Why is this newborn bleeding?

By Maureen Edelson, MD, and Steven E. McKenzie, MD, PhD

General pediatricians can perform the initial evaluation of newborns with bleeding disorders and, often, reach a diagnosis and make treatment decisions. Sometimes, however, it's best to call in a specialist.

Even though hemostatic functions in infants differ from those in children and adults, bleeding is an uncommon problem in healthy neonates born at term. In dealing with a neonate with bleeding, for example from mucous membranes or intracranially, pediatricians need to have a clear diagnostic and therapeutic approach and know when to consult a specialist.

LEARNING OBJECTIVES

After reviewing this article the physician should be able to:

Normal hemostasis, the process that arrests bleeding to avoid hemorrhage after blood vessel injury, is achieved through normal functioning of platelets and coagulation proteins and by vascular integrity. Disruptions of one or more of these factors results in bleeding. The neonatal bleeding disorders in Table 1 are categorized by which of the three factors is compromised: platelets, coagulation proteins, combinations of platelets and coagulation proteins, or vascular integrity. We will discuss the diagnosis and treatment of some of these disorders, emphasizing those that are most common.

Table 1
Bleeding disorders of newborn infants

The right approach

We recommend the following general approach to evaluating the clinical presentation of the neonate with bleeding, taking the history and performing the physical examination, and ordering laboratory evaluations.

The clinical presentation of bleeding in newborns may differ from that of children and adults. There may be oozing from the umbilicus, bleeding into the scalp, large cephalohematomas, bleeding following circumcision, oozing from peripheral venipuncture sites, and bleeding into the skin. Only rarely is a bleeding disorder signaled by intracranial hemorrhage. Sick newborns can bleed from mucous membranes, the bladder, and sites of invasive procedures. Bleeding from joints is unusual.

History and physical examination. Before ordering any laboratory tests, obtain a full maternal medical and obstetrical history and the history of the delivery. Pertinent features include any family history of bleeding disorders, complications of pregnancy, administration of vitamin K, and children born earlier who had bleeding disorders. Ask about nosebleeds, menorrhagia, bleeding with childbirth, and bleeding with tooth extraction or tonsillectomy. Conduct a complete physical examination of the infant, paying particular attention to the vital signs to document adequate cardiorespiratory reserve, and to the skin and extremities for signs of hemorrhage or malformations, such as petechiae on the skin, scalp hematomas, hematoma at injection sites, or thumb or radial anomalies. The neurologic examination should focus on signs of an intracranial process, including somnolence, irritability, seizures, or respiratory instability, such as apneic events.

Laboratory evaluation. Appropriate screening studies for infants with bleeding include a complete blood count (CBC) with platelet count, a prothrombin time (PT), activated partial thromboplastin time (PTT), and a fibrinogen level. It is appropriate for the physician or qualified hematology laboratory staff to review the peripheral blood smear to confirm any abnormal counts and to look for abnormal cell forms. Further work-up is tailored to pursue any abnormal results or clinical suspicions. Specific coagulation factor assays, such as for factor VIII or factor IX, should be obtained for boys with prolonged PTT values and boys who have a significant family history for a particular deficiency. The PT/PTT screening tests are normal in infants with deficiencies of factor XIII and

2-antiplasmin, so if you suspect these rare abnormalities, assays for the deficiencies must be performed directly.

Platelet disorders

Platelet disorders can be broadly grouped into two types: too few platelets and impaired platelet function.

Thrombocytopenia (platelet count <150,000/µL) is far more common than platelet function disorders. From the time the fetus is viable (22 to 24 weeks' gestation) through childhood and adulthood, the normal lower limit for platelet count is 150,000/µL. Aside from anemia caused by iatrogenic blood drawing, thrombocytopenia is the most common hematologic abnormality in newborn infants. A recent review notes that 1% to 4% of babies born at term can be thrombocytopenic and up to 40% to 72% of sick preterm babies are thrombocytopenic in the first month of life.¹ In the first 72 hours of life, the leading causes of thrombocytopenia are neonatal alloimmune thrombocytopenia and thrombocytopenia that is secondary to maternal factors, such as preeclampsia. Congenital thrombocytopenia syndromes are implicated only rarely. After the first three days of life, new-onset thrombocytopenia in a newborn most often represents sepsis or necrotizing enterocolitis, or is associated with thrombosis accompanying an indwelling arterial or venous catheter.

