Haematological Disorders Flashcards
Where does haematopoiesis take place in Utero? Post natal?
Liver, spleen
Bone marrow
How does Hb and haematocrit compare in newborn to normal? Why? How does this change?
High (14-20g/dL) due to low oxygen tension in Utero.
Value declines over 2-3 months to give a physiological anaemia (9g/dL)
In preterm infants does the physiological anaemia take longer or shorter to decline?
It’s faster (7/52)
What happens during the physiological anaemia of newborn
Erythroid hyperplasia (increased growth of RBCs) in the marrow & a change from fetal (HbF) to adult (HbA) haemoglobin
What is anaemia
Decrease of circulating haemoglobin
Most common cause of anaemia
Dietary iron deficiency
How is anaemia Classified
Colour - mono/hypochromic
Size - micro/normo/macrocytic
Causes of microcytic hypochromic anaemia
Iron deficiency
Chronic inflammation
Thalassaemia
Causes of intrinsic RBC defects
Spherocytosis, sickle cell disease, G6PD deficiency
Causes of extrinsic RBC defects
Rh incompatibility (immune mediated)
Haemorrhage eg. Menstruation, meckels diverticulum
Hypoproduction disorders - renal disease (RBCs), marrow aplasia, leukaemia (pancytopenia)
What causes macrocytic anaemia
Bone marrow megaloblastic - b12/folate deficiency
Not megaloblastic - hypothyroidism, fanconi anaemia
Describe anaemia in iron deficiency
Hypochromic, microcytic
How does the fetus receive iron? How long does it have reserves for after birth ?
Placenta
4/12
Dietary sources of iron ? How to increase absorption ? What decreases absorption ?
Red meat, dark green veg, bread (10% absorbed)
Increased by ascorbic acid (vit c)
Decreased by tannins (eg. Tea)
Causes of iron deficiency
Nutritional - preterm infants, poor diet (associated with low socioeconomic status)
Menstruation, recurrent epistaxis (nose bleed)
Malabsorption
Features of iron deficiency ? O/e?
Mild - asymtomatic
Irritability, lethargy, fatigue, anorexia
O/e - pallor of skin, conjunctiva, other mucous membranes
Why do preterm infants get iron deficiency
Breast milk / cows milk low in iron
Diagnosis of iron deficiency anaemia
Blood count & film + ferritin
Management of iron deficient anaemia
Oral - 6mg/kg/day PO
This equals - 30mg/kg/day ferrous sulphate for 3-6 months
What are the DDs of microcytic hypochromic anaemia
Iron deficiency
Chronic disease
Thalassaemia
Sideroblastic anaemia
Where is the defect in thalassaemia
Globin synthesis
Two types of thalassaemia
Alpha and beta in their respective globin chains
Pathology of thalassaemia ? 2 ways it causes damage?
Mutations lead to reduction/ absence of globin chains -> excess globin chants of the other subtype remain unpaired -> join to form insoluble tetramers that precipitate membrane damage:
1 - cell death within the bone marrow (ineffective erythropoesis)
2- premature removal by the spleen (resulting in haemolytic anaemia)
Who is likely to get b-thalassaemia ? What are the two types?
Mediterranean & middle eastern
B-Thalassaemia major - homozygous
B-T-minor - heterozygous (“b-thalassaemia trait)
What happens in b-T-Major
Usually complete absence of B-globin chains -> HbA cannot be synthesised
Features of b-T-MAJOR? What happens if left untreated?
Usually present at 6/12 with *severe haemolytic anaemia, jaundice, failure to thrive and hepatosplenomegaly
Bone marrow hyperplasia -> maxillary hyper trophy, skull bossing*
Diagnosis of b-t-M
Hb electrophoresis - decreased HbA and increased HbF
Treatment of B-T-M? Side effects?
Regular blood transfusions aiming to keep the Hb >10g/dL
Iron deposition in heart, skin, liver, pancreas, gonads
Prognosis of B-T-M
Many die from congestive heart failure due to cardiomyopathy in their 2nd/3rd decade
What can B-T-m be misdiagnosed as? What is the type of anaemia ? Usual symptoms?
Iron deficiency anaemia
Hypochromic, microcytic anaemia
Asymtomatic
Diagnosis of B-T-m
Increased HbA2 (50% have mild increase in HbF)
How bad is A-T
Manifestations and severity depend on number of genes deleted.
Eg a-T-M -> death in Utero, hydrops fetalis
What causes haemolytic anaemias? What are they characterised by (4things)?
