Data supporting ef \201 cacy and effectiveness also remain relatively sparse and the curre nt evidence-based medicine summaries do not comprise a comprehensive review of child and ad olescent mental health prescribing (see Cochrane Library). Many protocols are listed; over time it is hoped there will be more consistent coverage from completed reviews. Despite thi s lack of evidence, psychotropic medication prescribing has increased exponentially over th e past 15yrs. Fortunately, recent changes in legisla- tion in the US and Europe have meant that far more psychiatric drugs are being trialed and licensed for use in children. For speci \201 c prescribing information, indications, contraindications, pre- cautions, s ide-effects, and dosage regimes the reader should consult an up-to-date formulary and the p rimary literature. One reference text offers the following useful headings in a section on general principles.1 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 First do no harm. Know the disorder and use drugs when indicated. Choose the best drug. Und erstand the drug and its properties. Minimize drug use and dosage. Keep things simple. Avoi d polypharmacy. Don \200\231t be a \201 ddler or follow fads. Take particular care with c hildren. Establish a therapeutic relationship. Compliance (adherence) with treatment. Whilst some mild mental health presentations may respond to medica- tion alone, in individu als with multiple comorbidities, impairment across domains, or distressed parents, medicati on is almost invariably adjunctive to or part of a more comprehensive and sophisticated man agement plan. Reference 1 Werry JS, Aman MC. (1999). Practitioner \200\231s guide to psychoactive drug fo r children and adolescents, 2nd edn. New York: Plenum Medical Book Co. 16_McClure_16.indd 606 11/14/2012 3:42:48 PM 607 Chapter 17 Hematology Peripheral blood \201 lm 608 Anemia 610 Haemolytic anaemias 612 De \201 ciency anaemias 614 Red blood count membrane defect anaemias 616 Red blood count enzyme defect anaemias 618 Sickle cell disease 620 Thalassaemia 622 Immune haemolytic anemia 624 Red blood cell fragm entation 625 Aplastic anemia 626 Failure of red cell production (pure red cell aplasia) 628 Polycythaemia 630 Abnormal bleeding or bruising 632 Coagulation studies 634 Disseminated i ntravascular coagulation 635 Hemophilia A 636 Hemophilia B 637 von Willebrand disease 638 P latelet function disorders 640 Thrombocytosis 641 Thrombocytopenia 642 Acute immune thrombo cytopenia 643 Thrombophilia 644 Blood transfusion 646 Blood transfusion reactions 648 17_McClure_17.indd 607 11/14/2012 3:50:12 PM CHAPTER 17 Hematology 608 Peripheral blood \201 lm Table 17.1 FBC and blood \201 lm abnormalities and their causes Abnormality Cause(s) Acanthocytes Abetalipoproteinaemia, severe liver disease, Vitamin E de \201 ciency in premature neonate s, hereditary acanthocytosis Basophilia Myeloproliferative disorders, chronic myeloid leukemia (CML), basophilic leukemia, reactive disorders, e.g. ulcerative colitis, infection Basophilic stippling Ineffective erythropoiesis; haemoglobinopathies, recovering bone marrow, lead poisoning Echinocytes (Burr cells) Renal failure, pyruvate kinase de \201 ciency, liver disease, HUS, burns Hereditary ellipt ocytosis (b p.616) Parasitic infections, allergic states, e.g. asthma, eczema, drugs, polya rteritis Elliptocytes Eosinophilia Fragmented red blood cells (RBC) Microangiopathic and mechanical haemolytic anaemias, DIC (b p.625), HUS (b p.376), renal fa ilure G6PD de \201 ciency (b p.618), haemoglobinopathies, post-splenectomy, hyposplenism, Heinz body haemolysis Heinz bodies (intracellular Hb precipitate) Howell \200\223Jolly bodies (intracellular DNA fragments) Normal neonatal blood picture, hyposplenia, post-splenectomy, megaloblastic anemia Leukemia (b p.656) Infection, mainly viral, malignancy, stress, vomiting, burns, anorexia, drugs, S LE, Crohn \200\231s disease, immunode \201 ciency states (SCID, diGeorge syndrome, acquire d, e.g. HIV), marrow failure, aplastic anemia, leukemia Leucocytosis Lymphocytopenia (lymphopenia) Lymphocytosis Viral and non-viral (pertussis, mycoplasma, malaria) infection, leukemia, atypical lymphocy tosis (EBV, CMV, adenovirus), stress, exercise, status epilepticus Vitamin B12 or folate de \201 ciency (b p.615), aplastic anemia (b p.626), normal neonatal blood picture (b p.192) Iron de \201 ciency (b p.614), thalassaemia (b p.622), anemia of chronic disease Macrocytic RBCs Microcytic RBCs Monocytopenia Autoimmune disorders, e.g. SLE, drugs, e.g. corticosteroids, chemotherapy Monocytosis Chronic bacterial infection, malaria, typhoid, TB, infective endocarditis, post-chemotherap y See b pp.627, 724 Neutropenia 17_McClure_17.indd 608 11/14/2012 3:50:12 PM PERIPHERAL BLOOD movie 609 Neutrophilia Infection, in \202 ammation, chronic