You are called to the nursery because the term male newborn on whom you performed a circumcision just hours earlier does not look right. He is afebrile but lethargic. The small cephalhematoma is a little larger. The newborn was delivered by the vaginal route with the help of low forceps. There is no family history of a bleeding disorder, and he was given vitamin K shortly after birth. You order some laboratory tests. There is prolonged oozing from the puncture site. The prothrombin time is normal for age, the activated partial thromboplastin time is prolonged, and the platelet count is normal. What should you do next?
Pediatricians occasionally encounter the above scenario in the newborn nursery. Knowledge of the types of bleeding problems and their diagnoses may be helpful in the management of such newborns. There are several reasons why it is important for the pediatrician to diagnose newborns with bleeding early and appropriately. These are described below.
The obstetrician often lets the pediatrician know about the impending delivery of an affected newborn by a hemophilia carrier. (The newborn's affected sibling may be the pediatrician's current or former patient.) The pediatrician is vital in facilitating meaningful communication among all involved (the pediatrician, the obstetrician, the hematologist, and the neonatologist) so that the newborn and the mother can be treated safely and appropriately.
In recent years, the therapeutic armamentarium for the treatment of bleeding disorders has expanded considerably. It now includes low-volume recombinant factor concentrates and clotting factor concentrates treated to inactivate viruses. The latter includes fresh frozen plasma treated with solvent detergent. In some cases, this has allowed in utero factor replacement to prevent hemorrhages or treat those diagnosed by fetal ultrasound. In addition, the availability of the newer clotting factor concentrates has substantially decreased the use of cryoprecipitate and untreated fresh frozen plasma, thereby decreasing the potential transmission of blood-borne pathogens.
Once the diagnosis of an inherited bleeding disorder is confirmed, parents can be provided with appropriate information regarding the disorder, such as when to seek medical advice, what to look for, and how to care for the child. Furthermore, the local hemophilia treatment center can help pediatricians and parents obtain information and educational materials.
NEONATAL HEMOSTASIA AND LABORATORY DIAGNOSIS OF A BLEEDING DISORDER IN THE NEWBORN
Appropriate diagnosis and treatment of a newborn with bleeding requires the pediatrician to be knowledgeable about the newborn hemostatic process. Hemostasis in the newborn is dynamic and the balance between bleeding and thrombosis is often delicate.1 The following screening tests help assess the degree of hemorrhage and the adequacy of hemostasis: complete blood cell count, platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen. PT measures factors VII, X, V, and II and fibrinogen; APTT measures factors VIII, LX, XI, X, V, and II and fibrinogen (Table 1).
Screening Tests for Hemostasis in the Newborn
Any unexplained or prolonged bleeding in a newborn should raise the suspicion of hemophilia. In this case, these screening tests must be followed by appropriate factor assays. These can often be done from the same citrated blood sample. Values for most of the blood-clotting factors are age dependent and significantly lower in the fetus and the newborn compared with older infants and adults.1,2 Low levels of contact factors (factors involved in the initial activation of the intrinsic system, such as factor XII, factor XI, prekallikrein, and high-molecular-weight kininogen) and vitamin K-dependent factors (factors II, VII, IX, and X), combined with liver immaturity, often prolong screening tests such as PT and APTT.
Because none of the clotting factors cross the placenta, the diagnosis of an inherited coagulation protein deficiency can usually be made from a cord blood sample (obtained by drawing a blood sample from a vein on the fetal side of the placenta) or a peripheral blood sample obtained after birth. Pediatricians should be aware that infants with hemophilia may have a normal PT and APTT for age and yet be at risk for bleeding.
When confronted with a newborn with bleeding, it is important to elicit the family history of bleeding disorders. Several key elements can help identify the type of bleeding disorder. These include the type and the severity of bleeding in family members, the frequency of the disorder, and whether the disorder is sex linked (hemophilia A and B) or autosomal (von Willebrand disease [VWD], homozygous factors II, V, VII, X, XI, and XIII, and fibrinogen deficiencies). The family history is negative in autosomal recessive traits and in 30% of newborns with hemophilia.3
Bleeding in a healthy newborn may be congenital due to coagulant factor deficiencies or acquired as a result of alloimmune thrombocytopenia or vitamin K deficiency. Critically ill newborns may bleed as a result of disseminated intravascular coagulation, sepsis, or liver disease.4 Nonetheless, the pediatrician should be aware that a critically ill newborn with an acquired bleeding problem may have an underlying congenital coagulant clotting deficiency, making the diagnosis difficult and challenging. Information obtained from the history, the physical examination, and screening tests should lead to appropriate assays and a correct diagnosis (Fig. 1). Bleeding in term male newborns who are otherwise healthy should raise suspicion for hemophilia A or B, which are the most common types of neonatal congenital bleeding disorders.
