Haematology Flashcards
Erythrocyte life cycle
Maturation process
What happens to old RBCs?
What are the breakdown components and what happens to them?
Bone marrow: Stem cell (myeloid progenitor cell) -\> proerythroblast -\> erythroblast -\> reticulocyte: spends 3 days in BM then enters blood stream
Blood stream
Retic matures into erythrocyte over 24-48 hrs -> Erythrocyte: circulates in blood stream over about 120 days
Old/abnormal erythrocytes (120 days) -> travel to spleen/liver -> broken down by macrophages and monocytes into components globin and heme
Heme -> bilirubin and iron
Globin -> amino acids
- Amino acids enter back into circulation and travel back to bone marrow to be involved in erythropoeisis
- Iron travels back to blood stream attached to transferrin via liver to be involved in heme production
- Bilirubin travels to liver to be excreted into intestine via bile ducts -> excreted via faeces or urine or reabsorbed
How does O2 circulate in blood
O2 travels around blood via RBC (bound to Hb within RBC)
Configuration of deoxyhaemoglobin
How does this change with O2 binds
Deoxy (no O2 bound) = Tight structure
-> has 2,3 DPG bound with DECR affinity for O2
When 1 O2 molecule binds, it becomes more relaxed which further increases its affinity/ability for O2 to bind (can bind max 4 O2 molecules)
What factors affect affinity of O2 for Hb (shift in oxyhaemoglobin dissocation curve)
pH
pCO2
altitude
temperate
2,3 DPG
methaemoglobin
HbF (foetal)
What shape is the Hb dissociation curve?
At what point in the Hb-dissociation curve does Hb affinity for O2 decrease
Sigmoidal shape
X-axis pO2 of 50mmHg corresponds to y axis % Hb saturation of 90%
- above this O2 remains tightly bound (plateau)
- below this O2 is easily removed from Hb (exponential decr)
What causes a RIGHT shift in oxyhaemoglobin dissociation curve
Right = Reduced affinity of Hb for O2 -> O2 released into tissues
Occurs in tissues normally (placenta, muscle cells)
Other factors
- Incr CO2
- Low pH (acidosis/incr H+)
- Incr temp/fever
- Incr 2,3 DPG (created during glycolysis, reduces affinity for O2)
***To remember: an exercising muscle is hot, hypercarbic, acidic, glycolysis active, and benefits from increased unloading of O2 ie lower affinity = right shift***
What causes a LEFT shift in oxyhaemoglobin dissociation curve
Higher affinity of Hb for O2 -> O2 BOUND more tightly to Hb (occurs in lungs)
Other factors
- Decr CO2
- High pH (alkalosis/low H+)
- Decr temp/hypothermia
- Decr DPG
- Abnormal Hb (sickled, methaemoglobin)
***To remember: an exercising muscle is hot, hypercarbic, acidic, glycolysis active, and benefits from increased unloading of O2 ie lower affinity = right shift***
Effect of fetal Hb on O2 dissociation curve
Why does this occur?
How long does this persist?
From 10-12 weeks in utero
Persists until 6 mo of life
Shift of Hb dissociation curve to the LEFT -> greater affinity for O2 (Can bind more O2 at lower pO2)
So can as has to obtain O2 from mother’s blood stream
This is due to decreased affinity of fetal Hb to 2,3 diphosphoglycerate (DPG), so O2 can bind with higher affinity
Persists to ~6mo of life
Difference in structure between fetal and adult HbF
When does the switch occur?
Fetal Hb = alpha2gamma2
- 2x alpha and 2x GAMMA subunits
Adult Hb = alpha2beta2
- 2xalpha and 2 x BETA subunits
Switch from fetal to adult around 3-6mo
Function of 2,3 diphosphoglycerate (DPG)
Binds to adult Hb and decreases its affinity for O2 -> causes RIGHT shift in O2 dissociation curve
(Present in de-oxy form of Hb, TIGHT structure without O2)
What are the various forms of Iron and what are their relative sources?
Which form can be absorbed?
What is the absorption process for iron?
Iron is a avilable in 2 forms
- Ferrous 2+ from animal sources (‘heme iron’) - readily absorbed in SI (so give supplemental iron in this form)
- Ferric 3+ from vegetable sources (‘non-heme iron’) - not absorbed so must be converted to ferrous iron (Fe2+) via VITAMIN C ferrireductase in lumen of duodenum (enterocyte) then absorbed via DMT1 transporter
- Converted back to Ferric form (Fe3+) when absorbed into bloodstream
- Travels in blood bound to transferrin (transporter molecule) to target organs (liver for storage as ferritin and BM to be incorperated into haem)
Apo-transferrin
Vs Transferrin
Transporter of iron
Apo-transferrin - when unbound
Transferrin - when bound to Ferric (Fe 3+) in blood (can carry 2x)
Fate of Fe in bloodstream
75% - to bone marrow for haematopoeisis (Hb, carries O2)
25% - to liver for storage of iron as ferritin (3+)
Transferrin receptor
- where is it located and what does it do?
Present in liver and bone marrow
Enables passage of transferrin (with Fe3+ bound) via endocytosis
Hepcidin
- where is it located/made
- what does it do
Master iron regulator
Produced by liver
Decreases Fe3+ in plasma
- Prevents iron release from cellular storage by blocking ferroportin transporter
- Prevents absorption of Fe in small intestine
Ferroportin
Transporter in liver through which Fe3+ is released from storage (ferritin) into circulation
Hereditary haemochromatosis
What is this caused by?
What does this result in?
