Bleeding in Neonates and Children

Anthony K. C. Chan

Elizabeth A. Chalmers

Sam Schulman

Alan D. Michelson

Neonates and children may be born with a congenital bleeding disorder or they may acquire a bleeding disorder as a consequence of a disease process. Correct diagnosis is crucial to management of the disease and to reduce morbidity and mortality associated with any bleeding diathesis. The natural history of diseases in children can differ substantially from that observed in adult patients due to developmental differences in their hemostatic system amongst other causes. Thus, treatment and management of children with bleeding disorders is often age specific and cannot simply be extrapolated from adult data. The following chapter highlights some common bleeding disorders in neonates and children and where available, treatment recommendations are summarized.

NEONATAL THROMBOCYTOPENIA

Platelet production begins in fetal life and progressively increases to adult levels by the end of the first trimester (≥22 weeks gestational age). The normal range for adult platelet count of 150 to 450 × 10⁹/L is reached in the healthy fetus by 22 weeks of gestation. Therefore, neonates with platelet counts <150 × 10⁹/L are considered to have neonatal thrombocytopenia. Otherwise, healthy neonates commonly have platelet counts in the range of 100 to 150 × 10⁹/L, but these are mostly transient thrombocytopenias and need no further investigation unless the clinical condition worsens.¹ Developmental differences in the size of the megakaryocytes between neonates and adults, such as smaller megakaryocytes, might predispose neonates to thrombocytopenia.²

The overall incidence of neonatal thrombocytopenia has been estimated to be 0.7% to 0.9%. However, the incidence is considerably higher in neonates admitted into the neonatal intensive care unit (NICU), where it is estimated to be 22% to 35%.¹ Neonatal thrombocytopenia can be caused by increased platelet consumption, decreased platelet production, hypersplenism, or a combination of any of these. Underlying causes include immune deficiency, infections, placental insufficiency, disseminated intravascular coagulation (DIC), genetic disorders, and medication-induced thrombocytopenia (Table 120.1).

In general, the underlying cause may be determined by the timing of the onset of thrombocytopenia as different conditions lead to either early-onset (within 72 hours of life) or late-onset (>72 hours) thrombocytopenia.¹ Although there can be significant overlap between pathologies underlying neonatal thrombocytopenia, specific diseases associated with early-onset type include alloimmune disease, parasitic infections, placental insufficiency, chromosomal defects (notably trisomies 13, 18, and 21), and familial thrombocytopenias.¹ Late-onset thrombocytopenias are usually associated with fungal infections, medication use (some antibiotics, heparin, anticonvulsants), and necrotizing enterocolitis (NEC).¹

As stated, approximately three-quarters of all neonates with thrombocytopenia are transient or mild in nature and do not usually require further intervention. However, the remaining cases (20% to 25% or 2% to 9% of NICU admissions) require platelet transfusions in order to treat or decrease the risk of bleeding.¹ Although neonates with active major bleeds (intracranial, pulmonary, gastrointestinal [GI], hepatic or renal) with platelet counts <100 × 10⁹/L receive platelet transfusions, the majority of platelet transfusions are given to thrombocytopenic neonates without bleeding events and with platelet counts <50 × 10⁹/L.², ³, ⁴ There is only one randomized controlled study⁵ investigating the effectiveness of platelet transfusions on reducing the incidence/severity of intracranial hemorrhage (ICH) in sick preterm infants with thrombocytopenia. The authors found no significant difference in the frequency or severity of ICH in the treatment group (platelet transfusions for platelet count <150 × 10⁹/L) compared to the control group (platelet transfusions only for clinical indications or for a platelet count of <50 × 10⁹/L). Although, platelet transfusion increased platelet counts and shortened bleeding times, it did not have an effect on the incidence or severity of ICH.⁵

There is a lack of solid evidence for guiding platelet transfusions in neonates, but several guidelines have been published,¹, ³, ⁶, ⁷, ⁸, ⁹, ¹⁰ providing a starting point of treatment options for thrombocytopenic neonates. Although there is a range of transfusion practices, since the early 1990s, there is a trend toward accepting a lower threshold of platelet count before starting platelet transfusions in nonbleeding sick and stable preterm infants (from platelet count <100 × 10⁹/L to <30 × 10⁹/L before initiating platelet transfusion).¹

