Page 2457 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 150 Disorders of Coagulation in the Neonate 2195

kg is sufficient. The overall prognosis of vitamin K deficiency bleed- Prolonged PT and aPTT
ing is good.
The association of bleeding with prolongation of both the PT and
Inherited Coagulation Disorders aPTT in a healthy newborn may indicate vitamin K deficiency or
congenital deficiencies of prothrombin, FV or FX, as well as rare
combined deficiencies. Routine prophylactic administration of
Prolonged aPTT vitamin K 1 to newborns can complicate the diagnosis of vitamin K
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deficiency bleeding in neonates. More commonly, combined PT
In neonates, the aPTT is physiologically prolonged compared with and aPTT prolongation occurs in sick newborns with DIC or severe
adult values. Hemophilia is the most common inherited coagulation hepatic disease. Combined factor deficiencies are rare but must be
disorder, as discussed in detail in Chapter 135. Evaluation for FVIII, considered when the laboratory findings or clinical course is confus-
FIX, and FXI deficiencies should be undertaken immediately in any ing. Autosomal recessive mutations in LMAN1 (ERGIC-53) or
neonate bleeding with an isolated prolongation of the aPTT or a MCFD2 can lead to combined FV and FVIII deficiency because of
positive family history. Cord blood samples can be used in those with defective intracellular processing of the factors. Mutations in
a family history, thereby avoiding the need for peripheral venipunc- γ-glutamyl carboxylase are associated with inherited combined defi-
ture, but careful sampling is important to avoid maternal contamina- ciencies of all the vitamin K–dependent proteins. FVII deficiency has
tion of the sample. In term and preterm infants, FVIII levels are rarely been reported in combination with FV, FVIII, FIX, FX, FXI,
within the normal adult range despite physiologic differences in the and protein C defects, as reviewed by Girolami et al. 17
hemostatic system. Thus confirmation of hemophilia A is possible in
the neonatal period, regardless of gestational age of the child or
severity of the condition. However, because the levels of the vitamin FXIII Deficiency
K–dependent clotting factors, including FIX, are reduced at birth
(and even lower in preterm infants), diagnosis of hemophilia B, FXIII is a transglutaminase that cross-links fibrin, thereby rendering
particularly mild hemophilia B, is difficult in the neonatal period. it resistant to lysis. FXIII deficiency is inherited in an autosomal
Male newborns with a family history of hemophilia should be recessive manner, and the prevalence of FXIII deficiency is estimated
evaluated before receiving intramuscular injections, including vitamin to be 1 in 3 million to 1 in 5 million. Homozygotes usually have
K. Typically newborns with hemophilia and bleeding appear well. FXIII levels of less than 1% and have a severe bleeding diathesis.
Male infants far outnumber females in this population, given the Patients with heterozygous FXIII deficiency are usually asymptomatic
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location of both FVIII and FIX genes on the X chromosome. but have reduced levels of FXIII. Neonates with FXIII deficiency
However, severe FVIII or FIX deficiency can, albeit rarely, present in may present with umbilical bleeding a few days after birth, a frequent
females, such as in Turner syndrome or extreme lyonization. Approxi- finding that occurs in 80% of cases. More severe bleeding, including
mately one-third of cases of hemophilia are the result of spontaneous ICH, occurs in 25% to 30% of patients, a frequency higher than that
mutations; consequently a family history may be lacking. FXI defi- in patients with hemophilia. ICH is the major cause of death and
ciency is inherited in an autosomal dominant or recessive manner, so disability in neonates with FXIII deficiency, and ICH in a child with
female newborns with bleeding and isolated prolongation of the no other risk factors should prompt a search for FXIII deficiency.
aPTT should also be tested. Evaluation of hemophilia carrier status FXIII deficiency is not detected with screening PT, aPTT, or
in mothers of unknown status (e.g., single prior affected child or thrombin time assays. Specific assays for FXIII or urea clot solubility
positive history in maternal grandmother) can be performed geneti- testing are used for diagnosis. The clot solubility test is sensitive to
cally because factor levels in carriers are variable and can overlap with very low levels of FXIII (<1%) but is normal if FXIII levels are in
normal levels. Most bleeding episodes in newborn males occur after the 1% to 3% range. Consequently, FXIII immunoassays are
circumcision or umbilical stump separation, although ICH is reported perferable. 18
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in approximately 3.5% of newborns with hemophilia, and cephal- Treatment of FXIII deficiency includes FFP, cryoprecipitate, or
hematoma is common. Joint bleeding is unusual in the neonatal plasma-derived FXIII concentrate. The prognosis is excellent, but
period. Patients with known or suspected hemophilia and those with affected patients face a lifelong risk for bleeding, and those with severe
severe deficiencies of FVII, FX, or FXIII should be screened for ICH. deficiency require prophylaxis. In 2013, the US Food and Drug
Although cranial ultrasonography is often used for screening pur- Administration approved a new recombinant FXIII A-subunit for use
poses, computed tomography or magnetic resonance imaging is more as routine prophylaxis in patients with FXIII deficiency.
sensitive for detection of small parafalcine bleeds, which can also
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occur in a small percentage of normal neonates. Neonates with
hemophilia A or B are treated with recombinant FVIII or FIX con- Other Inherited Deficiencies Associated
centrates, respectively. Routine prophylaxis is controversial after With Neonatal Bleeding
uncomplicated term delivery but is recommended for high-risk situ-
ations, such as prolonged labor, forceps delivery, or for preterm vWD, which is the most common inherited bleeding diathesis, is
infants. described in detail in Chapter 138. vWD is rarely associated with
neonatal bleeding and may be associated with the most severe sub-
types. In a case series that included 55 newborns with vWD, there
Isolated Prolonged PT were no bleeding complications, although cases of scalp hematomas
and bleeding after vitamin K injection or umbilical stump detach-
In term neonates, the PT is normal. Inherited FVII deficiency is a ment were reported. Acquired forms of vWD also are rare but may
rare, autosomal recessive condition with a strong gene dosage effect. complicate obstetric management of affected mothers and can affect
Neonatal bleeding can occur in severe cases (i.e., homozygosity or their newborn babies. A family history of vWD, especially type 2
compound heterozygosity for two mutations in the FVII gene). FVII vWD, should prompt vWD evaluation in the neonate before circum-
deficiency can be associated with microcephaly or midline defects cision and possibly before intramuscular injections. There is a possible
because disruption of chromosome 13q can lead to loss of adjacent association of vWD with acute idiopathic pulmonary hemorrhage.
genes. As a vitamin K–dependent protein, FVII deficiency can occur The diagnosis of vWD may be difficult because vWF concentrations
in association with deficiencies of the other vitamin K–dependent are high at birth and there is a large proportion of high-molecular-
clotting proteins with abnormalities of the vitamin K pathways. Low weight vWF multimers. Children with a diagnosis of type 3 vWD
doses of rFVIIa can be used for treatment of isolated FVII deficiency; should be tested for mutations that predispose them to inhibitory
FFP and/or vitamin K can be used for management of combined alloantibody formation before aggressive replacement with exogenous
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deficiencies. vWF. Treatment of neonates with vWD involves administration of