bleeding, post- splenectomy, drugs, e.g. corticostero ids Reticulocytosis/polychromatic RBCs Haemolysis, bleeding, response to haemotinics (e.g. iron), marrow in \201 ltration Sickle cell anemia (b p.620) Normal neonatal blood picture, hereditary spherocytosis (p.616), immu ne mediated haemolytic disease, post-splenectomy Severe iron de \201 ciency (b p.614), sic kle cell disease, thalassaemia, liver disease, post- splenectomy, asplenia See b pp.642 \200\223643 See b p.641 Sickle cells Spherocytes Target cells Thrombocytopenia Thrombocytosis 17_McClure_17.indd 609 11/14/2012 3:50:12 PM CHAPTER 17 Hematology 610 Anemia Red cell indices vary considerably with age. Hemoglobin (Hb) at birth may be as high as 22g/dL, but then falls rapidly to about 11g/dL by 3mths. A mild hypochromic microcytic picture normally seen between 6mths and 6yrs. Sex differences in red cell indices do not ap pear until puberty. Symptoms and signs of anemia \200 \200 \200 \200 \200 \200 Fatigue, lethargy. Pallor. Poor feeding, anorexia. Poor growth. Dyspnoea on exertion. Rarel y stomatitis or koilonychia. Diagnostic approach to anemia History \200 \200 \200 \200 \200 Familial/ethnic causes (sickle cell, thalassaemia). Diet (cow \200\231s milk, vegan). Overt blood loss. Duration of symptoms. Drug history, e.g. NSAIDs. Examination \200 \200 Height and weight (FTT, malabsorption). Dysmorphic features, e.g. micrognathia, cleft palat e, abnormal/absent thumbs (Fanconi \200\231s anemia, Diamond \200\223Blackfan anemia). Jaun dice (haemolysis). Adenopathy/organomegaly (underlying malignancy). \200 FBC and \201 lm (See Table 17.2) \200 Red cell indices: mean cell volume (MCV), mean cell hemoglobin (MCH), mean corpuscular hemo globin concentration (MCHC) (anemia may be microcytic, macrocytic, normocytic, and/or hypoc hromic). RBC: Other cytopenias. \200 spherocytes, sickle cells, Howell Jolly bodies. 17_McClure_17.indd 610 11/14/2012 3:50:12 PM anemia 611 Table 17.2 Investigations for different anemia types Anemia type Investigate for Microcytic anemia Iron de \201 ciency, thalassaemias, sideroblastic anaemias, anemia of chronic disease Macrocytic anemia Bone marrow failure syndromes (reticulocytopenic anaemias; pure red cell aplasia, aplastic anemia, Diamond \200\223Blackfan anemia), myelodysplastic syndromes, megaloblastic anemia ( B12/folate de \201 ciency), dyserythropoeisis, drugs Normocytic anemia Haemolysis, sequestration, anemia of chronic disease, recent signi \201 cant bleeding, combined iron and B12/folate de \201 ciency, i.e. severe malnutrition Inves tigate as described on b p.612 Haemolytic anemia 17_McClure_17.indd 611 11/14/2012 3:50:13 PM CHAPTER 17 Hematology 612 Haemolytic anaemias Haemolysis causes reduction in the normal mean RBC survival of 120 days . Causes can be intrinsic (RBC membrane defects, enzyme defects, or haemoglobinopathies) or extrinsic (immune mediated or mechanical RBC fragmentation). Diagnosis History \200 Symptoms: abdominal pain (intravascular haemolysis). Possible precipitating factors: fava b eans in G6PD de \201 ciency. Ancestry: of G6PD de \201 ciency in boys. Family history: e.g. headache, dizziness, fever, chills, dark urine, back or e.g. infection, medications, foods such as e.g. African, Mediterranean, or Arabic ancestry is suggestive e.g. gallstones in spherocytosis. Examination Speci \201 c examination should include temperature, pallor, jaundice, splenom egaly. Look for leg ulcers. Investigations FBC and blood \201 lm \200 Increased reticulocyte count suggests increased RBC production in response to haemolysis or blood loss. Platelet count: thrombocytopenia with normal clotting suggests HUS, thrombotic thrombocytopenic purpura (TTP); with abnormal clotting suggests DIC. Pancytopenia: Abnorma l blood \201 lm: parasites, features of RBC fragmentation (schistocytes, burr cells). \200 consider viral infection, malignancy, hypersplenism. e.g. spherocytes or other RBC abnormalities, malaria Speci \201 c tests include the following: \200 \200 \200 Unconjugated bilirubin: Lactate dehydrogenase: Free plasma Hb, haemoglobinuria, haemosideri n in urine (all increased in intravascular haemolysis). Coombs antiglobulin test to establi sh if there is immune or non- immune haemolysis. Positive direct Coombs test (DCT) = antibo dies on RBC surface. Positive indirect Coombs test = antibodies in serum. If DCT +ve, scree n serum for red cell isoimmune antibodies, e.g. neonatal rhesus or ABO haemolytic disease ( see b Chapter 6, p.xxx,). If DCT +ve, IgG- and C3- speci \201 c reagents suggest warm and cold antibody autoimmune haemolysis respectively. IgM for mycoplasma; CMV; EBV; rubella; fo r cold antibody autoimmune haemolysis. Hb electrophoresis for sickle cell anemia, thalassae mias, unstable Hbs, e.g. Hb Koln. Flow cytometry for hereditary spherocytosis. RBC enzyme a ssays