Neonatal Alloimmune Thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAIT) occurs when there is an incompatibility of fetomaternal human platelet antigens (HPAs). The incidence of NAIT has been estimated to be 1 in 5,000, but the incidence was higher (1 in 1,000) in screening studies using only HPA-1a incompatibility criteria.¹¹, ¹², ¹³ Severe NAIT can occur even in the first pregnancy (˜50% of the cases). In the most severe cases, there is massive ICH, but the presentation can in other cases be mild bleeding that is easily managed. The diagnosis is established by verification of incompatibility between the platelets of the mother and the baby. It is important to provide effective treatment quickly as NAIT is associated with 11% to 21% risk of ICH.¹⁴ Screening studies have indicated that
neonatal platelet count <50 × 10⁹/L identified 90% of patients with NAIT.¹⁵, ¹⁶, ¹⁷

Table 120.1 Neonatal thrombocytopenias and their typical time of presentation

Etiology	Examples	Onset
Alloimmune	Maternal antibodies against HPA-1a or -5b	Fetal—neonatal <72 h
Congenital infections	Cytomegalovirus, rubella, toxoplasma, HIV	Fetal—late neonatal
Aneuploidy	Trisomy 18/13/21; triploidy	Fetal
Autoimmune	ITP, systemic lupus	Fetal—neonatal <72 h
Severe Rhesus disease		Fetal
Congenital-inherited	With abnormal platelet function Wiskott-Aldrich, Bernard-Soulier, X-linked thrombocytopenia, or Chediak-Higashi syndrome, Quebec platelet disorder, giant platelet syndromes Without abnormal platelet function TAR, CAMT, Fanconi anemia, May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, Epstein syndrome, autosomal dominant thrombocytopenia	Fetal—late neonatal
Placental insufficiency	Intrauterine growth retardation, preeclampsia, diabetes	Neonatal <72 h
Perinatal asphyxia		Neonatal <72 h
Perinatal infection	Escherichia coli, group B Streptococcus, Haemophilus influenza	Neonatal <72 h
DIC		Neonatal <72 h
Thrombosis	Arterial or venous	Neonatal <72 h
Congenital leukemia		Neonatal <72 h
Kasabach-Merritt syndrome		Early-late neonatal
Metabolic disease	Propionic acidemia, methylmalonic acidemia	Early-late neonatal
Late-onset sepsis	NEC	Neonatal >72 h
CAMT, congenital amegakaryocytic thrombocytopenia; HIV, human immunodeficiency virus; ITP, immune thrombocytopenic purpura; NEC, necrotizing enterocolitis; TAR, thrombocytopenia absent radius syndrome.

Recommended platelet transfusion thresholds include neonates with severe thrombocytopenia (platelet count <30 × 10⁹/L), neonates with minor bleeding events and a platelet count of <50 × 10⁹/L or those with a sibling who previously had ICH, or neonates with severe bleeding with a platelet count of <100 × 10⁹/L.¹ The standard platelet dose is 10 mL/kg. However, dosing can be increased or repeated if response is insufficient.¹⁸ The majority of antibodies are against HPA-1a and HPA-5b platelet antigens (79% and 9%, respectively).¹⁹ Thus, platelet transfusion from HPA-1a/HPA-5b negative donors should be effective in increasing platelet counts in most cases of suspected or proven NAIT.¹⁹, ²⁰ When compatible platelets are unavailable, high-dose intravenous immunoglobulin (IVIG) and/or a trial with random donor platelets may be a viable alternative. The recommended dose for IVIG is 1 to 2 g/kg administered as 0.4 g/kg daily for 3 to 5 days or 1 g/kg daily for 1 or 2 days.²¹ Neonates with NAIT will respond to incompatible platelet transfusions;²², ²³ thus random platelet transfusions can be used as first-line therapy, with close monitoring, for neonates with severe thrombocytopenia regardless of etiology.¹⁸ Head sonography should be performed on thrombocytopenic neonates in order to determine the presence of ICH and to set appropriate platelet threshold for the treatment of the neonate. NAIT often resolves within 2 to 4 weeks, but platelet count should be followed until normal levels are attained off treatment to exclude inherited or other forms of thrombocytopenia.¹⁸