Figure 1 . Algorithm for diagnostic considerations and workup of a neonate with bleeding. DIC = disseminated intravascular coagulation; VKDB = vitamin K deficiency bleeding; Cl = gastrointestinal; F = factor; VWD = von Willebrand disease; PT = prothrombin time; APTT = activated partial thromboplastin time; NAIT = neonatal alloimmune thrombocytopenia.
Bleeding manifestations in a newborn differ considerably from those in infants or older children. For instance, scalp bleeds (as in the scenario described at the beginning of this article) and umbilical oozing are more common in the newborn. Intracranial hemorrhage may occur in a small proportion of term newborns and is often the initial manifestation of hemophilia. Although circumcision is perhaps the most common procedure performed in the newborn period, it is not always associated with bleeding, despite low levels of clotting proteins. Hemarthroses and muscle hematomas, the hallmarks of hemophilia in older children, are also rare in the newborn period. On the other hand, critically ill newborns often present with diffuse mucous membrane bleeding, hematuria, pulmonary hemorrhage, and bleeding from puncture sites.
INHERITED BLEEDING DISORDERS
Hemophilia A and B and VWD represent approximately 80% to 85% of inherited bleeding disorders. Deficiencies of fibrinogen, prothrombin, factors V, VII, X, XI, and XIII, and combined factors V and VIII account for most of the remaining 15% to 20%. The incidence, clinical presentation, and treatment of congenital coagulation deficiencies are described in Table 2.1AS7 It is important to know the type of bleeding disorder because specific therapy with products such as recombinant and virally purified concentrates is available for some of these disorders.
Hemophilia A and B
Factor VHI deficiency (hemophilia A) and factor IX deficiency (hemophilia B) are X-linked bleeding disorders that affect all racial groups. Hemophilia A occurs in approximately 80% to 85% of cases (1 in 5,000 male births) and hemophilia B occurs in approximately 15% to 20% (1 in 30,000 male births). Plasma levels of factor VHI or IX coagulant usually correlate with disease severity. Hemophilia is classified as mild (> 5% to < 40%), moderate (1% to 5%), or severe (< 1%) based on these levels.
Congenital Coagulation Factor Deficiencies in the Newborn
In most cases of hemophilia, a bleeding event eventually leads to the diagnosis. Although bleeding soon after birth is diagnosed within days, the mean age at diagnosis of hemophilia seems to be approximately 10 months (range 6 to 18 months). This implies that despite the availability of specific therapy, many of these newborns are treated with fresh frozen plasma and cryoprecipitate. Nonetheless, 38% to 54% of cases of hemophilia are currently diagnosed in the newborn period, an improvement from 10% in the 1960s.5
A recent review5 of bleeding episodes in newborns with hemophilia A and B revealed that the most common site of bleeding was within the cranium. Figure 2 shows the sites of bleeding in 344 newborns with hemophilia. Intracranial hemorrhage accounted for 100 (28%) of the bleeds, whereas 50 (14%) were subgaleal hemorrhage or cephalhematoma. Puncture site bleeds (venous, arterial, heel stick, and intramuscular) and hematomas were reported in 65 (18%) of the cases, and 101 (30%) of the cases were circumcision bleeds. Umbilical stump bleeding accounted for 23 (6%) of the cases, whereas 4% of the bleeding was a result of gastrointestinal or mouth, parenchymal organ (spleen, liver, lungs, or kidneys), joint, or subcutaneous bleeding. Many newborns presented with bleeding at more than one site. Hemophilia A accounted for 87% and hemophilia B for 13% of the cases. Most newborns with hemophilia and intracranial hemorrhage were delivered by vacuum or forceps, a known risk factor for this problem. Vaginal delivery appears safe when mothers are carriers of hemophilia.8 Written guidelines for the management of pregnant women who are carriers of hemophilia or their newborns are available.9
Intracranial Hemorrhage and Subgaleal Hemorrhage or Cephalhematoma
Of all of the bleeding events in a newborn with hemophilia, intracranial hemorrhage is perhaps the most serious because it has such high rates of mortality and rebleeding and many who survive have permanent disability. Intracranial hemorrhage in newborns with hemophilia can occur at birth, is almost always related to trauma, and can occur irrespective of the mode of delivery. Because of its critical nature, it is vital that every attempt be made to recognize intracranial hemorrhage early so that prompt treatment can be instituted. The incidence of intracranial hemorrhage among newborns with hemophilia is approximately 1% to 4% and the mean age at diagnosis of intracranial hemorrhage is 4.5 days (range 0 to 28 days).10
Although intracranial hemorrhage is generally diagnosed within a matter of days after birth, it often takes much longer, sometimes months, to diagnose hemophilia. This may be due to a lack of awareness that intracranial hemorrhage can occur regardless of the severity of hemophilia and may be the first indication that a newborn has hemophilia. The absence of a family history of hemophilia also increases the chances that the diagnosis will be delayed.
