17 Haematology

Anaemia 610

Haemolytic anaemias 612

Deficiency anaemias 614

Red blood count membrane defect anaemias 616

Red blood count enzyme defect anaemias 618

Sickle cell disease 620

Thalassaemia 622

Immune haemolytic anaemia 624

Red blood cell fragmentation 625

Aplastic anaemia 626

Failure of red cell production (pure red cell aplasia) 628

Polycythaemia 630

Abnormal bleeding or bruising 632

Coagulation studies 634

Disseminated intravascular coagulation 635

Haemophilia A 636

Haemophilia B 637

von Willebrand disease 638

Platelet function disorders 640

Thrombocytosis 641

Thrombocytopenia 642

Acute immune thrombocytopenia 643

Thrombophilia 644

Blood transfusion 646

Blood transfusion reactions 648

Pallor.

Poor feeding, anorexia.

Poor growth.

Dyspnoea on exertion.

Rarely stomatitis or koilonychia.

Diet (cow’s milk, vegan).

Overt blood loss.

Duration of symptoms.

Drug history, e.g. NSAIDs.

Dysmorphic features, e.g. micrognathia, cleft palate, abnormal/absent thumbs (Fanconi’s anaemia, Diamond–Blackfan anaemia).

Jaundice (haemolysis).

Adenopathy/organomegaly (underlying malignancy).

RBC: spherocytes, sickle cells, Howell Jolly bodies.

Other cytopenias.

Possible precipitating factors: e.g. infection, medications, foods such as fava beans in G6PD deficiency.

Ancestry: e.g. African, Mediterranean, or Arabic ancestry is suggestive of G6PD deficiency in boys.

Family history: e.g. gallstones in spherocytosis.

Platelet count: thrombocytopenia with normal clotting suggests HUS, thrombotic thrombocytopenic purpura (TTP); with abnormal clotting suggests DIC.

Pancytopenia: consider viral infection, malignancy, hypersplenism.

Abnormal blood film: e.g. spherocytes or other RBC abnormalities, malaria parasites, features of RBC fragmentation (schistocytes, burr cells).

Lactate dehydrogenase: raised activity = increased RBC production.

Free plasma Hb, haemoglobinuria, haemosiderin in urine (all increased in intravascular haemolysis).

Coombs antiglobulin test to establish if there is immune or non-immune haemolysis. Positive direct Coombs test (DCT) = antibodies on RBC surface. Positive indirect Coombs test = antibodies in serum.

If DCT +ve, screen 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- specific reagents suggest warm and cold antibody autoimmune haemolysis respectively.

IgM for mycoplasma; CMV; EBV; rubella; for cold antibody autoimmune haemolysis.

Hb electrophoresis for sickle cell anaemia, thalassaemias, unstable Hbs, e.g. Hb Koln.

Flow cytometry for hereditary spherocytosis.

RBC enzyme assays for RBC enzyme defects, e.g G6PD.

If history suggestive, immunophenotyping (CD55 + CD59) for paroxysmal nocturnal haemoglobinuria (PNH).

After exclusive breastfeeding >6mths, delayed introduction of iron-containing solids, excessive cow’s milk (protein enteropathy);

Adolescent females (growth spurt and menstruation);

Low iron-containing diet due to poverty, fad diets, or strict vegans.

Infancy and early childhood: low level of dietary iron, e.g. high milk intake (low iron), GI blood loss, e.g. cow’s milk protein enteropathy.

↑ Demand due to rapid growth: e.g. following prematurity or puberty.

Malabsorption: e.g. coeliac disease, IBD.

Rarely blood loss: e.g. Meckel’s diverticulum, oesophagitis. Bleeding may be occult into cysts, tumours or s to drugs, e.g. NSAIDs.

Intestinal parasites: e.g. hookworm (in less developed world).

Pallor, lethargy, poor feeding, breathlessness (only in severe anaemia).

May also develop symptoms associated with iron deficiency, including neurological effects of listlessness and irritability (infants), mood changes, reduced cognitive and psychomotor performance (can occur at levels of mild/moderate deficiency before anaemia develops), and rarely, pica (eating unusual items, e.g. soil, chewing on pencils).

Blood film: microcytic, hypochromic anaemia.

Serum ferritin ↓ (indicative of iron stores): it may be low before anaemia. Check C-reactive protein, as ferritin may be falsely raised due to acute phase reaction (↓ serum iron and ↑ total iron binding capacity (TIBC) confirms iron deficiency).

Encourage iron-containing diet, e.g. iron fortified formulas and breakfast cereals, meat, green vegetables, beans, egg yolk, foods rich in vitamin C (↑ iron absorption).

Avoid prolonged cow’s milk consumption to detriment of solids intake.