General pediatricians who care for newborn infants should be able to recognize neonatal alloimmune thrombocytopenia (NAIT) and know how it develops.² This relatively common condition (one to two cases per 1,000 newborn infants), can be severe and leads to poor outcome, even death, but is treatable.

NAIT arises from an incompatibility between antigens on the surface of the platelets the baby inherits from the father and antigens on the surface of the mother's platelets. During pregnancy, with the inevitable mixing of maternal and fetal blood (even without procedures such as amniocentesis or chorionic villus sampling), the mother becomes sensitized to the "foreign" fetal platelet antigen and forms immunoglobulin G (IgG) antibodies that cross the placenta and destroy the baby's platelets. This is the platelet equivalent of Rh-incompatibility in maternal-fetal red blood cells, with one major difference. In NAIT, first pregnancies are affected, representing up to half of cases. The mother's platelet count is normal because she lacks the platelet surface antigen to which her antibody is directed. Because sensitization can occur throughout pregnancy and quantities of IgG are delivered transplacentally through the third trimester, thrombocytopenia is present in utero.

NAIT often presents as diffuse petechiae or mucosal surface bleeding in an otherwise healthy baby. The platelet count can be very low, often below 10,000/µL to 20,000/µL. Since intracranial hemorrhage may occur around the time of birth or in the first few days of life, a head ultrasound exam is indicated when NAIT is suspected. Babies with platelet counts of less than 20,000/µL and those with platelet counts of less than 50,000/µL and bleeding signs need treatment, and consultation with pediatric hematology and transfusion medicine specialists is warranted. A platelet count between 50,000/µL and 150,000/µL merits careful observation and a daily CBC and platelet count for a few days until the count becomes stable. The maternal antibody may persist in the infant's circulation for eight to 12 weeks, but the platelet count generally rises slowly toward a normal level during that time. If intracranial hemorrhage occurs, consult a specialist in neonatal medicine, pediatric hematology, or pediatric neurology.

The diagnostic workup proceeds on the principle that it is better to draw large amounts of blood from the mother and father than from the baby. The diagnosis of NAIT is established when it is shown that the platelet antigens of the mother and father are incompatible and that IgG antibody in the mother's serum reacts with the antigen on the father's platelets. Many regional blood bank referral centers can perform the tests to determine if these criteria have been met. In Caucasians, incompatibility for human platelet alloantigen HPA-1 (formerly called PlA1/2) is by far the most common cause of NAIT, so testing for this incompatibility is more widespread than for others. National referral labs are best for other incompatibilities in Caucasian patients or families of other ethnic origins. The Blood Center of Southeastern Wisconsin in Milwaukee has given us excellent service over the years.

The physician often must make a treatment decision while waiting for the test results for NAIT. Because the mother is negative for the offending platelet antigen and HPA-1 incompatibility is a good bet in Caucasian patients, HPA-1a antigen-negative platelets often can be transfused with good effect, but if they are obtained from the mother (or from another woman who has had children), they should be washed with saline to remove antibody-containing plasma. If platelets are unavailable or do not cause a rise of the platelet count to greater than 50,000/µL one hour after transfusion, intravenous gamma globulin (IVGG) should be administered. We use a dose of IVGG of 1 g/kg, and repeat it once the next day if the count still has not risen. For reasons that are incompletely understood, transfusion of random- donor platelets also often leads to a measurable increase in platelet count in these babies, as it does not in idiopathic thrombocytopenic purpura (ITP) of childhood or other alloimmune thrombocytopenias, where random-donor platelets are ineffective. So if antigen-negative platelets are not available and there is significant bleeding or severe thrombocytopenia (less than 10,000/µL), random-donor platelets can be given. Each hospital blood bank has its guidelines for platelet products. For transfusing newborn infants, we use platelets that are irradiated, cytomegalovirus-negative, antibody and ABO­compatible, and leukocyte-depleted. The dose is 10 to 15 mL/kg.

