Page 2458 - Hematology_ Basic Principles and Practice ( PDFDrive )

2196 Part XII Hemostasis and Thrombosis

plasma-derived concentrates that contain vWF (e.g., Humate-P or D-dimer occur because of delayed hepatic clearance. Assays of FV,
Alphanate), dosed initially at 40 to 60 ristocetin cofactor units/kg. FVII, and FVIII can help distinguish between liver disease, vitamin
Although most of the bleeding problems in neonates are acquired, K deficiency, and consumptive coagulopathy (e.g., DIC). FV and
patients with severe deficiencies of coagulation factors can present in FVIII are not vitamin K–dependent clotting factors. FV is synthesized
the neonatal period. Autosomal recessive deficiencies, in either in the liver, whereas FVIII is synthesized in multiple cell types, and
homozygous or compound heterozygous state, are grouped as rare the levels of both in neonates are similar to those in adults. Deficiency
coagulation disorders that can manifest as severe bleeding diatheses. of all three implies consumption, whereas decreased levels of FV and
In the neonatal period, severe deficiencies of fibrinogen, FVII, FX, FVII with a normal FVIII level suggest liver disease.
and FXIII are the most likely disorders to present with bleeding Treatment should include replacement with FFP and/or cryopre-
conditions. One common feature of these disorders is the association cipitate, as well as platelet transfusion. Fibrinogen concentrate has
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with ICH. Deficiency of fibrinogen can manifest with bleeding in been used as an alternative to cryoprecipitate. Patients with biliary
the soft tissues, bleeding after circumcision, or bleeding after umbili- atresia or other cholestatic liver failure syndromes may also benefit
cal stump detachment. The diagnosis can be established with fibrino- from parenteral vitamin K. The outcome is dependent on treatment
gen assays, and treatment involves replacement with cryoprecipitate of the underlying cause of liver disease.
or, if available, fibrinogen concentrate (see box on Recommended
Dosing for Transfusion in Neonatal Hemorrhage). Severe FXI defi-
ciency is more prevalent in Ashkenazi Jews and can present with Intraventricular Hemorrhage
bleeding in newborns after hemostatic challenges, such as circumci-
sion. FV and prothrombin deficiencies are the other rare autosomal Intraventricular hemorrhage (IVH) is associated with significant
recessive homozygous deficiencies that can cause hemorrhagic morbidity and mortality in the newborn period, particularly in pre-
symptoms. 11 mature infants. In the United States, it is estimated that approximately
Not all deficiencies result in a bleeding diathesis. Even complete 12,000 premature infants and 20% to 25% of very low-birth-weight
deficiencies of the contact factors, which include high-molecular- infants develop IVH each year. With improvements in neonatal care,
weight kininogen, prekallikrein, and FXII, are not associated with a the incidence of IVH is decreasing.
bleeding phenotype. Autosomal recessive deficiencies of α 2 AP and The etiology of IVH is multifactorial and includes prematurity of
PAI-1 have been associated with bleeding, but not in the neonatal the cerebral vasculature and ischemia-reperfusion injury related to
period. ventilatory support, blood pressure lability, and ECMO. Other risk
factors for IVH include vaginal delivery, severe respiratory distress
syndrome (RDS), low Apgar scores, pneumothorax, hypoxia, hyper-
Liver Disease capnia, seizures, patent ductus arteriosus, and infection. Many of
these risk factors induce IVH by altering cerebral blood flow. Coagu-
Acute liver disease or hepatic failure is uncommon in neonates. Liver lopathy and thrombocytopenia can contribute to IVH, but their role
disease in neonates may be caused by viral hepatitis, parenteral nutri- in the pathogenesis of IVH is uncertain. One study reported hypo-
tion, cholestasis, hypoxic injury, or metabolic disease. Rare disorders fibrinogenemia, thrombocytopenia, or prolonged clotting time in 11
that cause liver failure in neonates include hereditary tyrosinemia, of 15 neonates with IVH and in only 5 of 35 unaffected newborns.
neonatal hemochromatosis, and hemophagocytic lymphohistiocyto- Hemorrhage complicating cerebral vein thrombosis may explain
sis. Liver dysfunction can affect the hemostatic balance, resulting in some cases of IVH (especially in full-term infants), and heterozygosity
activation of the coagulation and fibrinolytic systems, reduced syn- for the FV Leiden mutation was reported in 18% of neonates with
thesis of coagulation factors, poor clearance of activated hemostatic grades 2 to 4 IVH compared with 3% of controls. Cerebellar hemor-
components, thrombocytopenia, platelet dysfunction, loss of coagu- rhage should raise suspicion of organic acidemia, such as methylma-
lation proteins into ascites fluid, and failure to use vitamin K. 21 lonic, propionic, or isovaleric acidemia.
Owing to reduced synthesis of multiple coagulation proteins, Vitamin K, indomethacin, AT, FFP, FXIII, tranexamic acid, and
laboratory workup typically reveals a prolonged PT and aPTT. Acute ethamsylate has been evaluated for prevention of IVH with mixed
liver disease also results in elevated liver enzyme levels, direct hyper- results. rFVIIa may be useful for treatment of IVH, but additional
bilirubinemia, and elevated ammonia concentrations. The platelet studies are needed to determine its efficacy and safety.
count may be reduced, especially if hypersplenism is present, and
platelet dysfunction is common. Hypofibrinogenemia is a late mani-
festation of liver disease, and elevated fibrin degradation products and Extracorporeal Membrane Oxygenation

