Haem + Cancer Flashcards
What is the general phenotypic rule for autosomal recessive vs dominant haematological disorders?
Recessive –> Metabolic defects
Dominant –> Structural defects
What is haemophilia? How is it inherited?
Deficiency of F8 (A) or F9 (B) - an intrinsic pathway defect. It is X linked recessive (therefore if females are affected, they likely have Turner’s disease)
How may haemophilia present?
Sx:
- Usually around 1yo (where walking and falling begins)
- Haemarthrosis (–> arthritis)
- Suspicions of NAI (if no FHx)
- Some present at neonatal age (40%) with intracranial haemorrhage, bleeding circumcision or prolonged bleeding from venepuncture/Vit K injection/umbilical cord separation
How can F8/9 deficiency severity be generally estimated?
Mild (>5%) F8/9 levels - bleeding after surgery
Moderate (1-5%) - bleeding after minor trauma
Severe (<1%) - spontaneous bleeding i.e. joints/muscles
How would you investigate suspected haemophilia?
Ix:
- Neonatal history (previous prolonged bleeding)
- FHx
- Clotting studies (PT/INR for extrinsic pathway which PT will be normal; and APTT for intrinsic pathway which will be PROLONGED)
- Platelet count (FBC) and factor 8 levels (F8 is low in vWD in addition to Haemophilia A)
How would you manage a child with haemophilia? What must you avoid and what are some complications?
MDT based (Haemophilia centres):
- Mild HA only -> Desmopressin (stimulates F8 and vWF release)
- Severe Haemophilia - prophylactic factor replacement via Hickman line (central venous line) which is done at home at 2-3yo, 2-3x/week -> raise baseline to >2%
IF actively bleeding - give infusion of F8/9 concentrate where you are raising to either 30% normal to treat minor bleeds or 100% normal and maintain at 30% for 2/52 to prevent secondary haemorrhage
AVOID - IM injections, aspirin and NSAIDs
complications = chronic arthropathy, compartment syndrome, haematuria, HBV (transfusion-related)
What is ITP and how does it present?
ITP = idiopathic thrombocytopenic purpura
- most common cause of thrombocytopenia in childhood
- presents between 2-6yo, often 1-2w POST-VIRAL infection
- caused by immune destruction of platelets by IgG autoantibodies
Sx:
- short history (days-weeks)
- petechiae, purpura rash
- superficial bruising
- may see epistaxis and other mucosal bleeding
- no systemic symptoms
How would you investigate suspected ITP?
Ix:
- FBC (exclude cancers e.g. ALL by checking no pancytopenia and only PLATELETS reduced)
- Blood smear
How would you manage ITP? [Acute vs Chronic]
Mx:
- 80% of children it is acute, benign and self limiting; resolves in 6-8w and are just OBSERVED - treatment only if evidence of major bleeding (e.g. intracranial) or persistent minor bleeding
Major bleeding (plts<20x10^9):
- IVIG + Corticosteroids +/- anti-RhD*
- ++ plt transfusion for life threatening haemorrhage (raises levels for a few hours)
*Anti-RhD coats the RBCs and is preferentially removed by the reticuloendothelial system instead of Ab-covered platelets thereby conserving plt levels
Chronic disease: (Plts low for 6/12 post-diagnosis) - Myocphenolate mofetil - Rituximab - Eltrombopag (thrombopoeitin agonist) - 2nd line is splenectomy
note: avoid NSAIDs/Aspirin
What are the main causes of IDA in infants/children? How may children with IDA present?
Causes:
- Malabsorption
- Blood loss
- Inadequate intake
Sx:
- Asymptomatic (until <60-70g/L)
- Feed slowly/tire quickly
- “Pica” - eating ice, dirt
What are some iron sources?
- Breast milk (low content but 50% absorbed)
- Infant formula
- Cow’s milk (high content but 10% absorbed)
- Solids introduced at weaning e.g. cereals
How would you Ix IDA?
