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Flashcards in Haematological Disorders Deck (139):

When is HbF very low in healthy children - when is it not?

By age 1
Increased proportions of HbF are indicators of severe inherited disorders of haemoglobin production - haemoglobinopathies


Hb at birth

14-21.5g/dl to compensate for low oxygen concentration in fetus


What happens to Hb after birth

Falls over first few weeks of life, mainly due to reduced red cell production, to 10g/dl at 2 months of age


What happens to Hb after birth in pre-term babies?

It has a steaper fall to a mean of 6.5-9g/dl at 4-8 weeks chronological age


What are the iron, B12 and folic acid stores like in term and preterm infants at birth and after birth?

Iron, B12 and folic acid are adequate at birth in term and preterm babies
However in preterm babies stores of iron and folic acid are lower and are depleted more quickly leading to deficiency after 2-4months if recommended daily intakes are not maintained by supplements


Anaemia value in neonate

Hb less than 14g/dl


Anaemia value in 1-12months old

Hb less than 10g/dl


Anaemia value in 1-12 years

Hb less than 11g/dl


What is red cell aplasia

Complete absence of red cell production


What is ineffective erythropoeisis?

Red cell production is normal/increased rate but differentiation or survival of red cells is defective


What are the main causes of iron deficiency anaemia x3

Inadequate intake (common in infants)
Blood loss


Which milk is not good for maintaining infant iron levels?

Cows milk because it has a higher iron content than breast milk but only 10% of the iron is absorbed
Therefore infants should not be fed unmodified cows milk


At what Hb level do children become symptomatic with anaemia?



How do children with iron deficiency anaemia present?

Pica- eating non-food materials such as soil, chalk, gravel or foam rubber


What are indicators on blood tests of iron deficiency anaemia

Microcytic, hypochromic anaemia (low MCV and MCH)
Low serum ferritin


Management of iron deficiency anaemia in infants?

Increase oral iron intake with supplementation - Sytron or Niferex are best tolerated preparations
Or just increase iron rich foods


What are the 3 main causes of red cell aplasia in children?

1) Diamond-Blackfan anaemia - congenital red cell aplasia
2) Transient erythroblastopenia of childhood
3) Parvovirus B19 infection in children with haemolytic anaemia


Diagnostic features of red cell aplasia x4

Low reticulocyte count despite normal Hb
Normal bilirubin
Negative direct antiglobulin/Coombs test
Absent red cell precursors on bone marrow examination


What is Diamond-Blackfan anaemia?

It is a rare congenital disease of red cell aplasia


Inheritance of Diamond-Blackfan anaemia

20% family history - remaining 80% are sporadic mutations
RPS (ribosomal protein) genes implicated in some cases


Presentation of Diamond-Blackfan anaemia

Most present at 2-3 months of age but 25% present at birth


Features of Diamond-Blackfan anaemia x2

Also congenital abnormalities such as short stature or abnormal thumbs


Treatment of Diamond-Blackfan anaemia x2

Oral steroids
Monthly red cell transfusions for children not responsive to steroids


What is transient erythoblastopenia of childhood?

Red cell aplasia usually triggered by viral infections
Same haemotological features as D-Blackfan anaemia


Prognosis of transient erythroblastopenia of childhood

Always recovers - usually within several weeks (hence differs from d-blackfan)


Inheritance of transient erythroblastopenia of childhood

No family history


When does haemolysis lead to anaemia?