When RBC lifespan is under 120 days
Anaemia, reticulocytosis, increased erythropoesis in bone marrow, unconjugated hyperbilirubinaemia
Egs of haemolytic anaemias
Hereditary sphereocytosis, sickle cell, G6PD deficiency, pyruvate kinase deficiency
What is hereditary sphereocytosis ? Genetics?
AD caused by abnormalities in spectrin (major RBC membrane support protein) (25% cases are sporadic)
Cells are spherical and lifespan reduced by early destruction by spleen
Features of spherocytosis
*Severe anaemia aged 1-3 months with unconjugated *jaundice & splenomegally
Complications of spherocytosis ? Why?
- Aplastic crisis* secondary to parvovirus B19 (Vth disease, “slapped-cheek”)
- gallstones* - due to increased bilirubin excretion
Diagnosis of spherocytosis ?
Spherocytes on blood film. Confirmed by osmostic fragility test
How does the osmotic fragility test work?
Spherocytes already have maximum SA:volume ratio therefore they rupture more easily than biconcave RBCs in hypotonic solution
Management of spherocytosis ? What’s needed for life after?
Splenectomy - transfusion dependency, uncompensated haemolysis
Prophylactic penicillin for life following splenectomy
Pathophysiology of sickle cell ?
Homozygous mutation of B-globin gene - HbS aggregates into long polymers that distort the RBCs into a sickle shape.
Point mutation which substitutes glutamine for valine at codon 6 in B-globin.
Who gets sickle cell
Black Afro-Caribbean, middle eastern
Why does having sickle cells cause issue
Reduced life span
Get trapped in microvasculature
Features of sickle cell? Neonate? Presentation
Synthesis of HbF offers protection until 4-6 months
-> progressive anaemia with jaundice & splenomegaly then develops
Present with episode of dactylitis or overwhelming infection
What commonly triggers the vaso-occlusive crises in sickle cell
Infection, dehydration, chilling or vascular stasis
Features of a vaso-occlusive crisis ? Where are they uncommon?
Most are painful, particularly in long bones & spine
Cerebral and pulmonary vasculature
What happens if there is a vasoocclusive crisis in pulmonary vasculature?
‘acute chest syndrome’ - fever, Crepitations, chest pain & shadowing on chest X-ray
What happens to the spleen in sickle cell disease
Infancy - splenomegaly
But recurrent infarction -> autosplenectomy spleen regresses and is impalpable by 5 years
What are you at risk of if your spleen regresses?
Hypo function -> risk of overwhelming infection with capsulated organisms eg. H. Influenzae, S. Pneumonae
What are the long term consequences of sickle cell?
Myocardial damage and HF Gall stones Aseptic necrosis of long bones Renal papillary necrosis Leg ulcers
Management of sickle cell
Prophylaxis - penicillin though childhood, pneumococcus & meningococcus immunisations (+standard Hib)
Daily folic acid - meet demands of increased RBC breakdown
Management of vasocclusive crisis
Supportive - analgesia (opioids), oxygen, hydration with IV fluids
When is an exchange transfusion indicated in sickle cell
Acute chest syndrome, stroke or priapism
Cure for sickle cell?
Bone marrow transplant - must come from HLA-identical sibling
Hydroxyurea which increases HbF production is being trialled
What is the genotype of sickle cell carrier - Hb…? What are their symptoms ?
HbAS
Asymtomatic unless subjected to hypoxic stress (eg. General anaesthetic)
What happens if you get HbS & HbC from parents?
Get no HbA, but are mostly asymtomatic
Need to look out for retinopathy in adolescence
What happens if you get HbS and B-thalassaemia from parents?
Similar presentation to sickle cell
2 RBC enzyme deficiencies
Glucose-6-phosphate dehydrogenase
Pyruvate kinase
Genetics of g6pd ? Who gets it? What does g6pd usually do?
X linked recessive
Afro-c, mid-east, Mediterranean, oriental
prevents oxidative damage to RBC
Features of g6pd deficiency
Neonatal jaundice - usually in first 3/7 of life
Acute haemolysis - induced by infection, oxidant drugs & fava beans
fever, malaise, passage of dark urine
Egs of oxidant drugs
Antimalarials, some Abx eg Ciproflaxacin, quinolones
Gene transfer of pyruvate kinase deficiency? What can happen ?
