571 anemia OF PREMATURITY 572 CHAPTER 12 Pediatric hematology Haemolytic anemia in the neonate Normal red cell life span in term infants is <80d, in pre- term infants <50d. Red cell \200\230cull \200\231 in 1st month with jaundice is physiologi cal. Pathological haemolysis, when present, is most commonly due to iso- immune HDN 2 to fetomaternal blood group incompatibility in Caucasian populations. In other ethnic groups G 6PD defi ciency and con- genital infection are major causes. Pathophysiology Physiological haemolysis occurs soon after birth and there is a marked drop in the Hb and RBC count in the 1st weeks of life. Neonatal RBCs are more susceptible to ox idative stress and there is altered RBC enzyme activity compared to adult RBC and reticuloc ytes. So pathological hae- molysis occurs in the neonatal period more than at any other tim e. Causes of haemolytic anemia Haemolysis may be due to intrinsic defects of the RBC, usually congen- ital, or to acquired extracorpuscular factors which may be immune or non-immune. Clinical features Pathological jaundice may be clinically obvious at birth or within 24h (d istinguishing it from the common physiological anemia which occurs >48h after birth, E Haem olytic disease of the newborn, p.578). \200 Anemia may be severe depending on cause. \200 Infections are common cause of hyperbilirubinaemia (E Haemolytic disease of the newborn, p.578 with specifi c clinical fi ndings. In utero inf ections (TORCH) do not usually cause severe jaundice cf. post-natal bacterial sepsis where jaundice may be striking and associated with MAHA. Splenomegaly at birth indicates a prenatal event; when noted later it may be 2 to splenic clearance of damaged RBC and is non-specifi c. Kernicterus is the major complication of neonatal hyperbilirubinaemia. Family history and drug history may be informative. Laboratory diagnosis of haemolysis \200 i unconjugated bilirubin with anemia is hallmark of haemolytic anemia. i reticulocytes (haptoglobins are unreliable in the newborn). \200 Blood fi lm \200\224ma y show RBC abnormalities, e.g. spherocytes, elliptocytes, fragmented cells. DAT, if +ve indicates immune haemolysis; \210\222ve does not rule this out \200\224 especially consider ABO HDN. Heinz body test \200\224+ve in drug-induced haemolysis, G6PD defi ciency and occasionally other enzyme disorders. Intravascular haemolysis \200\224look for haemoglobinuria/ haemoglobinaemia. 573 HAEMOLYTIC anemia IN THE NEONATE 574 CHAPTER 12 Pediatric hematology Congenital red cell defects Pathophysiology The neonate is uniquely disadvantaged when it c omes to handling patho- logical haemolysis because of hepatic immaturity and altered enzyme activity. Thus congenital defects of the RBC commonly present in the newborn except for de fects involving the globin chain (e.g. SCD, thalassaemia) which become clinically man ifest several weeks after birth but can be diagnosed in utero, or in the neonatal period if suspected. HS is the commonest congenital haemolytic anemia in Caucasian populations; half present in the neonatal period. Worldwide, G6PD defi ciency occurs in 3% population; neona tal presentation is common in Mediterranean and Canton peoples. thalassaemia is incompat ible with life causing hydrops fetalis (all 4 globin genes deleted), or may present as H bH disease (3 of the 4 globin genes deleted) with mild-to-moderate haemolysis in neonate . Hereditary RBC defects in neonatal haemolytic anemia \200 Membrane defects: Hereditary spherocytosis, hereditary elliptocytosis and variants, e.g. stomatocytosis and p yropoikilocytosis (Afro-Americans). Hemoglobin defects: \200 thalassaemia. \200 Unstable haemoglobins (e.g. HbK ln, HbZurich). Enzyme defects: Glycolytic pathway; pyruvate kinase and other enzyme defi ciencies. \200 Hexose monophosp hate shunt; G6PD defi ciency, other enzymes. Clinical features Congenital haemolytic anemia with mild or moderate unconjugated hyperbili rubinaemia. No gross excess of bile pigments in urine (old col- lective name for these dise ases was \200\230acholuric jaundice \200\231), hepatosple- nomegaly. A +ve family histo ry is common but not invariable. Laboratory investigation May be diffi cult to diagnose in neonate, especially if post-trans fusion. Often have to wait until clinically stable some weeks/months later. \200 Exclude acquired disorders, and immune lysis (DAT). \200 RBC morphology is one key to diagnosis a nd further investigation, but spherocytes not specifi c for HS. Further tests for suspected: Membrane defect (osmotic fragility, autohaemolysis, dye binding, membrane chemistry). Hb defect; Hb electrophoresis, HbF, HbA2 measurement. \200 Enzyme defect; Heinz body prep , screening tests for specifi c enzymes, G6PD, PK. Heinz body test +ve: Drug or chemical induced in neonate without hereditary defect. \200 Enzyme defi ciency: G 6PD commonest but consider others. \200 Unstable Hb. \200 thalassaemia. 