for RBC enzyme defects, e.g G6PD. If history suggestive, immunophenotyping (CD55 + CD 59) for paroxysmal nocturnal haemoglobinuria (PNH). raised level = increased RBC destruction. raised activity = increased RBC production. \200 \200 17_McClure_17.indd 612 11/14/2012 3:50:13 PM HAEMOLYTIC ANAEMIAS 613 17_McClure_17.indd 613 11/14/2012 3:50:13 PM CHAPTER 17 Hematology 614 De \201 ciency anaemias Iron de \201 ciency Commonest nutritional de \201 ciency. Occurs in 10 \200\22330% of those at high risk: \200 \200 Preterm, LBW infants, multiple births; After exclusive breastfeeding >6mths, delayed introd uction of iron- containing solids, excessive cow \200\231s milk (protein enteropathy); Adol escent females (growth spurt and menstruation); Low iron-containing diet due to poverty, fa d diets, or strict vegans. \200 Causes \200 commonest cause, e.g. prolonged and exclusive consumption Dietary: of cow \200\231s or brea st milk with late introduction of iron containing solids. Infancy and early childhood: inta ke (low iron), GI blood loss, e.g. cow \200\231s milk protein enteropathy. Demand due to ra pid growth: e.g. following prematurity or puberty. low level of dietary iron, e.g. high milk i \200 \200 \200 Malabsorption: Rarely blood loss: be occult into cysts, tumors or s to drugs, e.g. NSAIDs. Intestinal parasites: e.g. coeliac disease, IBD. e.g. Meckel \200\231s diverticulum, oesophagitis. Bleeding may e.g. hookworm (in less developed world). Presentation \200 Most cases are subclinical. Onset of symptoms of anemia is usually insidious. Profoundly ir on de \201 cient toddlers usually adapt to their anemia and tolerate surprisingly low Hbs. Pallor, lethargy, poor feeding, breathlessness (only in severe anemia). May also develop s ymptoms associated with iron de \201 ciency, including neurological effects of listlessnes s and irritability (infants), mood changes, reduced cognitive and psychomotor performance ( can occur at levels of mild/moderate de \201 ciency before anemia develops), and rarely, p ica (eating unusual items, e.g. soil, chewing on pencils). \200 Diagnosis Iron de \201 ciency anemia is a sign not a diagnosis \200\224always look for und erlying cause (usually dietary or GI disease). \200 Hb d, MCV & MCH & MCHC d (below normal range for age), FBC: platelets often raised. Blood \201 lm: d (indicative of iron stores): it may be low before anemia. Serum ferritin Check C-reactive protein, as ferritin may be falsely raised d ue to acute phase reaction (d serum iron and i total iron binding capacity (TIBC) con \201 rms iron de \201 ciency). \200 microcytic, hypochromic anemia. Treatment Give 5mg/kg elemental iron/day (as oral ferrous salt) given in 2 \200\2233 divide d doses (max dose of 200mg/day). Response in reticulocyte count is usually within 5 \200 \22310 days. Continue for 3mths after Hb normalizes to replenish body stores. If indices do n \200\231t improve once Hb normalized, screen for thalassaemia trait. Prevention in high risk groups \200 Iron supplementation in preterm infants. 17_McClure_17.indd 614 11/14/2012 3:50:13 PM DEFICIENCY ANAEMIAS 615 Encourage iron-containing diet, e.g. iron forti \201 ed formulas and breakfast cereals, me at, green vegetables, beans, egg yolk, foods rich in vitamin C (i iron absorption). Avoid p rolonged cow \200\231s milk consumption to detriment of solids intake. Macrocytic anemia Vitamin B12 de \201 ciency Vitamin B12 (cobalamin) usually sourced from animal products. Vegan or other diets lacking meat most at risk. Alternatively, can have de fective absorption due to intrinsic factor de \201 ciency (congenital autosomal recessive (AR) or juvenile autoimmune pernicious anemia), defective B12 transportation (transcobalami n II de \201 ciency), intestinal disease causing malabsorption (ileal resection, IBD, coel iac disease), or bacterial over-growth in small bowel. Folate de \201 ciency A common nutritional de \201 ciency worldwide. Causes include: \200 Malnutrition (marasmus, kwashiorkor), goat \200\231s milk feeding. \200 Malabsorpti on, e.g. coeliac disease, IBD, other small intestinal disease; \200 Increased requirement s, e.g. rapid growth, chronic haemolytic anaemias (give daily folic acid prophylactically), hypermetabolic states (infection, hyperthyroidism), severe skin disease. Drugs, e.g. pheny toin, valproate, trimethoprim, nitrofurantoin. Disorders of folate metabolism: \200 Lesch \200\223Nyhan syndrome; orotic aciduria. Presentation for folate or vitamin B12 de \201 ciency \200 Insidious onset of pallor, fatigue, anorexia, glossitis, developmental delay, and hypotonia . In severe cases, subacute combined degeneration of cord (rare in children): paraesthesia of hands/feet, ataxic gait, loss of vibration sense. Diagnosis of macrocytic anaemias \200 Hb d, MCV i (above the normal range for age, i.e. Macrocytic anemia: >82 aged 1yr, >90 aged 6 \200\22312yrs or >125fL as a newborn). WBC Seru m B12 or d folate level (red cell folate level is more reliable than serum folate, which re \202 ects recent intake). Bone marrow, if indicated, shows megaloblastic appearance. Rare ly, intrinsic factor autoantibodies or test of B Schilling test. d \200 d, hypersegmented neutrophils, platelets d, bilirubin i. \200 12 absorption, e.g. Treatment Improve diet. Depending on whether vitamin B12 or folic acid is de \201 cient: B \200 12 de \201 ciency: IM hydroxocobalamin (1mg) \200\224usually response is within 1wk . Watch K+ level as it may drop. Treat 3 times/wk until Hb normal; then give 2 \200\2233-mo nthly if the underlying problem persists (important to identify cause). Folate prompt (with in few days). \200 \200 (cid:1) never treat with folic acid alone unless serum B12 leve l is known to be normal, as subacute combined degeneration of the cord can be precipitated. de \201 ciency: daily oral folic acid (500micrograms/kg). Response is look for underlying cause (usually GI). 17_McClure_17.indd 615 11/14/2012 3:50:13 PM CHAPTER 17 Hematology 616 Red blood count membrane defect anaemias Hereditary spherocytosis (HS) \200 71/5000 (northern Autosomal dominant (AD) in 75% cases. Incidence European). Various RBC membrane skeletal de fects occur; commonest involves ankyrin (750 \200\22360%). Mild to moderate anemia in compe nsated cases. Anemia can be severe with transfusion requirement. Splenomegaly is usually pr esent. Infection exacerbates haemolysis with worsening jaundice. Aplastic (red cell) crisis can occur with parvovirus B19 infection. The severity of anemia depends on degree of basel ine haemolysis (worst in those with high reticulocyte counts due to sudden decompensation). Folate de \201 ciency can occur with massively increased RBC turnover so oral supplementa tion with 5mg/day folic acid should be given routinely. Laboratory investigation includes: on blood \201 lm; red cell indices may be slightly low, but clue is in the MCHC, which is raised, i.e. hyperchromic due to the spherical shape of the RBCs. Direct Coombs test \200 \223ve (excludes autoimmune causes). In the past the osmotic fragility was performed, but n ow diagnosis can be made on clinical and basic hematological features of indices, reticuloc ytes and blood \201 lm. Diagnosis in dif \201 cult cases can be made by \202 ow cytome try, but is expensive and usually not clinically warranted. Provide supportive treatment, e .g. folic acid supplementation, blood transfusion if anemia severe during aplastic crises. Ideally, if splenectomy is indicated it is best performed after 5yrs of age but before pube rty. Consider if: \200 \200 \200 i reticulocytes, ii spherocytes anemia is not compensated and child is not thriving physically, socially, or educationally; chronic haemolysis resulting in gallstone formation; persistent jaundice is a rare indicat ion for cosmetic reasons. \200 Splenectomy requires pre-operative vaccination against Haemophilus in \202 uenza ty pe B (HiB) and meningococcus C, as well as post-operative 5-yearly boosters, annual in \202 uenza vaccination, lifelong penicillin V prophylaxis (250mg bd from 5yrs until adolesc ence, then 500mg bd). pneumococcus, Hereditary elliptocytosis (HE) Heterogeneous group of disorders with mainly AD inheritance. Incidence 1:25,000. Severity varies from asymptomatic chronic compensated haemo- lysis (ma jority) to transfusion dependence. Presentation and management similar to HS. Blood \201 lm shows elliptical RBCs. 17_McClure_17.indd 616 11/14/2012 3:50:13 PM RED BLOOD COUNT MEMBRANE DEFECT ANAEMIAS 617 Hereditary pyropoikilocytosis In this disorder RBCs are extremely sensitive to raised tempe rature. Hb usually 77 \200\2239g/dL. Jaundice and splenomegaly present. Good response to sp lenectomy in those severely affected. Hereditary stomatocytosis This condition has AD inheritance and is of variable severity. 17_McClure_17.indd 617 11/14/2012 3:50:13 PM CHAPTER 17 Hematology 618 Red blood count enzyme defect anaemias Glucose-6-phosphate-dehydrogenase de \201 ciency (G 6PD) \200 X-linked recessive: homozygous females, with variable expression in heterozygous females (d epending on Lyonization. Endemic in Mediterranean, South-East Asia, West Africa, and Middle East. There are over 400 enzyme variants. African (A \200\223) (10 \200\22360% enzyme acti vity) and Mediterranean (3% activity) are most clinically relevant. RBC G6PD levels fall ra pidly as cells age, with impaired elimination of oxidants and reduced cell integrity. Inter mittent acute haemolytic episodes (intravascular haemolysis) are associated with febrile in fections (most common), oxidant drugs (antimalarials, sulphonamides, dapsone, aspirin, phen acetin, cipro \202 oxacin), foods (fava beans), chemicals (naphthalene - common