Iron storage disorder
Caused by mutation in HFE protein gene
(Autosomal recessive condition)
-> hepcidin will not work to inhibit Fe from intesine or prevent release of Iron from storage in liver->
Results in iron overload and deposition in tissues
Presentation
- Usually presents in middle age
- Bronze discolouration of skin
- Chronic tiredness
- Joint pain
- Memory problems
Hepcidin: what is its role and what factors act to produce/increase the levels of hepcidin
Hepcidin acts to decr [fe3+] in plasma (by reducing dietary absorption and inhibiting release of iron from cellular storage)
Hepcidin levels increase with:
- Expression of HFE protein (made by HFE gene or haemochromatosis gene)
- Incr serum Fe3+ (neg feedback)
- Inflammatory cytokines (is an acute phase reactant)
- Lipopolysaccharides
What is transcobalamin 1 and 2 and what are their roles
Transport proteins for vitamin B12
- Transcobalamin 1 = haptocorrin
- Derived from salivary glands in mouth
- Binds Vitamin B12 and protects it from degradation by stomach acid
- Transcobalamin 2
* Binds vit B12 in serum after it has been absorbed and transports it to target tissues
Absorption of vitamin B12
B12 ingested -> binds to haptocorrin (transcobalamin I) in saliva to protect B12 from degradation by HCl in stomach
- > HCl and intrinsic factor produced by parietal cells in stomach
- Passes into duodenum
- Pancreas produces proteases through pancreatic duct indo duodenum -> release haptocorrin from B12
- > IF binds B12 in duodenum
- IF-B12 complex transported through SI to terminal ileum where IF binds IF-receptor and complex is absorbed and B12 is released into blood
- B12 binds to transcobalamin II and transported to liver and kidneys
- B12 stored in liver
- B12 reabsorbed and excreted through urine (is water soluble)
Role of vitamin B12
Causes of low B12
Ix findings of B12 deficiency
ROLE:
- DNA, RNA synthesis
- RBC production
- Lipid (neuronal myelin sheath) synthesis
- Acts as a cofactor for enzymatic activation for production of
- homocysteine -> methionine
- MMA -> succinyl coA
Causes
- Vegans (in animal products only)
- Impaired absorption:
- Ileal resection
- Coeliac or crohn disease
- Bacterial overgrowth
- Pernicious anaemia (IF factor deficiency)
- Inborn errors of metabolism
Ix
- Macrocytic anaemia with hypersegmented nuclei
- Elevated LDH
- Increased serum homocysteine and urine MMA levels (metabolic precursors)
What does a lack of vitamin B12 lead to in terms of sx
*Mouth, skin and neuropathy*
1) Axonal demyelination -> NEUROPATHIES *specific to B12 def*
- > motor problems/Muscle weakness and unsteady movement
- > numbness tingling
- > developmental delay/regression
- > seizures
2) Anaemia -> fatigue, SOB, pallor, GLOSSITIS, angular stomatitis
3) Mild jaundice, purpura, melanin pigmentation
Pernicious anaemia
- what is it
- what does it result in
Autoimmune disorder, T-cell mediated
Attacks parietal cells
Results in lack of IF production
Prevents absorption of vitamin B12
Leads to vitamin B12 deficiency
Folate
- what is it derived from
- where is it absorbed
- what does it do
- how long do stores last
ie folic acid or Vitamin B9
Derived from diet (green, leafy foods and fortified foods)
Absorbed in jejunum
Precursor for formation of tetrahydrofolate (THF) which acts as a carbon donator and acts as a cofactor for many enzymes involved in nucleic acid and amino acid synthesis (DNA and protein synthesis)
Stores limited to several weeks (deficiency can develop in hospitalised pts)
Causes of deficiency
- malabsorption: coeliac disease, crohn disease
- inadequate dietary intake
- incr physiological demand: prematurity and pregnancy
- incr utilisation: haemolysis, malignancy, inflammatory disease
- liver disease
- anti-folate drugs: MTX, phenytoin, trimethoprim
Affect of methotrexate on folate metabolism
Inhibits metabolism of folate to its active form
- Prevents action of dihydrofolate reductase and thus prevents formation of tetrahydrofolate
(note tetrahydrofolate (THF) which acts as a carbon donator and acts as a cofactor for many enzymes involved in nucleic acid and amino acid synthesis)
Causes of microcytic anaemia
TAILS
Thalassaemia
Anaemia of chronic disease (ESRF)
Iron deficiency
Lead poisoning
Sideroblastic anaemia (XLR) - very rare!!
Someone has a normocytic anaemia
What is the next ix you would look at
What are causes of such
Reticulocyte count; plt and WCC (?pancyopaenia)
High Retics
- Haemolysis
- Bleeding
Low retics = marrow failure
- Pancytopaenic
- Aplastic anaemia
- MDS
- Leukaemia
- Myelofibrosis
- TB
- Amyloidosis, sarcoidosis
- drugs (chemo)
- Non pancytopaenic
- Anaemia of chronic disease
- Renal disease
- Mixed nutritional deficiency (iron+B12)
- TEC
Someone has a macrocytic anaemia
What is the next ix you would look at
What are causes of such
Blood film to differentiate between megaloblastic (large immature RBCs) or non-megaloblastic and presence/absence of hyper-segmented neutrophils
Megaloblastic anaemia
- Vit B12 or folate deficiency
- Inborn errors of metabolism (ex orotic aciduria)
- Drug side-effect (Mtx)
Non-megaloblastic
- Brisk reticulocytosis/haemolysis
- Myelodysplastic syndrome
- Marrow failure: Fanconi and Diamond-Blackfan anaemia
- Congenital dyseryrthropoeitic anaemia
- Osteoporosis
- Hypothyroid
- Liver disease, Alcohol
- Post-splenectomy
Blood markers of haemolytic anaemia
Blood
- Reticulocyte count = elevated
- Unconjugated hyperbilirubinaemia
- Elevated LDH
- Elevated free plasma Hb
- Low or absent haptoglobin (binds free Hb from lysed RBCs and are removed from circulation)
Increased Urinary urobilinogen and faecal stercobilinogen
Causes of aneamia - decr production
- Bone marrow disorders (aplastic anaemia)
- CKD (low erythropoeitin)
- Hypothyroid (TSH helps stimulate erythropoeis)
- Vit B12 deficiency
- Iron deficiency
- Chronic inflammatory disease (decr RBC lifespan and causes iron deficiency)
Causes of haemolysis: Intrinsic/cellular
HEREDITARY
Membrane
- hereditary spherocytosis
- elliptocytosis
Enzyme
- G6PD deficiency
- Pyruvate kinase (PK) deficiency
Haemoglobinopathies
- Sickle cell disease
- thalasseamia
ACQUIRED
Autoimmune
- Warm Ab (SLE, dermatomyositis)
- Cold Ab (CMV, mycoplasma)
Alloimmune
- Transfusion reaction
- Haemolytic disease of newborn
- transplant (BMT, cardiac)
Microangiopathic
- HUS
- TTP
- DIC
- meningococcal septicaemia
Infx: malaria
Systemic disease: renal or liver disease
What causes hereditary spherocytosis
Presentation
Ix findings - FBE, Coombs, diagnostic test
Treatment
- AD Gene mutations (ANK1) cause red blood cells to have an abnormal, spherical shape with decreased flexibility (=spherocytes) .
- Due to misshapen proteins in cytoskeleton (most commonly ankyrin-1; spectrin, band 3)
- The spherocytes are taken out of circulation prematurely and sent to the spleen to be destroyed (hemolysis).
Presentation
- *May be asymptomatic
- Neonatal jaundice
- Splenomegaly
- May have pigment gallstones at early age
- Aplastic or anaemic crises esp w PARVOVIRUS infections
Ix:
- Macrocytic anaemia w reticulocytosis
- Elevated bili and LDH
- NEG Coombs/DAT
- RBC Membrane studies/EMA binding is diagnostic (used to do osmotic fragility)
Treatment
- Folic acid supps
- Transfusions if severe anaemia, poor growth, aplastic crisis, age < 2 years
- Splenectomy if regular transfusions required
- Cholecystectomy if gallstones
Complications of haemolytic anaemia
- Erythroid hyperplasia (esp with thalassaemia)
- medullary spaces expand in skull and long bones at expense of cortical bone -> leads to pathological fractures - Gallstones (due to deposition of calcium bilirubinate)
- iron deficiency (iron loss in urine secondary to breakdown of RBCs)
What is an aplastic crisis?