575 CONGENITAL RED CELL DEFECTS Outcome Given supportive management including transfusion if necessary, most problems due t o congenital red cell defects other than haemoglo- binopathies will improve during the 1st weeks and months of life as the infant matures. Where the haemolysis is likely to be chronic folic supplementation should be commenced. 576 CHAPTER 12 Pediatric hematology Acquired red cell defects These may be either immune or non-immune. Main cause of the latte r will be underlying infection either acquired in utero or in the days fol- lowing delivery . Drug-induced haemolysis in the newborn is rare. Pathophysiology Neonatal RBCs have i sensitivity to oxidative stress due to altered enzyme activity, and are more liable to be destroyed by altered phys- ical conditions, mechanical factors, toxins, and drugs than adult RBC. Infection acquired in utero postnatally is a com mon cause of mild-to- moderate haemolytic anemia. The mechanism is multifactorial, and incl udes i reticuloendothelial activity and microangiopathic damage. Drug-induced haemolysis an d Heinz body formation is occasionally noted as a transient phenomenon in normal neonatal R BCs as a result of chemical or drug toxicity but is much more often seen when there is an u nderlying RBC defect such as G6PD defi ciency. Acquired RBC defects causing congenital haemolytic anemia \200 Infection: Congenital TORCH infections also rare but serious are malaria (can cause stillbirth) and syphilis. Post-natal, either viral or (more commonly) bacterial. Microangiopathy \200\2242 to severe infections DIC, also Kasabach \200\223Merritt syndrome (giant haemangioma with haemolysis and thrombocytopenia). \200 Drug or chemically induced. \200 Infantile pyknocytosis. \200 (Rare) metabolic disease such as Wilson disease, galactosaemia. Clinical features Congenital infections: all rare with adequate antenatal care. Most infant s with herpes simplex will be symptomatic with DIC and hepatic dysfunc- tion \200\224haemol ysis is not a major fi nding. Haemolytic anemia is also mild in CMV and rubella infections but 50% infants with toxoplasmosis will be anemic (may be severe). Postnatal infections: viral, bacterial and protozoal (congenital malaria can be delayed for some days or weeks or it can be acquired early in life). Anemia can be severe and associat ed with DIC. MAHA 2 to toxic damage to the endothelium is rare in the neonate outside the context of D IC and sepsis, and is seen in burns and (classically) in the Kasabach \200\223Merritt syndr ome \200\224a visible or covert giant haemangioma with haemolysis, RBC damage and profound thrombocytopenia. 577 ACQUIRED RED CELL DEFECTS Drugs/chemical exposure is more likely to cause Heinz body haemolysis in premature babies o r those with G6PD defi ciency. Incriminating agents include sulfonamides, chloramphenicol, mothballs, aniline dyes, maternal intake of diuretics, and, in the past, water-soluble vita min K analogs. Vitamin E (a potent antioxidant) has a number of RBC stabilizing activi- tie s. Now rare due to dietary supplements, defi ciency used to be seen occasionally in prematu re infants, following O2 therapy and diets rich in polyunsaturated fatty acids. Clinical fi ndings included haemolysis, preti- bial oedema, and CNS signs. Acanthocytosis/pyknocytosis of the RBC is characteristic, and this may have been the main cause of infantile pyk- nocy tosis. Infantile pyknocytosis: indicates the diagnostic feature of this uncommon acquired disorder . Haemolysis with i numbers (>6 \200\22350%) of pyknocytes (irregularly contracted RBCs wit h multiple projections) in the peripheral blood. Cause unknown, though may be associated wi th vitamin E defi - ciency. Anemia may be severe and present at birth, and is most striking at 73 weeks (Hb <5g/dL reported). Exchange transfusion occasionally required but the condi tion spontaneously remits by 73 months. Its self- limiting nature and ill-understood pathol ogy means that it may not be a distinct clinical entity. Metabolic disorders \200\224rare. Laboratory investigation Criteria set out earlier in this topic will establish the diagnosi s of haemolytic anemia. A +ve DAT points to an immune process \200\224probably Rh/ABO disea se. If non-immune, further tests to look for a congenital abnor- mality. The diagnosis may be made by: \200 Peripheral blood fi ndings. \200 Heinz body +ve \200 \224?chemical/drug-induced haemolysis. \200 RBC enzyme screen to exclude G6PD or PK defi ciency. \200 Hb electrophoresis to exclude Hb defects. Often no defi nitive cause is found and the HA will be presumed 2 to underlying systemic illness. Management 1. General supportive measures for hyperbilirubinaemia (E Hyper- bilirubinaemia, p.582). 