When the bone marrow can no longer increase red cell production to compensate for the premature destruction of red cells


Main causes of haemolytic anaemias in children? What is uncommon children

Intrinsic abnormalities of RBCs (membrane and enzyme disorders and haemoglobinopathies)
Immune haemolysis is uncommon


What does haemolysis from increased RBC breakdown lead to? x4

Hepatomegaly and splenomegaly
Increased blood levels of unconjugated bilirubin
Increased urinary urobilinogen


Diagnostic clues to haemolytic anaemia x4

Increased reticulocyte count
Unconjugated bilirubinaemia and urinary urobilinogen
Abnormal appearance of red blood cells on film (spherocytes, sickle shaped or very hypochromic)
Increased red blood cell precursors in bone marrow


Incidence of hereditary spherocytosis

1 in 5000 live births in caucasians


Inheritance of hereditary spherocytosis

Usually autosomal dominant inheritance - BUT in 25% there is no family history and it is sporadic mutation


What is pathology of hereditary spherocytosis?

Mutation in gene for protein in red blood cell membrane - therefore RBC looses part of its membrane when it goes through the spleen
Therefore reduced surface-to-volume ratio and cell becomes spherical
Therefore less deformable than normal RBC and destruction of microvasculature of spleen


What are the clinical features of hereditary spherocytosis? x5

Clinical manifestations vary and patients can be completely asymptomatic or present during childhood or be intermittent - but can have:
- Jaundice
- Anaemia
- Mild-moderate splenomegaly
- Aplastic crisis with parvovirus B19
- Gallstones


Management of hereditary spherocytosis x2

Many have mild and therefore only require folic acid supplementation
Splenectomy is beneficial but only indicated if poor growth or troublesome symptoms - usually deferred until after 7 years old because of risk of sepsis


Management of aplastic crisis in hereditary spherocytosis

Usually requires 1 or 2 blood transfusions over 3-4 weeks whilst no red blood cells are produced


What is incidence of Glucose-6-phosphate dehydrogenase deficiency?

G6PD is commonest red cell enzymopathy - affects 100million people worldwide
10-20% of individuals from central africa, mediterranean and the middle east and far east


What is pathology of G6PD deficiency?

G6PD is an enzyme required to prevent oxidative damage to red cells - therefore red cells lacking the enzyme are susceptible to oxidant-induced haemolysis


Inheritance of G6PD deficiency?

It is x-linked therefore predominantly affects males. Heterozygous females are usually clinically normal and homozygous females (or one deletion + one mutation) will be affected


Clinical presentation of G6PD in children x2

1) Neonatal jaundice - onset in first 3 days of life - severe
2) Acute haemolysis precipitated by infection, certain drugs, fava beans (broad beans) and naphthalene (mothballs)


Details of haemolysis in G6PD - where does it occur and what does it cause x4

Mostly intravascular
Causes fever, malaise, passage of dark urine
Rapid fall in Hb


Diagnosis of G6PD

Between episodes almost all patients have a completely normal blood picture therefore diagnosis by looking at G6PD activity
During an episode G6PD may be misleadingly high due to increased reticulocyte production


Management of G6PD

Parents should be given advice about signs of acute haemolysis and provided with a list of what to avoid
Transfusions are rarely required even for acute episodes


When do B-thalassaemias present?

Delayed until after 6months of age when most of HbF (no B chains) has been replaced by HbA (with B chain)


Prevalence of sickle cell disease

1 in 2000 live births in UK


What does sickle cell disease encompass?

Sickle cell anaemia, sickle cell trait, HbSC disease and Sickle B-thalassaemia


What is HbSC disease?

One HbS and one HbC from other parent - HbC is point mutation in B-globin therefore also have no HbA


Features of sickle B-thalassaemia

Also have no normal B chains therefore no HbA and similar symptoms to sickle cell anaemia


Features of sickle cell trait?