Malabsorption, e.g. coeliac disease, IBD, other small intestinal disease;

Increased requirements, e.g. rapid growth, chronic haemolytic anaemias (give daily folic acid prophylactically), hypermetabolic states (infection, hyperthyroidism), severe skin disease.

Drugs, e.g. phenytoin, valproate, trimethoprim, nitrofurantoin.

Disorders of folate metabolism: Lesch–Nyhan syndrome; orotic aciduria.

In severe cases, subacute combined degeneration of cord (rare in children): paraesthesia of hands/feet, ataxic gait, loss of vibration sense.

WBC ↓, hypersegmented neutrophils, platelets ↓, bilirubin ↑.

↓ Serum B₁₂ or ↓ folate level (red cell folate level is more reliable than serum folate, which reflects recent intake).

Bone marrow, if indicated, shows megaloblastic appearance.

Rarely, intrinsic factor autoantibodies or test of B₁₂ absorption, e.g. Schilling test.

Folate deficiency: daily oral folic acid (500micrograms/kg). Response is prompt (within few days).

Various RBC membrane skeletal defects occur; commonest involves ankyrin (˜50–60%).

Mild to moderate anaemia in compensated cases. Anaemia can be severe with transfusion requirement.

Splenomegaly is usually present.

Infection exacerbates haemolysis with worsening jaundice.

Aplastic (red cell) crisis can occur with parvovirus B19 infection. The severity of anaemia depends on degree of baseline haemolysis (worst in those with high reticulocyte counts due to sudden decompensation).

Folate deficiency can occur with massively increased RBC turnover so oral supplementation with 5mg/day folic acid should be given routinely.

Laboratory investigation includes: ↑ reticulocytes, ⇈ spherocytes on blood film; 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 −ve (excludes autoimmune causes).

In the past the osmotic fragility was performed, but now diagnosis can be made on clinical and basic haematological features of indices, reticulocytes and blood film. Diagnosis in difficult cases can be made by flow cytometry, but is expensive and usually not clinically warranted.

Provide supportive treatment, e.g. folic acid supplementation, blood transfusion if anaemia severe during aplastic crises.

Ideally, if splenectomy is indicated it is best performed after 5yrs of age but before puberty. Consider if:

Splenectomy requires pre-operative vaccination against pneumococcus, Haemophilus influenza type B (HiB) and meningococcus C, as well as post-operative 5-yearly boosters, annual influenza vaccination, lifelong penicillin V prophylaxis (250mg bd from 5yrs until adolescence, then 500mg bd).

Endemic in Mediterranean, South-East Asia, West Africa, and Middle East.

There are over 400 enzyme variants. African (A–) (10–60% enzyme activity) and Mediterranean (3% activity) are most clinically relevant.

RBC G6PD levels fall rapidly as cells age, with impaired elimination of oxidants and reduced cell integrity.

Intermittent acute haemolytic episodes (intravascular haemolysis) are associated with febrile infections (most common), oxidant drugs (antimalarials, sulphonamides, dapsone, aspirin, phenacetin, ciprofloxacin), foods (fava beans), chemicals (naphthalene - common in moth balls, henna).

May present as neonatal jaundice or chronic haemolytic anaemia.

During haemolysis, findings of RBC destruction (bite cells and Hb puddling (ghost cells)), increased RBC production (raised reticulocyte count), spherocytes and Heinz bodies on blood film, DCT −ve.

Definitive diagnosis is by measuring reduced G6PD enzyme activity (may be falsely normal during acute haemolysis; repeat 6wks later).

Blood transfusion if symptomatic anaemia.

Support of aplastic crisis, e.g. blood transfusion.

Splenectomy in severe cases.

Found in Caribbean, Africa, Middle East, Mediterranean, and India. In Jamaica, carrier rate is 10%, with disease (HbSS) in 1 in 300 births. HbC carriers represent 3.5% of Jamaicans. Heterozygous carriers of HbS have increased resistance to malaria, accounting for the high gene prevalence in malarial regions. In England SCD now occurs in more than 1 in 2000 live births.

Young children: infection from encapsulated organisms (if not vaccinated and on penicillin V prophylaxis) and parvovirus, vaso-occlusive crises in long bones, upper airway obstruction, stroke.

Older children: vaso-occlusive crises, avascular necrosis and stroke.

Risk of pneumococcal sepsis greatest in the first 3yrs of life.

Acute 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 treatment essential.

Sequestration: body organs trap sickled RBCs. Splenic sequestration is more common in first year; later liver and lung sequestration occurs. Rapid fall in Hb may be fatal. Recurrent episodes warrant splenectomy.

Stroke: most common in 5–10-yr-olds, and by 20yrs up to 20% will have had silent stroke. Untreated, mortality is 20%; recurrence rate is 70% within 3yrs. Requires prompt treatment with exchange transfusion to reduce HbS <20%. All UK children over the age of 2yrs require an annual transcranial Doppler: those with high velocity flow should start serial exchange transfusion to prevent stroke.

