhage (e.g. gastrointestinal or cerebral) and it is not clear that the baby received adequate vitamin K supplementation at birth.

Deficiency is characterised by increased PT due to reduced active prothrombin. Babies born to mothers on anticonvulsants (phenytoin, carbamazepine) are at increased risk. VKDB classically presents between 2-7 days of life in breastfed babies who did not receive prophylactic vitamin K at birth. It may also occur late, between 2-8 weeks of age, presenting with ICH and in association with previously undetected hepatic dysfunction.10

Investigations

  • INR (Prothrombin Ratio) - PT raised

Newborn Management

  • Intramuscular Vitamin K prophylaxis at birth (intramuscular is preferred over oral preparation for efficiency and reliability of administration).
  • Infants with VKDB should be given intravenous Vitamin K and may require fresh frozen plasma (FFP).
  • Consider prophylaxis in infants with known liver disease.

Protein C, Protein S, and Antithrombin Deficiency

These are conditions which predispose to thrombosis. The classic presentation of Protein C deficiency is purpura fulminans occurring within hours or days of birth. Infants with homozygous Protein C deficiency often have significant in utero thrombotic events (cerebral or ophthalmic) and severe DIC and large vein thromboses. Heterozygous Protein C deficiency has been associated with neonatal thrombotic events. Coagulation screens are usually normal but may show an elevated platelet count and increased fibrin degradation products. Protein S deficiency has been very rarely reported in neonates. Antithrombin deficiency most commonly presents in adulthood, although there are reports of neonates with significant thromboses.

The ranges for protein C and protein S in normal neonates may be as low as 20-30% of the normal adult value.

Investigations

  • Discuss with a paediatric haematologist
  • Infants presenting with neonatal stroke may need investigation which is usually repeated around 3- 6 months.

Newborn Management

  • Avoid indwelling central intravenous or intra-arterial catheters
  • Fresh frozen plasma or replacement products (Protein C or Antithrombin concentrates) if symptomatically indicated after discussion with a paediatric haematologist.

Factor V Leiden Mutation

This may be found because of investigations performed on mothers with a history or pre-eclampsia or recurrent miscarraige.  It is generally associated with an increased lifetime risk of thrombosis, although most individuals with Factor V Leiden mutation will remain well.  A severe neonatal form has been described.

Investigations

  • No investigations are indicated at birth or in the neonatal period.

Newborn Management

  • No specific investigations

Thalassaemias

These are hereditary conditions with decreased or absent synthesis of at least one globin chain.  α- and β- thalassaemia refer to deficiencies of the α and β chains, respectively.

α-thalassaemia conditions are usually due to deletion of the α-globin gene. There are 4 copies of the α-globin gene. Deletion of one or two α-globin genes leads to α-thalassaemia trait. The red cell changes are mild and may not be detected clinically or may present with mild microcytic anaemia that should be differentiated from iron deficiency. Deletion of three α-globin genes results in HbH Disease with chronic mild to moderate anaemia but the patient is not transfusion dependent. The most severe form of α-thalassaemia condition is Hb Bart's hydrops foetalis. All the four α-globin genes are absent, and the condition is lethal with the affected baby dying in utero or soon after birth.

β-globin production is controlled by a pair of β-globin gene. β-thalassaemia conditions arise from different genetic defects not limited to deletion. Defect of one β-globin gene leads to β-thalassemia trait, which can be asymptomatic or more usually associated with mild microcytic anaemia. When both β-globin genes are defective then there is no or very little β-globin produced. This leads to β-thalassaemia major. Usually this presents as a transfusion dependent chronic anaemia, but the severity of disease is dependent on the interaction of a number of complex genetic factors, and some patients are not transfusion dependent even though they have a moderate anaemia.

At birth the predominant circulating haemoglobin is Hb F (α2γ2).  Adult haemoglobin, Hb A (α2β2), becomes the predominant haemoglobin after birth.  Therefore, infants with α-chain abnormalities tend to be symptomatic at birth (or before) whereas those with β-chain problems develop symptoms usually after 4-6 months.  The cord blood red cells from infants with either α-thalassaemia trait or HbH Disease are microcytic, and the level of Hb Bart's (an abnormal haemoglobin composed of only γ-chains) in the cord blood is raised.

