Haematological disease in a child (haemophilia, idiopathic thrombocytopenic purpura, iron-deficiency anaemia, sickle cell, thalassaemia) Flashcards
What is the chance of inheritance of haemophilia in a male child from a mother who is a carrier and a father who has haemophilia?
50% - father’s genetics do not play a part here as it is X linked-recessive.
In which female patients can haemophilia occur?
Turner’s syndrome (XO) affected due to having only one X chromosome. NB: Turner’s syndrome is a female only disease.
What clotting abnormalities does liver impairment e.g. in viral hepatitis cause?
Viral hepatitis e.g. due to A-E, CMV, EBV, parvovirus.
Reduced production of vitamin K essential for some clotting factors (II, VII, IX, X) which prolongs INR if there is deficiency
Which bloods should be done to investigate the cause of bruising? What are the findings in haemophilia A?
- APTT
- Blood film
- FBC
- INR
APTT is elevated with a normal INR, bleeding time and platelet count in haemophilia A
What is the clotting abnormality in ITP?
P is characterised by isolated thrombocytopenia, often with less than 10×10/9 platelets. Other cell lines are usually unaffected.
What may cause a pancytopaenia in a child?
acute leukaemia
What is Christmas diseaese? How common is it compared to haemophilia A?
Haemophilia B (factor IX deficiency - gives same results as in haemophilia A)
6 times less common
What clotting abnormalities can be caused by meningococcal septicaemia?
DIC
Which factor is reduced in haemophilia A?
Factor VIII
What are the complications of haemophilia?
- Haemarthroses - spontaneous or following trauma, must educate about head injury in particular. Can lead to…
- chronic arthropathy of knees, hips and elbows
- compartment syndrome if bleed into muscles
- haematuria with risk of blood clots causing renal colic
- Infections - hepatitis B and other blood-borne viruses
What lifestyle things should be avoided in haemophilia? How are immunisations given?
Avoid contact sports
Avoid NSAIDs as they affect platelet function
Immunisations - subcut rather than IM
List some of the main acquired disorders of coagulation affective children.
- Haemorrhagic disease of the newborn due to Vit K deficiency (required for synthesis of F II, VII, IX, X, and proteins S and C –> prolonged PT –> increased risk of bleeding)
- Liver disease
- ITP (immune thromocytopaenia)
- DIC (diseminated intravascular coagulation)
Define thrombocytopenia.
Platelet count <150 x109/L
What is mild, moderate and severe thrombocytopenia?
Mild - 50-150 x109/L
Moderate - 20-50 x109/L - risk of excess bleeding during operations of trauma but low risk of spontaneous bleeding
Severe - <20 x109/L - risk of spontaneous bleeding
What is a differential for purpura or easy bruising?
-
Increased platelet destruction or consumption
- Immune - ITP, SLE, alloimmune neonatal thrombocytopenia
- Non-immune - HUS, DIC, CHD, TTP, hypersplenism
-
Impaired platelet production
- Congenital - Faconi anaemia, other syndromes.
- Acquired - aplastic anaemia, marrow infiltration, drugs
-
Platelet dysfunction
- Congenital - rare e.g. Glanzmann thrombasthenia
- Acquired - uraemia, cardiopulmonary bypass
-
Vascular disorders
- Congenital - Ehlers-Danlos, Marfan, hereditary haemorrhagic telangiectasia
- Acquired - severe infections e.g. meningococcal, vasculitis (Henoch-Schonleinm SLE), scurvy
NB: 1+2 = platelet count reduced/thrombocytopenia, 3+4 = platelet count normal
What is the most common cause of thrombocytopenia in childhood? What is the underlying cause?
ITP - has an incidence of 4 per 100,000 per year
There is destruction of platelets by IgG autoantibodies - megakaryocytes may be increased in bone marrow in response.
What are the antibodies in ITP directed against?
Against the glycoprotein IIb/IIIa or Ib-V-IX complex.
What is a common trigger of ITP in children? Which sex is most affected?
- it is typically more acute than in adults
- equal sex incidence
- may follow an infection or vaccination
What are the clinical features of ITP?
Most present between age 2-10 years
Within 1-2 weeks after a viral infection
Usually lasts days or weeks
- Petechiae and purpura
- +/- superficial bruising
- Epistaxis and mucosal bleeding is uncommon despite platelets often <10 x 109/L
How is ITP diagnosed? What if ITP is found in a very young child?