What is the most common cause of aplastic crisis?
Erythroid marrow failure leading to decr reticulocytes and rapid reduction in Hb and Hct to extremely low levels (within 10-14 days)
Can be life-threatening
Most common cause is parvovirus B19
Causes of extracellular haemolysis
Autoimmune
- Warm ab
- Cold ab
Fragmentation Haemolysis (fragments of RBCs will be found in urine)
- DIC (disseminated intravascular coagulation)
- Haemolytic uraemic syndrome
- Artificial heart valve (shear stress)
- Thrombotic thrombocytopaenic purpura
- Hypersplenism
Plasma factors
- Liver disease
- Infection (malaria)
- Wilson’s disease
What is the role of the direct vs indirect Coombs test
Direct (DAT) - detects Ab or complement bound to RBC surface
- Patients RBCs are added to coombs reagent (which are Ab against human globulin)
- Use to detect autoimmune haemolysis, drug-induced or alloimmune hemolysis (newborn or transfusion reaction)
Indirect - detects Ab in serum (RBCs have been removed)
- Add patient’s plasma to RBCs of known Ag
- Then add Coombs reagent (which are Ab against human globulin)
- Use for cross-matching (pre-transfusion) or pre-natal Ab screen (rhesus)
Agglutination = positive test
(NOTE can be initially negative if haemolysis is very rapid)
Indirect Coombs test
If agglutination occurs with patient’s plasma and with donated RBCs of known AB, A but not to B or O, then what sort of blood can this patient be given if they need a transfusion?
Pt cannot be given A blood (Ab would attack -> haemolysis of RBCs)
But CAN safely be given O and B type blood.
What is the Flow cytometric EMA (eosin-5-maleimide) binding test used to diagnosis due to its high predictive value?
Hereditary spherocytosis
Evans syndrome
Autoimmune Haemolytic anaemia + ITP
Cold autoimmune haemolysis
- Optimal temp for agglutination
- Immune cells involved
- Causes
- presentaiton
- ix
- tx
- Optimal temp for Ab attachment to RBC = 4 C
- IgM mediated -> complement cascade -> C’ mediated intravascular (mostly) and liver destruction of RBCs
Causes:
Idiopathic
Infections
- Mycoplasma pneumoniae (most common cause in kids)
- EBV, CMV infection
Lymphomas
Paroxysmal cold haemoglubinuria
Presentation
- Often occurs 1-2 weeks post febrile illness with dark urine following exposure to cold
- Intravascular haemolytic anaemia
- Haemoglobinuria - dark urine
- ACROCYANOSIS
Ix
- Macrocytic anaemia w reticulocytosis
- Positive Coombs to C3b at 4C
Tx
- Treat cause as able
- Cold avoidance/keep warm
- Rituximab
- Folic acid
- NOTE: splectomy not done, GC less useful
Warm autoimmune haemolysis
- Optimal temp for agglutination
- Immune mediator(s)
- Causes
- presentaiton
- ix
- tx
- Destruction in spleen (extravascular) at temps >= 37C
- IgG mediated
Causes
- Primary (idiopathic - 40-50%)
- Secondary to underlying disease such as
- Lymphoma
- SLE, RhA
- Evans syndrome (assoc immune mediated thrombocytopaenia)
Presentation
- Extravascular haemolytic anaemia
- Splenomegaly
- Evans syndrome = assoc ITP +/- neutropenia
Ix
Macrocytic anaemia w reticulocytosis
DAT positive for IgG at 37C
Spherocytes on blood film (not a feature in Cold AIH)
Tx for severe disease
- Treat cause if possible
- GC (not for Cold AIH)
- > IVIG if refractory to GC
- Immunosuppression
- Folic acid, blood transfusions as necessary
- Splenectomy if poor response to medical mx
Beta thalassaemia
Partial (minor) or complete deficiency in betaglobin chains that make up Hb molecules (present in adult but not fetal Hb) with excess alpha chains
Due to POINT MUTATION in beta globin gene on chromosome 11
Minor (trait) - asymptomatic (often picked up incidentally with mild microcytic hypochromic anaemia)
- *Major -** symptoms develop around ~4-6mo (when switch from gamma to beta chain normally occurs). NO HbA.
- > haemolytic anaemia and transfusion dependence
- Hepatosplenomegaly due to haemolysis and extramedullary haemopoeisis
- Thalassaemic facies (frontal bossing nad maxillary hyperplasia)
- Elevated bili, jaundice and gallstones
- Bone deformities and osteoporosis due to extramedullary haematopoeisis
- FTT
- Effects of iron overload from regular blood transfusions (endocrine effects: DI, hyothtyroid, hypoPTH, hypogonadism, GH deficiency, renal disease) and also from hepcidin deficiency (which increases GI iron absorption)
Inheritance of beta thalassaemia
Autosomal recessive
beta 0 = no beta globin produced
beta + = reduced beta globin production
Beta thal Major - 2 x beta 0 mutations - no beta globin chains
- Severe Transfusion dependent disease
- HbF and HbA2, no HbA
Intermitae - 2 beta + (reduced) mutations or beta+/beta0
Minor - 1 beta 0 or + mutation, 1 normal beta gene
- Asymptomatic (often picked up incidentally with mild microcytic hypochromic anaemia)
- Relative excess of alpha chains (elevated HbA2)
Structural variants
- Beta thal/HbE - severe transfusion dependent disease
- Beta thal/HbS - sickle cell disease
Complications of hemochromatosis (iron overload)
-
Liver – cirrhosis, carcinoma
* more common in sickle cell and Diamond blackfan anaemia -
Heart (most common cause of death) – cardiomegaly, arrhythmias, CCF
* more common in beta thal -
Endocrine
- IDDM
- Growth failure
- Delayed puberty
- hypothyroid
- hypoparaythoid
- more common in beta thal
4. osteoporosis and poor growth
Ix
- ferritin (should be less than 1000 to avoid toxic effects; correlates w survival and cardiac effects but correlates poorly w liver effects)
- echo
- endocrine ix
- MRI to look for iron stores
Ix for beta thalassaemia major
Ix
Radiology
- ‘hair on end’ on Skull Xray from expansion of medullary cavities in skull from new bone formation (incr bone marrow activity for production of new retics)
- Hepatosplenomegaly (extramedullary haematopoeisis)
- FBE: microcytic hypo chromic anaemia
- Film: target cells, basophilic stippling, nucleated red cells
- May have normal or elevated serum iron/ferritin
Confirm with Hb electrophoresis
- Elevated HbA2 (alpha2delta2) and HbF (alpha2gamma2) levels
- Decr HbA (alpha2beta2)
Mgmt beta thalassaemia
Minor - no tx
Major and intermedia
- Periodic blood transfusions q4-6wkly
- Hydroxyurea (induces production of HbF which is protective)
- Iron chelating agents (desferrioxamine) as blood transfusions can worsen iron overload (hemochromatosis)
- Folic acid daily
- Vit C daily (incr iron excretion)
- Splenectomy to decr blood requirements (only if >6y)
- HSCT
- Gene therapy
- Hepcidin supplement is a new threapy… (as in thalassaemia is a low hepcidin state)
Alpha thalassaemia
Inheritance
Deficiency in alpha globin chain in Hb (present in both fetal and adult Hb)
- 4x Genes on chromosome 16 (2 from mo, 2 from fa)
- HAve 4 alpha genes, 2 inherted from mo and 2 inherited from father
- alpha0: no alpha globin production at all.