2. Treatment of specifi c conditions: Haemolytic disease of the newborn \200\224E Haemolytic disease of the newborn, p.578. Neonatal infection as appropriate. \200 Exchange transfusion almost never needed. Outlook Prognosis is that of the underlying condition. Anemia will usually respond as the u nderlying condition is brought under control. 578 CHAPTER 12 Pediatric hematology Haemolytic disease of the newborn Arises when there is blood group incompatibility between mother and fetus. Maternal Abs produced against fetal RBC antigens cross the placenta and d estroy fetal RBCs. Most commonly caused by the Rh (D) antigen, but maternal passive immuniz ation with Rh (D) immunoglobulin (anti-D) introduced in the late 1960s transformed the outl ook. Despite this, HDN due to anti-D and other red cell antibodies (e.g. anti-c, anti-Kell) still remains an important cause of fetal morbidity. Pathogenesis Placental transfer of fetal cells l maternal circulation is maximal at deliver y; the condition does not usually present in the fi rstborn (Note: ABO incompatibility is a n exception). Previous maternal transfusion, abortion, amniocentesis, chorionic villus samp ling (CVS), or obstetric manipulations can cause antibody formation. Maternal IgG crosses p la- centa, reacts with Ag +ve fetal RBCs. Rh HDN Classically presents as jaundice in fi rst 24h of life. \200 Mild HDN: may go unno ticed and presents as persistent hyperbilirubinaemia or late anemia weeks after birth. Severe HDN: may result in a macerated fetus, fresh stillbirth, or severely anemic, grossly oedematous infant (hydrops fetalis) with hepato-splenomegaly 2 to compensatory extramedullary haemopoiesis in utero. Kernicterus: neurological damage 2 to bilirubin deposition in the brain, depends on a number of factors including the unconjugated bilirubin level, maturity of the baby, the use of interacting drugs. Diagnosis Rh HDN is the commonest cause of neonatal immune haemolysis; routine antenatal sc reening should identify most cases prior to delivery allowing appropriate action. In suspected case at delivery cord blood is tested for: \200 ABO and Rh (D) group. \200 Presence of antibody on fetal RBCs by DAT. \200 Hb and blood fi lm (spherocytes, i polyc hromasia, NRBCs). \200 Serum bilirubin (i). Maternal blood is tested for: \200 ABO and Rh (D) group. \200 Serum antibodies against fetal cells (by indirect antiglobulin test, IAGT). \200 Antibody titre. \200 Kleihauer test \200\224detects and quantitates fetal RBCs in maternal circulation. Diagnostic \201 ndings include: \200 DAT +ve haemolytic anemia spherocytosis in the infant. \200 Maternal anti-D, or other anti Rh antibody \200\224the next most common to produce severe disease is anti-c. 579 HAEMOLYTIC DISEASE OF THE NEWBORN ABO HDN Theoretically should occur more frequently since 71 in 4/5 babies and mothers are A BO incompatible. Usually occurs in group O mothers who may have high titres of naturally oc curring IgG anti-A or B, and with a boost to this during pregnancy haemolysis can occur. Clinical features 1st pregnancies are not exempt, but condition is usually mild. Presentati on is later than with Rh HDN (2 \200\2234d, but may be weeks after birth). Diagnosis May be diffi cult \200\224DAT commonly and puzzlingly \210\222ve, but off ending antibody can be eluted from infant RBC. Antibody studies Maternal high titre anti-A/B almost always in a group O mother cord- blood /infant \200\231s serum \200\224an inappropriate antibody (e.g. anti-A in a group A baby). Other blood group antibodies Can occasionally produce severe HDN; anti-Kell in particular. Serological testing will establish diagnosis. Maternal autoimmune haemolytic anemia may pro duce a similar picture to alloimmune HDN where the auto-anti-body cross-reacts with the inf ant RBC. Usually the diagnosis will have been made antenatally. Severity in infant varies d epending on maternal condition. Management \200\224prevention Routine antenatal maternal ABO and Rh D grouping and antibody testing carried out at booking visit (712 \200\22316 weeks). \200 If antibody +ve repeat at intervals to check the antibody titre. \200 If antibody \210\222ve and Rh D \210 \222ve repeat at 728 weeks \200\231 gestation. Establish if paternal red cells heterozygous, homozygous, or \210\222ve for the specifi c Ag. Anti-D prophylaxis \200 250IU IM during pregnancy to Rh D \210\222ve women without antib odies to cover any intrauterine maneuver or miscarriage. After delivery, a standard dose of 500IU anti-D within 72h unless baby is known to be Rh (D) \210\222ve. If Kleihauer test result shows a bleed of >4mL give further anti-D. Treatment of aff ected fetus \200\224before delivery Treatment depends on past obstetric hi story, the nature and titre of the antibody, and paternal expression of the antigen. The fe tal genotype can be established by CVS, fetal blood sampling, and PCR. 580 CHAPTER 12 