- Anti-platelet autoantibodies (IgG)
- +/- BM aspiration showing megakaryocytes - should be done before starting steroids to rule out leukaemia only. If thrombocytopenia is isolated then no need for BM biopsy.
- ITP is a diagnosis of exclusion.*
- In very young children suspect congenital causes such as Wiskott-Aldrich or Bernard-Soulier syndromes.*
- In anaemia, neutropenia, hepatosplenomegaly, lymphadenopathy a BM examination should be done to exclude leukaemia or aplastic anaemia.*
Why should BM examination be done before treating children with ITP with steroids?
Treeatment with steroids could temporarily mask ALL (which can mimick ITP), and reduce the chance of early treatment and cure.
What is the management of acute ITP?
In 80% of children it is acute, benign and self limiting within 6-8 weeks.
Treatment given only if there is evidence of major bleeding (e.g. GI or intracranial) or persistent minor bleeding (e.g. epistaxis or menstrual)
- Oral prednisolone (80% of patients respond)
- IV anti-D or IV immunoglobulins
- Platelet transfusions reserved for life-threatening haemorrhage
Avoid trauma and contact sports.
What is chornic ITP? How common is it? What are the principles of management?
- Affects 20% of children with ITP
- Lasts >6 months
- Treatment mostly supportive but specialist help includes rituximab (anti B cells), thrombopoietic growth factors, splenectomy (if all else fails, but this requires lifelong abx and increased risk of infection). Screen for SLE in chronic ITP as it may develop.
What is the diagnosis and management?
Sian, aged 5 years, developed bruising and a skin rash over 24 hours. She had had an upper respiratory tract infection the previous week. On examination she appeared well but had a purpuric skin rash with some bruises on the trunk and legs (Fig. 23.17). There were three blood blisters on her tongue and buccal mucosa, but no fundal haemorrhages, lymphadenopathy, or hepatosplenomegaly. Urine was normal on dipsticks testing. A full blood count showed Hb 115 g/L with In children with immune thrombocytopenic purpura, in spite of impressive cutaneous manifestations and extremely low platelet count, the outlook is good and most will remit quickly without any intervention normal indices, WBC and differential normal, platelet count 17 × 109/L. The platelets on the blood film were large; the film was otherwise normal.
- ITP
- Parents educated and given emergency numbers - told to avoid contact sports, trauma but to continue attending school.
Over the next 2 weeks she continued to develop bruising and purpura but was asymptomatic. By the third week, she had no new bruises, and her platelet count was 25 × 109/L; the blood count and film showed no new abnormalities. The following week, the platelet count was 74 × 109/L and a week later it was 200 × 109/L. She was discharged from follow-up.
What is the prognosis with ITP?
Good overall and most remit without intervention
How is DIC differentiated from warfarin, hepatin and aspirin treatment?
What are the causes of DIC?
- Severe sepsis or shock due to circulatory collapse e.g. in meningococcal septicaemia
- Trauma or burns
- Malignancy
What is the pathophysiology of DIC?
DIC is a disorder characterised by coagulation pathway activation leading to diffuse fibrin deposition in the microvasculture and consumption of coagulation factors and platelets.
A critical mediator of DIC is tissue factor (TF) which is a transmembrane glycoportein usually present on the surface of many cells and only released in response to vascular damage e.g. after exposure to cytokines, TNF, endotoxin.
Upon activation, TF binds coagulation factors which triggers the extrinsic pathway (via F VII) which then triggers the intrinsic pathway (XII to XI to IX).
TF is abundant in lungs, brain and placenta which is why DIC often develops in extensive trauma.
How is DIC diagnosed?
FBC, clotting profile - low plt, low fibrinogen, high PT and APTT, high fibrinogen degradation products, high D-dimer, low anticoagulants (protein S/C and antithrombin)
Blood film - schistocytes due to microangiopathic haemolytic anaemia
What are the clinical features of DIC?
- Bruising
- Purpura
- Haemorrhage
- Purpura fulminans (skin necrosis) may also occur due to microvascular thrombosis
What is the management of DIC?