About 40% HbS - do not have symptoms but are carriers and can pass on to children


Pathology of sickle

HbS polymerises forming stiff sickle shape with can get trapped in microcirculation - causing vaso-occlusion and therefore ischaemia
Exacerbated by low O2 tension, dehydration and cold


Clinical features of sickle x7

Anaemia (moderate 6-10g/dl)
Painful vaso-occlusive crises
Acute anaemia (eg. in crises)
Long term problems


Types of infection risk in sickle

Infection from encapsulated organisms such as pnemococci and haemophilus influenzae
Increased osteomyelitis by salmonella
Due to hyposplenism and microinfarction in spleen in infancy


When is sepsis risk greatest in sickle

In early childhood - post-spleen destruction in infancy


Where is most commonly affected in painful crises of sickle x2

Bones of limbs and spines
Chest most serious as leads to hypoxia


What can cause acute anaemia in sickle? x3

Haemolytic crises (sometimes associated with infections)
Aplastic crises (B19)
Sequestration crises (sudden splenic or hepatic enlargement due to accumulation of sickled cells in spleen)


What needs to be done if priaprism in sickle

Urgent treatment with exchange transfusion as may lead to fibrosis in corpora cavernosa and erectile impotence


What age is splenomegaly common in sickle?

Common in younger children but not older children


What are long-term problems for sickle?x 6

Stroke and cognitive problems
Adenotonsillar hypertrophy - causing sleep aponea syndrome
Cardiac enlargement, heart failure - from anaemia
Renal dysfunction
Pigment gallstones
Leg ulcers


Prophylaxis in sickle? x3

Fully immunised against pneumococcal, haem infl type B and meningococcus infections
Daily oral penicillin throughout childhood
Folic acid


Lifestyle managements in sickle

Avoid cold, dehydration, excessive exercise, undue stress or hypoxia


Treatment of acute sickle crisis x4

Oral or IV analgesia
Good hydration
Antibiotics for infection
Oxygen if O2 sats reduced


Which 3 acute sickle crisis require exchange transfusion in sickle?

Priaprism, acute chest crisis and stroke


Common painful presentation of sickle in childhood?

Hand-foot syndrome due to dacylitis causing swelling and pain in fingers and/or feet from vaso-occlusion


Management for children with recurrent sickle crises? x2

Hydroxyurea which increases HbF concentration
requires monitoring for white blood cell suppression

If this doesn't work then bone marrow transplant can be offered


Cure rate in sickle with bone marrow transplant

Cure rate is 90%
5% risk of fatal transplant-rated complications


How is sickle diagnosed early

Guthrie heelprick test at birth


SC disease difference from sickle anaemia x3

Have fewer painful crises but may develop proliferative retinopathy in adolescence - therefore check eyes periodically
Also prone to osteonecrosis of hips and shoulders


Where is B-thalassaemia common

Indian subcontinent, mediterranean and middle east


Two different types of b-thalassaemia?

Major and intermedia- intermedia is milder


Clinical features of b-thalassaemia x3

Severe anaemia - transfusion dependant from 3-6months of age
Failure to thrive/grow
Extramedullary haemopoiesis - prevented by transfusions but if no transfusions then hepatosplenomegaly and bone marrow expansion - classic facies with maxillary overgrowth and frontal bossing


Management of b-thalassaemia

Lifelong transfusions
Can lead to iron overload therefore iron chelation with desferrioxamine or deferasirox from age 2-3


Cure for b-thalassaemia

Bone marrow transplantation (90-95% success with HLA matched identical twin)


B-thalassaemia trait features x3

Usually asymptomatic
Hypochromic and microcytic red cells
Anaemia mild or absent


What happens in a-thalassaemia major

All four a-globin genes are deleted therefore hydrops fetalis - death in utero or within hours of birth
Can only survive with intrauterine transfusions and then lifelong


What happens in HbH disease - a-thalassaemia

Three a-globin chains deleted
Mild-moderate anaemia but occasionally they are transfusion dependant


Features of alpha-thalassaemia trait

1 or 2 chain deletions
Usually asymptomatic
Anaemia is mild or absent


What can b and a-thalassaemia traits be confused with?

Diagnostically they can be confused with mild iron deficiency


What is immune haemolytic anaemia of the newborn due to?