Pediatric hematology Examination of the amniotic \202 uid to assess the degree of hyperbilirubi- naemia is ind icated with a poor past history (exchange transfusion or stillbirth in previous baby) and h igh titre (1:8 \200\2231:64) of an antibody likely to cause severe HDN (e.g. anti-D, anti-c , or anti-Kell). The amniotic fl uid bilirubin at optical density 450nm dictates treatment according to the Liley chart (Fig. 12.1), which estimates the blood concentration. Options include intrauterine transfusion (IUT) if fetus is not deemed mature enough for del ivery (check lung maturity on phospholipid levels) or induction of labor if it is. Intensiv e maternal plasmapheresis may be useful to reduce antibody titre. Advances in management of very premature babies are such that nowadays IUT rarely performed. After delivery \200 Full pediatric support \200\224metabolic, nutritional, and respirator y. \200 If unconjugated hyperbilirubinaemia not a problem, treat anemia (Note: cord blood Hb <14.0g/dL) by simple transfusion. Exchange transfusion with Rh (D) \210\222ve and (if possible) group specifi c blood for: \200 A severely aff ected hydropic anemic baby. \200 Hyperbilirubinaemia (bi lirubin level at or near 340mmol/L (20mg/ dL) or rapidly rising level, e.g. >20mmol/h) in f i rst few days of life. Signs suggesting kernicterus \200\224exchange transfusion may have to be repeated. Phototherapy to reduce the bilirubin level. \200 Follow-up required \200\224late anemia c an be severe particularly if exchange transfusion has not been carried out. Outcome With modern techniques, the outlook is good even for severely aff ected infants. 581 HAEMOLYTIC DISEASE OF THE NEWBORN 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Zone 3 0.3 0.2 D O \224 0.1 0.09 0.08 0.07 0.06 0.05 0.04 Zone 2 0.03 Zone I 0.02 0.01 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 WEEKS Fig. 12.1 Liley chart. The amount of bilirubin can be quantitated by spectrophotometrically measuring absorbance at 450nm wavelength in a specimen of amniotic fl uid that has been sh ielded from light. The results (delta 450) are plotted on a \200\230Liley \200\231 curve, which is divided into 3 zones. A result in zone I indicates mild or no disease. Fetuses in zone I are usually followed with amniocentesis every 3 weeks. A result in zone II indicates intermediate disease. Fetuses in low zone II are usually followed by amniocentesis every 1 \200\2232 weeks. A result above the middle of zone II may require transfusion or urgent de livery. 582 CHAPTER 12 Pediatric hematology Hyperbilirubinaemia Bilirubin results from the breakdown of haem, mostly Hb haem. It may be unconjugated, water insoluble, pre-hepatic (a mark of excessive RBC breakdown) or conjugat ed, soluble, post-hepatic (i in cholestasis). Unconjugated bilirubin i in most neonates and is usually physiological; conjugated hyperbilirubinaemia, on the other hand, is almost alw ays pathological. Pathophysiology Physiological jaundice is defi ned as a temporary ineffi cient excretion of bilirubin which results in jaundice in full-term infants between days 2 \200\2238 of life. Occurs in 790% of healthy neonates. Hepatic immaturity and i RBC breakdown overloads the n eonate \200\231s ability to handle the bilirubin which is mainly unconjugated. The bilirubi n is rarely >100micromol/L, though between 2 \200\2235d occasionally can be >200 in a term baby or 250 in a healthy pre-term. Levels much above this need investigation. Reaches a max imum by day 3 \200\2236 and usually d to normal by day 10. In premature neonates it may tak e longer to settle. HDN due to blood group incom- patibility accounts for 710% cases of hyp erbilirubinaemia and about 75% of those requiring exchange transfusion. Causes See Table 12.3. Table 12.3 Causes of hyperbilirubinaemia Unconjugated Conjugated Physiological jaundice Mechanical obstruction Haemolytic anemia Bile duct abnormalities (e.g. atresia, cysts) Haematoma Hepatocellular disorders Polycythaemia Hepatitis Biochemical defects Clinical features \200 2Note: clinical jaundice in the fi rst 24h of life is always patho logical. \200 Presenting after this, the jaundice may/may not be pathological \200\224 us ually not. Inadequate food/fl uid intake with dehydration can aggravate the physiological b ilirubin. A higher concentration is acceptable for the full-term breast-fed baby (serum bil irubin 240micromol/L) than bottle-fed baby (190micromol/L). Jaundice in an active healthy infant is likely to be physiological. \200 In a sick infant the underlying cause of the jaundice may be clinically evident \200\224e.g. infection, ane mia, shock, asphyxia, hemorrhage (may be occult). Physical examination \200\224hepatosplenomegaly is pathological. \200 Maternal history (d rugs, known condition) and family history may help. 583 HYPERBILIRUBINAEMIA Laboratory