ECMO is occasionally used for treatment of neonates with severe
pulmonary hypertension or cardiomyopathy. The ECMO pump,
Recommended Dosing for Transfusion in Neonatal Hemorrhage oxygenation membrane, and large-bore catheters can induce throm-
bosis, which necessitates administration of high-dose systemic anti-
PRBC: 10 to 15 mL/kg single-donor PRBC infused over 4 hours coagulation, thereby placing patients at risk for bleeding. Thrombosis
Platelets : 10 mL/kg raises platelet count by 75,000 (goal >50,000 if and hemorrhage are common complications in pediatric ECMO
a
bleeding, >20,000 if not bleeding)
FFP: 10 to 20 mL/kg every 6 to 12 hours for purpura fulminans patients, particularly if ECMO is initiated after open heart surgery.
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Cryoprecipitate: 0.15 units/kg raises fibrinogen about 100 mg/dL Approximately 15% of neonates on ECMO sustain an ICH.
(goal >150 mg/dL if bleeding, >50 mg/dL if not bleeding) With the doses of heparin used during ECMO, the PT and aPTT
vWF: 40 to 60 ristocetin cofactor units/kg of plasma-derived FVIII/ may not correlate with the activated clotting time (ACT). Further-
vWF preparations more, there is evidence that the heparin dose provides prognostic
Factor VIII: for hemophilia A—50 units/kg load, then 25 units/kg information in ECMO patients independent of the ACT, suggesting
every 12 hours; recombinant factor preferred (monitor FVIII) that an ACT of 180 to 220 seconds may not provide adequate
Factor IX: for hemophilia B—80 to 100 units/kg daily; recombinant anticoagulation. Prolonged ECMO is associated with depletion of
factor preferred (monitor FIX) clotting factors and high levels of fibrin degradation products.
Factor VIIa: for severe factor VII deficiency—20 to 30 µg/kg every
6 to 12 hours Consequently, the aPTT and ACT are prolonged and the levels
FFP, Fresh frozen plasma; PRBC, packed red blood cells; vWF, von Willebrand of D-dimer are increased even when low doses of heparin are
factor. administered.
a Volume limits transfusion of platelets by the “unit” in small neonates. Practices A retrospective study of 29 nonsurvivors of ECMO revealed that
vary; follow institutional guidelines for volume dosing or volume reduction.
most patients have a coagulopathy characterized by a prolonged PT
and aPTT, as well as being thrombocytopenic, and most had low