Infections: patients are functionally hyposplenic by 1yr, resulting in high risk of infection from Pneumococcus, Meningococcus, Haemophilus Inf. B. Ensure vaccination is up to date and give penicillin V prophylaxis.

Aplastic crises: typically after infection with parvovirus B19. Reticulocytes and consequently Hb falls. Spontaneous recovery usually occurs in 10 days. The patient may require transfusion.

Priapism: affects 3–5% of pre- and 30–40% of post-pubertal boys. May be acute fulminant (painful, lasting >3hr) or minor ‘stuttering’ 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: hip joint, humerus or any bone.

Renal impairment: hyposthenuria (urine concentration defect) with high urine output and susceptibility to dehydration. Enuresis is common. Papillary necrosis causes haematuria. Chronic renal failure can occur later.

Retinopathy: small vessel occlusion → neovascularization → vitreous haemorrhage → resorption → fibrous strands → retinal detachment. More common in HbSC disease. Surveillance needed. Treat with photocoagulation (see  p.920).

ENT problems: adenotonsillar hypertrophy is common and may lead to nocturnal hypoxia precipitating crises. Ask about ‘snoring’.

Leg ulcers: uncommon in childhood.

Growth and development: generally delayed although final height is usually normal. Specific SCD growth charts exist.

Clinical suspicion: required in unscreened population

Haematology: Hb 5–9g/dL, reticulocytes ↑, sickle cells on blood film. Hb electrophoresis (HPLC) is definitive test.

Routine screening of Afro-Caribbean children prior to anaesthesia.

Prenatal diagnosis: may be performed on fetal red cells or fibroblasts.

Hydration: aim for 150% normal maintenance (oral or IV).

Analgesia: titrate to severity of pain. Initially treat at home with simple analgesia, e.g. paracetamol, NSAIDs; give opiates if required.

Antibiotics: broad spectrum cephalosporin, after blood culture if fever >38°C. Add a macrolide if atypical pneumonia.

Oxygen: to maintain arterial oxygen saturation (SaO₂) >95%. Keep warm.

Blood: transfusion for aplastic crisis, sequestration, or anaemia; exchange transfusion for sequestration, chest syndrome, or stroke.

Vaccination: see  p.728.

Lifetime oral penicillin V prophylaxis.

Daily oral folic acid.

Hydroxycarbamide (hydroxyurea): may reduce crises and need for blood. A rise in MCV shows compliance and myelosuppression is most common adverse effect. Use in patients with moderate to severe disease.

Bone marrow transplantation: if successful is curative.

HbA (α₂β₂) is comprised of two A globin chains that are encoded by two A-globin genes on each chomosome 16 (i.e. each cell has 4 A-globin genes), designated as (αα/αα).

The two β globin chains are encoded by only one β-globin gene on each chromosome 11, designated (β/β).

HbF has 2 α globin chains combined with 2 γ (αα/γγ). HbA₂ has 2 α chains combined with 2 δ chains (ααδ).

There are various forms of thalassaemia, e.g. β thalassaemia (β chains are not produced), A thalassaemia, δ-β thalassaemia.

Thalassaemia genes can be null mutants, which make no globin chains, e.g. β^o or α^o, or can make minimal amounts of globin chains, e.g. β⁺, or α⁺.

Thalassaemia major describes the homozygous disease state, e.g. (β^o/β^o)

Thalassaemia minor (also called thalassaemia trait) describes carriers (heterozygotes) of either β^o or β⁺ genes or α^o or α⁺ genes.

Thalassaemia intermedia describes the spectrum of phenotypes between major and minor (i.e. 3 α gene deletion causes HbH disease, or a β⁺ mutation with another β⁺ mutation.

α-thalassaemia trait (αα/−−) or (α−/α−): Two α gene deletion. Asymptomatic with hypochromic microcytic picture (Hb may be ↓, MCV ↓, MCH ↓). May mimic iron deficiency, if RBC >5.0 x 10¹²/L with microcytic, hypochromic film, then thalassaemia trait more likely.

Hb H disease (α−/−−): Three α gene deletion or equivalent. Variable chronic anaemia with mild hepatosplenomegaly and jaundice. Hypochromic anaemia with target cells and reticulocytes ↑. HbH inclusions (tetramers of β globin) are seen on special staining. Folic acid supplements required, and occasionally transfusions. Splenectomy may be beneficial.

Hb Bart’s hydrops fetalis (−−/−−). Four α gene deletion. Causes hydrops fetalis leading to stillbirth or early neonatal death. Hb analysis shows mainly Hb Bart’s (G4). Most often seen in South-East Asia where frequency of (αα/−−) carriers is high.

Asymptomatic with mild Hb ↓, MCV ↓, MCH ↓.