in moth ba lls, henna). May present as neonatal jaundice or chronic haemolytic anemia. disease occurs in heterozygous males and Laboratory investigation \200 \200 Normal during non-haemolytic state. During haemolysis, \201 ndings of RBC destruction (bi te cells and Hb puddling (ghost cells)), increased RBC production (raised reticulocyte coun t), spherocytes and Heinz bodies on blood \201 lm, DCT \200\223ve. De \201 nitive diagn osis is by measuring reduced G6PD enzyme activity (may be falsely normal during acute haemo lysis; repeat 6wks later). Management Avoid oxidant drugs and foods, maintain good urine output with \202 uids, tran sfuse if required, give folate supplements in chronic haemolysis or in patients recovering from acute episodes, treat hyperbilirubinaemia in newborns. Pyruvate kinase (PK) de \201 ciency A rare congenital autosomal recessive (AR) condition. Chronic haemo- lytic anemia results from de \201 ciency of pyruvate kinase. Enzyme de \201 - ciency leads to d RBC ATP generation and i 2,3- diphosphoglycerate (DPG) production (shifts O2 dissociation curve to right). Severity is vari- able. Neonatal jaundice is commo n. Patients can have persistent, severe hyperbilirubinaemia. Parvovirus B19 infection can c ause (red cell) aplastic crisis. Laboratory \201 ndings are of i RBC destruction and prod uction, d PK enzyme level. Blood \201 lm pre-splenectomy not very informative. Management \200 \200 \200 \200 Oral folate supplements. Blood transfusion if symptomatic anemia. Support of aplastic crisi s, e.g. blood transfusion. Splenectomy in severe cases. 17_McClure_17.indd 618 11/14/2012 3:50:13 PM RED BLOOD COUNT ENZYME DEFECT ANAEMIAS 619 17_McClure_17.indd 619 11/14/2012 3:50:13 PM CHAPTER 17 Hematology 620 Sickle cell disease \200 SCD is autosomal recessive. The most severe form is homozygous sickle hemoglobin HbSS, with less severe disease in compound heterozygotes, e.g. HbSC, HbSD, HbSB0, or HbSB+ thalassaem ia. A mutation in codon 6 of B-globin gene (chromosome 11) with single amino acid substitut ion (glutamine for valine). Found in Caribbean, Africa, Middle East, Mediterranean, and Ind ia. In Jamaica, carrier rate is 10%, with disease (HbSS) in 1 in 300 births. HbC carriers r epresent 3.5% of Jamaicans. Heterozygous carriers of HbS have increased resistance to malar ia, accounting for the high gene prevalence in malarial regions. In England SCD now occurs in more than 1 in 2000 live births. The disease is due to vaso-occlusion and haemolysis. RBCs show i blood viscosity, reducing \202 ow through small vessels causing tissue infarction. Sickle RBCs are prematurely dest royed resulting in a haemolytic anemia. Clinical features A spectrum of disease, ranging from asymptomatic to severe, frequent cris es and organ damage. Usually presents between 3mths and 6yrs. \200 Infancy: high HbF is protective (reduces tactoid formation) in the \201 rst months of lif e. Common problems are dactylitis, splenic sequestration and pneumococcal sepsis (if not va ccinated and on penicillin V prophylaxis). infection from encapsulated organisms (if not va ccinated Young children: and on penicillin V prophylaxis) and parvovirus, vaso-occlusive cr ises in long bones, upper airway obstruction, stroke. Older children: Risk of pneumococcal sepsis greatest in the \201 rst 3yrs of life. \200 vaso-occlusive crises, avascular necrosis and stroke. Sickle crises and problems \200 Vaso-occlusive (VOD)crises: joints, commonly involving ha nds and feet, becoming more central with increasing age. Dactylitis is an early manifestati on of disease. It is precipitated by cold weather, dehydration, infections and hypoxia. Acu te chest syndrome: can be precipitated by chest infection with shortness of breath, cough, chest pain, falling SpO2. CXR changes may be late, and progress within hours. Prompt treatm ent essential. Sequestration : body organs trap sickled RBCs. Splenic sequestration is more common in \201 rst year; later liver and lung sequestration occurs. Rapid fall in Hb may be fatal. Recurrent episodes warrant splenectomy. Stroke: most common in 5 \200\22310-yr-o lds, and by 20yrs up to 20% will have had silent stroke. Untreated, mortality is 20%; recur rence rate is 70% within 3yrs. Requires prompt treatment with exchange transfusion to reduc e HbS <20%. All UK children over the age of 2yrs require an annual transcranial Doppler: th ose with high velocity \202 ow should start serial exchange transfusion to prevent stroke . Infections: patients are functionally hyposplenic by 1yr, resulting in high risk of infec tion from Pneumococcus, Meningococcus, Haemophilus Inf. B. Ensure vaccination is up to date and give penicillin V prophylaxis. presents as excruciating pain in bones and 17_McClure_17.indd 620 11/14/2012 3:50:13 PM SICKLE CELL DISEASE 621 Aplastic crises: typically after infection