Hematology

Congenital anemia ((Diamond Blackfan anemia, congenital dyserythropoietic anemia, etcetera)

Congenital anemia (Diamond Blackfan anemia, congenital dyserythropoietic anemia, etcetera)

What every physician needs to know about congenital anemia:

Congenital anemia is present at birth or during the first few weeks of life. Cord blood hemoglobin (Hb) at birth in full term infants is 16-17g/dL, does not decrease appreciably during the first week of life, and then declines slowly to a physiological nadir of 11g/dL by 8-12 weeks. While most premature infants have a similar Hb at birth, the level declines more rapidly (even in the first week), and can reach 8g/dL by 4-8 weeks in infants weighing less than 1500g.

Anemia at birth (Hb <13.5g/dL) may be due to blood loss, hemolysis or impaired red cell production. A detailed history, including family history, ethnic origin and, of course, sex, taken together with clinical findings and basic hematology tests, should allow one to classify the anemia into one of these 3 categories.

Clinical manifestations will depend on the degree of anemia and rapidity with which it occurred. Acute blood loss at the time of delivery may be characterized by minimal pallor that worsens over the first 24 hours, with rapid, shallow or gasping respiration, tachycardia, and shock with low blood pressure. In contrast, chronic intrauterine blood loss manifests as marked pallor and little distress, although signs of congestive failure such as hepatomegaly may be present; anemia (microcytic, hypochromic) is present at birth. Very severe anemia in infancy presents as hydrops fetalis, which carries a high mortality.

What features of the presentation will guide me toward possible causes and next treatment steps:

A careful history and examination is essential, paying particular attention to obstetric and family history, ethnicity, examination for pallor with or without jaundice, congenital anomalies, signs of intrauterine infection, internal hemorrhage and hepatosplenomegaly.

Information about the blood type of mother and infant should be sought, together with results of the maternal indirect antiglobulin test. If the mother is Rh- or O-negative and the baby Rh- or A/B-positive isoimmunization should be considered.

A traumatic obstetric history should make one suspect bleeding, and acute distress with pallor (which may only develop during the first 24 hours), shallow, rapid respiration, tachycardia, and weak pulses should raise suspicion of acute blood loss. On the other hand chronic blood loss is characterized by pallor out of proportion to distress and possibly signs of congestive cardiac failure, including hepatomegaly.

Very severe anemia in a fetus may present as hydrops fetalis in a neonate, and should make one think of alpha thalassemia (4 gene deletion), Diamond Blackfan anemia (DBA) or parvovirus infection. If no obstetric screening has been done Rhesus isoimmunization is another possibility.

A maternal history of bacterial, viral (rubella, cytomegalovirus [CMV], herpes simplex virus [HSV], coxsackievirus, adenovirus), toxoplasma, or spirochetal or fungal infection during pregnancy can cause a hemolytic anemia and/or impaired red cell production in infancy. If suspected, specific clinical and radiological signs should be sought:

  • rubella: blueberry muffin lesions (extramedullary hematopoiesis)

  • CMV: periventricular calcifications

  • toxoplasmosis: chorioretinitis, hydrocephalus, intracranial calcifications

  • syphilis: snuffles

Is there a family history of anemia, jaundice, transfusion requirement, or early cholecystectomy or splenectomy, raising suspicion for an inherited membrane defect such as hereditary spherocytosis? Does the ethnic origin of the patient offer a clue? The highest incidence of thalassemia and hemoglobinopathies is in the Mediterranean, equatorial sub-saharan Africa, the Middle East, India and South East Asia, including Indonesia and Papua New Guinea.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The initial laboratory investigations should include a complete blood count with red cell indices, reticulocyte count, direct antiglobulin test, blood smear and a Heinz body test. Bilirubin (total and direct) and lactate acid dehydrogenase (LDH) should also be obtained.