HbA₂ characteristically ↑ on Hb electrophoresis to > 3.5%.

No treatment required, but important to detect for genetic counselling purposes, especially if partner also has haemoglobinopathy.

Severe anaemia (3–9g/dL); markedly ↓ MCV and MCH, ↑ reticulocytes, target cells, and nucleated RBCs.

Secondary growth 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.

Iron overload is major problem, with haemosiderosis affecting the heart, liver, endocrine organs, and pancreas.

Chelation of iron starts when ferritin level >1000micrograms/L (usually following 10–20 transfusions). Desferrioxamine by SC infusion 5–7 nights per week. Side-effects include: cataracts, hearing loss, Yersinia gut infections. Alternatively, in children over 6yrs give desferiserox (a new oral iron chelator). Start at dose of 20mg/kg/day and monitor renal function.

Splenectomy may help if massive splenomegaly or increased transfusion requirements.

Bone 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 patients with no end organ damage. The procedure carries significant risks.

ABO incompatability.

Other blood group incompatibilities, e.g. Kell, Duffy, blood groups.

Majority are idiopathic.

Other causes: drugs (e.g. penicillin), lymphoid malignancies, autoimmune diseases (e.g. SLE, IBD).

Variable haemolytic anaemia, mild jaundice, splenomegaly, DCT +ve.

Warm autoantibodies—often non-specific.

RBC antibody reacts most actively <32°C to cause intravascular RBC haemolysis.

Idiopathic or secondary to EBV or Mycoplasma infection.

Acrocyanosis in cold, splenomegaly.

Chronic haemolytic anaemia, DCT −ve for IgG, +ve for C3.

IgM autoantibodies react best at 4°C.

Acute onset of intravascular haemolysis, after fever and chills.

Due to a biphasic antibody, called Donath Landsteiner antibody.

Antibody fixes on the cells in the cold peripheries and lyses in the central warmth of the body—protect from cold.

Transfuse as required. Condition is self limiting.

Infection: e.g. meningococcal, pneumococcal, malaria (black water fever- intravascular haemolysis), viral haemorrhagic fevers, Clostridium perfringens.

Burns.

Mechanical: e.g. prosthetic heart valves, March haemoglobinuria.

Hereditary acanthocytosis: rare genetic condition of abetalipoproteinaemia with mental retardation, ataxia, retinitis pigmentosa, and steatorrhoea.

Envenomation from several of the worlds venomous snakes, spiders, etc.

Blood film: reticulocytes, nucleated RBC ⇈, RBC fragmentation, shistocytes, irregularly contracted cells, microspherocytes, acanthocytes.

Possible platelets ↓ or clotting prolongation with consumption.

In malaria, visible parasites on thick/thin blood film.

Correct haematological abnormalities, e.g. blood +/− platelet transfusion, fresh frozen plasma to correct clotting abnormalities.

Give iron or folate supplements if required.

Infection: particularly bacterial and fungal. Due to WCC ⇊, particularly if neutrophils <0.5 × 10⁹/L (severe aplastic anaemia, SAA), <0.2 × 10⁹/L (very severe aplastic anaemia, VSAA).

Mucosal bleeding, purpura, and bruising. Due to platelet count ⇊.

Bone marrow aspirate and trephine: aplasia (marrow cellularity <25%).

CD55/CD59 immunophenotyping to exclude PNH (see Paroxysmal nocturnal haemoglobinuria (PNH)).

Cytogenetics and chromosomal breakage studies to detect myelodysplastic syndrome (MDS), Fanconi’s anaemia or dyskeratosis congenita.

Depending on severity: RBC +/− platelet transfusion.

Bone marrow transplant (BMT) may be curative.

Immunosuppression, e.g. rabbit anti-thymocyte globulin followed by ciclosporin is best second line therapy for those with no BMT donor.

Usually associated with background aplasia, allowing PNH clone a positive selective advantage.

Complement lysis leads to chronic haemolytic anaemia, with intermittent haemoglobinuria but persistent haemosidinuria. Urine is Hb +ve.

High risk of recurrent and fatal venous thrombosis e.g. Budd Chiari, venous thrombosis, cerebral sagittal sinus.

FBC: ↑ reticulocytes, ↓ WBC, and ↓ platelets

Bone marrow is hypoplastic with erythropoietic islands.

Flow cytometry detects CD55 and CD59 deficient cells.

Usually presents with bruising and purpura or insidious onset anaemia.

Associations: short stature (80%); skin hyperpigmentation (café au lait spots, 75%); skeletal abnormalities, particularly upper limb and thumb (66%); renal malformations (30%); microcephaly (40%); cryptorchism (20%); mental retardation (17%); deafness (7%); abnormal facies.

Bone marrow: hypoplastic, dyserythropoietic, or megaloblastic changes.

Chemically-induced cell culture lymphocyte chromosomal breakages.