with parvovirus B19. Reticulocytes and consequen tly Hb falls. Spontaneous recovery usually occurs in 10 days. The patient may require trans fusion. Priapism: affects 3 \200\2235% of pre- and 30 \200\22340% of post-pubertal boys. Ma y be acute fulminant (painful, lasting >3hr) or minor \200\230stuttering \200\231 priapism (shorter <3hr, self-limiting episodes). May result in erectile dysfunction. Major episodes require urgent urology. Recurrent stuttering priapism is managed with exercise, warm baths or oral etilefrine. Avascular necrosis: Renal impairment: urine output and susceptibility to dehydration. Enuresis is common. Papillary necrosis causes haematuria. Chronic renal fai lure can occur later. small vessel occlusion l neovascularization l vitreous Retinopathy: h emorrhage l resorption l \201 brous strands l retinal detachment. More common in HbSC dis ease. Surveillance needed. Treat with photocoagulation (see b p.920). ENT problems: nocturn al hypoxia precipitating crises. Ask about \200\230snoring \200\231. Leg ulcers: Growth an d development: usually normal. Speci \201 c SCD growth charts exist. \200 hip joint, humerus or any bone. hyposthenuria (urine concentration defect) with high adenotonsillar hypertrophy is common and may lead to \200 uncommon in childhood. generally delayed although \201 nal height is Diagnosis \200 C \200 \200 In the UK all newborns are screened linical suspicion: required in unscreened population Hb 5 \200\2239g/dL, reticulocytes i, sickle cells on blood \201 lm. Hematology: Hb electrophoresis (HPLC) is de \201 nitive test. Routine screening Prenatal \200 of Afro-Caribbean children prior to anesthesia. diagnosis: may be performed on fetal red cells or \201 broblasts. Management of acute crises \200 Hb d, reticulocytes i, blood culture, U&E, creatinine, Investigations: LFT, CRP (i with sickling/infection), group and save, CXR. aim for 150% nor mal maintenance (oral or IV). Hydration: Analgesia: titrate to severity of pain. Initially treat at home with simple analgesia, e.g. paracetamol, NSAIDs; give opiates if required. An tibiotics: >38*C. Add a macrolide if atypical pneumonia. Oxygen: Blood: transfusion for apl astic crisis, sequestration, or anemia; exchange transfusion for sequestration, chest syndr ome, or stroke. \200 broad spectrum cephalosporin, after blood culture if fever \200 to maintain arterial oxygen saturation (SaO2) >95%. Keep warm. Maintenance treatment \200 Avoid precipitating factors: \200 see b p.728. Vaccination: \200 Lifetime oral penicillin V prophylaxis. \200 Daily oral folic acid. \200 Hydroxy carbamide (hydroxyurea): blood. A rise in MCV shows compliance and myelosuppression is most common adverse effect. Use in patients with moderate to severe disease. Bone marrow transp lantation: e.g. hypoxia (air travel), cold, dehydration. may reduce crises and need for if successful is curative. 17_McClure_17.indd 621 11/14/2012 3:50:13 PM CHAPTER 17 Hematology 622 Thalassaemia A inherited defect in synthesis of one or more globin chains (globin chain lin ked to haem group = Hb) resulting in imbalanced globin chain produc- tion l ineffective ery thropoiesis l precipitation of excess chains l hae- molysis l variable severity anemia. \200 At birth the major Hb is HbF ( 2 and into adulthood the major Hb is HbA ( and only 1 \200\2232% is HbF. 2) is comprised of two A globin chains that are encoded HbA ( by two A-globin genes on each chomosome 16 (i.e. each cell has 4 A-globin genes), designated as ( / ). The two each chromosome 11, designated ( / ). HbF has 2 chains combined with 2 chains ( ). There are various forms of thalassaemia, e.g. are not produced), A tha lassaemia, - thalassaemia. Thalassaemia genes can be null mutants, which make no globin chains, e.g. o or o, or can make minimal amounts of globin chains, e.g. +, or +. T halassaemia major describes the homozygous disease state, e.g. ( o/ o) Thalassaemia minor (also called thalassaemia trait) describes carriers (heterozygotes) of either o or + g enes or o or + genes. Thalassaemia intermedia describes the spectrum of phenotypes betw een major and minor (i.e. 3 gene deletion causes HbH disease, or a + mutation with ano ther + mutation. 2). By the end of the \201 rst year of life 2), 2), 72. 