- alpha+: reduced alpha globin production
- 1 or 2 loci of alpha gene deleted (aa/a- or a-/a- or aa/–) = ‘trait/minor’, asymptomatic (hypo chromic microcytic cells +/- mild anaemia)
No MGMT required - 3 alpha genes deleted = a-/– = HbH ( has high O2 affinity, L shift of curve)
Results in unpaired beta globin chains (HbH = beta x 4)
Moderatively severe hemolytic anaemia, splenomegaly
Usually diagnosed late childhood.
Transfusions as needed (sometimes w illnesses, pregnancy) - 4 loci deleted = Bart’s hemoglobin (gammax4 in fetus with NO alpha chains at all)
- > unable to carry O2 = non-viable
- > results in hydrops fetalis/death in utero
- > all postnatal Hb contain alpha chains, so incompatible w life
- > massive hepatosplenomegaly and signifiant morbidity for mo during pregnancy
- > survivors are transfusion dependent
Most accurate test for diagnosing thalassaemia
African/mediterranean/SE asian populations
Antenatally
- CVS or amniocentesis for foetal DNA analysis
- Foetal blood sampling in 2nd trimester via cord blood for Hb electrophoresis
Neonatal diagnosis
- Hb electrophoresis at birth (however may ned to be redone at 6 months due to switch from gamma to beta chairs occurring at 3-6mo)
How does iron overload cause cell damage?
Highly toxic labile iron -> free radical -> lipid peroxidation, DNA modifications, protein damage
i. TGF-β1 -> collagen synthesis -> fibrosis
ii. Organelle damage -> cell death
iii. Resultant organ damage
Sickle cell disease
pathophys/genetics
What is the difference between sickle cell anaemia and sickle cell disease and sickle cell trait?
Affects HbA due to mutation in Hb beta globin gene (HBB gene) resulting in misshapen Hb molecule (sickle) when exposed to low O2 conditions
-> single base pair change (valine instead of glutamic acid)
The sickled cells bock areas of microcirculation resulting in microinfarcts
- SS anaemia = HbS/HbS = Both β-globin alleles have the sickle cell mutation (βs)
- SS disease = Compound heterozygote one β-globin allele includes the sickle cell mutation and the second β-globin allele includes a gene mutation other than the sickle cell mutation ie. HbS/HbC, HbS/β-thalassemia
- SS trait = One allele of the beta globin gene carries the sickle mutation and the other allele is normal, producing haemoglobin SA (HbSA)
Sickle trait
Clinical features
No health problem unless exposed to EXTREME trigger (altitude/hypoxia/dehydration)
Decreases severity of malaria (plasmodium falciparum)
-> heterozygote advantage in ppl of African/mediterranean/indian/SE asian descent
Haematuria is commonest symptom
What triggers sickling and what does this lead to?
Triggers
- hypoxia
- dehydration
- acidosis
- Changes shape when de-oxygenated -> crescent shape (sickled)
- Sickled erythrocytes are rigid and obstruct small blood vessels (VOC)
- Leads to premature destruction/hemolysis of RBCs
-> Vaso-occlusion and micro infarcts
Howell Jolly Bodies are a path feature of what condition?
Sickle cell anaemia (have functional asplenia)
Splenic dysfunction/asplenism
Inx for diagnosis of sickle cell
Blood smear (sickled cell, target cells, howell jolly bodies, polychromasia from retics) Hb electrophoresis (HbS present) Sickledex test (HbS sickles when deoxygenated with dithionite and Na2HPO4) Macrocytic anaemia, reticulocytes high
Mx of sickle cell disease
General
- Avoid triggers (hypoxia, dehydration, acidosis)
- Folic acid
- Prophylactic penicillin until age 5
- Immunizations (pneumococcal, HIB nad meningovax essential)
- Health maintenance – nutrition, social supports, education
- Chronic PRBC (Aim is Hbsickle <30%) – growth failure, frequent hospital admissions, stroke (secondary prevention) or primary prevention (elevated Transcranial doppler or TCD, a measure of risk of hypoxaemic stroke)
- Hydroxyurea: increase HbF and decr frequency of crises = organ protective
- Red cell exchange - quickly reduces HbS
Bone marrow transplant is curative (indicated for ACS, stroke, abnormal TCD)
Sickle cell genetics
b. Single base-pair change
c. Thymine for adenine (GAG to GTG) at the sixth codon of the β-globin gene
- > valine instead of glutamine
Mechanism of action Hydroxyurea + what condition does it treat and what effects does it have?
Used as prophylaxis for sickle cell anaemia
-> Reduces the frequency of painful episodes, Acute chest syndrome, dactylitis
Actions:
- Increases gamma globin, incr prop of HbF (doesn’t include the beta globin) and thus reduces HbS (as in SS you can only make HbS and HbF) so reduces sickling of RBCs
- Improves NO metabolism
- Reduces interaction between RBC and endothelium
Haemophilia A vs B
What is it
How is it inherited
Sx
Ix
Tx
A - Factor 8 deficiency
B - Factor 9 deficiency
-> inability to form fibrin clot adequately
X-linked recessive (male predominant, A - 1/5000 and B -1/30000)
Sx - Delayed bleeding 'Deep' bleeds (joints, muscle - iliopsoas) Spontaneous haemarthoses (ankles, knees, elbows) As neonate may present with intracranial hemorrhage or bleeding w circumscision.
Ix
- decr factor 8 or 9 activity,
- incr/prolongued aPTT -> normalisation with mixing studies
- normal INR/PT
Tx -
Avoid trauma, aspirin/NSAIDs
A: Desmopressin=DDAVP (mild sx) or factor 8 concentrate and tranexamic acid as prophylaxis for more severe form
-> give factor 9 concentrate if Factor VIII Ab present
B: Factor 9 concentrate and tranexamic acid
Presentation of iliopsoas muscle haemorrhage
What condition may be underlying this?