A convenient way to organize and think through the workup of an anemic infant would be:

1. Reticulocyte count: • decreased = Diamond Blackfan anemia, drugs, marrow infiltration • increased = hemolytic anemia (Rh incompatibility, hemoglobinopathy, membrane or enzyme disorder, etc.)2. Direct antiglobulin test • positive = Rh, ABO or other blood group incompatibility • negative = hemoglobinopathy, bone marrow failure, membrane disorder, iron deficiency3. Red cell indices: mean corpuscular volume (MCV)/mean corpuscular hemaglobin (MCH) • low = chronic fetal anemia: fetomaternal or twin-to-twin hemorrhage, thalassemia • normal or high - folate or B-12 deficiency, hemolytic anemia or bone marrow hypoplasia4. Red cell indices: mean corpuscular hemaglobin concentration (MCHC) • high = hereditary spherocytosis or xerocytosis5. Blood smear • abnormal = hereditary elliptocytosis hereditary stomatocytosis pyknocytosis, hereditary pyropoikilocytosis disseminated intravascular coagulation (DIC)/microangiopathy helmet and bite cells = G6PD or unstable hemoglobin: Heinz body positive • normal = other enzyme defects: pyruvate kinase infection acute blood loss other: galactosemia, hypothyroidism

What conditions can underlie abnormality:

Blood loss

Blood loss may be acute at the time of delivery, leading to pallor; rapid, shallow or gasping respiration; tachycardia; shock with low blood pressure. The Hb may be normal initially and anemia (normochromic, normocytic) develops during the first 24 hours. In contrast, chronic blood loss is associated with marked pallor and little distress, although signs of congestive failure such as hepatomegaly may be present; anemia (microcytic, hypochromic) is present at birth.

Causes of acute bleeding such as rupture of the umbilical cord may be associated with precipitous deliveries, and the cord may bleed from vascular abnormalities, inflammation or incision during cesarean section; velamentous insertion of the cord can also lead to fetal blood loss and carries a high mortality.

Placental abnormalities such as abruptio placenta or placenta previa can result in fetal hemorrhage. Internal hemorrhage that occurs at the time of delivery appears in the first 24-48 hours and is not associated with jaundice.

Subdural, subarachnoid or intraventricular (50% infants birth weight <1500 g) bleeds and cephalohematomas can all be of sufficient size to result in anemia. Subaponeurotic hemorrhage can be much larger, leading to severe anemia and shock. Internal hemorrhage into adrenals, kidneys, spleen or retroperitoneal area can occur with breech or traumatic delivery.

Occult hemorrhage may occur before birth due to fetomaternal hemorrhage or twin-to-twin transfusion. Fetal-to-maternal hemorrhage greater than 30mL (normal < 2mL) can occur in the context of abdominal trauma, amniocentesis (third trimester), external cephalic version, or placentalpathology (abruptio placenta or tumors). Twin-to twin transfusion occurs in 6-33% of monozygotic, monochorial twin pregnancies with anemia in one twin and polycythemia in the other, and significant transfer exists when the Hb difference is greater than 5g/dL.

Hemolytic anemia

Hemolytic anemia results in shortened red cell survival with reticulocytosis and indirect hyperbilirubinemia. It may be acquired through:

  • immune etiologies(Rh, ABO or other blood group incompatibility, maternal autoimmune, drugs)

  • infectious etiologies(bacterial sepsis, rubella, CMV, disseminated herpes simplex virus, adenovirus, toxoplasmosis, malaria, syphilis)

  • disseminated intravascular coagulation or microangiopathic mechanisms such as cavernous hemangioma or coarctation of the aorta

  • prolonged or recurrent acidosis can be associated with hemolysis

Inherited causes of hemolytic anemia include the red cell membrane disorders such as hereditary spherocytosis, or elliptocytosis presenting as hereditary pyropoikilocytosis, hereditary enzyme deficiency (G6PD, pyruvate kinase) and hemoglobinopathies of the major globin chains, alpha and gamma, expressed at birth (alpha or gamma thalassemia or globin structural defects). Beta-chain thalassemic or structural (e.g., sickle cell) mutations do not usually present at birth unless unmasked by premature destruction of the fetal (high HbF red cells), such as blood group incompatibility or fetal blood loss, which accelerates the switch to adult (beta-chain synthesis).