Investigate to detect renal abnormalities or hearing loss.

Most of the 12 FA genes have been cloned and can be screened for in families where the mutation is known. Diagnosis is essential as standard BMT conditioning is fatal and appropriate modifications are essential.

Immunosuppression with corticosteroids and androgens (oxymetholone).

Successful BMT curative for haematological defects but problems post BMT as FA is a constitutional and multi-organ disorder.

Diamond–Blackfan syndrome.

Drugs.

Viral, e.g. parvovirus B19.

Isoimmune haemolytic disease in newborn, e.g. anti-Kell.

Congenital dyserthropoietic anaemia (CDSs).

Megaloblastic anaemia (aplastic phase).

Thumb abnormalities in 10–20%; triphalangeal thumbs; absent radii.

Deafness.

Renal defects (>50%).

CHD.

Musculoskeletal defects.

Short stature and growth retardation.

Monitor FBC to ensure this is not a leukaemic prodrome.

Blood transfusion if required.

Commonest in the newborn: exists when venous or arterial Hct >65%.

Polycythaemia-hyperviscosity syndrome is diagnosed in infants when Hct > 65–75% and usually requires partial exchange to reduce to ˜55%.

Very rare in childhood, but seen in teenagers with early onset myeloproliferative disorders, which should be suspected if Hct is raised > 3–4 SD above age specific mean.

Platelet deficiency or dysfunction: presents as purpura, petechia, mucosal bleeding e.g. recurrent epistaxis, menorrhagia, or GI or GU tract haemorrhage

Microvascular abnormalities: palpable purpura suggestive of vasculitis, i.e. not a haematological cause

History of recent trauma.

Concurrent disease.

Age, e.g. haemorrhagic disease of the newborn several days after birth.

Any maternal disease (if newborn), including maternal ITP.

Diet.

Drug history.

Family history.

Hepatosplenomegaly, suggests haemolysis or hypersplenism.

Dysmorphic signs: e.g. absent radius in thrombocytopenia-absent radius (TAR) syndrome.

Signs of anaemia: e.g. prolonged blood loss, bone marrow failure syndrome.

Pattern of purpura or bruising: e.g. extensor and lower limb pattern of HSP.

Palpable purpura in vasculitis: e.g. HSP.

Associated features: e.g. arthritis (HSP), albinism (Hermansky-Pudlack syndrome), haemangioma (Kasabach–Merritt syndrome), eczema (Wiskott–Aldrich syndrome).

Depending on presentation also consider: fibrinogen, TT (presence of heparin).

If clotting screen abnormal, i.e. prolonged, perform a 50:50 mix to exclude an inhibitor, and if suggestive request lupus anticoagulant screen and anti-cardiolipin antibody screen. If 50:50 mix suggests a coagulation factor deficiency, then request factor assays according to whether PT, APTT or both prolonged.

If clotting screen is normal perform:

Correct known coagulation or platelet abnormalities if required.

If there is catastrophic bleeding without diagnosis, treat with blood, FFP (20mL/kg) ± platelets (10–20mL/kg) as indicated until the precise defect is known.

Avoid IM injections, arterial puncture, and NSAIDs.

If the patient is a young male bleeding post circumcision then usually diagnosis is haemophilia, or, rarely, some other clotting factor deficiency.

Important to involve haematologist and blood bank early in presentation to get appropriate expert help.

PT or INR (monitoring warfarin therapy): assesses ‘extrinsic’ pathway.

Thrombin time (TT): only used to differentiate between heparin contamination, dysfibrinogenaemia and DIC. This test is not used routinely and needs to be requested specifically.

Serum fibrinogen: useful if DIC or haemophagocytic lymphohistiocytosis (HLH) is suspected.

PFA: In vitro test of platelet function. This test is easy to perform provided the platelet count >100 × 10⁹/L. Ranges in children have been produced.

Bleeding time: tests platelet function. Now virtually obsolete.

Fibrin degradation products (FDPs): Components released into the blood following clot degradation. Levels rise after any thrombotic event. Can be used to test for DIC. The most notable subtype of FDPs is D-dimer.

D-dimer: principally used to screen adults for thrombotic disorders, e.g. deep vein thrombosis (DVT). Rarely used in children except possibly to help monitor management of DIC (possibly along with FDPs). Note: DIC is a clinical diagnosis and is not made my measuring D-dimers or FDPs.

Other specific tests include screening tests of coagulation inhibitor, e.g. lupus anticoagulant, or individual clotting factor level.

Activation of intravascular thrombosis with both macro- and microthrombi formation leading to end-organ damage.

Widespread activation of fibrinolysis leading to further bleeding.

Microangiopatic haemolytic anaemia (‘RBCs destroyed in fibrin mesh’).