Can result in large amount of blood loss resulting in shock
- Present with vague referred pain in groin, hip held in flexed internally rotated position
- Diagnosis clinically and confirmed with imaging
Haemophilia A or B
Chronic complications of haemophilia
Chronic arthropathy (from inflammation following haemarthosis)
Development of inhibitor to factor 8 (occurrs shortly after factor replacement tx initiated, usually igG ) - usually disappears with continued regular infusions (=immune tolerance)
-> give factor 9 concentrate if Factor VIII Ab present
Transfusion-transmitted infx
Complications of CVC access
Obesity (joint disease)
ITP
What does it stand for?
Pathophys?
Primary vs secondary
Acute vs chronic
Sx
Ix
Tx
Immune thrombocytopaenia (purpura) Problem in primary haemostasis (plt aggregation) IgG against plt aggregation receptor (GP2b/3a) -\> plt destruction
Primary - idiopathic
Secondary to known cause
- Vaccination
- Infection: EBV, chicken pox, HIV, measles
Acute- children (following viral illness)
Chronic - adolescents/adults (50% adol/adults develop chronic following acute episode)
Sx -
- mucocutaneous (superficial) bleeding (petechiae, non palpable purpura, echhymoses)
- 1-4 weeks following viral illness or vaccination
- NO deep bleeding/hemarthosis or systemic signs
Ix
Plt number low (Hb and WCC normal)
Bleeding time prolonged
Normal PT and aPTT
Tx
- *Note - do NOT give plt as will be destroyed*
- Steroids (1mg/kg for 5 days)
- IVIG
- Rituximab for chronic ITP
- Splenectomy only if severe chronic ITP
What is the most common cause of acute thrombocytopaenia in an otherwise well child
ITP
Usually seocndary to viral illness (EBV)
Types of hemolytic disease of newborn
What is another name for HDN?
General pathophys
ABO hemolytic disease
Rh hemolytic disease (more dangerous than ABO!)
HDN = erythroblastosis fetalis
Destruction of fetal RBC by maternal IgG antibodies due to the presence of Ag not present in maternal blood
Ab produced when fetal RBC produce Ag not expressed by the mother
Rh hemolytic disease
Pathophys
What blood groups does it occur in (mo and baby)
Presentation
In-utero maternal blood exchange with the fetus (fetal and maternal blood mixing)
Occurs only in Rh neg mother and Rh pos fetus
First pregnancy - nothing happens to baby.
- Rh neg mo gets exposed to Rh + fetal blood during pregnany at which point she develops Anti-D IgG (or can occur with a transfusion)
- In subsequent pregnancies, maternal Anti-D IgG can cross placenta to attack baby Rh+ -> haemolysis
Presents as jaundice within first 24 hrs of life
Hemolytic anaemia
Hydrops fetalis possible in severe cases
ABO hemolytic disease
Pathophys
What blood groups does it occur in
Presentation
Caused by in-utero maternal blood exchange w fetus
Type O mother (will have anti-A and anti-B Abs), A/B/AB fetus
Mother’s Anti-A and Anti-B IgG crosses placenta -> haemolysis in fetus
Presents as mild juandice within first 24 hrs of life w hemolytic anaemia but NO hydrops fetalis
Prevention of hemolytic disease of newborn (screening)
Tx of hemolytic disease of newborn
Prevention/prenatal
i. Maternal blood group and antibody screening, serial antibody titres if positive or at risk – indirect Coomb’s test
ii. Anti-D 2 x throughout pregnancy
iii. If high antibody titers, measure serial fetal MCA velocities – increased MCA velocity correlates with fetal anaemia
Tx /postnatal
- Delivery at tertiary centre
- Immediate FBE, DCT, BG, SBR on cord sample
- Serial SBR
- Phototherapy
- Exchange transfusion if severe (rids of maternal Ig)
- PRBC transfusion in severe anaemia (match to mothers blood)
DIC pathophys
Widespread thrombohaemmhoragic disease resulting from any life-threatening systemic disease assoc w hypoxia/acidosis/tissue necrosis, leading to endothelial damage
- > widespread activation of clotting cascade
- > Widespread microvascular thrombosis -> haemolysis due to mechanical obstruction of RBCs by thrombosis in small vessels
- > excessive consumption of clotting factors leads to deficiency of plt and clotting factors (↓ plt, ↓ fibrinogen, prolongued INR/PT/APTT, ↓ fibrin degradation product)
- > haemmhorage/bleeding
- > shock
Triggers of DIC
any life-threatening systemic disease assoc w hypoxia/acidosis/tissue necrosis, leading to endothelial damage and activation of coag cascade
Pregnancy
Malignancy (esp haematological)
Sepsis
Trauma
Shock/asphyxia
Snake/insect bites
Certain haem disorders
Presentation of DIC
a. Accompanies a severe systemic disease process, usually with shock
b. Bleeding frequently first occurs from sites of venepuncture or surgical incision
c. Petechiae, ecchymoses
d. Tissue necrosis – infarction of large areas of skin, subcutaneous tissue, kidneys
e. Anaemia secondary to haemolysis may develop rapidly owing to microangiopathic anaemia
Treatment of DIC
- Treat trigger (ex infx)
- Treat shock/acidosis/hypoxia
- Blood component replacement tx
- FFP for APTT and INR (contains coagulation factors)
- cryoprecipitate for fibrinogen (aim >1.0)
- platelets for thrombocytopaenia (aim > 50)
- consider FIIa
- consider heparin if not bleeding (in chronic DIC)
Ix for DIC
FBE - low HB, plt
Film - schistocytes (fragmented, burr and helmet shaped RBC)
Coag factors 2, 5, 8 reduced
APTT and PT/INR prolongued
High d-dimer
What conditions give the following:
Prolonged aPTT
Normal PT/INR
a) aPTT corrects with mixing study
b) aPTT does not correct with mixing study
Intrinsic and common pathway problem
a) corrects -> Factor deficiency (haemophilia)
b) does not correct -> inhibitor present, such as heparin or Antiphospholipid antibody syndrome (lupus anticoagulant)
What conditions give the following:
Normal aPTT
Prolonged PT/INR
Note PT/INR reflect the extrinsic pathway, involves factor 7 and tissue factor release following endothelial/tissue damage
Factor 7 deficiency
Liver disease
Warfarin effect
Vitamin K deficiency
What conditions give the following:
Prolongued aPTT
Prolonged PT/INR
Multiple factor deficiencies
Liver disease
Warfarin
Vitamin K deficiency
DIC (consumption)
Inhibitor to multiple steps in coagulation cascade (heparin, APL ab syndrome)
Factor 8 deficiency can be a feature of both haemophilia A and vWD - how to differentiate between the two?