Treat underlying cause e.g. sepsis + provide intensive care
- FFP - replace clotting factors
- Cryopreciptate
- Platelets
- Antithrombin and protein C may be used in severe meningococcal septicaemia with purpura fulminans. Use of heparin is controversial.
What is anaemia defined as in:
- neonate
- 1month-12 months
- 1 year -12 years
- neonate - Hb <140g/L
- 1month-12 months - Hb<100g/L
- 1 year -12 years - Hb<110g/L
What 3 mechanisms cause anaemia?
- reduced red cell production – either due to ineffective erythropoiesis (e.g. iron deficiency, the most common cause of anaemia) or due to red cell aplasia
- increased red cell destruction (haemolysis)
- blood loss – relatively uncommon cause in children
Which mechanisms of anaemia are present in anaemia of prematurity?
Combination of all three mechanisms may be present
How does Hb concntration and type change over first 2 months of life?
HbF is replaced by HbA and HbA2 during infancy
Concentration is high at >140g/L at birth and falls to lowest level at 2 months
What are the causes of anaemia in children due to impaired RBC production?
- ‘Ineffective erythropoiesis’: RBC production occurs at a normal or increased rate but differentiation and survival of the red cells is defective e.g. iron deficiency, folic acid deficiency, chronic inflammation (JIA), CKD and others
- Complete absence of red cell production (red cell aplasia). e.g. parvovirus B19, Faconi anaemia, leukaemia
How is ineffective erythropoiesis diagnosed?
- Normal reticulocyte count
- Abnormal MCV e.g. low in Fe def anaemia, high in folic acid deficiency
What are the main causes of Fe deficiency anaemia? What is a common cause in infantc?
- Inadequate intake
- Malabsorption
- Blood loss.
Iron deficiency may develop because of a delay in the introduction of mixed feeding beyond 6 months of age or to a diet with insufficient iron-rich foods, especially if it contains a large amount of cow’s milk. Iron absorption is markedly increased when eaten with food rich in vitamin C (fresh fruit and vegetables) and is inhibited by tannin in tea.
What is the Fe requirement of a 1yr old infant? How does this compare to adults?
Increased Fe is needed to keep up with growth: 1yr old requires almost same intake of iron as an adult male (8mg/day) but half of mother’s req (15mg/day)
What are the sources of iron for infants? How does the iron content compare?
- breastmilk (low iron content but 50% of the iron is absorbed)
- infant formula (supplemented with adequate amounts of iron)
- cow’s milk (higher iron content than breastmilk but only 10% is absorbed)
- solids introduced at weaning, e.g. cereals (cereals are supplemented with iron but only 1% is absorbed)
Why should infants not be fed unmodified cow’s milk?
It has low iron content which is very poorly absorbed
What are the clinical features of iron deficiency anaemia?
- Asymptomatic until Hb drops below 60-70g/L
- Tire easily
- Infants feed slowly
- Pallor - confirm by looking at conjunctivaea, tongue, palmar creases
- ‘Pica’ - inappropriate eating of non-food materials such as soil, chalk, gravel, or foam rubber
- Fe def may be detrimental to behaviour and intellectual function*
- Ask about blood loss and symptoms/signs of malabsorption.*
What are good dietary sources of iron for children? What foods should be avoided in excess in toddlers to prevent Fe deficiency anaemia?
Case history: Iron deficiency anaemia Ayesha, aged 2 years, was noted to look pale when she attended her general practitioner for an upper respiratory tract infection. A blood count showed Hb 50.0 g/L, MCV 54 fl (normal 72–85 fl) and MCH 16 pg (normal 24–39 pg). She was drinking three pints of cow’s milk per day and was a very fussy eater, refusing meat. She had started eating soil when playing in the garden. Because of the inappropriately large volume of milk she was drinking, she was not sufficiently hungry to eat solid food. Replacing some of the milk with iron-rich food and treatment with oral iron produced a rise in the Hb to 75 g/L within 4 weeks. Her pica (eating nonfood materials) stopped. Oral iron was continued until her Hb had been normal for 3 months.
How is Fe deficiency anaemia diagnosed?
- Microcytic, hypochromic anaemia (low MCV and MCH)
- Low serum ferritin.
What are differentials for microcytic aanemia other than Fe deficiency?