Impaired red cell production

Impaired red cell production in infancy is rare.

Diamond Blackfan anemiacan present at birth, although it usually presents at around three months of age; low birth weight and congenital anomalies of the head (microcephaly, cleft palate, hypertelorism), neck (webbed) and radial aspects of the arm (thumb) may be present, and the anemia (Hb ~ 9g/dL) at birth is characterized by a low reticulocyte count, high erythrocyte adenosine deaminase and bone marrow with erythroid hypoplasia but normal myelopoiesis and megakaryocytes.

Other inherited bone marrow failure syndromes that can present with anemia at birth include Pearson's syndrome, due to a 5-kb mitochondrial deletion (exocrine pancreatic defect, vacuolated erythroblasts and ring sideroblasts, variable thrombocytopenia, neutropenia); X-linked sideroblastic anemia, due to ALAS2 mutation (hypochromic microcytic anemia that develops within a few months of birth); and congenital dyserythropoietic anemia (CDA) type I, characterized by anemia and early jaundice, variable hepatosplenomegaly, and megaloblastic erythroblasts with chromatin bridges and binuclearity.

When do you need to get more aggressive tests:

The history, examination and initial laboratory results should allow one to narrow the diagnostic possibilities, and further testing will depend on the suspected diagnosis. It is simple and convenient to use a pathophysiological approach that considers the etiology from the outside-in, (i.e., hemorrhage, vascular damage, plasma factors, membrane abnormalities, metabolic conditions and hemoglobinopathies). While acute and rapidly evolving anemia requires urgent diagnosis and management, more chronic anemia, in particular hemolysis, can be difficult to diagnose in infancy and may require further investigation at 3–6 months of age.

If acute hemorrhage is suspected in an infant with a history of possible perinatal bleeding and signs of shock the hemoglobin at birth may be normal, but should be repeated at 6 and 12 hours after birth. Anemia that occurs in the first 24 hours that is not associated with jaundice but with a traumatic delivery is often due to internal hemorrhage. While bleeding due to obstetric accidents, malformations of the cord, or extracranial bleeding may be obvious, bleeding into the adrenal glands, kidneys, spleen, liver, or intraventricular hemorrhage may require radiological imaging such as plain films of the abdomen (erect and supine to look for free fluid in the case of hepatic or splenic rupture) with paracentesis, or computerized tomography (CT) scan of the head if ventricular or subarachnoid hemorrhage is suspected.

The diagnosis of chronic anemia due to occult fetomaternal hemorrhage can be confirmed by demonstrating fetal cells in the maternal circulation with the Kleihauer-Betke technique (resistance of fetal cells to acid elution), differential agglutination, or flow cytometry. In twin-to-twin transfusion, chronic hemorrhage can be inferred if the anemic twin has a reticulocytosis and weighs less than 20% of the weight of the larger twin.

Vascular damage: While the Kasabach-Merritt syndrome is usually due to solitary hemangiomas of the extremities, neck or trunk, visceral lesions should be suspected in infants with unexplained thrombocytopenia and a schistocytic anemia, with or without laboratory evidence of DIC (prolonged prothrombin time [PT], partial thromboplastin time [PTT], low fibrinogen, increased D-dimer). Diagnosis may require brain, liver, spleen, gastrointestinal tract and retroperitoneal radiographic imaging (MRI).

Plasma factors such as antibodies cause anemia characterized by spherocytes that result from splenic sequestration. Modern obstetric practice with administration of anti-D immunoprophylaxis to RhD negative women during pregnancy and within 72 hours postnatally has prevented 96% of cases of RhD sensitization in developed countries. However, this is still a considerable problem in poorer countries. Infants suspected or diagnosed with isoimmune hemolytic anemia should have a baseline measurement of bilirubin and then regular measurements to monitor the rate of increase. More severely affected infants require monitoring of liver function, acid base balance, and a coagulation screen. If the direct antiglobulin test is negative, hemolysis in infancy can usually be recognized if the reticulocyte count is increased and/or the hemoglobin decreases rapidly in the absence of hemorrhage.