Mode of inheritance
Haemophilia A - x-linked recessive, males predominantly affected
- prolongued APTT
vWD - suspect in females with isolated factor VIII deficiency, & family history consistent with autosomal dominant inheritance rather than X linked
- normal APTT
- prolongued bleeding time
- decr VWD levels
Fanconi anaemia
- what is it
- pathophys
- Presentation/clinical features
- Diagnosis and FBE results
- Tx
What is it
- AR congenital aplastic anaemia (bone marrow failure syndrome)
- Tends to present at 3-14 yrs of age
Pathophys
- Mutation in FANC gene
- Cells can’t repair DNA damage -> chromosomal breakages
- Leads to bone marrow failure, predisposition to malignancy (MDS, AML) and incr sensitivity to cytotoxic chemotherapy
Clinical features
- Fanconi Café – ‘short MAC’
(Short stature, MDS, AML, Café au lait)
- Microcephaly
- Absent radii or thumbs
- Developmental delay or ID (25%)
- VACTERL assoc (CHD/TOF, hypospadius, imperforate anus etc)
- Congenital hip dislocation
FBE
- Begins with isolated THROMBOCYTOPAENIA (plt have shortest lifespan) or macrocytopaenia initially and eventually progresses to pancytopaenia
Diagnosis: chromosomal breakage test
Tx
- Androgen tx delays progression of disease
- Bone marrow transplant is only cure (without this most die from AML or BM failure at <30y)
Clinical picture for Wiskott Aldrich syndrome
Young males with small platelets
Phx – eczema, recurrent infection (immunodefiency)
Bernard Soulier syndrome
What is it
Pathophys
Presentation
Ix
Severe congenital disorder of platelet function
Rare +++
Due to absence or severe deficiency of the VWF receptor (GPIb complex) on the platelet membrane -> impaired plt aggregation
Mutation caused by genes coding for GPIb complex
Present with petechiae and purpura shortly after birth, especially after vaginal delivery
FBE - thrombocytopaenia, GIANT platelets
Prolongued bleeding time
Normal vWD studies
Confirm diagnosis via flow cytometry of platelet glycoproteins
Lupus anticoagulant/APL syndrome
Causes
Pathophys
Clinical presentation
Ix
Tx
Causes
- Primary condition
- Assoc w SLE
Pathophys
- Several different Ab directed against phospholipid binding protein (includes anticardiolipin Ab, anti-beta-2 glycoprotein antibody, lupus anticoagulant )
Clinical presentation
- Fetal loss
- Predisposition to venous/arterial thrombosis
- Bleeding sx possible but rare
Ix
- Lupus anticoagulant antibody, anticardiolipin antibody, anti β2 glycoprotein antibodies
Tx
- Long term anticoagulation (high risk of recurrence)
vWD
What is it?
Sx
Ix
Tx
AD condition, variable expression, worse in F
Deficiency in quality of quantity of vWF which results in impaired plt adhesion. Also results in low factor 8 (impaired binding of factor 8 and so factor 8 gets degraded by protein C and S -> Results in impaired fibrin clot formation)
Sx
- asymptomatic or mild mucocutaneous bleeding, menorrhagia
- (RARE) severe cases of spontaneous joint, muscle, GI bleeding
- worsened with anti-plt/anticoagulant medication
Ix -
- VWD screen: VWF activity LOW +/- factor VIII levels LOW
- Bleeding time prolonged
- aPTT prolonged (correctible with mixing study) if Factor 8 low
- PT/INR normal
Tx
- Acute bleed:
- severe disease: VWF and factor 8 concentrate =/- tranexamic acid
- milder disease: DDAVP (vasopressin analog) causes the release of VWF, FVIII, and tissue plasminogen activator into the plasma
Role of von willebrand factor
Clot formation
- Platelet adhesion
- Carrier protein for factor 8: Binds factor 8 and protects it from early degradation by protein C and protein S
Inheritance of vWD, types
- associated results of vWF Ag, ristocetin and FVIII assays for each type
vWF gene on chromosome 12
Type 1 - 80% of all cases
- low count of vWF
- Autosomal dominant
- Low vWF Ag > Ristocetin
- Normal FVIII
Type 2 - 20% of all cases
- normal quantity of vWF but impaired quality
- Low Ristocetin > vWF Ag
- Normal or reduced FVIII
Type 3 - most severe form but rarest
- Autosomal recessive
- No factor in bloodstream, assoc w severe factor 8 deficiency
- Absent vWF Ag and Ristocetin
- Reduced Factor VIII
Acquired
- secondary to SLE (auto-Ab against vWF)
- secondary to medications
What is the Most common inherited bleeding disorder
vWD
Drugs that can cause thrombocytopaenia
Antiepileptics
- Valproate
- Phenytoin
- Carbemazepine
Abx
- Vanc
- Bactrim
Mechanism of action of the following meds
- Aspirin
- NSAIDs
- Clopidogrel
Aspirin - irreversibly inhibit COX -> inhibits platelet aggregation
NSAIDs - reversibly inhibit COX
Clopidogrel - inhibits plt aggregation
TTP vs HUS - how to tell the difference?
Both ft
- haemolytic anaemia
- thrombycytopaenia
- fever
- renal sx
- neuro sx
TTP: CNS/neuro > renal signs
HUS: renal > CNS/neuro sx
What genetic condition results from the deficiency in ADAMTS-13 gene
What does ADAMTS-13 code for
What is the tx
TTP (Thrombotic Thrombocytopaenic Purpura )
ADAMTS-13 is a protease that cleaves VWF multimers
Without this protease, ultra-large vWF multimers circulate causing microvascular plt thrombi
Results in microangiopathic haemolytic anaemia and thrombocytopaenia and arteriolar thrombi
Classic pentad
i. Fever
ii. Microangiopathic haemolytic anaemia
iii. Thrombocytopaenia
iv. Abnormal renal function - ischaemic damage
v. CNS changes - fluctuating neurological signs
Tx is FFP (ADAMTS13 replacement)
Plasmapheresis
Steroids, cytotoxics
1a) What is the main cause of HUS in children? (haemolytic uraemic syndrome)
b) What are less common causes?
2) What are the clinical manifestations?
3) Tx
1a. ‘typical’ or diarrhoeal form: mainly caused by E-coli (shiga-toxin producing) gastroenteritis
1b. ‘atypical’: main cause is strep pneumonia
Also can be genetic (DGKE gene mutation leading to mutations in C’ gene)
2.
Haemolytic anaemia
Thrombocytopaenia
Acute renal failure - nephritic syndrome (protein, RBCs, casts in urine)
- Supportive tx
- Fluid management
- Dialysis
- Plasmapheresis if neurological involvement
Ix/monitoring of hemochromatosis
Ix
- Serum ferritin high (can be unreliable) AND transferrin saturation (high)
- Genetic testing for confirmation (HFE gene, encodes HFE protein which functions to regulate circulating iron uptake by regulating the interaction of the transferrin receptor with transferrin)
- Liver bx no longer performed
Monitoring for complications
- Annual MRI liver and LFTs
- Echo yearly
- Cardiac T2 2nd yearly from age 10
- Endocrine investigations
Mx of hemochromatosis
- Get rid of excess iron (chelation therapy)
- Monitor serum ferritin (3monthly)
- Monitor and treat complications
- Annual MRI liver and LFTs
- Echo yearly
- Cardiac T2 2nd yearly from age 10
- Endocrine investigations
Main causes hemochromatosis
- hereditary (autosomal recessive, mutation in HFE protein gene)
- beta thalassaemia major
- sickle cell
- transfusions
What bacteria is siderophilic and what associations does it have?