The other main causes of microcytic anaemia are:
- β-thalassaemia trait (usually children of Asian, Arabic, or Mediterranean origin)
- Anaemia of chronic disease (e.g. due to chronic kidney disease).
Children with α-thalassaemia trait (usually children of African or Far Eastern origin) also have a microcytic/ hypochromic blood picture but most of these children are not anaemic.
What is the management of Fe deficiency anaemia?
Dietary advice
Supplementation of oral iron -
- Sytron (sodium iron edetate) or Niferex (polysaccharide iron complex) do not stain the teeth.
- Continue until normal Hb achieved + further 3 months to replenish stores.
- Should rise 10g/L per week in good complicance otherwise non-compliant or malabsorption (e.g. Coeliac or Meckel diverticulum)
Blood transfusion should never have to be necessary for dietary iron deficiency
What might be an early indicator of iron deficiency when Hb is normal?
Ferritin may be low before Hb falls but treatment here is controversial as oral iron is very toxic and can cause poisoning.
How common is sickle cell disease in the UK?
Affects 1 in 2000 live births in UK
Most common inherited disorder affecting children in many European countries
What is the pathophysiology of SCD?
Autosomal recessive inheritance of HbS causing haemoglobinopathy
HbS forms due to point mutation in codon 6 of the beta-globin gene –> change in the aa from glutamine to valine
What are the 3 main forms of SCD?
Sickle cell anaemia (HbSS) - homozygous for HbS i.e. virtually all Hb is HbS with small amount of HbF and _no HbA (_bc both beta-globin genes mutated)
HbSC disease (HbSC) - HbS inherited from one parent and HbC from the other
Sickle beta-thalassaemia - HbS inherited from one parent and beta-thalassaemia trait from the other. Normal beta-globin genes. Usually do not make HbA so similar symptoms to sickle cell anaemia
What is the inheritance pattern of SCD?
Autosomal recessive
What is the pathogenesis of SCD?
HbS polymerises within RBC –> rigid tubular spiral bodies –> RBC deformed into sickle cell shape
Sickling is irreversible and these RBC can then become trapped in microcirculation –> vaso-occlusion –> ischeamia of organ or bone
HbSS is the most severe form but severity can vary with amount of HbF i.e. higher means less severe SCD
When do patients with SCD usually present? How?
3-6 months of age when the HbF levels are falling
Anaemia, jaundice, pallor, lethargy, growth restriction and general weakness
Splenomegaly may be present in infancy
What are the main clinical manifestations of SCD?
Anaemia - Hb usually 60-100g/L from chronic haemolysis. Acute anaemia may occur due to haemolytic crisis, aplastic crisis or sequestration crisis.
Infection - especially encapsulated organisms such as pneumococci and H. influenzae; osteomyelitis by Salmonella etc; risk of sepsis
Painful crises - aka vaso-occlusive crises, commonly presents in infancy with hand-foot syndrome where there is dactylitis with swelling of fingers +/- feet. Bones of limbs and spine are also common sites.
Priapism - requires immediate exchange transfusion to prevent fibrosis of corpora cavernose and subsequent erectile impotence
Splenomegaly - common in young children only
What is the cause of increased infection especially by encapsulated organisms in SCD?
Due to hyposplenisms from chronic sickling and microinfarction of the spleen in infancy
What factors preipitate vaso-occlusive crises in SCD? Which organs/body parts can be affected?
Precipitants: cold exposure, dehydration, excessive exercise, stress, hypoxia, infection
- Hand-foot syndome - commonly presents in infancy with dactylitis and swelling of the hands +/- feet
- Bones of the limbs and spine
- Avascular necrosis of the femoral head
- Acute chest syndrome - most serious type of painful crisis; can require mechanical ventilation and emergency transfusion
What are the long term complications of SCD?
Short stature and delayed puberty
Stroke and cognitive problems - 1 in 10 children have a stroke, but twice as many have subtle manifestations too, often shown as poor school performance and concentration
Adenotonsillar hypertrophy - cause sleep apnoea leading to nocturnal hypoxaemia which may precipitate crisis
Cardiac enlargement and heart failure- from chronic uncorrected anaemia
Renal dysfunction - may exacerbate enuresis bc unable to concentrate urine
Pigment gallstones - due to increased bile pigment production
Leg ulcers - uncommon in children
Psychosocial problems - time off school may worsen education and behavioural problems
What 3 events may cause acute anaemia in SCD?