investigations \200 FBC, reticulocyte count, and fi lm \200\224?haemolytic ane mia. \200 Serum bilirubin \200\224?conjugated or unconjugated: Unconjugated hyperbilirubinaemia: \200\224DAT, maternal and neonatal blood group serology. \200\224Infection evaluation inc luding TORCH. \200\224Thyroid function. \200\224Reducing substances. Conjugated hyperbilirubinaemia: \200\224Abdominal USS, bile pigments in stool, liver pathology. \200 Further investigati on as determined by results and clinical picture. Management \200 General \200\224adequate hydration, nutrition, other supportive measures. \200 Treat underlying cause \200\224antibiotics, metabolic disturbances. \200 Haemolyt ic anemia \200\224blood transfusion. \200 Specifi c phototherapy (light source with wavel ength of 400 \200\223500mm) eff ective in treating most causes of unconjugated hyperbilirubinaemia. Note: contraindicated in conjugated hyperbilirubinaemia. Exchange transfusion \200\224the indications are complex. Main indication is severe haemoly tic anemia and is used in full-term infants when the bilirubin is >340micromol/L and at a l ower concentration in premature infants. Hyperbilirubinaemia due to mechanical obstruction may need surgery. Outcome In most infants hyperbilirubinaemia resolves by 2 weeks. When pathology has been ex cluded the commonest cause of prolonged hyper- bilirubinaemia persisting beyond this period is breastfeeding. In 20% healthy breast-fed infants the bilirubin is still signifi cantly i at day 21. Kernicterus is not a complication but the condition causes concern before it s pontaneously remits. 584 CHAPTER 12 Pediatric hematology Neonatal haemostasis Neonates can develop bruising and/or purpura due to defects in plate- lets, coagulation factors, or both. Coagulation tests should be inter- preted with caution because in the term infant the concentration of vitamin K-dependent proteins (II, VII, XI, and X together with protein C and protein S) are 50% of normal adult values, contact factor s (XI, XII, PK, and HMWK) are 30 \200\22350% of adult concentrations, and all are lower in pre-terms. Factors VIII, V, and vWF are normal. Thrombin inhibitors antithrombin (AT, previ ously called antithrombin III) and HCII are d but 2-M is i. Platelet count is the same as adults in both term and pre-term infants. There are technical problems in obtaining uncont aminated (heparin from catheters or IV lines) and adequate venous samples from neonates, ca using in vitro inhibition or pre-test activation of clotting factors or dilution due to sho rt sampling and thus excess anticoagulant. All can give spurious results. Pathophysiology Haemostatic and fi brinolytic system in neonates is immature. Sepsis, liver disease, necrotizing colitis and RDS can precipitate DIC easily. Thrombocytopenia can be c aused by DIC and also immune mechanisms or marrow failure. (See Table 12.4.) Clinical features \200 Petechiae indicate problems with small vessels or platelets, bruis es can be due to platelet defi ciencies and/or coagulation disorders. Oozing from multiple venepunture sites in sick infants usually indicates generalized haemostatic failure and DIC. Haemorrhagic disease of the newborn due to functional vitamin K defi ciency presents in 3 forms with bruising, purpura, and GI bleeding in otherwise well b abies; early (within 24h) usually due to maternal drugs such as warfarin; classical (d2 \200\2235) in babies who have not been given adequate vitamin K prophylaxis and who have be en breast-fed; and late, a variant of the classical form (i.e. insuffi cient vitamin K, bre ast-fed) arising at 2 \200\2238 weeks and with a higher morbidity and i incidence of ICH. Thrombosis usually catheter related, can be rarely associated with AT III defi ciency or homozygous protein C and protein S defi ciency (neonatal purpura fulmina ns \200\224a life-threatening condition with widespread peripheral gangrene). Hemophilia and other coagulant defi ciencies can cause large haematomas but rarely cause trouble in the neonatal period except factor XIII lack \200\224 typically presents with bleeding from the umbilical stump. In well babies, petechiae and bruises with thrombocytopenia suggests immune basis \200\224antibody usually from mother (alloimmune or autoimmune). Rarely, infan ts under a month can develop endogenous ITP. Clear symptoms of thrombocytopenia with normal platelet count suggests major functional defect \200\224Glanzmann \200\231s. Marrow failure due to infi ltration, aplasia. 