Ix:
- FBC - low Hb
- Blood film - microcytic, hypochromic RBCs
- Low ferritin
- Reticulocytes (normal/high)
- Normal BR (raised in haemolysis)
How would you manage IDA?
Mx:
- Dietary advice -> green leafy veg, red meat, apricots/raisins, fortified cereals
- Oral ferrous sulphate 200mg TDS until normal Hb, then continue at least 3/12 after
- > recheck iron levels 2-4w after therapy (at 3w, Hb should rise 2g/100ml)
- > if normal, check at 2-4m; if not address compliance
- > advise that black stools are common and normal SE, but reduced by eating with food or reducing dose
State the causes of microcytic, normocytic and macrocytic anaemia?
Microcytic (TAILS):
- Thalassaemia
- Chronic disease (ACD)
- IDA
- Lead poisoning
- Sideroblastic anaemia (congenital)
Normocytic (MR I CALM):
- Marrow failure
- Renal failure
- Iron deficiency (early)
- Chronic disease (early)
- Acute blood loss, aplastic anaemia
- Leukaemia
- Myelofibrosis
Macrocytic (alcholics may have liver failure):
- Alcohol
- Myelodysplasia, MM
- Hypothyroidism, HA
- Liver failure
- Folate/B12 deficiency
How is the structure of haemoglobin controlled?
By chromosome 11 (beta, gamma and delta chains) and chromosome 16 (alpha and epsilon*)
HbA synthesis becomes predominant around 6m of life as HbF falls and HbA takes over.
Describe 2 haemoglobinopathies and how they are caused?
- Sickle cell disease
- defective beta global chain (point mutation at codon 6 in X11 - glutamine->valine)
- autosomal recessive
- RF = African/afro-caribbean descent
Phenotypes:
- BB^ = trait = reduced HbA and + HbS (mild anaemia)
- B^B^ = SCD = greatly reduced HbA and +++ HbS and raised HbF also
- B^cB^ = HbC disease = milder sickling than SCD with reduced HbA and + HbC - Thalassaemia
- B-thalassaemia is the reduced synthesis of beta globin chain
- autosomal recessive, manifesting after the first 3-6m of life after the decrease of HbF
Phenotypes:
- B-thal:B (trait/minor) - reduced HbA, increased HbA2 –> asymptomatic or microcytosis
- B-thal:B-thal (intermediate) - reduced HbA and increased HbA2 and HbF –> mild anaemia
- B-thal:B-thal (major) - greatly reduced HbA, increased HbA2 and greatly increased HbF –> major anaemia
Alpha thalassaemia:
- can be major/Hb Parts (x4 a-globin deletion) –> hydrops fetalis and death in utero
- HbH disease (x3 a-globin deletion –> mild-moderate anaemia with occasional transfusion dependency)
- alpha-thalassaemia trait (1-2 a-globin deletion –> asymptomatic w mild/no anaemia)
How may a child with sickle cell disease present?
Sx:
- Hand and foot syndrome (dactylitis) - painful and swollen hands and feet (earliest signs)
- Acute chest syndrome
- splenic sequestration (anaemia, shock, death)
- painful crises/vasoocclusive, stroke (+/- priapism)
- Infection (pneumococcus, parvovirus**)
- Splenomegaly (children only)
**Parvovirus B19 infection infects RBC precursors causing an aplastic anaemia (therefore reticulocyte counts will be LOW)
What is important to remember about the anaemia in SCD?
The anaemia in SCD is NOT due to haemolysis alone - the HbS is lower affinity and therefore releases O2 more readily to the tissues, thereby reducing the EPO-drive and causing anaemia
What investigations would you consider for a child with suspected SCD?
Ix:
- FBC
- Blood smear - sickle cells, Howell-Jolly bodies (hyposplenism), reticulocytes
- Family origins questionnaire (ethnicity)
- Solubility test (if cloudy, then do..)