Haemolytic crisis - sometimes associated with infection
Aplastic crisis - Hb may fall precipitously; parvovirus causes complete though temporary cessation of RBC production
Sequestration crisis - sudden splenic/hepatic enlargement, abdominal pain and circulatory collapse from accumulation of sickled cells in sleep
What prophylaxictic treatments are provided in SCD patients? What should be avoided?
Immunisation - against encapsulated organisms like S. pneumoniae and H. influenzae type B and meningococci.
Daily oral penicillin - given throughout childhood to cover all pneumococcal subgroups
Folic acid - given once daily due to increased demand for folic acid from chronic haemolytic anaemia
Avoid exposure to cold, dehydration, excessive exercise, undue stress, hypoxia. So dress children warmly and give drinks especially before exercise.
How are acute crises treated?
- Analgesia oral or IV - may require opiates
- Hydration oral or IV
- +/- Antibiotics - in presence of infection
- +/- Oxygen - if saturation reduced
- +/- Exchange transfusion - if stroke, acute chest syndrome or priapism
How do you manage the chronic problems present in SCD?
- Blood transfusions - may be required for severe anaemia or to reduce HbS if there are lung or CNS complications. Partial exchange transfusions may be required in acute situations. But iron chelation therapy needs to be started alongside regular transfusions.
- Hydroxycarbamide (hydroxyurea) - considered in recurrent hospital admissions for painful crises or acute chest syndrome. This increases HbF production but requires monitoring for WCC suppression.
- BM transplant - in severe cases unresponsive to hydroxycarbamide. Only possible if there is a HLA-identical sibling who can donate . 90% cure rate but 5% risk of fatal transplant-related complications.
What is the prognosis with SCD?
50% of patients with the most severe disease die before age 40
Mortality rate during childhood is 3% from bacterial infection
How is SCD diagnosed in the UK?
Guthrie test
Can also be detected by prenatal testing via chorionic villus sampling at the end of the first trimester if parents wish
Princess, a 9-year-old girl with known sickle cell anaemia (HbSS), presented with increasing chest pain for 6 hours. She had a nonproductive cough. On examination, she had a fever of 39.7° C. Her breathing was laboured, respiratory rate increased and there was reduced air entry at both bases.
Investigations
- Haemoglobin 60 g/L, white blood cells (WBC) 14 × 109/L, platelets 350 × 109/L
- Chest X-ray
- Oxygen saturation – 89% in air
- Arterial PO2 – 9.3 kPa (70 mmHg) breathing face-mask oxygen
- Blood cultures were taken and viral titres performed
What is the diagnosis? What is the management?
A diagnosis of acute sickle chest syndrome was made, a potentially fatal condition. She was given oxygen by continuous positive airways pressure (CPAP). An exchange transfusion was performed. Broadspectrum antibiotics were commenced.
She responded well to treatment.
What is a common complication in HbSC?
Usually have a normal Hb and few painful crises than HbSS but may develop proliferative retinopathy in adolescence so their eyes should be checked periodically
Also at risk of osteonecrosis of the hips and shoulders
Why do patients with sickle trait need to be screened before surgery as a precaution?
To ensure that additional effort to prevent hypoxia is made since sickling is theoretically possible is carriers are exposed to low oxygen tension
What is the phenotype of sickle cell trait?
60% HbA and 40% HbS
Laboratory tests normal with no anaemia
Protects from malaria
Which groups are most affected by SCD?
Black patients from tropical Africa or the Caribbean but also found in the Middle East and some northern Europeans
What investigations are used to diagnose SCD?
FBC and blood film - anaemia with sickled erythrocytes and features of hyposplenism
Hb analysis by electrophoresis - ALWAYS needed to confirm the diagnosis (should show no HbA, 80-95% HbSS and 2-20% HbF)
Sickle solubility test - mixture of HbS in a reducing solution such as sodium dithionite gives a turbid appearance because of precipitation of HbS, whereas normal haemoglobin gives a clear solution.
Other: renal function tests, LFTs, lung function and routine monitoring. If acute then abdo US, CT head ect may be required.
Which groups are most affected by beta-thal?