Yersinia
- requires iron for its growth
- transmission is food-borne (pork)
- may be confused w appendicitis in its presentation or present w diarrhoea (+/- pharyngitis - can be helpful diagnostic clue!)
Associated with morbidity in iron overload syndromes
- Treatment with iron chelating agents (desferrioxamine) makes iron more available to the bacteria so can lead to infection/sepsis
What sort of anaemia does lead poisoning give you and why?
What is the typical presentation
What ix would you perform
What is the management?
Microcytic sideroblastic anaemia due to defective heme molecule synthesis
Lead blocks an enzyme involved in the production of the heme molecule
Presentation:
In setting of old houses with chipping paint
Dark pigmentation in gingiva of gums (Burton lines)
Can also see lead on metaphysis on long bones on Xr
CNS changes
Abdo pain
Ix
- Plasma lead levels
- Blood smear - microcytic aneamia with sideroblasts (ringed appearance of nucleus of RBC)
Mx
- Lead chelation
(Succimer in kids -> ‘sucks the lead out’)
What is sideroblastic anaemia
Mechanism
Causes
Ix
Bone marrow produces RINGED SIDEROBLASTS instead of normal RBCs
Type of microcytic anaemia caused by disordered haem synthesis
Mechanism - defect in an enzyme involved in production of heme molecule and incorperation of Fe
Underlying causes
- Genetic (x-linked)
- Acquired (Myelodysplasia, malignant disease of BM)
- Reversible
- Alchohol
- LEAD POISIONING
- Vitamin B6 deficiency
- Cu deficiency
- Medications (isoniazid)
Ix
- Microcytic hypochromic anaemia
- ELEVATED ferritin and iron (as unable to incorporate the iron into Hb)
- Peripheral smear: basophilic stippling if lead poisoning
- Bone marrow smear: ringed sideroblasts
- What is diamond black-fan anaemia
- Key features
- Main differential dx
- When does it tend to present?
- Mx
- Rare congenital aplastic anaemia (bone marrow failure syndrome)
- Pure red cell aplasia
- AR inheritance
- Ribosomal synthesis defect intrinsic to erythroid progenitor cell - Initially pale in neonatal period; profound sx-atic anaemia by 2-3 mo of age
- Congenital abnormalities (50% craniofanical, 38% GU, 30% skeletal, 30% cardiac)
- -> short stature
- –> triphaengeal thumbs
- Malignancy predisposition
Ix
- Normochromic, macrocytic (or normocytic) anaemia
- Low retics
- BM trephine bx: Insufficient/absent RBC precursors
- Incr iron
- Elevated HbF levels
- INCR ADA activity
- TEC (transient erythroblastopaenia of childhood) -> ADA differentes the two (normal in TEC but RAISED in DBA)
- Presents <1yo (2-6mo) in 90% cases
- Mx
- Steroids (80% responsive)
- Transfusions as necessary
- If unresponsive, androgens and HSCT can be tried
- What is TEC
- Key features
- Main differential dx
- When does it tend to present?
- Mx
- Acquired red blood cell anaemia
- Often following viral illness in previously healthy toddlers
- Severe transient (lasts 1-2 months) hypoplastic anaemia that develops slowly and becomes symptomatic only with severe anaemia
- Normocytic anaemia
- Reticulocytopaenia - Diamond blackfan anaemia (presents younger, no viral trigger, often has syndromic presentation, macrocytic)
- Presents age 1-3 (toddlers)
- Self resolution, only blood transfusion if severe anaemia
What virus is commonly associated with red cell aplasia?
Underlying risk factors for this
Relevant Ix for diagnosis
Parvovirus B19
- Anaemia only occurs in immunocompromised patients and/or those with chronic haemolysis (reduced RBC lifespans)
Ix
- Parvovirus IgG/IgM + PCR
- Blood smear
- Bone marrow
- Pathogenesis of anaemia of chronic disease
- What conditions does this include
- What sort of anaemia does this give you
- Mx
- Immune system induces
- Impaired erythropoeisis (make less)
- Decr red cell life span (last less long)
- Incr uptake of iron from the circulation into the reticuloendothelial system results in functional iron deficiency -> impaired heme synthesis and iron-restricted erythropoiesis - Conditions with ongoing immune activation:
- Infection
- Malignancy
- Autoimmune cdtns
- GVHD - Normocytic normochromic anaemia
- Treat underlying condition
+/- EPO (erythropoitic stimulating agents
+/- Iron transfusion (may not be beneficial as persistent inflammation impairs iron absorption and utilisation)
Pathophysiology of thrombus formation
Endothelial damage of vessel wall -> exposes collagen (vWF) -> platelets GPIIb receptor binds to vWF on collagen -> plt activated -> release thromboxane A2 -> recruits more plt -> fibrin binds to GPIIb receptors which links plts together and traps RBCs within matrix -> more fibrin forms and cycle continues = THROMBUS formation
How to cox inhibitors work?
Give example of such a drug
Blocks thromboxane A2 production so plt won’t stick together and thus thrombi cannot form
Ex - Aspirin
Intrinsic coagulation cascade
What is the pathway
12, 11, 9, 8
Important in AMPLIFICATION of cascade
‘contact’ pathway as has activation by negatively charged surfaces
Factor 12 -> Factor 12a (activated) -> Factor 11 to 11a -> factor 9 to 9a and factor 8 to 8a -> converts factor 10 to 10a
Common
10a -> prothrombin to thrombin via factor 5a -> fibrinogen to fibrin -> cross-linked fibrin to form stable clot via 1a and 13a
Extrinsic coagulation cascade
What is the pathway
What is it important for
7
Important in INITIATION of cascade
Tissue factor released from damaged tissue -> converts factor 7 to 7a -> converts factor 10 to 10a
Common
10a -> prothrombin to thrombin with help of factor 5a -> fibrinogen to fibrin-> cross-linked fibrin to form stable clot via 1a and 13a
Common coagulation pathway
Factor 10 to 10a -> prothrombin to thrombin with help of factor 5a -> fibrinogen to fibrin -> cross-linked fibrin to form stable clot via 1a and 13a
Thrombin amplifies cascade by accelerating production of factor 11a, 8a and 5a to help produce necessary amt of fibrin in a short period of time
How to cox inhibitors work?