Although most bleeding episodes in the head are due to intracranial hemorrhage, a smaller proportion result from bleeding of the scalp (ie, subgaleal hemorrhage or cephalhematoma). These may occur concomitantly with intracranial hemorrhage. In a recent review of 331 episodes of cranial bleeding in 138 newborns (including intraventricular hemorrhage in 2 premature newborns with hemophilia), 65% were due to intracranial hemorrhage and 35% to subgaleal hemorrhage or cephalhematoma.10
Intracranial hemorrhage can occur in full term newborns as a consequence of birth trauma. Other clotting factor deficiencies, such as factor XIII, II, V, VII, and X deficiencies, inherited fibrinogen disorders, and vitamin K deficiency, can also cause intracranial hemorrhage in the newborn period (Table 3).
Causes of Intracranial Hemorrhage In Newborns
The signs and symptoms of intracranial hemorrhage may be dramatic (eg, seizures, paralysis, a bulging fontanelle, and apnea) or subtle (eg, poor feeding, anemia, irritability, jaundice, and lethargy) (Fig. 3). Because the signs and symptoms of intracranial hemorrhage mimic those of sepsis, a high degree of clinical suspicion is warranted, especially prior to invasive procedures such as a lumbar puncture. Other conditions such as disseminated intravascular coagulation, vitamin K deficiency, or prematurity may contribute to the severity of these cranial hemorrhages. Although bleeding in the scalp does not usually cause neurologic disability directly, large volumes of blood can be trapped under the skin and lead to hypotension and shock.
Computed tomography and ultrasound of the head are safe and noninvasive, and are definitive means of diagnosing intracranial hemorrhage. Occasionally, a bloody lumbar puncture may lead to a suspicion of hemophilia. However, in newborns with hemophilia, procedures such as lumbar punctures can be dangerous and may lead to further bleeding, resulting in compression of the spinal cord and paralysis. Magnetic resonance imaging, although more expensive, can also be used to confirm the presence of intracranial hemorrhage.
The mainstay of management of hemophilia is the prevention of bleeding and, once bleeding occurs, prompt treatment to limit further tissue damage. Antenatal diagnosis of hemophilia coupled with prenatal ultrasound (and proper communication among all involved) in known carriers enhances safety in the delivery of newborns with hemophilia. This includes avoidance of vacuum deliveries. To confirm the diagnosis of hemophilia, all male offspring of hemophilia carriers should have factor assays done on a cord blood sample at delivery (or, if this has not been done, by venipuncture as early as possible).
Although most newborns with hemophilia do not bleed in the newborn period, in some instances hemorrhage may be so profound that therapy must be instituted before a precise diagnosis can be made. In such cases, 15 to 20 mL/kg of fresh frozen plasma can be given pending diagnosis. Activated recombinant factor VII (recombinant factor Vila) has been used in newborns with congenital factor VII deficiency and in individuals with hemophilia with inhibitors because it bypasses the need for factors VIII and IX. Although its efficacy is unproved, recombinant factor Vila can be used as a low-volume alternate therapy for the bleeding newborn with hemophilia.11
Once the diagnosis of hemophilia is made, recombinant concentrates are preferred over plasma or plasma-derived products because of their increased margin of safety for transmitting viral infections. If recombinant clotting factor concentrates are unavailable, highly purified virally inactivated factor VIII or IX products derived from plasma should be used. For newborns strongly suspected of or confirmed as having hemophilia, the pediatrician might even consider administering a prophylactic dose of factor VIII or IX concentrate (250 IU or one vial) shortly after birth to offset the trauma of labor.12
Treatment of suspected head bleeds consists of appropriate recombinant coagulation factor replacement. In the case of a newborn with hemophilia and intracranial hemorrhage, the goal is to increase plasma levels of factor VIII or IX to 100%. For patients with hemophilia A, this involves administering a bolus of 50 U /kg of recombinant factor VIII concentrate, followed by continuous infusion of 2 to 3 U /kg/ h for 7 to 14 days. Additional days of therapy may be required if the bleed is large and surgery for evacuation is performed. The goal is to keep factor VIII levels at or above 100% for at least 24 hours and above 50% from day 2 onward. For hemophilia B, the recommended dose is a bolus of 80 U /kg of recombinant factor IX concentrate, followed by 20 to 40 U /kg every 12 to 24 hours to maintain levels of factor IX above 40% for the first 5 days and above 30% for 5 to 10 days.