5% is HbA2 ( 2 2 2 globin chains are encoded by only one -globin gene on globin chains combined with 2 ( / ). HbA2 has 2 thalassaemia ( chains The severity of anemia and clinical picture are related to the number and nature of gene mu tation and deletions and consequent imbalanced globin chain production. Thalassaemia is com mon in malaria-affected regions of the world (the trait is probably protective), i.e. parts of Africa, Mediterranean, Middle East, India, and Asia. -thalassaemia \200 \200 -thalassaemia ( / \210\222): one gene deletion. Asymptomatic. Silent -thalassaemia trait ( / \210\222 \210\222) or ( \210\222/ \210\222): Two g ene deletion. Asymptomatic with hypochromic microcytic picture (Hb may be d, MCV d, MCH d). May mimic iron de \201 ciency, if RBC >5.0 x 1012/L with microcytic, hypochromic \201 l m, then thalassaemia trait more likely. Hb H disease ( Variable chronic anemia with mild he patosplenomegaly and jaundice. Hypochromic anemia with target cells and reticulocytes i. Hb H inclusions (tetramers of B globin) are seen on special staining. Folic acid supplements r equired, and occasionally transfusions. Splenectomy may be bene \201 cial. Hb Bart \200 \231s hydrops fetalis ( \210\222 \210\222/ \210\222 \210\222). Four hydrops fetalis leading to stillbirth or early neonatal death. Hb analysis shows mainly Hb Bart \200\231s (G4). Mo st often seen in South-East Asia where frequency of ( / \210\222 \210\222) carriers is h igh. \210\222/ \210\222 \210\222): Three gene deletion or equivalent. gene deletion. Causes 17_McClure_17.indd 622 11/14/2012 3:50:13 PM THALASSAEMIA 623 -thalassaemia This disorder is not obvious until chain production falls off at around 6mths of age and HbF ( / ) levels fall. B thalassaemia trait ( \200 o/ ) or ( +/ ). \200 \200 \200 d, MCV d, MCH d. Asymptomatic with mild Hb HbA No treatment required, but important to detect for genetic co unseling purposes, especially if partner also has haemoglobinopathy. 2 characteristically i on Hb electrophoresis to > 3.5%. B thalassaemia major Presentation \200 Presents in \201 rst year to 18mths as HbF drops, but no Hb A is made leading to anemia. Severe anemia (3 \200\2239g/dL); markedly target cells, and nucleated RBCs. Secondary growt h and development failure. Extramedullary haematopoiesis causes skeletal deformity (frontal bossing of skull, maxillary swelling) and hepatosplenomegaly in older children who are not adequately transfused. Hb electrophoresis shows mainly HbF, but no HbA. d MCV and MCH, i reticulocytes, \200 Management \200 Regular transfusions (every 3 \200\2234wks) to maintain Hb level that suppresses extramedul lary haematopoiesis and sustains growth and development. Iron overload is major problem, wi th haemosiderosis affecting the heart, liver, endocrine organs, and pancreas. Chelation of iron starts when ferritin level >1000micrograms/L (usually following 10 \200\22320 transfus ions). Desferrioxamine by SC infusion 5 \200\2237 nights per week. Side-effects include: ca taracts, hearing loss, Yersinia gut infections. Alternatively, in children over 6yrs give d esferiserox (a new oral iron chelator). Start at dose of 20mg/kg/day and monitor renal func tion. Splenectomy may help if massive splenomegaly or increased transfusion requirements. B one marrow transplantation is the only cure and is usually successful when carried out as a planned procedure in a unit that specializes in the procedure, and in well chelated patien ts with no end organ damage. The procedure carries signi \201 cant risks. Thalassaemia intermedia Has a variable phenotype depending on the genotype from asymptomati c to a moderately severe anemia, similar to thalassaemia major, that may require intermitte nt transfusions. This disorder is usually due to co-inheri- tance of an ameliorating condit ion, e.g. triplicated globin chains, and HbF (hereditary persistence of fetal Hb), A tha lassaemia trait. 17_McClure_17.indd 623 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 624 Immune haemolytic anemia In this group of disorders, RBCs react with autoantibody +/ \200 \223 complement, which leads to their destruction by the reticuloendothelial system. Many d rugs can induce antibody-mediated haemolysis, e.g. penicillins, cepha- losporins, ibuprofen , anti-malarials, rifampicin, antihistamines. Mechanisms are variable. Immune haemolytic an emia can be divided into isoimmune and autoimmune forms. Isoimmune See b p.194. Sensitization induces maternal red cell antibodies that cross placen ta and haemolyse fetal and neonatal red cells. Usually, direct Coombs test +ve. \200 \200 \200 Rhesus haemolytic disease. ABO incompatability. Other blood group incompatibilities, e.g. K ell, Duffy, blood groups. Autoimmune Warm antibody type \200\224mostly IgG \200 \200 \200 Rare. Majority are idiopathic. Other causes: diseases (e.g. SLE, IBD). Variable haemolytic anemia, mild jaundice, splenomegaly, DCT +ve. Warm autoantibodies \200\224often non-speci \201 c. drugs (e.g. penicillin), lymphoid malignancies, autoimmune \200 Treatment Give oral prednisone. If no response give rituximab (anti-CD 20 antibody). Consid er splenectomy if severe or poorly responsive to immunosuppression. Cold antibody type \200\224mostly IgM \200 Very rare in children except PCH (see Paroxysmal cold haemoglobinuria). RBC antibody reacts most actively <32 haemolysis. Idiopathic or secondary to EBV or Acrocyanosis in cold, sple