Occasionally, some infants with NAIT experience intracranial hemorrhage in utero.³ In a first pregnancy, it is not clinical practice to anticipate or treat such an event. Because the risk of recurrence of NAIT is high, however, it is the standard of care for the mother and fetus in subsequent pregnancies to be managed in a high-risk obstetrics/perinatology center. Determination of the in utero platelet count by percutaneous umbilical blood sampling and treatment of the mother with intravenous immunoglobulin or corticosteroids are possible interventions. The recent delineation of women at particular risk for NAIT suggests that screening in pregnancy for this disorder may soon be universal.⁴

Thrombocytopenia secondary to maternal factors is relatively common. Maternal ITP, whether active (mother has a low platelet count) or previously treated with splenectomy (mother's platelet count has normalized but she still produces antiplatelet antibodies that cross the placenta), is one such factor. True maternal ITP, if not present before pregnancy, can be difficult to distinguish from gestational incidental thrombocytopenia, in which the mother's platelet count is mildly decreased to between 75,000/µL to 120,000/µL. While no evidence-based consensus exists on how to treat maternal ITP or the risk it poses for thrombocytopenia in the newborn, ITP appears much less likely to result in severe thrombocytopenia than in NAIT.

Maternal factors associated with neonatal thrombocytopenia that are unrelated to the immune system include preeclampsia or eclampsia, maternal hypertension, the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and diabetes. A baby with intrauterine growth retardation also is at risk. Fortunately, in these babies the thrombocytopenia usually is moderate or mild, and in the absence of other risks for bleeding resolves spontaneously in from seven to 14 days. Platelet transfusion has been reported to be successful when bleeding is associated with a platelet count of less than 50,000/µL.

Acquired thrombocytopenias are associated with sepsis and necrotizing enterocolitis and with indwelling vascular catheters, which should be removed when they may be causing the problem. Congenital thrombocytopenias are numerous; some are familial and some are associated with congenital anomalies. The TAR syndrome (thrombocytopenia-absent radius) is marked by major orthopedic anomalies, as the name suggests, and significant thrombocytopenia. Because the thrombocytopenia most often resolves spontaneously within two years, surgical corrections should await improved platelet counts and newborn care is supportive. Fanconi anemia can present in the newborn period with low platelet counts and often is associated with pigmentary, genitourinary, gastrointestinal, and cardiac anomalies.

In two of our patients, clinical presentation and lab testing indicated a diagnosis of NAIT, but the thrombocytopenia persisted beyond 12 weeks of age, when the platelets should have reached a normal level. Both of these infants later proved to have a congenital thrombocytopenia. These cases illustrate the importance of documenting when NAIT resolves since the absence of resolution warrants further investigation. We also have seen several children who maintained low platelet counts despite undergoing multiple surgeries for anomalies; the true diagnosis of Fanconi anemia in these children was delayed for months to years. Children with congenital anomalies and abnormal blood counts should see a hematologist and geneticist sooner rather than later.

Babies with Down syndrome are at risk for a transient myeloproliferative syndrome in the first month of life, manifested as a high white blood cell count, blast forms in the peripheral blood, and low platelet counts. Not a true leukemia, the transient myeloproliferative condition resolves with supportive care. About 25% to 33% of these children will develop true leukemia, however, often of megakaryocytes (platelet precursors), in the next three years. Thus, children with Down syndrome who have had hematologic abnormalities need to be followed jointly by their pediatrician and a pediatric hematologist.

Platelet function abnormalities should be considered in the presence of persistent mucosal bleeding, or intracranial bleeding with a normal platelet count and normal coagulation protein assays. The family history may include platelet function abnormalities. Specific diagnoses include Glanzmann thrombasthenia, Bernard-Soulier syndrome, and platelet storage pool defects. Findings suggesting these diagnoses call for consultation with a pediatric hematology specialist.