Less common: severe IUGR, RDS, aspiration pneumonitis, NEC, rhesus isoimmunization, dead twin, severe haemorrhage, purpura fulminans, profound hypothermia.

Less common: profound shock, hepatic failure, anaphylaxis, severe blood transfusion reactions.

Oozing and bleeding from venepuncture sites, wounds, mucosal membranes, GI, pulmonary, and GU tracts.

Microthrombi causing renal impairment, cerebral dysfunction, localized skin necrosis.

Acute RDS (ARDS).

Microangiopathic haemolytic anaemia.

Supportive care: O₂, volume replacement for shock, blood transfusion.

Platelet transfusion: if uncontrolled bleeding, or pre-procedure, but not for oozing. Indiscriminant use of platelets can ‘fuel the fire’ and cause more thrombosis.

Coagulation factor replacement as required to control bleeding, e.g. fresh frozen plasma (FFP), cryoprecipitate if fibrinogen <500mg/L.

Exchange transfusion may be beneficial, e.g. sepsis, rhesus isoimmunization, or polycythaemia (removes causative toxins or antibodies, and replaces clotting factors).

Use of heparin is controversial, but may be needed if there is large thrombi or significant organ damage from microthrombi. Seek expert advice from a paediatric haematologist.

<1% activity = severe disease, with ‘spontaneous’ haemathroses, significant bleeding if cut, mucosal bleeds, and lumpy (pea-sized) bruises as infants. Most require prophylaxis with FVIII concentrate (see Management, p.636).

2–5% = moderate disease. Bleeding rarely occurs, and tends to involve muscles and soft tissues, secondary to trauma. Requires FVIII concentrate when bleeding occurs but no prophylaxis.

5–20% = mild disease. Rarely bleed. May present after surgery or trauma. Prophylaxis with DDAVP or FVIII concentrates for surgery.

Easy bruising. In younger children often get pea-sized lumpy bruises.

Bleeding into joints (haemarthroses): knees > ankles > elbows > hips > wrists. The joint is painful, swollen, tender, warm, with severe limitation of movement, +/− unable to weight bear. Uncontrolled recurrent bleeding can lead to degenerative joint disease.

IM bleeds: can be difficult to differentiate between muscle strain and bleed. May lead to compartment syndrome, nerve compression, or ischaemic contracture.

Intracranial bleeds: may be extradural, subdural, or intracerebral. Usually follows minor head trauma. All patients should seek medical attention, and those with severe disease need immediate FVIII.

Perform cranial CT scan if any suspicion of intracranial bleed.

US scans are useful for possible joint bleeds and muscle haematomas.

Major bleeds: treat with recombinant FVIII product except in those with FVIII inhibitors. The dose depends on bleeding site, child’s weight and serum half life of FVIII (usually ˜10hr). In those with severe disease on prophylactic therapy, regular screens are made to assess exactly how much FVIII is required to treat a joint or a major bleed. The dose for joint bleed aims to get FVIII to 40–50%, whilst for head injury to 100%, i.e. treat intracranial bleeds with twice the dose used for a joint bleed.

Major surgery: preparation with a haematologist to plan timing and dose of factor. Give analgesia as required, but not NSAIDs (↓ platelet function).

Minor surgery or persistent bleeds: IV, SC, or intranasal DDAVP in those with moderate/mild haemophilia may suffice.

Mouth bleeding: tranexamic acid suspension/tablets (20–25mg/kg tds).

Avoid IM injections: including vitamin K at birth, if disease suspected (give IV). All vaccinations should be given subcutaneously.

Educate family: about PRICE guidelines for supportive care of a bleed: Pressure dressing, Ice (bag of frozen peas), Rest (non-weight bearing), Compress (cold if possible), Elevation of limb.

Daily physiotherapy: following a bleed is important to avoid muscle weakness or contractures once joint bleeding has resolved.

Home FVIII treatment: parents, and in due course the boys themselves, should be trained to give IV FVIII concentrates. Central venous ‘ports’ are only used when peripheral access is deemed impossible.

Transmission of hepatitis B, hepatitis C, HIV: now rare since virally inactivated plasma concentrates and recombinant FVIII concentrate is given. All children should be vaccinated against hepatitis B.

FVIII inhibitor development: is suggested by bleeds not responding to treatment. Measure FVIII inhibitor titre. Difficult to treat but most are started on immune tolerance induction with high dose FVIII. Acute bleeds are treated with increased FVIII dose or other products, e.g. rFVIIa or FEIBA.

Incidence ˜1:5000.

M = F.

Type II: autosomal dominant or recessive. 25% of cases. Mild–moderate severity. In Type IIb there is usually thrombocytopenia.

Type III: autosomal recessive. Almost complete absence of vWF. <5% cases. Severe.

Minor bleeding may respond to local pressure or tranexamic acid (locally with mouthwash or systemically 20–25mg/kg tds for ˜4–5 days).