nomegaly. Chronic haemolytic anemia, DCT \200\223ve for IgG, +ve for C3. IgM autoantibodie s react best at 4 C to cause intravascular RBC \200 \200 \200 Mycoplasma infection. C. Treatment Treatment rarely needed. Warmth, immunosuppression, plasma exchange, and splen ectomy may help. Usually, the condition is self-limiting if there is an infectious cause. Paroxysmal cold haemoglobinuria (PCH) s \200 \200 \200 \200 to infections (varicella, measles, syphilis) and vaccinations. Acute onset of intravascular haemolysis, after fever and chills. Due to a biphasic antibody, called Donath Landsteiner antibody. Antibody \201 xes on the cells in the cold peripheries and lyses in the central warmth of the body \200\224protect from cold. Transfuse as required. Condition is self lim iting. 17_McClure_17.indd 624 11/14/2012 3:50:14 PM RED BLOOD CELL FRAGMENTATION 625 Red blood cell fragmentation Causes \200 Microangiopathic haemolytic anaemias (MAHA): includes \200\224HUS, TTP, giant capillary hae mangioma (Kasabach Merritt syndrome), and DIC. Infection: fever- intravascular haemolysis), viral haemorrhagic fevers, Clostridium perfringens. Burns. Mechanical: Hereditary acanthoc ytosis: abetalipoproteinaemia with mental retardation, ataxia, retinitis pigmentosa, and st eatorrhoea. Envenomation from several of the worlds venomous snakes, spiders, etc. e.g. meningococcal, pneumococcal, malaria (black water \200 \200 e.g. prosthetic heart valves, March haemoglobinuria. rare genetic condition of Clinical features Depend on underlying cause and severity of anemia. Laboratory investigations \200 \200 d. Hb Blood \201 lm: shistocytes, irregularly contracted cells, microspherocytes, acantho cytes. Possible platelets In malaria, visible parasites on thick/thin blood \201 lm. reticulocytes, nucleated RBC ii, RBC fragmentation, \200 d or clotting prolongation with consumption. Treatment \200 \200 Treat underlying disease. Correct hematological abnormalities, e.g. blood +/ \200\223 plate let transfusion, fresh frozen plasma to correct clotting abnormalities. Give iron or folate supplements if required. 17_McClure_17.indd 625 11/14/2012 3:50:14 PM CHAPTER 17 Hematology 626 Aplastic anemia Due to severe bone marrow suppression of RBC, WBC and platelet pre- cursors (pancytopaenia). Rare. May be acquired or congenital. Acquired aplastic anemia Causes Idiopathic is most common. Rarely, s to radiotherapy, chemo therapy, idiosyncratic reaction to drugs or chemicals (chloramphenicol, carbamazepine, phen ytoin, NSAIDs, mesalazine, several solvents), viral (hepatitis A, B, C; CMV; EBV; parvoviru s \200\224more common in adults). Note: Bone marrow invasion, e.g. malignant cells, osteope trosis, displaces normal marrow; causes pancytopenia, not aplastic anemia. Presentation Features of pancytopenia \200 \200 due to dd RBC production. Anemia: particularly bacterial and fungal. Due to WCC dd, particu larly Infection: if neutrophils <0.5 \227 109/L (severe aplastic anemia, SAA), <0.2 \227 109/L (very severe aplastic anemia, VSAA). Mucosal bleeding, purpura, and bruising. Due to platelet count dd. Investigations \200 \200 \200 WBCd, platelets < 20 \227 109/L, reticulocytes < 20 \227 109/L. FBC: Bone marrow aspirate and trephine: aplasia (marrow cellularity <25%). CD55/CD59 immuno phenotyping to exclude PNH (see Paroxysmal nocturnal haemoglobinuria (PNH)). Cytogenetics a nd chromosomal breakage studies to detect myelo- dysplastic syndrome (MDS), Fanconi \200 \231s anemia or dyskeratosis congenita. Treatment \200 \200 \200 \200 Remove or treat underlying cause, e.g. drugs. Depending on severity: RBC +/ \200\223 platel et transfusion. Bone marrow transplant (BMT) may be curative. Immunosuppression, e.g. rabbi t anti-thymocyte globulin followed by ciclosporin is best second line therapy for those wit h no BMT donor. Prognosis Depends on underlying cause. Some patients recover sponta- neously. Most will pro gress to more severe disease, PNH or leukemia. Long-term survival is unlikely in severe dis ease without good response to immunosuppressive therapy or BMT. Paroxysmal nocturnal haemoglobinuria (PNH) \200 Rare, acquired clonal disorder of marrow cells de \201 cient in glycosylphosphatidylinosit ol (GPI) anchors that protect against complement lysis. Usually associated with background aplasia, allowing PNH clone a positive selective advantage. Complement lysis leads to chron ic haemolytic anemia, with intermittent haemoglobinuria but persistent haemosidinuria. Urin e is Hb +ve. High risk of recurrent and fatal venous thrombosis e.g. Budd Chiari, venous th rombosis, cerebral sagittal sinus. FBC: Bone marrow is hypoplastic with erythropoietic isla nds. Flow cytometry detects CD55 and CD59 de \201 cient cells. \200 \200 i reticulocytes, d WBC, and d platelets 17_McClure_17.indd 626 11/14/2012 3:50:14 PM APLASTIC anemia 627