Coagulation protein disorders

Coagulation proteins are synthesized independently by the fetus and do not cross the fetal-placental barrier.⁵ Compared with adults, healthy neonates have low levels of prekallikrein, high-molecular-weight kininogen (HMWK), and factors II, VII, IX, IX, XI, and XII. These low levels lead to a prolonged PT and PTT compared with adult values⁶ and can make it difficult to diagnose inherited and acquired hemostatic disorders. The factor "deficiencies" in infancy are balanced by a diminished fibrinolytic mechanism, notably plasminogen levels that are at 25% to 75% of adult levels. Thus, the coagulation and the fibrinolytic mechanisms are kept in dynamic equilibrium in the normal neonate and protect healthy infants from hemorrhagic complications.⁵ This precarious balance can be upset by a variety of conditions.

The immaturity of the neonatal hemostatic system places sick infants at risk for bleeding. Serious hemorrhagic complications can occur during the first week of life and are most often acquired pathologic conditions. Inherited conditions like severe congenital factor deficiencies often become apparent in early infancy. Hemorrhage in term infants who are otherwise healthy should raise the index of suspicion for a congenital factor deficiency.

Congenital factor deficiencies of factors II, V, VII, XI, XII, prekallikrein, and HMWK are rare autosomally inherited conditions. Consanguinity is common in families of affected infants. Deficiencies of factor XII, prekallikrein, and HMWK do not cause bleeding. Deficiencies of factors VIII and IX are X-linked recessive disorders and are the most common inherited cause of bleeding in the newborn. Severe factor VII deficiency is the most common inherited factor deficiency causing intracranial hemorrrhage in neonates. Deficiencies of factors II, V, VIII, IX, X, XI, or XIII also can cause neonatal intracranial hemorrhage. In severe deficiencies of factors V, VII, VIII, IX, and XIII, factor levels are significantly lower than physiologic neonatal plasma concentrations. In homozygous deficiencies of factors II, X, and XI, plasma concentrations overlap neonatal physiologic ranges, however. Thus, diagnosing these three deficiencies can be difficult in the neonatal period, requiring study of the parents.

In factor VII deficiency, neonates with factor VII levels of less than 1% have severe bleeding complications, while those with levels greater than 5% experience only mild bleeding. Most neonates with severe factor VII deficiency suffer an intracranial hemorrhage, which in many cases is lethal. The treatment for factor VII deficiency is replacement with factor VII concentrate. Prenatal diagnosis of factor VII deficiency and in utero factor replacement are possible.

Factor VIII deficiency, or hemophilia A, is an X-linked recessive disorder that can present in the neonatal period. About 10% of baby boys with severe factor VIII deficiency bleed during the neonatal period and 70% of patients with severe factor VIII deficiency experience a bleeding event by 18 months of age. Factor VIII deficiency can be classified based on plasma concentrations as severe (<1%), moderate (1%­5%), or mild (5%­30%).

Because neonatal factor VIII levels are the same in infants as in adults, factor VIII deficiency can be diagnosed readily in the newborn period. Treatment consists of factor VIII replacement therapy. Prenatal diagnosis of factor VIII deficiency and in utero replacement are possible.

Factor IX deficiency, or hemophilia B, is an X-linked recessive disorder that may present during the neonatal period as bleeding from a circumcision, intracranial hemorrhage, bleeding from venipuncture sites, hematomas, or umbilical bleeding. Like factor VIII deficiency, factor IX deficiency is classified by plasma concentrations: 1% represents severe disease, 1% to 5% moderate disease, and 5% to 30% mild disease. Physiologic neonatal concentrations of factor IX overlap levels in mild disease, making the diagnosis challenging in the neonate. Factor IX deficiency is treated with factor replacement. Prenatal diagnosis and in utero factor replacement are possible.

Factor XIII deficiency can present in the neonatal period with prolonged bleeding from the umbilicus or intracranial hemorrhage. Infants with plasma concentrations of factor XIII of less than 1% are treated with cryoprecipitate or factor XIII concentrates.

Inherited bleeding disorders. Von Willebrand's disease is the most common inherited bleeding disorder. Usually autosomal dominant, its inheritance can be recessive in some variants. The disorder rarely presents in the newborn period because levels of von Willebrand factor antigen are physiologically increased.