585 NEONATAL HAEMOSTASIS Table 12.4 Disorders causing bleeding in neonates Inherited (rare) Acquired (common) Hemophilia DIC (sepsis, necrotizing colitis, hypoxia, RDS) \200 Vitamin K defi ciency von Willebrand disease (only type 3) Other inherited factor Liver disease defi ciencies Inherited thrombotic Acquired thrombotic disorders disorders Glanzmann thrombasthenia Neonatal alloimmune thrombocytopenia \200 Maternally derived ITP \200 Endogenous ITP \200 Aplasia \200 Leukemia Inherited BM failure syndromes 586 CHAPTER 12 Pediatric hematology Neonatal alloimmune thrombocytopenia Occurs when mothers form alloimmune antibodies against fetal platelet- specifi c antigens that their own platelets lack. These antibodies react w ith fetal platelets in utero causing thrombocytopenia which can be severe, and in some case s life-threatening in late pregnancy and early life. A more serious condition with greater morbidity than thrombocytopenia due to maternal autoantibodies against platelets \200\224i. e. where the mother has ITP. Pathophysiology In >90% cases the mother will be HPA-1a (old term = PLA1) \210\222ve with anti-HPA-1a antibodies against the HPA-1a +ve fetus; only 2% popula- tion are HPA-1a \210 \222ve (i.e. homozygous HPA-1b). Incidence of NAIT is 1/1000 pregnancies and accounts for 1 0 \200\22320% cases of neonatal throm- bocytopenia. Other antigens may be involved, e.g. HP A-5 (Br) and HPA-3 (Bak) are the commonest. Clinical features \200 Commonly presents in fi rst-born infant and recurs in 85 \200\2239 0%. \200 Maternal platelet count normal with no past history of ITP. \200 Bleeding mani festations in 10 \200\22320% evident within the 1st few days of life, e.g. umbilical hemorrhage, petechiae, ecchymosis, internal hemorrhage, intracranial h emorrhage (ICH). Baby \200\231s platelet count i to normal over the next 2 \200\2233 weeks as the antibody is cleared. Hemorrhage in utero with fatal ICH in 71% cases. See Table 12.5 for laboratory diagnosis. Management Of bleeding neonate Transfuse platelets \210\222ve for Ag (usually HPA-1a \210 \222ve); use random donor platelets in an emergency. Maternal platelets (irradiated) are a good source. Repeat platelet transfusion PRN. IVIg as for ITP can be used in exceptional ca ses (response within days). Close observation (ICH is potentially lethal \200\224screen usi ng USS). Of subsequent pregnancies Cordocentesis in utero at 724 weeks; take 1 \200\2233mL blood for platelet count and phenotype. If aff ected, treatment needs to be started imme- diately. Options 1. In utero CMV \210\222ve compatible platelet transfusions at 2 \200\2234-weekly intervals (depending on severity and history). Invasive and technically demanding. Keep pla telet count >50 \227 109/L (platelets d rapidly so frequent follow-up mandatory). 2. Maternal administration of IVIg (1g/kg) weekly from 724 weeks onwards: check fetal plate let count 74 weeks later and again near term; response variable \200\224around 75% respond \200\224transfuse platelets if non-responsive. Check cord blood at birth and treat as neces sary. 587 NEONATAL ALLOIMMUNE THROMBOCYTOPENIA Outcome With aggressive treatment the outcome is good, death in utero and ICH occur rarely. A history of a previous ICH correlates with severe throm- bocytopenia in subsequent pregna ncies. Table 12.5 Laboratory diagnosis Baby Parents Severe thrombocytopenia Mother \200\231s platelet count normal platelets <20 \227 109/L in 50% \200 BM has megakaryocytes ++ Serology: (not usually necessary) Mother \200\231s platelets usually HPA-1a \210\222ve Rarer Ab include anti-HPA-3, HPA-5b, HPA-4 (Yuk/Pen) Mother \200\231s serum contains anti-platelet antibody (Note: antibody titre cannot predict degree of thrombocytopenia in fetus in subsequent preg nancies) Father \200\231s platelets carry off ending antigen 588 CHAPTER 12 Pediatric hematology Congenital dyserythropoietic anaemias A rare group of inherited lifelong anaemias with morp hologically abnormal marrow erythroblasts and ineff ective erythropoiesis. 3 clini- cally d istinguishable types are recognized where inheritance may be reces- sive (types I and II) o r dominant (type III), see Table 12.6. A number of families have been described that share some features but do not fi t with the typical patterns. Pathophysiology Ineff ective erythropoiesis (cell death within the BM); RBC survival in PB is not much reduced (III). Abnormal serological and haemolytic character- istics (type II C DA) and membrane abnormalities are described but as yet no defi ning shared defect in all c ases of CDA. Clinical features \200 Age of presentation variable; but usually in older children (>10 y ears). Can rarely present as neonatal jaundice and anemia. Anemia \200\224in type I, Hb 8.0 \200\22312.0g/dL; type II anemia may be more severe, patie nt may be transfusion dependent. Type III (rare) anemia is mild/moderate. Jaundice (2 to intramedullary RBC destruction). \200 Gallstones. \200 Splenomegaly co mmon. Laboratory diagnosis \200 Peripheral blood \200\224normocytic/macrocytic RBC with anisopo ikilocytosis. \200 WBC and platelets usually n; reticulocytes slightly i. \200 BM appea rance \200\224striking, showing i cellularity with excess abnormal erythroblasts. Type II shows +ve acidifi ed serum test. \200 i serum ferritin due to i Fe absorption; ha emosiderosis can occur without transfusion dependence. Type III very occasionally Fe defi cient due to intravascul ar haemolysis and haemosiderinuria. Genetic analysis for CDAN1 and SEC23B. Diff erential diagnosis \200 CDA variants (CDA types IV to VII) \200\224not all CDA falls neatly into 3 subtypes on BM fi ndings, serology, or clinical features. PNH \200\224acidifi ed serum test is +ve with heterologous and autologous serum. In HEMPAS +ve with heterologous serum only. Other megaloblastic/dyserythropoietic anaemias \200\224including vitamin B12 and folate defi ciency. 