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.

Thrombocytopenia

See the Thrombocytopenia guideline.

Haemophilia

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.  von Willebrand Disease is also classified as a haemophilia although it is clinically less severe than Factor VIII and IX Deficiencies.

Factor VIII Deficiency (Haemophilia A)

This is the "classical" haemophilia, inherited as an X-linked recessive gene (affecting males), and causes approximately 75% of all significant inborn coagulopathies.  There may be a family history of affected males on the maternal side.  The incidence is approximately 1:10,000 male births.  The underlying abnormality is a defect in factor VIII.  It may present as severe bleeding after procedures (including intramuscular injection of vitamin K), or even intracranial bleeding.

Factor IX Deficiency (Haemophilia B, Christmas Disease)

This accounts for about 12% of all patients with haemophilia, is sex-linked (affecting males), and is clinically indistinguishable from Factor VIII Deficiency (that is, it may present with significant bleeding in the newborn period).

Other comments about Haemophilia A and B

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

• The result should be sensitively communicated to the parents by experienced staff
• Take a further factor VIII/IX level
• Follow the neonate closely for a minimum of 7 days after birth through daily phone contact from the Haemophilia Centre or GP, and frequent midwife visits.
• Educate parents regarding the symptoms and signs of intracranial haemorrhage (poor feeding, irritability, listlessness, full fontanelle, pallor, convulsions)
  • Do a CT (In preference to ultrasound) if there is suspicion of an intracranial haemorrhage.
• Suggest that Factor VIII/IX levels are done on females born to carrier mothers to detect the occasional carrier female with low levels at risk of symptomatic bleeding.

von Willebrand Disease (VWD)

This 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.  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.  There are 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, with more severe bleeding problems being rare.  Bleeding after dental extractions can be serious in some individuals.  The diagnosis is made by platelet function analysis (PFA) and specific tests for vW antigen and activity.  Bleeding times are rarely performed.

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.

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.

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.

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.

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 sometimes also be affected).  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 moth balls 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.

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.

References