Acquired bleeding disorders. Deficiency of vitamin K, an essential cofactor for coagulation factors II, VII, IX, and X, is the most common of the acquired bleeding disorders.^7,8 At birth, vitamin K concentrations are undetectable. By the fourth day of life, levels approximate adult vitamin K plasma concentrations. Vitamin K deficiency is classified as early, classic, or late. In the early form, bleeding occurs within 24 hours of birth. This rare condition arises in infants whose mothers took medications that inhibit production of vitamin K, such as carbamazepine, phenytoin, barbituates, cephalosporins, rifampin, isoniazid, and warfarin. To prevent vitamin K deficiency, pregnant women should not take such medications or, if they do, should receive vitamin K prophylaxis.

Classic vitamin K deficiency becomes apparent between 2 and 7 days of age in breastfed infants whose milk intake is marginal. Bleeding manifestations include gastrointestinal bleeding, umbilical bleeding, bleeding from a circumcision or venipuncture sites, or intracranial hemorrhage. Adequate breastfeeding and oral or intramuscular vitamin K prophylaxis in the infant prevent the condition. In our experience, the intramuscular vitamin K prophylaxis may have inadvertently been omitted when the baby's delivery and first few hours of life are difficult. A high PT in a bleeding baby should be documented and a repeat dose of vitamin K administered if the adequacy of the vitamin K level is uncertain.

Poor intake or malabsorption of nutrients causes late vitamin K deficiency, which occurs between 2 weeks and 6 months after birth. Infants with late vitamin K deficiency are at high risk for intracranial bleeding and its associated high morbidity and mortality. Single intramuscular or repeated oral doses of vitamin K prevent the condition.

Laboratory evaluation for suspected vitamin K deficiency reveals a prolonged PT and deficiencies in factors II, VII, IX, and X; platelet count and fibrinogen are normal. Other diagnostic possibilities include liver disease, disseminated intravascular coagulation (DIC), and isolated coagulopathies. Rare cases of absence of the vitamin K­ dependent carboxylase in the liver have also been reported. Measurements of vitamin K levels do not help make the diagnosis because the levels are physiologically decreased in the newborn. The diagnosis of vitamin K deficiency is confirmed when treatment with vitamin K resolves the bleeding and normalizes the PT.

Combination abnormalities

DIC, associated with a variety of underlying diseases in newborns, is a common combination abnormality that causes bleeding in newborns. Coagulopathies associated with liver disease are far less common.

DIC may be secondary to asphyxia, respiratory distress syndrome of the newborn, sepsis, necrotizing enterocolitis, hypothermia, and meconium or amniotic fluid aspiration, among other disorders. No specific tests confirm DIC, but most infants have prolonged PT and PTT, increased fibrin degradation products and D-dimers, thrombocytopenia, decreased fibrinogen and factors V and VIII, and increased thrombin/ antithrombin complexes. Successful treatment of DIC depends on accurate diagnosis and treatment of the underlying condition. In the absence of clinical bleeding, newborns with DIC probably do not require treatment of their coagulation disorder. Clinically significant bleeding calls for administration of plasma products. Reasonable treatment goals are to maintain a platelet count of greater than 50,000/µL, more than 100 mg/dL of fibrinogen, and PT and PTT values within the physiologic range for postnatal or gestational age.

Coagulopathies in babies with liver disease manifest as prolonged PT and low plasma concentrations of many coagulation factors, such as factor V, the vitamin K­dependent factors, and fibrinogen. Causes of neonatal liver disease include inherited disorders, hypoxic damage, viral infections, shock, hydrops, and complications of total parenteral nutrition. Replacement therapy for neonates with liver disease is supportive, and definitive therapy depends on cure of the underlying disease process. If liver disease is a manifestation of congenital viral infection, for example with cytomegalovirus, it may be accompanied by thrombocytopenia.

Disorders of vascular integrity

Intraventricular hemorrhage resulting from abnormal blood vessels and hemangiomas and other vascular malformations are common causes of newborn bleeding.