1 /acquired sideroblastic anemia. \200 Erythroleukaemia (M6 AML). Treatment \200 Mostly unnecessary. \200 Avoid blood transfusion if possible (Fe overloa d) \200\224Fe chelation as necessary. Splenectomy not curative but may decrease transfusion requirements. \200 Type I may respo nd to high-dose interferon alfa; not recommended as routine therapy. 589 CONGENITAL DYSERYTHROPOIETIC ANAEMIAS Natural history Severity of CDA varies considerably and many patients have good QoL with no therapy. Haemosiderosis is a long-term complication which may impact on survival. Table 12.6 Types of congenital dyserythropoietic anaemias Type Bone marrow Blood \201 ndings Inheritance Recessiveb Macrocytic RBC I Megaloblastic + intra-nuclear chromatin bridges II (HEMPAS)a Recessive Normocytic RBCs pluripolar mitosis. Lysis in acidifi ed serum (not autologous serum) Bi/multinuclearity with peripheral arrangement of the endoplasmic reticulum III Giant erythroblasts with multinuclearity Macrocytic Dominant a Hereditary erythroblast multinuclearity with +ve acidifi ed serum test; commonest form, f ound in 766% cases. b The CDAN1 gene is mutated in majority of type 1 patients. The SEC23B gene is mutated in type II patients. 590 CHAPTER 12 Pediatric hematology Congenital red cell aplasia First described by Josephs in 1936 and subsequently by Diamond and Blackfan in 1938. Has come to be known as Diamond \200\223Blackfan anemia (DBA). Incide nce now estimated to be 4 \200\2237/million live births. Pathophysiology DBA is a heterogeneous disorder with evidence for at least 3 genetic subtyp es. Approximately 60% of DBA patients will have a heterozy- gous mutation in 1 of 10 riboso mal genes (RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPL5, RPL11, RPL26, RPL35A). These gene s encode com- ponents important in ribosome biogenesis. DBA therefore appears to be constit utional disorder arising from disruption of a key housekeeping pathway. This is associated with pleotropic eff ects in many systems but the maximal impact is on erythropoiesis result ing in a defi ciency of red cells. Clinical features \200 Usually presents in the 1st year of life: in 25% at birth and 90% <6 months of age. Rarely presents >1 year. Mildly aff ected individuals may rarely be detected as older children or adults during family studies. Associated physical anomalies in 50%; abnormal facies with abnormal eyes, webbed neck, malformed (including triphalangeal) thumbs, other skeletal abnormalities , short stature, congenital heart lesions, renal defects. Anemia usually severe and child commonly transfusion dependent. \200 Susceptibility to in fection is not i. \200 Hepatosplenomegaly absent. \200 Family history is +ve in only 10 \200\22320% cases; most are sporadic. \200 i risk of AML in long survivors; 75% in bigge st series reported to date. Laboratory diagnosis \200 d Hb, d reticulocytes, i MCV (> n for age), WBC and platelets n ot d. \200 Red cells \200\224n morphology to red cell anisocytosis/macrocytosis, have i i antigen positivity, i ADA activity. i HbF, i EPO, i serum Fe/ferritin. \200 BM fi ndings \200\224usually absent erythroid pre cursors; other cell lines n. \200 No evidence of parvovirus infection. \200 Radiologica l investigation to defi ne other congenital defects. \200 Genetic diagnosis possible in 6 0% of DBA patients (RPS19 gene). Diff erential diagnosis \200 TEC (E Transient erythroblastopenia of childhood, p.592; lat er presentation, transient, no other defects). Drugs, malnutrition, infection. \200 Haemolytic anaemias in hypoplastic phase, with parvo virus B19, delayed recovery in HDN. Megaloblastic anemia in aplastic phase. 