The recurrence of thrombocytopenia is very high and usually results in increased severity in subsequent pregnancies. Most of the current information is mainly derived from retrospective data. The highest risk of NAIT-related complications in subsequent pregnancies is among infants whose sibling had antenatal ICH.²⁴ Current management of subsequent pregnancies of women with a history of a child diagnosed with NAIT is focused on the prevention of ICH in the fetus during pregnancy and
delivery.²⁵ Antenatal diagnosis can be made with genotyping on chorionic villi or on amniotic cells. The titer of the maternal anti-HPA-1a antibody seems to be correlated with severe events to the fetus. The fetal development is followed with ultrasonography to detect ICH, preferably at tertiary care centers. The therapeutic options are weekly maternal injections with high-dose immunoglobulin, possibly with the addition of corticosteroids or, if that fails, weekly intrauterine transfusions with antigen negative platelets. A severely affected fetus should be delivered by cesarean section.

Neonatal purpura or hematoma as well as more serious bleeding complications is investigated with complete blood count and coagulation screening. The thrombocytopenia is severe in case of HPA-1a or -3a immunization, whereas the mother has a normal platelet count. The platelet phenotype and genotype of both parents and antibodies should be analyzed to verify the diagnosis. However, already with a strong suspicion of NAIT and a platelet count below 30 × 10⁹/L, the baby should be transfused with washed and irradiated maternal platelets or with HPA-1b/1b platelets. Babies with higher platelet count should be followed closely and transfused in case of a sudden drop in platelet count. This monitoring is necessary for 1 to 2 weeks until the platelet count normalizes. ICH should be excluded with ultrasonography or magnetic resonance imaging. However, optimal management of high-risk pregnancies is still under debate. High-risk obstetric and adult hematologist with appropriate experience should be consulted.

Immune Thrombocytopenic Purpura

Immune thrombocytopenic purpura (ITP) is the result of platelet destruction by platelet autoantibody production coupled with impaired platelet production. Previously, it was thought that only macrophages in the reticuloendothelial system were involved in this process,²⁶, ²⁷ but emerging evidence now supports the involvement of both the cellular immune (T-cell abnormalities) and humoral immune (antibody secretion) systems.²⁸, ²⁹, ³⁰ ITP is one of the most common acquired bleeding disorders in children with complete resolution of thrombocytopenia in the majority of affected individuals within weeks or months of onset, regardless of whether therapy was instituted. It is estimated that 20% to 30% of these children will go on to have persistent thrombocytopenia (more than 6 months duration since diagnosis) but over 25% of these with persistent thrombocytopenia will have disease resolution by 12 months.³¹

Clinical Characteristics of ITP

ITP presentation can be at any age in childhood, with approximately 70% presenting between 1 and 10 years of age, peaking at age 5 to 6 years.³² The majority of children do not have any documented infection prior to ITP presentation. However, in some children, it is preceded by a presumed viral illness or live-virus vaccination such as the measles, mumps, and rubella vaccine.³³, ³⁴

Before ITP diagnosis, other causes of thrombocytopenia should be excluded by careful consideration of history, physical examination, and peripheral blood smear assessment.³⁵ Presentation symptoms in children include mucocutaneous bleeding, bruising, petechiae, purpura, epistaxis, hematuria, and menorrhagia (teenage girls). Physical findings and complete blood count are otherwise normal except for thrombocytopenia with large platelets. ITP with atypical clinical or laboratory findings warrant further investigations.³⁶ Even with severe thrombocytopenia (platelet count <20 × 10⁹/L) at the onset of ITP, the incidence of severe or life-threatening bleed is minimal.³², ³⁷, ³⁸ The long-term outcome for children with ITP is favorable.³⁹, ⁴⁰, ⁴¹

Treatment of ITP

Many children with mild-to-moderate thrombocytopenia and minimal bleeding events require only close observation, although some with severe thrombocytopenia with overt bleeding will require therapy. The aim is to increase platelet counts to prevent hemorrhage while minimizing therapy side effects. Currently, there is no standard of care for children with symptomatic, acute, or chronic ITP. Thus, each case should be considered on an individual basis with benefits and risks of each treatment assessed when creating a management plan. Table 120.2 outlines some of the available therapies used for children with ITP.³⁶ These treatments do not cure or alter the disease course but are only helpful in the management of symptomatic ITP.