Abnormal blood vessels can contribute to bleeding. Though in principle these abnormalities may be present even when platelet count and function are normal and coagulation factors are at their physiologic levels for gestational age, the cause of the bleeding often is complex. The friable vessels in the germinal matrix of the preterm infant's developing brain can rupture, resulting in intraventricular hemorrhage.

Hemangiomas and other vascular malformations, which may be occult, also can rupture and hemorrhage. Cavernous hemangiomas can trap platelets and fibrin in the tortuous vessels and cause thrombocytopenic bleeding, a condition called Kasabach-Merritt syndrome. Because these hemangiomas "grow with the baby" in the first year of life, this condition can progressively worsen and require care coordinated by the primary care physician and the hematology specialist.

Bleeding with no abnormality. Some babies bleed for anatomic reasons or because of surgical technique, for example, following circumcision, and have no demonstrable hematologic abnormality. Local measures, such as pressure dressings or suture, are appropriate; blood product replacement therapy is indicated only rarely.

A rational approach

Diagnosis and management of bleeding in the newborn infant calls for a rational approach, outlined in the algorithm in Figure 1. The algorithm focuses on common conditions and is not comprehensive. Diagnostic and therapeutic considerations that go beyond this algorithm call for consultation with pediatric hematology specialists. In working up an infant with bleeding, keep in mind that not all laboratory abnormalities are pathologic. In particular, coagulation protein levels must be compared with gestation-and age-matched controls, not with adult values.

Looking ahead

Improved ways to diagnose risk for specific bleeding disorders, such as recurrent NAIT and certain congenital thrombocytopenias, are on the horizon.⁴ These new techniques use serology and molecular diagnostics. We also are seeing advances in treatment. Platelet and plasma replacement products that are more effective, less likely to transmit viruses, and less costly than the products in use today should become more widely available. These products include plasma treated with solvent detergent and recombinant coagulation proteins, including factor VIIa.

REFERENCES

1. Roberts IA, Murray NA: Management of thrombocytopenia in neonates. Brit J Haematology 1999;105:864

2. Skupski DW, Bussel JB: Alloimmune thrombocytopenia. Clin Obstet Gynecol 1999;42:335

3. Bussel JB, Zabusky MR, Berkowitz RL, et al: Fetal alloimmune thrombocytopenia. N Engl J Med 1997;337:22

4. Williamson LH, Hackett G, Rennie J, et al: The natural history of fetomaternal alloimmunization to the platelet-specific antigen HPA-1a (PlA1,Zwa) as determined by antenatal screening. Blood 1998;92:2280

5. Andrew M: Developmental hemostasis: Relevance to newborns and infants, in Nathan DG, Orkin SH (eds): Hematology of Infancy and Childhood, ed 5, Philadelphia, PA, WB Saunders, 1998

6. Edstrom CS, Christensen RD, Andrew M: Developmental aspects of blood hemostasis and disorders of coagulation and fibrinolysis in the neonatal period, in Christensen RD (ed): Hematological Problems of the Neonate, Philadelphia, PA, WB Saunders, 2000

7. Sutor AH, von Kries R, Cornelissen EA, et al: Vitamin K deficiency bleeding in infancy. Thromb Haemost 1999; 81:456

8. Zipursky A: Prevention of Vitamin K deficiency bleeding in newborns. Br J Haematology 1999;104:430

DR. EDELSON is Attending Physician, Division of Hematology/Oncology, AI duPont Hospital for Children, Wilmington, DE.

DR. McKENZIE is Associate Professor of Pediatrics, Jefferson Medical College, Philadelphia, PA, and Hematology Research Laboratory Head, Division of Hematology/Oncology, AI duPont Hospital for Children, Wilmington, DE.

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FACULTY DISCLOSURES

Jefferson Medical College, in accordance with accreditation requirements, asks the authors of CME articles to disclose any affiliations or financial interests they may have in any organization that may have an interest in any part of their article. The following information was received from the authors of "Why is this newbvorn bleeding?"

Maureen Edelson, MD, has nothing to disclose.

Steven E. McKenzie, MD, PhD, has nothing to disclose.

 

Steven McKenzie. Why is this newborn bleeding?. Contemporary Pediatrics 2000;7:60.