Bleeding
Stacy E. Croteau
This is a revision of a chapter from the seventh edition by Ellis J. Neufeld.
KEY POINTS
Normal levels of pro- and anticoagulant proteins are age-dependent. The physiologic balance of pro- and anticoagulant proteins and platelet function differs in the neonate compared to the older child or adult. Despite this “developmental hemostasis,” the healthy neonate is not predisposed to hemorrhage or thrombosis.
Cord blood samples may be sent for coagulation testing; venipuncture blood draw is the method of choice if cord blood samples are not obtained. Heel sticks and arterial draws should be avoided.
One-third of patients with severe hemophilia have de novo mutations, so family history alone cannot exclude the diagnosis.
Vitamin K is essential for normal production of several coagulation factors. Lack of administration to neonates increases their risk for severe bleeding over the first several days to weeks of life.
I. ETIOLOGY
A. Deficient clotting factors
1. Transitory deficiencies of the procoagulant vitamin K-dependent factors II, VII, IX, and X and anticoagulant proteins C and S are characteristic of the newborn period and may be accentuated by the following:
a. The administration of total parenteral alimentation or antibiotics or the lack of administration of vitamin K to premature infants
b. Term infants may develop vitamin K deficiency by day 2 or 3 if they are not supplemented with vitamin K parenterally because of negligible stores and inadequate intake.
c. Liver disease may interfere with the production of clotting factors by the liver.
d. Transplacental exposure to certain drugs can cause bleeding in the first 24 hours of life.
i. Phenytoin (Dilantin), phenobarbital, and salicylates interfere with the effect of vitamin K on clotting factor synthesis.
ii. Warfarin and related compounds given to the mother interfere with the synthesis of vitamin K-dependent clotting factors by
both the maternal and fetal livers; bleeding may not be immediately reversed by administration of vitamin K.
both the maternal and fetal livers; bleeding may not be immediately reversed by administration of vitamin K.
2. Disturbances of clotting
a. Disseminated intravascular coagulation (DIC) may be due to infection, shock, anoxia, necrotizing enterocolitis (NEC), renal vein thrombosis (RVT), or the use of vascular catheters.
b. Extracorporeal membrane oxygenation (ECMO) in neonates with critical cardiopulmonary disease is a special case of coagulopathy related to consumption of clotting factors in the bypass circuit plus therapeutic anticoagulation (see Chapter 39).
3. Inherited abnormalities of clotting factors
a. X-linked (expressed predominantly in males; affected females should raise concern of Turner syndrome, partial X deletions, or nonrandom X chromosome inactivation). One-third of patients with severe hemophilia have “new mutations,” so family history alone cannot exclude the diagnosis.
i. Factor VIII levels are decreased in the newborn with hemophilia A (1 in 5,000 males).
ii. Hemophilia B, or Christmas disease, is due to a deficiency of factor IX (1 in 25,000 males).
b. Autosomal dominant (expressed in boys and girls with one parent affected)
i. Von Willebrand disease (VWD) is caused by decreased levels or functional activity of von Willebrand factor (VWF), which acts as a carrier for factor VIII and plays a role in platelet aggregation. VWD is the most common inherited coagulation defect (up to 1% of the population as assayed by levels). Neonatal levels of VWF are elevated in normal neonates compared to older children and nonpregnant adults because of maternal estrogen.
ii. Dysfibrinogenemia (very rare) is due to fibrinogen structural mutations.
c. Autosomal recessive (occurs in both boys and girls born to carrier parents). In order of frequency, deficiencies of factors XI, VII, V, X, II, fibrinogen, and factor XIII are all encoded by autosomal genes. Factor XII is a special case because deficiency causes prolonged partial thromboplastin time (PTT) but never bleeding. Combined factors V and VIII deficiency is caused by a transport gene mutation, not mutations of the factor V and factor VIII genes.
i. Severe factor VII or factor XIII deficiency can present as intracranial hemorrhage in neonates. Bleeding from the umbilical stump is also a feature of factor XIII deficiency.
ii. Factor XI deficiency is incompletely recessive because heterozygotes may have unpredictable bleeding problems with surgery or trauma.
iii. VWD type III (rare, complete absence of VWF)
B. Platelet problems (see Chapter 47)
1. Qualitative disorders include hereditary conditions (e.g., storage pool defects, Glanzmann thrombasthenia, Bernard-Soulier syndrome, platelet-type VWD) and transient disorders that result from maternal use of antiplatelet agents.
2. Quantitative disorders include the following:
a. Immune thrombocytopenia (maternal idiopathic thrombocytopenic purpura [ITP] or neonatal alloimmune thrombocytopenia [NAIT])
b. Maternal preeclampsia or Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome (see Chapter 3) or severe uteroplacental vascular insufficiency
c. DIC
d. Inherited marrow failure syndromes, including Fanconi anemia and congenital amegakaryocytic thrombocytopenia
e. Congenital leukemia
f. Inherited thrombocytopenia syndromes, including gray-platelet syndrome and the macrothrombocytopenias (e.g., MYH9-related disorders, May-Hegglin syndrome)
g. Consumption of platelets, i.e., catheter-related thrombosis, RVT, NEC, or vascular anomalies, such as Kasabach-Merritt phenomenon (KMP) from kaposiform hemangioendothelioma or tufted angioma
h. Heparin-induced thrombocytopenia (HIT) results from antibody development to the complex of heparin with platelet factor IV. It is probably rare in neonates, although the antibody can be detected by enzyme-linked immunosorbent assay (ELISA) after cardiac surgery.
C. Other potential causes of bleeding
1. Vascular anomalies may cause central nervous system, gastrointestinal (GI), or pulmonary hemorrhage.
2. Trauma (see Chapter 6)
a. Rupture of spleen or liver associated with breech delivery
b. Retroperitoneal or intraperitoneal bleeding may present as scrotal ecchymosis.
c. Subdural hematoma, cephalohematoma, or subgaleal hemorrhage (the latter may be associated with vacuum extraction)
II. DIAGNOSTIC WORKUP OF THE BLEEDING INFANT
A. History
1. Family history of excessive bleeding or clotting
2. Maternal medications (e.g., aspirin, phenytoin)
3. Pregnancy and birth history
4. Maternal history of a prior infant with a bleeding disorder
5. Illness, medication, anomalies, or procedures performed on the infant
B. Examination
The crucial decision in diagnosing and managing the bleeding infant is determining whether the infant is sick or well (Table 43.1).
1. Sick infant. Consider DIC, viral or bacterial infection, or liver disease. Hypoxic/ischemic injury may lead to DIC.
2. Well infant. Consider vitamin K deficiency, isolated clotting factor deficiencies, or immune thrombocytopenia. Maternal blood in the infant’s GI tract will not cause symptoms in the infant.
Table 43.1. Differential Diagnosis of Bleeding in the Neonate | |||||||||||||||||||||||||||||||||||||||||||||||
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