- Indian subcontinent
- Mediterranean
- Middle East
- Greek in the past but reduced now due to genetic counselling
What are the types of beta-thalassaemia? What does severity depend on?
Beta-thal major - most severe, HbA (alpha2beta2) cannot be produced due to abnormal beta-globin gene
Beta-thal intermedia - milder and variable severity. Beta-globin mutation still allows a small amount of HbA or large amount of HbF to be produced.
Both characterised by severe reduction in production of beta-globin (and thereby HbA production). Severuty depends on amount of residual HbA and HbF production.
What are the clinical features of beta-thalassaemia?
Severe anaemia - from 3-6 months which is transfusion dependent and often also presents with jaundice
Faltering growth/growth failure
Extramedullary haemopoiesis - prevented by regular blood transfusions
Hepatosplenomegaly and BM expansion - in absence of regular blood transfusion; latter causes maxillary overgrowth and skull bossing
How is beta-thalassaemia managed?
B-thalassaemia major is fatal without regular blood transfusions - aim to maintain Hb above 100g/L; prevents growth failure and bone deformation
Iron chelation with subcutaneous desferrioxamine or oral desferasirox - starting at 2-3 years of age.
BM transplantation - curative but only reserved for children with a HLA-identical sibling as there is then a 90-95% chance of success (i.e. transfusion indepenence and long-term cure) but 5% chance of mortality
What are the complications of iron overload if left untreated?
- Cardiac - cardiomyopathy
- Liver - cirrhosis
- Pancreas - diabetes
- Skin - hyperpigmentation
- Pituitary gland - impaired growth and sexual maturation
- Growth failure
- Infertility
Apart from iron overload, what are the other complications of long-term blood transfusion in children?
Iron deposition - most important
Antibody formation (10% affected) - allo-antibodies are made to the transfused red cells in the patient which can make finding a compatible donor difficult.
Infection (now uncommon, <10% affected) - hepatitis A, B, C, HIV, malaria, prions (e.g. new variant CJD)
Venous access (common problem) - often traumatic in young children, central venous access devixe may be required but predisposes to infection (Portacath)
What is the prognosis of beta-thalassaemia?
If treated and comply well then >90% chance of living into 40s and beyond
But compliance is difficult and those who do not comply have high mortality in early adulthood from iron overload
When is prenatal testing for beta-thalassaemia offered? How is it diagnosed in the newborn?
Screening is not routine - offerred if both parents are heterozygous for beta-thalassaemia trait (and so there is 25% chance of having affected child). Done by DN analysis of chorionic villus sampling and offered alongside genetic counseling.
Not formally tested for in the Guthrie test but should be picked up anyway. Beta-thalassaemia will however, not be picked up.
What is the phenotype of beta-thalassaemia trait?
- Heterozygotes are asymptomatic in most cases
- RBC are hypochromic and microcytic
- Anaemia may be mild or absent but MCH and MCV will be reduced to about 18-22fl and 60-70fl respectively
- Usually have a raised HbA2 (~5%) which is diagnostic and in half there is HbF elevation (1-3%)
What is the main difference in bloods between beta-thalassaemia trait and iron deficiency? Why is this important?
Serum ferritin is low in Fe deficiency but not in beta-thalassaemia trait. So ferritin should always be measured in microcytic anaemia.
Knowing this prevents unnecessary iron therapy
What are the genetics of alpha-thalassaemia? Briefly describe the different types.
Healthy person has 4 alpha-globin genes. Manifestation of alpha-thalassaemia syndromes depends on the number of functional alpha-globin genes
-
Deletion of all 4 alpha-globin genes
- = Alpha-thalassaemia major / Hb Barts hydrops fetalis
- Presents in midtrimester with fetal hydrops (oedema and ascites) from fetal anaemia
- Fatal in utero or within hours of delivery - unless intrauterine transfusions given.
- No HbA can be produced (alpha2beta2)
- Diagnosed by HPLC or Hb electrophoresis
-
Deletion of 3 of the alpha globin genes
- = HbH diease
- Mild-moderate anaemia but sometimes transfusion dependent
-
Deletion of 1 or 2 alpha-globin genes
- Alpha-thalassaemia trait
- Usually asymptomatic with mild or absent anaemia
- RBC may be hypochromic and microcytic
- May be confused with iron deficiency anaemia