An alternative therapy for children with chronic ITP is splenectomy, but this should be reserved for children with severe thrombocytopenia in which conservative management is unsuccessful. There are many publications to support the effectiveness of splenectomy in children with ITP, citing successful response rates up to 85%.³⁵, ⁵¹, ⁵², ⁵³, ⁵⁴, ⁵⁵ However, long-term follow-up studies of children with splenectomy to assess failure/infection rates are lacking, and sepsis remains a significant risk. The recommendation from the American Society of Hematology group regarding consideration of splenectomy for children with chronic ITP include the following criteria: chronic thrombocytopenia >12 months duration, bleeding symptoms with severe thrombocytopenia, or thrombocytopenia that is unresponsive to “standard” therapy of corticosteroids, IVIG, and anti-D immune globulin.³⁵ Laparoscopic surgery is recommended for elective splenectomy with the patient immunized against Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenza type B prior to surgery. Children must undergo lifelong monitoring to prevent infection and should receive daily prophylaxis against pneumococcal infection with antibiotics up to the age of 16 and in case of continued high risk also thereafter.³⁶

Bleeding ITP patients who are refractory to steroids, IVIG, and anti-D immune globulin may be candidates for immunomodulatory therapy or thrombopoietin mimetics. Another second-line therapy in refractory patients with significant hemorrhagic problems may include rituximab. Standard doses of rituximab induce B-cell depletion for 3 to 6 months and is well tolerated in children, although the long-term effects of using this drug in children with immature immune systems is not known.⁵⁶ There are no randomized controlled studies of rituximab in children with ITP, but a review of cohort studies and case reports indicate that rituximab treatment results in a complete response (defined as platelet count >50 × 10⁹/L) in approximately 50% of the children with few adverse effects.⁵⁷ Prognostic indicators of response could not be identified.

INHERITED PLATELET DISORDERS

Hereditary disorders of platelet function are likely to be detected only when clinically relevant bleeding occurs. Many patients will have more than one hemostatic defect and will most likely already be undergoing evaluation for bleeding disorder so platelet dysfunction should be included as part of the investigative
process. Typical bleeding manifestations indicative of platelet function defects can include inexplicable or extensive bruising, prolonged epistaxis (>30 minutes, causing anemia or hospital admission), menorrhagia, oral cavity bleeding, or bleeding after dental extraction or invasive procedures.⁵⁸ Severe platelet function disorder can lead to ICH and subdural hemorrhage or excessive bleeding in the umbilical stump in the neonatal period. Milder forms of platelet function disorders are more likely to present later in life. The lack of well-defined testing system for platelet function disorder makes diagnosis more complicated for the clinician.⁵⁹, ⁶⁰ There are guidelines and recommendations published by International Society on Thrombosis and Haemostasis (ISTH) subcommittees, Permanent Paediatric Group of the German Thrombosis and Haemostasis Research Society, and other scientific panels for the diagnosis of patients with inherited platelet disorders.⁵⁹, ⁶¹, ⁶²

Table 120.2 “Standard” therapies for children with chronic ITP

Type of Therapy	Dose	Side Effects
Corticosteroids	Various dose and regimens Short-course, high-dose corticosteroids without a taper^42,43 Suggested high-dose corticosteroid of ˜4 mg/kg/d of prednisone or equivalent, orally or parenterally (for acute ITP) until cessation of bleeding or platelet count >20 × 10⁹/L⁴² Low-dose prednisone at 0.1-0.2 mg/kg/d orally⁴⁴	High dose not recommended for long-term therapy due to adverse side effects (immunosuppression, hirsutism, weight gain, growth delay, osteoporosis, and cataracts)
IVIG	0.8-1.0 g/kg IVIG × 1-2 doses, slow infusion⁴² , ⁴⁵ Repeated doses can be given every 2-6 wk for symptomatic thrombocytopenia⁴⁴	Higher doses are not recommended as it is associated with headaches⁴⁶ Infusion-related side effects include flushing, fever, headaches, allergic reactions, aseptic meningitis Minimal risk of pathogen transmission due to IVIG derived from pooled donor plasma
Anti-D immune globulin	75 µg/kg anti-D (used in children with ITP who are Rhesus+ with intact spleen)⁴⁷ , ⁴⁸ Given as a short infusion, though s.c. route is well tolerated and effective⁴⁹	Infusion-related headaches, chills, fatigue Mild anemia (Hb fall of 0.8-1.4 g/dL)⁴⁷ Severe hemolytic anemia with DIC and acute renal failure is rare (1 in 20,000-30,000 infusions)⁵⁰ Minimal risk of pathogen transmission due to anti-D derived from pooled donor plasma
DIC, disseminated intravascular coagulation; Hb, hemoglobin; ITP, immune thrombocytopenia purpura; IVIG, intravenous immunoglobulin; s.c., subcutaneous.