If intracranial hemorrhage is confirmed, clotting factor replacement should be continued as above for at least 2 weeks, followed by early institution of prophylaxis to prevent rebleeding. In some cases, neurosurgical intervention under proper clotting factor coverage may be required to evacuate the bleed. Recombinant factor VIII concentrate has been administered via the cord in utero before delivery of a hemophilic fetus to prevent further bleeding in the brain.13
OTHER CONGENITAL FACTOR DEFICIENCIES
Deficiencies of fibrinogen and factors II, V, VII, X, and XI can present as bleeding in the newborn period and may be indistinguishable from those of hemophilia. This includes intracranial hemorrhage, subgaleal hemorrhage or cephalhematoma, and umbilical, circumcision, and soft tissue bleeds. Table 2 outlines the frequency, the types of bleeds, and the treatment available for these disorders.6714
von Willebrand Disease
Bleeding manifestations of VWD, the most common type of bleeding disorder, are more frequent in the mother than in the newborn following delivery. However, there are rare reports of intracranial hemorrhage, thrombocytopenia (with type 2 VWD), cephalhematoma, and soft tissue bleeds in newborns with VWD.
Congenital afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia are rare quantitative and qualitative disorders of fibrinogen. Congenital afibrinogenemia is an autosomal recessive disorder with an incidence of 1 to 2 per million and a high rate of consanguinity. Acquired hypofibrinogenemia is usually secondary to disseminated intravascular coagulation, liver disease, and drugs. Intracranial hemorrhage and umbilical bleeding are common manifestations.
Factor V Deficiency
Factor V is synthesized in the liver and megakaryocytes. Platelets contain approximately 20% of the total body pool of factor V. There are two types of factor V deficiency - homozygous and heterozygous "true" factor V deficiency and combined factor V and factor VHI deficiency. In utero intraventricular intracranial hemorrhage (often recurrent) and subdural and umbilical bleeds and hematomas have been described in newborns with homozygous factor V deficiency.
Factor VII Deficiency
Factor VII deficiency occurs in 1 per 500,000 individuals and may mimic hemophilia. For a definite diagnosis, specific factor VII levels should be obtained. Recombinant factor Vila has been used for treatment of and prophylaxis for severe factor VII deficiency. Doses of recombinant factor Vila at 20 to 30 µg /kg seem effective and are lower than the doses used to maintain hemostasis in patients with hemophilia with inhibitors. Alternatively, 10 mL/kg of fresh frozen plasma every 6 to 12 hours or prothrombin complex concentrates can be used.
Factor II Deficiency
Congenital prothrombin deficiency, an autosomal recessive disorder, is extremely rare, with only 26 reported cases in the world literature/ The treatment of choice is prothrombin complex concentrates or fresh frozen plasma.
Factor XI Deficiency
Occurring primarily in persons of Jewish ancestry, factor XI deficiency is an autosomal recessive disorder. One newborn with factor XI deficiency was diagnosed following post-circumcision bleeding.6 Some patients with Noonan syndrome have also been found to have factor XI deficiency. Levels of factor XI may not correlate with bleeding; hence, the family history or the patient's medical history may be better predictors of the clinical course.