More significant bleeds or minor surgery may respond to DDAVP (avoid if type IIB as further reduces platelet count).

Severe bleeding or severe disease requires virally-inactivated plasma-derived factor VIII concentrate combined with vWD factor (no recombinant product currently available). Manage as for severe haemophilia A.

All have autosomal recessive inheritance.

The most common defects are those of fibrinogen (e.g. dysfibrinogenaemia or hypofibrinogenaemia) and specific deficiency of factors VII, II prothrombin, V, XI, XIII, and X. Factor XII deficiency results in prolonged APTT, but no bleeding tendency.

Coagulation factor deficiencies secondary to liver disease.

DIC (see  p.635).

Defective or deficient platelet granules (normal release induces coagulation cascade, vasoconstriction, platelet aggregation), e.g. TAR syndrome, Chediak–Higashi syndrome.

Mucocutaneous bleeding.

Menorrhagia.

Positive family history is common (although in most AR syndromes both parents are unaffected).

↑ Platelet size, e.g. giant platelets in BSS.

Prolonged PFA.

If congenital platelet functional disorder suspected, perform PFA followed by formal platelet aggregation studies using ristocetin, collagen, adenosine 5-diphosphate (ADP), arachidonic acid, and adrenaline; and platelet nucelotide ratios. Interpretation is complex, so seek haematologist help.

Correct underlying abnormality or stop responsible drug.

Give tranexamic acid for minor bleeding, e.g. mouth washes or systemically 20–25mg/kg tds for < 5 days.

Give platelet transfusion if bleeding severe or to cover for surgery. Note: Need to give HLA matched platelets to avoid HLA specific anti-platelet antibody formation, if child likely to need frequent transfusions.

Avoid drugs that inhibit platelet function, e.g. NSAIDs and IM injections.

Consider oral contraceptives in teenage girls to control menorrhagia.

Acute or chronic haemorrhage.

Trauma or surgery.

Kawasaki’s disease.

Iron deficiency anaemia.

Certain malignancies, e.g. Wilm’s tumour.

Any inflammatory disease, e.g. ulcerative colitis.

Primary myeloproliferative disorder, e.g. essential thrombocytheaemia (ET) or in association with chronic myeloid leukaemia (CML).

CRP/ESR: ↑ in inflammatory/malignant conditions.

Bone marrow aspirate only ever indicated if primary myeloproliferative disorder (MPD) such as essential thrombocytheaemia is suspected (which is very rare).

Watch and wait in reactive cases, as requires no treatment.

Give aspirin in Kawasaki’s disease (one of the few indications for aspirin in children).

Marrow failure: aplastic anaemia, Fanconi’s syndrome, severe IUGR, severe maternal pre-eclampsia, neonatal sepsis.

Marrow infiltration: leukaemia, neuroblastoma, osteopetrosis.

Marrow depression: radiotherapy, cytotoxic drugs, drug reaction.

Hereditary: Wiskott–Aldrich syndrome (X-linked recessive: boys present with early thrombocytopenia, eczema, and immunocompromise due to immunoglobulin abnormalities), BSS, TAR syndrome.

Nutritional deficiency: vitamin B₁₂ or folate deficiency.

Non-immune: DIC, giant haemangioma (Kasabach–Merritt syndrome), HUS, cardiac disease (prosthetic valves or cardiopulmonary bypass).

Hypersplenism: platelets pool in enlarged spleen from whatever cause—effect is dilutional, rather than destructive.

Examination: signs of bleeding, lymphadenopathy, hepatosplenomegaly, concurrent infection.

FBC and blood film.

Serology: anti-platelet antibodies (e.g. anti-HPA1) if NAIT suspected, autoimmune antibodies in those with chronic ITP, viral serology (CMV, EBV along with monospot if infectious mononucelosis suspected, or HIV if unusual unexplained thrombocytopenia).

Bone marrow aspirate and trephine: very rarely required in cases of unexplained thrombocytopenia.

Cranial CT scan: if any evidence of possible intracerebral haemorrhage.

Platelet transfusion if very low platelet count (prophylactically, and guided by haematologists, except for ITP) or life-threatening bleeding.

Splenectomy, e.g chronic ITP, hypersplenism.

Bone marrow transplant may be helpful in some inherited bone marrow failure syndromes.

60% have preceding viral infection, e.g. upper respiratory tract infection (URTI).

Bruising, purpura, petechiae, mucosal bleeding, menorrhagia.

Intracranial bleeds very rare (< 0.5%); often associated with trauma.

Physical examination otherwise usually normal, e.g. no splenomegaly.

Testing for platelet antibodies is not clinically useful.

Bone marrow in ITP normal, but striking increase in megakaryocytes.

Moderate bleeding can be controlled with tranexamic acid 20–25mg/kg tds for <5 days, provided haematuria is not present.