Disorders of Platelet Numbers

Inherited thrombocytopenias are a group of heterogeneous conditions that consequently present as early-onset thrombocytopenia. Although rare, the clinical symptoms, including bleeding, can be severe.

MYH-9 Disorders

MYH-9-related thrombocytopenias are rare autosomal dominant disorders defined by the presence of deleterious mutations within the MYH-9 gene, coding for the nonmuscle myosin heavy chain IIa, that influences a component of the contractile cytoskeleton in megakaryocytes, platelets, and other tissues.⁶³, ⁶⁴, ⁶⁵ Defective megakaryopoiesis is responsible for the thrombocytopenia. This disorder encompasses other previously defined disorders including May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome.⁶³, ⁶⁴ Bleeding severity is usually mild, and life-threatening bleeds are rare. Other phenotypic manifestations can include hearing loss, glomerulonephritis, and cataract.⁶⁶, ⁶⁷ These patients usually have platelet counts in the range of 20 to 130 × 10⁹/L, with most showing elevated mean platelet volume and a noticeable population of very large platelets with variable platelet morphology.⁶¹, ⁶³

A specific diagnostic strategy has been suggested by the Working Group on Standardisation in Perinatal and Pediatric Hemostasis for the group of children and neonates with inherited thrombcytopenias.⁶⁸ Differential diagnosis should include inspections of peripheral blood smear and platelet ultrastructural features as symptoms are similar to ITP or other causes of thrombocytopenia such as Bernard-Soulier syndrome.⁶⁹, ⁷⁰, ⁷¹ Treatment options for inherited platelet function disorders include antifibrinolytic agents such as tranexamic acid to treat mucous membrane bleeding, desmopressin (DDAVP) for storage pool disorders or for mild bleeding events where tranexamic acid alone was unsuccessful, platelet transfusion for severe disorders but there is a risk of alloantibodies to HLA antigens, and recombinant FVIIa (rFVIIa) that has only been approved for use in patients with Glanzmann thrombasthenia.⁶⁸ It is stressed that treatment strategies should be discussed on a case-by-case basis, taking into account personal and family history, to determine the risk-benefit ratio for each patient.

Congenital Amegakaryocytic Thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, recessive disorder caused by mutations in the MPL gene affecting the cytokine thrombopoietin receptor c-mpl that regulates megakaryopoiesis and platelet production.⁷², ⁷³ CAMT usually presents in the neonatal period with bleeding symptoms as a result of severe thrombocytopenia associated with absent or markedly decreased megakaryocyte numbers in the bone marrow. Disease progression leads to hematopoietic failure and the development of severe aplastic anemia.⁷⁴ Physical abnormalities were also noted including cardiac defects, growth anomalies, and retardation of psychomotor development.⁷⁵ Molecular analysis of MPL gene will give definitive confirmation of CAMT. Management of CAMT initially includes platelet transfusion, but patients will eventually require hematopoietic stem cell transplantation due to the progression of the disease to severe aplasia.⁵⁸&U20AC;-aminocaproic acid (EACA) used for bleeding episodes in adolescent and adult patients with amegakaryocytic thrombocytopenia decreases the need for platelet transfusions.⁷⁶

Amegakaryocytic Thrombocytopenia with Radioulnar Synostosis

Amegakaryocytic thrombocytopenia with radioulnar synostosis seems to be dominantly inherited with mutations in the HOXA11 gene,⁷⁷ which is thought to be involved in the regulation of megakaryocytic differentiation.⁷⁸ Platelet morphology is normal, but megakaryocytes are markedly decreased or absent in the bone marrow. This disease is similar to CAMT presenting with severe thrombocytopenia and bleeding symptoms early in the neonatal period but is associated with radioulnar synostosis, and some may present with other skeletal abnormalities.⁷⁹ Amegakaryocytic thrombocytopenia with radioulnar synostosis will lead to haematopoietic failure. Management of this disease includes platelet support, and some may need haematopoietic stem cell transplantation.⁵⁸

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