591 CONGENITAL RED CELL APLASIA Treatment \200 Prednisolone 1mg/kg PO in divided doses, slowly d over weeks; 70% respond well. Titrate to lowest dose to maintain Hb >7g/dL. Many achieve this on almost homeopathic doses despite true dependence. Around 10% need high-dose maintenance and have trouble with side eff ects. 30% steroid resistant. Transfusion dependency usual in those who cannot be maintained on very low-dose steroids. N eed chelation to prevent Fe overload. Use CMV \210\222ve leucocyte-depleted packed RBC. Splenectomy not helpful (unless hypersplenism). \200 BM transplantation worth considering for transfusion dependents with suitable sibling donor; risk stratifi cation as for severe thalassaemia (Fe overload). Complicated decision due to chance of spontaneous remission even after years of transfusio n dependency. Natural history Spontaneous remission in 10 \200\22320% (even after several years). Median survival estimated at 30 \200\22350 years, though data patchy. Death due to haemosiderosis, complications of steroid therapy, or evolution of AML or aplastic anemia. BMT may off er b etter outlook. DBA Registries are now prospectively gathering new data. 592 CHAPTER 12 Pediatric hematology Acquired red cell aplasia Isolated failure of erythropoiesis. Most commonly transient \200 \224either due to parvovirus B19 infection or transient erythroblastopenia of child- hood ( TEC). Acquired pure red cell aplasia (PRCA) seen in adults with or without thymoma and prob ably autoimmune in nature (E Aplastic anemia, p.102) virtually unknown in childhood, though very occasion- ally seen in adolescents. Parvovirus B19 infection Clinical features \200 Causes transient reticulocytopenia and (o ccasionally) neutropenia and thrombocytopenia in otherwise healthy individuals. In children with i red cell turnover for any reason (compensated haemolysis, ineff ective e rythropoiesis) or those with reduced red cell production (marrow suppression or hypoplasia) can produce dramatic falls in Hb ( \200\230aplastic crisis \200\231). Can aff ect any age. \200 Self-limiting as infection subsides following antibody response , 7 \200\22310d. \200 In immunosuppressed children (e.g. chemotherapy, HIV) anemia can occasionally become chronic with persisting viraemia. Pathogenesis Parvovirus shows tropism for red cells through the P antigen, and is cyto- tox ic for erythroid progenitor cells at the colony forming stage (CFU-E) in vitro. Transient erythroblastopenia of childhood Pathogenesis Serum and cellular inhibitors of ery thropoiesis and defective BM response to stimulating cytokines have been demonstrated. The condi- tion may be idiopathic or associated with viral infection. It is uncommon but not ex cessively rare and there may be many subclinical cases where a blood count is not done. Clinical features \200 Boys and girls equally aff ected: age range 6 months \200\2235 yea rs; most commonly around 2 years. Typically a previously well young child presents with symptoms and signs of anemia, sometimes but not invariably following an infection. Onset is insidious an d the child becomes listless and pale \200\224or just pale. Associated infections are usually viral (EBV, mumps), preceding the onset of TEC by some weeks. Fever is rare. \200 Pallor may be striking. \200 No lymphadenopathy or hepatosplenomega ly. \200 No physical abnormalities. Laboratory diagnosis \200 Normocytic, normochromic anemia which may be severe (Hb <5g/dL). 593 ACQUIRED RED CELL APLASIA Reticulocytes absent unless in early recovery phase; WBC and platelets usually n. Blood fi lm shows no abnormality other than anemia. \200 Biochemical profi le n. \200 B M shows normocellular picture with absent erythroid precursors. n Fe content. No karyotypic abnormalities. \200 Exclude parvovirus infection (E Parvovirus B19 infectio n, p.592). \200 No other investigation is of diagnostic help. Diff erential diagnosis \200 Exclude acute blood loss and anemia of chronic disease. \200 Exclude common ALL. \200 Diamond \200\223Blackfan anemia (E Congenital red cell apl asia, p.590). Usually presents within the fi rst 6 months of life and other abnormalities (skeletal malfo rmation, short stature, abnormal facies) are commonly present. Parvovirus infection (E Parvovirus B19 infection, p.592) Treatment Blood transfusion should be avoided but may be necessary if sympto- matic. Natural history Spontaneously remits (if not then diagnosis probably wrong) commonly within 4 \200\2238 weeks but may be up to 6 months. Relapse is rare. There are no long-term seque lae or associations. 594 CHAPTER 12 Pediatric hematology Fanconi anemia First described by Fanconi in 1927, Fanconi anemia (FA) is a clinically hete rogeneous disorder usually presenting in childhood with the common feature being slowly pro gressive marrow failure aff ecting all 3 cell lines (RBC, WBC, and megakaryocytes) and mani fest by peripheral blood pancytopenia and eventual marrow aplasia. It is usually an autosomal recessive disorder with several diff erent germline genetic muta tions involving at least 16 genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG , FANCI, FANCJ, FANCL, FANCM, FANCN, FANCO, FANCP, and FANCQ). One FA subtype (FAB) is X-li nked. The products of the FA genes are components of the \200\230FA-BRCA pathway \200\231 important in the maintenance of genomic stability of the cell.