Toxins (infection) and drugs can damage red cells through oxidant hemolysis (helmet and bite cells) or bacterial lipases, and suspected cases should be screened for TORCH and other infections.

Membrane: The common membranopathies are hereditary spherocytosis and elliptocytosis, but other membrane abnormalities lead to defects in cation permeability (stomatocytosis [overhydration] and xerocytosis [dehydration]). Osmotic fragility testing confirms the diagnosis of hereditary spherocytosis, while the latter two conditions can be suspected by morphological features as well as high MCV with low MCHC in stomatocytosis and high MCV and MCHC (a unique combination) in xerocytosis. Further testing of red cell cation content or cation permeability at different temperatures requires investigation in specialized laboratories. Abetalipoproteinemia can cause hemolysis characterised by acanthocytes, red cells with irregular spiky protrusions.

Metabolic: bite cells and irregular helmet shaped poikilocytes in a male infant suggests glucose-6 phosphate dehydrogenase, but other enzyme deficiencies (e.g., pyruvate kinase deficiency) may not have morphological abnormalities. Further testing includes a screening test for G6PD deficiency and a red cell enzyme panel.

Hemoglobinopathies:

  • Beta-chain defects:

Sickle cell anemia does not usually present clinically at birth but is usually easy to diagnose where

newborn screening (NBS) is standard practice (Hb FS for sickle cell disease or sickle cell-beta0 thalassemia; FAS for sickle trait; FSA for sickle-beta+ thalassemia, where the written order of the particular hemoglobins correlates with level, [i.e., F>S in a newborn with sickle cell anemia]) and can be evaluated in the context of family history and ethnicity. Similarly, beta-thalassemia does not usually manifest at birth because beta globin genes are not yet fully expressed, although loss of fetal cells through bleeding or blood type incompatibility can unmask beta-thalassemia syndromes (trait or homozygous beta thalassemia major). Other beta chain structural defects may also present under such circumstances.

  • Alpha-chain defects:

Alpha thalassemia silent carrier (one gene deletion) and trait (two gene deletion) is characterized by an increase in Hb Bart’s (four gamma chains) with the NBS showing FAB. Hemoglobin H disease (3 alpha gene deletion) results in large amounts of Hb Bart’s and some HbH (four beta chains) in the newborn period. Hemoglobin electrophoresis can be used to confirm these diagnoses. Alpha chain structural defects are usually benign in both neonates and adults, although exceptions exist when the fetal form is less stable than the adult form (e.g., Hb Hasharon).

  • Gamma-chain defects:

Only gamma 0 thalassemia would be expected to be lethal (no gamma chains) whereas deficiency of one or two gamma genes would be mild. Similarly structural defects are usually benign, although Hb Poole, an unstable variant, can cause a Heinz body positive hemolytic anemia in the newborn period. If not diagnosed in the neonatal period these conditions will be missed as HbF is replaced by HbA.

Impaired red cell production: Approximately 25% of patients with Diamond Blackfan anemia are anemic at birth, and the typical congenital abnormalities should be sought as well as red cell adenosine deaminase, which is frequently >3SD above the mean, and must be measured before transfusion. A bone marrow aspirate will show marked erythroid hypoplasia with normal myelopoiesis and megakaryocytes. Congenital parvovirus infection can lead to miscarriage, hydrops fetalis or chronic anemia, and giant pronormoblasts may be present in the marrow. Rubella, cytomegalovirus and adenovirus can also lead to impaired red cell production. A bone marrow aspirate will also be helpful in the diagnosis of other causes of impaired erythropoiesis such as:

  • Pearson syndrome (vacuolated erythroblasts, ring sideroblastic anemia, metabolic acidosis and exocrine pancreatic deficiency),

  • X-linked sideroblastic anemia (ring sideroblasts),

  • congenital dyserythropoietic anemia (megaloblastic erythroid precursors with binucleate forms and internuclear chromatin bridges) as well as acquired diseases such as congenital leukemia and the transient myeloproliferative disorder seen in some neonates with Down syndrome, although in Down syndrome a bone marrow aspirate is not usually required because the blood smear is so striking.

