Introduction
The coagulation system in the neonate [up to 4 weeks after delivery] is immature compared to the adult system (or the child at 6 months of age) but remarkably it results in few problems for the healthy term neonate. Reference ranges must be used for neonates and for the pre-term infant as the concentrations of many of the proteins and therefore the laboratory tests involved in/with haemostasis, vary with age.
There are a number of problems in establishing reference ranges in neonates and these include relatively small numbers of infants from which the data has been derived; the use of a wide variety of techniques and reagents for the assays and limited long-term follow-up of neonates. The published data should, therefore, be interpreted with caution.
Below is a summary of the Proteins/Tests that are low/prolonged in the neonate:
Screening Tests
| Test | Comment |
|---|---|
| PT | Marginally prolonged or normal. |
| APTT | Prolonged at birth - generally reaches adult values at 6-12 months of age, but it remains prolonged in the premature infant throughout the postnatal period. |
| Thrombin Time | Prolonged at birth due to the presence of 'fetal' fibrinogen |
| Fibrinogen | Levels are normal or near normal at birth but the presence of a Fetal fibrinogen due to alterations in its Sialic Acid content can prolong the Thrombin Time |
Procoagulant Proteins
| Protein | Comment |
|---|---|
| Factor II | All the Vitamin K dependent clotting factors are low at birth and reach adult values by 6 months of age [See also Protein C and S below]. However, Factor VII may take significantly longer to reach adult values - in some studies up to 16yrs of age. |
| Factor VII | |
| Factor IX | |
| Factor X | |
| Factor V | Normal or slightly decreased at birth. Reaches adult levels at 6-12 months of age |
| Factor VIII | Normal or slightly elevated at birth. |
| Factor XI | Low at birth. Reaches adult levels at 6-12 months of age |
| Factor XII | Low at birth. Reaches adult levels at 6-12 months of age |
| Von Willebrand Factor [VWF] Ag and Act |
Increased at birth. Reaches adult values at ~6 months of age |
| Factor XIIIa Factor XIIIb |
Borderline/Normal at birth Borderline/Normal at birth |
| Pre-kallikrein | Low at birth. Reaches adult levels at 6-12 months of age |
Natural Anticoagulants
| Protein | Comment |
|---|---|
| Protein C | Low at birth and although in many cases Protein C levels are normal by 6 months of age, in some individuals it may take longer - up to 16yrs of age. Heterozygous Protein C deficiency can be difficult to diagnose in the neonatal period due to the wide variation in levels. In contrast homozygous deficiency is readily diagnosed due to a complete absence of Protein C. |
| Protein S | Total Protein S levels are low at birth. Protein S exists in the neonate primarily in the Free form due to low levels of C4b binding protein. Free Protein S levels are low at birth and reach adult values at 3-4 months of age. |
| Antithrombin | Functional Antithrombin levels are low at birth and may be further reduced in the sick neonate. Levels normally reach adult values at ~3 months of age. |
| Factor V Leiden Prothrombin G20201A Mutation |
These mutations should be identified by DNA analysis if indicated. APCr screening assays can be unreliable due to the variation in FVIII levels in the neonate. |
Platelet Membrane Glycoproteins
Formal platelet function testing in the neonate is difficult using conventional platelet aggregometry due to the large volumes of blood that are required to generate Platelet Rich Plasma [PRP]. The FPA-100 and Flow cytometry can be useful in this situation. Platelet membrane glycoproteins are fully developed in the term/ premature neonate and flow cytometry can be very useful in establishing
the diagnosis of the congenital disorders such as Bernard Soulier
disease and Glanzmann’s Thrombasthenia.
Fibrinolytic System
| Protein | Comment |
|---|---|
| Plasminogen | Plasminogen levels are low at birth (~50% that of the adult). |
| T-PA | Raised at birth |
| α2-Antiplasmin | Levels are normal at birth |
| PAI-1 | Raised at birth |
| α2-macroglobulin | Levels are raised in children |
Thromboelastography [TEG] in term neonates
The TEG in neonates differs from that of older children and adults with shortened R and K times but an increased rate of Fibrinolysis [increased Lys30 and CLI]. The reference ranges and cut-off points for a Citrate-modified and Heparinase-modified TEG can be used to diagnose and evaluate haemostasis in term neonates.
The TEG measurements from term neonates are no different in neonates whether they are delivered vaginally or by caesarean section.
| Neonatal and Adult Haemostasis | Neonate | Overall Effect in the Neonate |
|---|---|---|
| Primary Haemostasis | ↑/↔ Platelet count ↑ VWF ↓ PFA-100 Closure Time |
Enhanced Primary Haemostasis |
| Coagulation Factors | ↓ FII, VII, IX, X, XI & XII ↔ Fibrinogen ↔ FV ↑/↔ FVIII |
Decreased Thrombin generation. Confirmed by a decrease in Thrombin Generation in specific assays |
| Inhibitors of Coagulation | ↓ Antithrombin, PC, PS | Decreased inhibition of activated clotting factors |
| Fibrinolysis | ↑ PAI-I ↓ Plasminogen ↓/↔ α2-Antiplasmin ↑ t-PA |
Decreased Fibrinolysis |