AR Infection induced (parvovirus B19) haemolysis
Deficiency / disorder of what 3 things could lead to bleeding disorders
Blood vessels
Platelets (thrombocytes)
Coagulation factors
Clinical features of bleeding disorders
Petichae / purpura
Prolonged bleeding after dental extraction, surgery or trauma
Recurrent bleeding into muscles or joints
Eg of disorders of blood vessels
Ehlers-Donlos syndrome
Henoch - schonlein purpura
What is Ehlers-Donlos syndrome ? What are the features
Inherited disorder (many types but vasuclar type is type IV) Capillary fragility & hereditary haemorrhagic telangiectasia
What platelet count for thrombocytopenia ? When does purpura occur?
<150x10^9 /L
<20
What is the commonest form of thrombocytopenia ? Incidence? pathology? Where does destruction occur? What else accompanies low platelet count?
Immune (‘idiopathic’) thrombocytopenia (ITP)
4/100,000/Year
Immune mediated destruction of circulating platelets due to anti platelet autoantibodies
Spleen
compensatory increase in megakaryocytes in marrow
Presentation of thrombocytopenia
Usually between 2-10 years, usually 1-2 weeks post viral infection
purpura and superficial bruising, mucosal bleeding (epistaxis / from gums after brushing teeth)
Profuse mucosal bleeding is rare as is intracranial haemorrhage
What are the differentials of ITP ?* what are features of other
Acute leukaemia (?lymphadenopathy ?hepatospenomegaly )
Aplastic anaemia
Non accidental injury
Investigations of ITP ?
FBC - decreased platelets ( all else normal)
Bone marrow - if abnormal features to exclude leukaemia / aplastic anaemia)
Prognosis of ITP
In most children it is acute, benign & self limiting within 6-8 weeks with no treatment
When do you treat ITP ? With what?
Major bleed (IC / GI), persistent minor bleed Oral prednisolone or IV immunoglobin
What do you always need to do if treating ITP with steroids
Examine bone marrow as treatment can mask features of acute leukaemia & aplastic anaemia
Egs of coagulation disorders
Haemophilia A / B
Von Willebrand disease
Haemophilia A is deficiency in what? Genetics? How common?
Factor VIII
X-linked recessive (1/3 new mutations)
1:5000
What are the components of factor VIII
VIII:C - (deficient in Haemophilia A) A low molecular weight unit
VIII: R - ‘Von Willebrand factor’ - high molecular weight unit
What determined the severity of haemophilia A
The levels of factor VIII
Levels of factor VIII and effect in haemophilia A?
1% Severe (spontaneous joint/muscle bleeds)
1-5% moderate (bleeds after mild trauma)
5-40% mild (increased bleeding after surgery/ dental work)
What is the characteristic feature of haem A ? How does it usually present and at what age? Later in life?
spontaneous or traumatic bleeding
Present at 12 months when start to crawl & walk (&fall) with easy brusing / bleeding
Later - recurrent soft tissue/muscle/joint bleeding is main problem
haemarthroses - cause pain & swelling of affected joint
Management of haem A?
Recombinant factor VIII by IV infusion to avoid chronic joint damage / arthritis
Deficiency in haem b? Genetics? Other name? Features? Management?
Factor IX
X-Linked recessive ( less common)
Similar features to A
Recombinant factor IX
Bon Willebrand deficiency? What does this factor usually do? How common is this? Genetics? Management?
VW factor (factor VIII:R) Acts as a carrier protein for VIII:C & facilitates platelet adhesion 1% of population AD - with variable penetrance Desmopressin (DDAVP)
What should be avoided in VW disease?
IM injections, aspirin & NSAIDs
What happens in disseminated intravascular coagulation?
Coagulation pathway activation leads to diffuse fibrin deposition in the microvasculature & consumption of coagulation factors & platelets
Causes of DIC with egs.
Damage to vascular endothelium (eg. Sepsis / renal disease)
Thromboplastic substances in circulation (eg. Acute leukaemia)
Impaired clearance of activated clotting factors (eg liver disease)
Features of DIC
Diffuse bleeding diathesis (eg. Arising from venopuncture site); bleeding from lungs; bleeding from GI tract
Investigations and diagnosis of DIC
Prolonged prothrombin time (INR), activated partial thromboplastin time (APTT) & thrombin time (TT).
Thrombocytopenia, increased D-diners and decreased fibrinogen
Treatment of DIC
Supportive and replacement of platelets & fresh frozen plasma
What other thrombotic disorders are there?
Factor V Leiden - abnormal fV protein that is resistant to protein C
Protein C deficiency - (usually inactivates the activated forms of factors V& VIII and stimulated fibrinolysis)
Protein S deficiency - co factor to protein C
Antithrombin III deficiency