What imaging studies (if any) will be helpful?

Imaging studies are indicated above.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Severe anemia due to bleeding in a neonate or a live hydropic baby (alpha thalassemia major, Diamond Blackfan anemia, congenital parvovirus) is a pediatric emergency that requires rapid evaluation and treatment to prevent hypoxia, congestive heart failure, and death.

The approach to blood transfusion can be divided into three levels of intervention, depending on the clinical findings and the laboratory data:

  • If bleeding has been controlled, vital signs are stable, the hemoglobin/hematocrit remains above 7-9g/dL, and further bleeding is considered unlikely, the initially cross-matched blood should be held for at least 24 hours and then released for other use if no longer required for this patient.

  • If bleeding has led to hypovolemic shock but tissue oxygenation is not critically affected, intravascular volume should be supported with crystalloid or colloid solutions until a cross-match has been performed and compatible donor blood is available. If necessary, group and Rh type-specific but non-cross-matched blood can be used. A similar approach should be used if the hemoglobin/hematocrit slowly falls to a level less than 6g/dL or if the hematocrit remains stable at a low level, but further bleeding is considered likely (e.g., esophageal varices).

  • Only when bleeding is life-threatening should non-cross-matched group O, Rh-negative blood be administered. Transfusion of blood with minor blood group incompatibilities may result in immediate hemolysis and renal failure or, more commonly, may result in sensitization of the recipient to red cell antigens, making future blood compatibility testing difficult. The determination of the patient's ABO or Rh blood group can be performed within a few minutes, so selection of ABO- and Rh-compatible donor units is almost always feasible.

In the case of severe Rh isoimmunization early exchange transfusion is indicated by rapidly increasing bilirubin (8-13µmol/L/hour), despite intense phototherapy, although these recommendations may not apply with improved antenatal care, phototherapy, and other supportive care.

What other therapies are helpful for reducing complications?

Erythropoietin can be considered in an attempt to avoid transfusion in infants with mild to moderate anemia due to hemolytic anemias such as hereditary spherocytosis.

What should you tell the patient and the family about prognosis?

Prognosis depends critically on accurate diagnosis and ranges from a guarded outlook in neonates with hydrops fetalis, through a requirement for long-standing expert hematological management in cases of sickle cell disease, thalassemia major or intermedia and inherited hemolytic anemia, to a prognosis of mild and transient illness in successfully managed babies with isoimmune hemolysis or gamma globin chain defects (often undiagnosed).

“What if” scenarios.

N/A

Pathophysiology

Covered in earlier sections

What other clinical manifestations may help me to diagnose congenital anemia?

Covered in earlier sections

What other additional laboratory studies may be ordered?

N/A

What’s the evidence?

Burgnara, C, Platt, OS, Orkin, SH, Nathan, DG, Ginsburg, D, Look, AT, Fisher, DE, Lux, SE. "The neonatal erythrocyte and its disorders". Nathanand Oski's Hematology of Infancy and Childhood. Saunders Elsevier. 2009. pp. 22-67.

Liley, HG, Orkin, SH, Nathan, DG, Ginsburg, D, Look, AT, Fisher, DE, Lux, SE. "Immune hemolytic disease of the newborn". Nathanand Oski's Hematology of Infancy and Childhood. Saunders Elsevier. 2009. pp. 68-103.

Nathan, DG, Orkin, SH, Nathan, DG, Ginsburg, D, Look, AT, Fisher, DE, Lux, SE. " Diagnostic approach to the anemic patient". Nathanand Oski's Hematology of Infancy and Childhood. Saunders Elsevier. 2009. pp. 456-468 .

[A wealth of detailed information can be found in the three chapters of the book detailed in the three references above.]
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