- ELECTROPHORESIS (gold-standard) –> normal beta chain is very positive (glutamine) but defective (HbS is neutral, and HbC is negative)
also:
- Guthrie testing after antenatal screening)
How would you manage a patient with SCD? What is their prognosis?
Mx:
- Education - minimise exposure for crises triggers e.g. cold, dehydration, hypoxia, excessive exercise
- Vaccination against encapsulated organisms (pneumococcus and HiB)
- Prophylaxis with OD oral penicillin and folic acid (inc cell turnover)
- Treatment of acute crises = analgesia (avoid morphine <12y), hydration, antibiotics, oxygen and exchange transfusion (ACS, stroke, priapism)
- Treatment for chronic problems = hydroxycarbamide (for recurrent admission for ACS or vaso-occlusive crises) which stimulates HbF production but monitor for WBC suppression, HSCT in severe cases
Prognosis
- premature death due to complications - 50% with most severe SCD die <40y
How may a child with thalassaemia present?
B-thalassaemia major:
- Anaemia at 3-6m age –> HF, growth retardation
- Extramedullary haematopoesis –> bone expansion, hepatosplenomegaly, frontal bossing
- Iron overload –> HF, gonadal failure
B-thalassaemia trait:
- Asymptomatic
- Microcytosis (normal/low Hb)
How would you investigate a child with thalassaemia?
Ix:
- FOQ - indian, mediterranean/middle-eastern + Guthrie testing after ante-natal screening
- FBC
- Blood smear - microcytic RBCs, tear drop cells!!, target cells, shistocytes, reticulocytes/nucleated RBCs
- Hb electrophoresis (gold-standard)
- Imaging for EMH i.e. abdo USS and plain XRs
How would you manage a child with beta-thalassaemia?
Mx:
- Prenatal diagnosis ideally by FOQ and genetic inquiry
- B-major = blood transfusion +/- iron chelation with desferrioxamine/deferiprone OR HSCT, usually for children with HLA-identical sibling
- B-minor requires no treatment
What is haemolytic disease of the newborn (HDN) caused by?
Maternal Abs against foetal blood group antigens
- <2days old
- Anti-D, Anti-A/B, anti-Kell groups are important
- Mother is always Rh-, baby always Rh+
- Mothers Abs cross the placenta or mix at delivery and cause haemolysis
- Sensitise when mother-baby blood mixing at delivery (then these Abs may attack next Rh+ foetus)
How may HDN present?
Sx:
- Yellow amniotic fluid
- Hydrops fetalis (hepatosplenocardiomegaly)
- Pallor
Jaundice 24-36h after birth (within 2 days)
How would you manage (Ix+Mx) a child with HDN?
Ix:
- Coombe’s test (DAT) (+ve)
- Haemolysis shown by raised uBR and high reticulocytes
- Amniocentesis sample, USS for organomegaly
Mx:
- Prevention:
- ->
Treatment:
- -> Phototherapy and IVIG if Br is rising >8.5 umol/l/h
- -> Severe/in utero then transfusion with O, Rh- blood into umbilical vein and delivery at 37-38w
What is G6PDD and how does it present? What are some RFs/causative agents?
Glucose-6-phosphate dehydrogenase deficiency - rate limiting enzyme in the pentose-phosphate shunt which prevents oxidative damage to RBCs
- X-linked (affects males, homozygous females or ‘lionised’ females)
- 10-20% from central Africa, middle/Far East, mediterranean
- Causative drugs = antimalarials (i.e. quinine), antibiotics (i.. nitrofurantoin), analgesics (i.e. high-dose aspirin) and chemicals (fava beans, moth balls)
Sx:
- Neonatal jaundice (<3d of life) = most common cause requiring transfusion)
- Acute intravascular haemolysis when precipitated by infection/drugs/fava beans etc = fever, malaise, abdominal pain and dark urine