Factor XIII Deficiency
Factor XIII stabilizes blood clots by crosslinking fibrin polymers. Deficiency is associated with reduced clot stability resulting in delayed bleeding and wound dehiscence. Congenital factor XIII deficiency is a rare autosomal recessive disorder. It is characterized by bleeding from the umbilical stump in 80% of affected newborns and by intracranial hemorrhage in 25% of such children and adults.7 Results of routine coagulation tests are normal. Because of the high incidence of intracranial hemorrhage, lifelong prophylaxis with periodic infusions of cryoprecipitate or factor XIII concentrates every 3 to 4 weeks is recommended. Plasma-derived virally purified factor XIII concentrate is available in the United States under a Food and Drug Administration Investigational New Drug Application.7
ACQUIRED BLEEDING DISORDERS
The major acquired bleeding disorders occurring in the newborn period are secondary to vitamin K deficiency, disseminated intravascular coagulation, liver disease, hyaline membrane disease, extracorporeal membrane oxygenation, and periventricular-intraventricular hemorrhage (in premature newborns). It is beyond the scope of this article to describe in detail all of these conditions. Although vitamin K deficiency bleeding can occur in healthy newborns, the other conditions are seen more often in sick neonates. Management includes treatment of the underlying disorder and supportive care with transfusions of blood, platelets, fresh frozen plasma, and cryoprecipitate as needed. Recombinant factor Vila has been used as a lowvolume alternative on a compassionate basis. It appeared to be effective in bleeding premature newborns 24 weeks of gestational age who weighed less than 1,000 g with abnormal results on coagulation assays secondary to immature livers.11
The term vitamin K deficiency bleeding is preferred to "hemorrhagic disease of the newborn" because not all bleeding in the newborn is due to vitamin K deficiency and bleeding due to vitamin K deficiency is not necessarily confined to the newborn.6 The diagnosis is confirmed when bleeding is rapidly reversed following administration of vitamin K and other causes of coagulopathy have been excluded.
Vitamin K deficiency bleeding is classified into early, classic, and late, based on the age at presentation. Early vitamin K deficiency bleeding is characterized by bleeding within the first 24 hours of life and is due to maternal ingestion of medications such as anticonvulsants, warfarin, cephalosporins, rifampin, and isoniazid. Classic vitamin K deficiency bleeding occurs between 2 and 7 days of age and is seen in breastfed newborns with poor intake or delayed onset of feeding. Late vitamin K deficiency bleeding occurs between 2 and 6 months of age and is classically seen in breastfed infants (due to low vitamin K content) or in newborns with underlying liver disease (inadequate absorption). It is associated with a high incidence of intracranial hemorrhage (59%) and long-term morbidity and mortality (33%).15
Newborns suspected of having vitamin K deficiency bleeding should be treated with intravenous vitamin K. To increase the efficacy of oral vitamin K prophylaxis, weekly dosing for a longer interval should be considered.
NEONATAL PLATELET DISORDERS
Qualitative platelet disorders such as Glanzmann thrombasthenia are rare in the newborn. Thrombocytopenia, a quantitative disorder, is perhaps the most common hemostatic abnormality encountered in the sick and the premature newborn.6 The topic of thrombocytopenia is addressed in the article by Buchanan in this issue. Thrombocytopenia in the healthy term newborn is often a result of maternal immunoglobulin G alloantibodies directed against the newborn's platelets. This is referred to as neonatal alloimmune thrombocytopenia. Intracranial hemorrhage can occur in 10% to 15% of such newborns. Petechiae, gastrointestinal hemorrhage, and hematuria can also occur. In contrast, autoimmune thrombocytopenia that results from maternal immune thrombocytopenic purpura has a milder presentation in the newborn period. Treatment includes administration of washed irradiated maternal platelets (for neonatal alloimmune thrombocytopenia), intravenous gammaglobulin, or both and, rarely, steroids.
In the scenario presented at the beginning of this article, the patient is a healthy newborn with a normal platelet count. The most likely diagnosis is hemophilia A or B. If there is a family history of hemophilia A or B, then blood should be drawn for appropriate factor determination and a single vial of recombinant factor VIII or IX should be administered immediately via the same needle. In the absence of a family history, factor assays should still be obtained, but 15 to 20 mL/kg of fresh frozen plasma can be administered. Shock should be treated, if present. The effectiveness of recombinant factor VII in situations such as this is unproved. Following replacement therapy, a computed tomography scan should be obtained to determine whether there is an intracranial hemorrhage and further need for factor replacement.
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11. Duncan A, Benson L, Critz A, Abshire T. Neonatal coagulopathy treatment with rFVIIa. / Pediatr Hematol Oncol. 2001;23:A28.
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13. Gilchrist GS, Muehlenbein L, Wilke J, Danilenko-Dixon DR, Gastineau DA. In-utero infusion of factor VHI (FVIII) to prevent neonatal intracranial hemorrhage (ICH). Blood. 1998;92:105b. Abstract.
14. Smith PS. Congenital coagulation protein deficiencies in the perinatal period. Semi« Perinatol. 1990,14:384-392.
15. Bor O, Akgun N, Yakut A, Sarhus F, Kose S. Late hemorrhagic disease of the newborn. Pediatr Int. 2000;42:64-66.
Screening Tests for Hemostasis in the Newborn
Congenital Coagulation Factor Deficiencies in the Newborn
Causes of Intracranial Hemorrhage In Newborns