Investigations

  • Cord blood for haemoglobin electrophoresis, particularly Hb Bart's quantitation if α-thalassaemia is suspected
  • Venous blood for haemoglobinopathy study.
    • If β-globin defect is suspected the specimen should usually be taken at 3 months at the earliest.
  • FBC (may be normal in thalassaemia traits)

Newborn Management

  • Haematology follow-up as indicated by particular haemoglobinopathy

Intravascular Haemolysis

This is relatively common in neonates.  It may be due to a variety of causes including infection, AV malformations, alloimmune haemolysis (such as ABO incompatibility), exposure to toxins (including bacterial toxins) and oxidant drugs, haemoglobinopathies, red cell enzyme and membrane abnormalities.  Often, no specific underlying cause is found, as in the transient Infantile Pyknocytosis often seen 4-6 weeks after birth.  Vitamin E deficiency should be rare nowadays but also needs to be considered in some cases, particularly very premature infants.  It is important to look at the blood film for evidence of haemolysis (spherocytes, cell fragment, polychromatic cells) or infection.  There may be prolonged or exaggerated jaundice.

Investigations

  • Exclude infection
  • Group and Direct Antiglobulin test
  • Reticulocyte count
  • Glucose-6-Phosphate Dehydrogenase screen
  • Pyruvate Kinase screen
  • Haemoglobinopathy study
  • Vitamin E level
  • Blood from both parents for Haemoglobin and blood film (to evaluate red cell morphology)

Newborn Management

  • Red Cell Transfusions may be required to maintain a normal haemoglobin
  • Monitor and treat neonatal jaundice
  • Discuss with a paediatric haematologist.

If no apparent cause is found, then further testing (such as investigations for red cell membrane defects or unusual haemoglobinopathies) should be discussed with the on-call paediatric haematologist.

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD)

This is a relatively common abnormality of red cell metabolic enzymes, inherited as a sex-linked disorder in males (although females can be affected due to lyonisation). G6PD is required to protect the haemoglobin and the red cell membrane from oxidative damage. The clinical presentation of G6PD deficiency varies. The severe forms can lead to severe haemolysis, which can be spontaneous or after exposure to drugs or chemicals (including fava bean and camphor or naphthalene used as insect repellents in closets). Infection can also precipitate haemolysis. It commonly manifests as severe jaundice in affected male babies. G6PD is ubiquitous but is most common in South East Asia, the Indian subcontinent, the Mediterranean area, and in tropical and subtropical Africa. Infants from these ethnic groups who develop jaundice severe enough to require phototherapy should be investigated.

Investigations

  • G6PD screen and/or G6PD assay
  • G6PD levels depend on the age of the red cell - the G6PD assay can be equivocal or even normal during acute haemolysis. If clinically appropriate, consider repeating the G6PD study when the acute haemolysis has settled.
  • Blood film may show evidence of haemolysis with red cell fragments, spherocytes, and "bite" cells.

Newborn Management

  • If G6PD confirmed, advise parents regarding medications, foods and other factors which may precipitate acute haemolysis.
  • Advise parents of early recognition of symptoms and signs of acute haemolysis, which can be a haematological emergency.
     

References

1

Kulkarni, R., Lusher, J.M. Intracranial and extracranial hemorrhages in newborns with haemophilia: a review of the literature. J Pediatr Hematol Oncol. 1999; 21: 289-295.
2  Ljung R.C.R. Intracranial haemorrhage in haemophilia A and B. Brit J Haematol 2007;140: 378-384.
3 Richards, M., Lavigne Lissalde, G. Combescure C. et al on behalf of the European Haemophilia Treatment and Standardization Board. Neonatal bleeding in haemophilia: a European cohort study. Br J Haematol 2012;156:374-82.
4 Kulkarni, R., Lusher, J.M. Perinatal management of newborns with haemophilia. British J Haematology. 2001; 112:264-274.
5 Kenet, G., Chan A.K.C., Soucie J.M. and Kulkarni, R. Bleeding disorders in neonates. Haemophilia 2010:16(S5):168-174.
6 Chalmers, E.A., Brown, S.A., Keeling, D. et al. On behalf of the Paediatric Working Party of UKHCDO. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007;13:149-55.
7 Smith, A.R., Leonard, N., Kurth, M.H. Intracranial haemorrhage in newborns with haemophilia: the role of screening radiologic studies in the first 7 days of life. Journal of Pediatric Hematology/Oncology. 2008;30(1):81-4.
8 Davis, J. & Kadir, R.A. Mode of delivery and cranial bleeding in newborns with haemophilia: a systematic review and meta-analysis of the literature. Haemophilia 2016;22: 32-38.
9 New Zealand Haemophilia guideline. http://www.haemophilia.org.nz/assets/Docs/NZ-Haemophilia-TreatmentGUIDELINE-March-2005.pdf
10 Mihatsch, W.A., Braegger C., Bronsky J., et al. Prevention of Vitamin K deficiency bleeding in newborn infants: A position paper by the ESPGHAN Committee on Nutrition. JPGN 2016;63: 123-129.