Antibodies against blood group antigens - most important are anti-D, anti-A or anti-B (ABO blood group)
Mother is always negative and baby is always positive therefore mother makes antibodies against baby's blood group


Diagnostic tool for immune haemolytic anaemia

Coombs test (direct anti-globulin) positive - only positive in antibody mediated anaemias


Which haemolytic anaemias commonly present in neonatal period

Mostly due to G6PD deficiency or hereditary spherocytosis
Haemoglobinopathies rarely present with clinical features in neonatal period (but are detected on Guthrie)


What is aplastic anaemia?

Bone marrow failure
- reduction or absence of all 3 main lineages in bone marrow


What does aplastic anaemia lead to?

Peripheral blood pancytopenia - reduction of all blood cell types


What causes aplastic anaemia?

Many are "idiopathic" because specific cause cannot be found
Some can be inherited
Some can be acquired (viruses eg. hepatitis, drugs or toxins)


Clinical presentation of aplastic anaemia? x3

Anaemia due to reduced RBC
Infection due to reduced WBC
Bruising and bleeding due to thrombocytopenia


What is Fanconi anaemia?

Most common inherited aplastic anaemia


Inheritance of Fanconi anaemia?

Autosomal recessive condition


Clinical features of Fanconi anaemia other than directly due to blood cells?

Majority of children also have congenital abnormalities including short stature, abnormal radii and thumbs, renal malformations and pigmented skin lesions


How does Fanconi anaemia present?

Can present either with signs of bone marrow failure (not usually until age 5-6) or congenital abnormalities


Management of Fanconi anaemia?

Bone marrow transplantation from healthy sibling because can progress to acute myeloid leukaemia


What is Shwachman-Diamond syndrome?

Rare bone marrow failure - autosomal recessive disorder


What features are present in Shwachman-Diamond syndrome? x3

Signs of bone marrow failure
Also pancreatic exocrine failure and skeletal abnormalities


Risk with Fanconi anaemia and Shwachman-Diamond syndrome?

Both can advance to acute leukaemia


What is a good way to establish if new onset bleeding disorder is acquired or inherited?

If previous surgical procedures or dental extractions were uncomplicated - suggests acquired


What sort of bleeding disorder is associated with mucous membrane bleeding and skin haemorrhage?

Platelet disorders or von Willebrand disease


What sort of bleeding disorder is associated with bleeding into muscles or joints?



What sort of disorder is associated with scarring and delayed haemorrhage

Disorders of connective tissue such as Marfans syndrome, osteogenesis or factor XIII deficiency


Clotting factors in neonate?

Levels of all (except FVIII and fibrinogen) are lower and preterm infants have even lower values - therefore have to compare with values for gestational age


How are haemophilia a and b inherited?

Both have x-linked recessive inheritance therefore only affect males


Deficiency in haemophilia a

FVIII deficiency


Deficiency in haemophilia b

FIX deficiency


Which haemophilia is more common

haemophilia a is a lot more common


Different types of both haemophilias

Disorder is graded as severe, moderate or mild


Features of severe haemophilia

Recurrent spontaneous bleeding into joints and muscles - leads to crippling arthritis if not properly treated
Present usually towards end of 1st year when starting to crawl and walk


How can haemophilia present if presents before crawling/walking age?

Can present in neonatal period (40%) with intracranial haemorrhage, bleeding post-circumcision or prolonged oozing from heel prick and venepuncture sites


Inheritance of severity of haemophilia?

Severity usually remains constant within a family


Acute management of haemophilia

Recombinant factor VIII or IX is given IV whenever there is acute bleeding
Usually raising level to 30% of normal is enough


When do factor levels need to be raised above 30% of normal in haemophilia?

Major surgery or life threatening bleeds - require raising to 100% and then maintained at 30-50% for 2 weeks to prevent secondary bleed


Prophylactic treatment for severe haemophilia a

Prophylactic FVIII - usually begins at age 2-3 years, given 2/3x per week


Prophylactic treatment of mild haemophilia a

Desmopressin may allow mild haemophilia a to be managed without blood products
Ineffective in haemophilia b


What is von Willebrand disease?