Active treatment is required if patient experiencing significant bleeding, mucosal haemorrhage, or haematuria, as all are associated with increased risk of internal bleeding.

First line therapy: 4mg/kg prednisolone for 4 days and then stop.

Second line therapy: IV IgG 1g/kg over 2 days if steroids not effective, alternatively can use anti-D antibody (if patient Rh+).

If bleeding life-threatening or intracranial, give 15–20mL^/kg of platelets, start prednisolone and IV IgG and consider emergency splenectomy.

Splenectomy for chronic ITP is indicated if disease is not steroid responsive and child over 5yrs.

For chronic severe ITP, rituximab has been used successfully in young children. Exclude other underlying immunedysregulatory or lymphoproliferative disorders such as X-linked lymphoproliferative (XLP).

Educate parents regarding ITP, including signs and symptoms that should prompt immediate return to hospital.

Child can carry on with normal activities, but should avoid contact sports and NSAIDs when platelet count is low.

Most inherited thrombophilias are asymptomatic or present in adult life. In children, most present in the newborn period or following thrombogenic events (trauma, surgery or pregnancy).

Newborns requiring intensive support often have multiple thrombotic risk factors including sepsis, dehydration, polycythaemia, and central vascular lines.

Inherited thrombophilia should be considered when there is an unexplained arterial or venous thrombosis, neonatal venous thrombosis, or positive family history.

Use of central lines;

Takayasu’s arteritis;

Kawasaki disease;

PNH;

Polycythaemia;

SLE, anti-phopholipid antibody;

s to development of anti-protein S antibodies post-Varicella zoster virus (VZV) infection; can cause (as with congential deficiency) necrotic skin bruises.

ESR/CRP (infection or inflammation).

LFTs (protein C and S, and prothrombin are vitamin K-dependent factors).

Standard coagulation screen.

Thrombophilia ‘screen’. Under guidance by your local laboratory, this usually includes APC resistance, with FVL, prothrombin G20210A variant testing, as well as protein C, protein S, antithrombin III, and homocystine levels.

Recurrent thrombosis: treatment depends on severity, presentation, coagulation defect, and risk factors. Long-term anticoagulation with warfarin may be appropriate (aim for INR of 3–4).

Major vessel or catheter-related thrombosis: can be treated with fibrinolytic agents, e.g. tissue plasminogen activator (TPA), urokinase.

Prophylaxis: give SC heparin during surgery or trauma in patients with established prothrombotic defects and a positive personal history. Alternatively, antithrombin III or protein C concentrate may be given if relevant.

Platelet concentrate volume: if child’s weight <15kg give 10–20mL/kg; if ≥15kg, single apheresis unit/standard ‘pool’ of 4U.

20% albumin is indicated to correct significant hypoproteinaemia.

Emergency therapy of non-specific coagulation failure.

To correct coagulation deficiencies where no specific concentrate available.

Volume is: 1U/10kg (= 5mL/kg), or if child weighs 15–30kg give 5U (1U = 1 bag), over 30kg give 10U.

Rarely, prophylaxis following infectious contact in immunocompromised, e.g. CMV, hepatitis A, measles, chicken pox;

Immunomodulation, e.g. ITP, neonatal alloimmune thrombocytopenia;

Specific IgGs also available, e.g. ZIG for prevention of potentially life-threatening chickenpox in immunocompromised children with no immunity.

Neonates and infants up to 1yr.

CMV seronegative recipients of allogeneic BMT ( since the introduction of universal leucocyte depletion of red cell products this is probably now unnecessary!).

Patients undergoing stem cell harvest for autografts (a week before until 3–6mths afterwards).

Patients undergoing allogenic haemopoietic stem cell transplant (a week before and indefinitely thereafter).

Patients with suspected and confirmed Hodgkin lymphoma.

Patients receiving purine analogues such as fludarabine, clofaribine, etc., indefinitely.

DiGeorge syndrome and other congenital T cell immunodeficiencies. Granulocyte transfusion.

New indications are for patients being treated for aplastic anaemia with ALG and cyclosporine.

Agitation, flushing, chest/abdominal/flank pain.

Fever, hypotension, haemoglobinaemia, haemoglobinuria, renal failure.

Keep IV line open with saline.

Monitor vital signs and urine output.

Recheck patient and blood unit ID number.

Give supportive care. Watch for hypotension, respiratory and renal failure.

Inform the blood bank.

Hepatitis C: 1 in 100 million.

HIV: 1 in 5 million.

Malaria: 0.5 in 1 million (US data only).

Bacterial infection: 2 in 1 million for RBC, higher for platelet transfusion (up to 1 in 2000).

Variant Creutzfeldt-Jakob disease (CJD): unknown (4 cases reported in UK up to 2010 in patients receiving non-leucocyte-depleted blood between 1996–1999).