Quantitative or qualitative deficiency of vWF


What does vWF do? x2

Faciliates platelet adhesion to damaged endothelium
Acts as carrier protein for FVIII


Pathology of vWD?

Defective platelet plug formation and also deficient in FVIII


Inheritance of vWD?

Autosomal dominant


Presentation age of vWD?

Commonest subtype - type 1 (60-80%) usually fairly mild and often not diagnosed until puberty or adulthood


Clinical features of vWD? x3

Excessive, prolonged bleeding after surgery
Mucosal bleeding such as epistaxis and menorrhagia


Management of mild vWD?

Mild can often be managed with desmopressin


When do you need to be careful using desmopressin?

Need to be used with caution in children under 1 because can cause hyponatraemia due to water retention and may cause seizures if fluid intake is not strictly regulated


Treatment of more severe vWD?

Treated with plasma derived FVIII concentrate (recombinant does not contain vWF therefore no good)


What should be avoided in haemophilia and vWD patients? x3

IM injections, aspirin and NSAIDs


What is the definition of thrombocytopenia?

Platelet count below 150 x10-9/L


Definition and presentation of severe thrombocytopenia

Platelets below 20 x 10-9/l
Risk of spontaneous bleeding


Definition and presentation of moderate thrombocytopenia

Platelets 20-50
Risk of excess bleeding during operations or trauma but low risk of spontaneous bleeding


Definition and presentation of mild thrombocytopenia

Platelets 50-150
Low risk of bleeding unless there is a major operation or severe trauma


What can thrombocytopenia result in? x4

Bruising, petechiae, purpura, mucosal bleeding (nose, gums)


What is immune thrombocytopenia? (ITP)

Commonest cause of thrombocytopenia in childhood - caused by destruction of circulating platelets by antiplatelet IgG autoantibodies


Typical presentation of ITP and age

Present between ages of 2 and 10 with onset often 1-2 weeks after viral infection


Clinical features of ITP x5

Most children have a short history of days/weeks of
Petechiae, purpura and/or superficial bleeding
Can also cause mucosal bleeding and epistaxis


Rare complication of ITP

Intracranial bleeding - rare but serious - mainly in those with a long period of severe thrombocytopenia


Diagnosis of ITP

Diagnosis of exclusion
Examine bone marrow to exclude aplastic anaemia or leukaemia


Management of ITP

80% of children have benign self-limiting disease - remitting within 6-8 weeks
But if persistent bleeding then oral prednisolone, IV anti-D or IV immunoglobulin
Platelet transfusions only for life-threatening haemorrhage


What is chronic ITP

20% in whom the platelet count remains low 6months after diagnosis


Management of chronic ITP

Supportive mostly
Drugs only for chronic bleeding
Monoclonal antibodies and other new drugs


What is disseminated intravascular coagulation? (DIC)

Disorder characterised by coagulation pathway activation leading to fibrin deposition in microvasculature and consumption of coag factors and platelets and therefore bleeding


Commonest causes of DIC x3

Severe sepsis or shock due to circulatory collapse (meningococcal septicaemia), or extensive tissue damage from trauma or burns


Clinical features of DIC x3

Bruising, purpura and haemorrhage


Management of DIC

Treat underlying cause whilst providing intensive care
Can give fresh frozen plasma, platelets and cryoprecipitate


EG's of prothrombotic disorders x4

Protein C and S deficiency
Antithrombin deficiency
Factor V Leiden


When do prothrombotic disorders present?

C and S heterozygotes - mostly in second or third decade and rarely in childhood
C and S homozygotes rare - thrombosis and widespread haemorrhage and purpura in neonatal period


Most common cause of thrombosis in children

95% of venous thromboembolic events in childhood are secondary to underlying disorder with hypercoagulable state