Give example of such a drug
Blocks thromboxane A2 production so plt won’t stick together and thus thrombi cannot form
Ex - Aspirin (irreversible)
NSAIDs (reversible)
Role of antithrombin III
Endogenous compound (present in body) Inhibits factor Xa and inhibits thrombin formation from prothrombin
Role of plasmin
What is plasmin made from?
Made from plasminogen via enzyme tPA
Degrades fibrin
How does heparin and LMWH work (What is the difference between the 2)?
What pathway does it primarily act on and what test do you perform to monitor levels?
Metabolism?
Is there a reversal factor?
Complications?
- Activators of antithrombin III -> inhibits factor Xa and inhibits thrombin formation -> prevents thrombus formation (good for prevention)
- Heparin ihibits factor Xa AND thrombin, continuous IV infusion
- LMWH inhibits factor Xa, not thrombin, so has delayed onset of action and longer duration of action (dosed less frequently but also unable to stop rapidly), is a BD S/C inj - Intrinsic pathway, monitor aPTT or anti factor Xa
- Heparin binding to macrophage cells is internalized and depolymerized by the macrophages.
For higher doses of heparin, endothelial cell binding will be saturated, such that clearance of heparin from the bloodstream by the kidneys will be a slower process. - Heparin can be reversed with protamine sulfate. LMWH less easily reversed by this.
- Complications
- bleeding
- osteoporosis
- Hep-induced thrombocytopaenia
How does tPA (tissue plasminogen activator) and streptokinase work?
Activate formation of plasminogen into plasmin -> degradation of fibrin
Good if thrombus already formed
Role of Gamma carboxyglutamic acid
Is an amino acid formed from glutamic acid when vitamin K is reduced, requires enzyme vitamin K reductase to catalyse reaction.
Component in formation of factors 2, 7, 9, 10
How does warfarin work?
What pathway does it primarily act on and what test do you perform to monitor levels?
How is it metabolised?
What is the reversal agent?
- Vitamin K antagonist
- Inhibits enzyme vitamin K reductase in liver -> prevents formation of gamma carboxyglutamic acid and thus prevents formation of factors 2, 7, 9, 10 - Primarily affects extrinsic pathway, thus monitor the PT/INR
- Metabolised in liver by enzyme CYP350 2C9 isoform
- Reverse with Vit K or FFP
Where does haematopoesis occur and how does this change in fetus vs at/post birth?
Medullary vs extramedellary haematopoesis
- Bone marrow (by birth and following this, main site)
- Mostly occurs in vertebrae, pelvis and sternum (medullary haematopoesis)
- Liver (majority pre-birth but no to minimal role post birth except during infection or disease)
- Spleen (second most common site pre-birth but no to minimal role post birth except during infection or disease)
- Lymph nodes (mostly during adulthood during periods of infection)
Extra-medullary haematopoeisis (liver, spleen, lymph nodes - infection or pathological)
Haematopoesis
Haematopoeitic stem cell -> common lymphoid or common myeloid progenitor cell
Common lymphoid progenitor
- > naive B cell
- > pre T-cell
- > Natural killer cell
- > dendritic cell
Common myeloid progenitor cell
a) myeloblasts
-> band neutrophil (Acute inflammation response to infection)
-> band basophil (parasitic infection and allergy)
-> band eosinophil (allergy and sensitivity)
Note - Band is immature form in blood, becomes mature form when enters tissues
b) Monocytes (circulating macrophages
- > become macrophages or dendritic cell when migrate into tissues)
c) Mast cell precursor
- > become mast cell in tissue (allergy and sensitivity)
d) megakaryocyte
- > release platelets into circulation (clotting)
e) erythroblast (nucleated immature RBC)
- > become RBCs in circulation following stimulation via erythropoietin from kidneys
Drugs that interact with warfarin and affect on PT/INR
Prolonged INR (incr effect)
- Azoles, amiodarone (inhibit CYP450 2C9)
- Bactrim, azoles, erythromycin (macrolides), fluroquinolones: alter intestinal flora to reduce intestinal vit K synthesis
Reduces INR (decr effect) - Carbemazepin, phenytoin (CYP450 2C9 inducers)
What is the standard target INR for warfarin?
How long does warfarin take for levels to become therapeutic and what do you do in the meantime?
5-7 days to reach target INR 2-3
Bridge with LMWH or UFH
How does dabigatran work?
How is this administered and is any monitoring needed?
Direct thrombin inhibitor
Anticoagulant
Fixed oral dose, no need for regular monitoring
How does apixaban and rivaroxaban work?
How is this administered and is any monitoring needed?
Both are inhibitors of factor Xa
Anticoagulant
Fixed oral dose, no need for regular monitoring
What is the indication for thrombolytic therapy?
Give an example of the agent used in children?
How does this work?
What are the absolute contraindications to this tx?
- When rapid clot resolution in necessary in setting of life or limb threatening thrombosis (due to high risk bleeding)
- tPA (tissue plasminogen activator)
- Activate fibrinolytic system – conversion of endogenous plasminogen to plasmin -> plasmin can degrade several plasma proteins including fibrin and fibrinogen
- Absolute CI
- Significant bleeding/haemmhoraging (IC/pulm/GI)
- Peripartum asphyxia w brain damage
- Uncontrolled HTN -> haemmhoragic stroke risk
- Severe thrombocytopaenia -> bleeding risk
Hereditary causes of thrombosis
Most common
- factor V leiden (then prothrombin mutation)
Deficiency/ abnormalities of coagulation inhibitors:
- Antithrombin deficiency
- Protein C/ S deficiency
- Activated protein C resistance (Factor V Leiden)
Metabolic defects
- Homocystinuria
Abnormality of coagulation enzyme/ cofactor
- Prothrombin mutation (results in excess production)
- Elevated factor 7/9/10/11
Factor V leiden
What causes this condition
What does it cause/pathophys
Ix for diagonsis of this condition
Mx of this condition
Single point mutation in factor V gene (Arg506- > Gln), preventing binding of factor V to activated protein C
5-7 fold incr in risk of VTE vs homozyg have RR of 80-100
Causes activated protein C resistance
- Protein C is activated by thrombin in order to slow down its formation
- aPC degrades factor Va, reducing thrombin formation (negative feedback loop)
Ix
- Activated protein C resistance assay (APTT in presence and absence of exogenous APC -> APC should prolong APTT; in FVL this doesn’t happen)
- DNA analysis via FISH
Mx is long-term anticoagulation in those with
- recurrent VTE
- other RF (pregnancy, HRT, travel)
- homozygotes (not for asymptomatic heterozygotes)b
Wiskott-Aldrich Syndrome
WASP and TIME
Wiskott Aldrick Syndrome Protein defect -> affects cell signalling
X-linked (boys) - presents in infancy
4 main features:
- Thrombocytopaenia with small platelets -> petechiae, easy bleeding
- Immunodeficiency -> infx w encapsulated organisms
- Malignancy risk (EBV associated)
- Eczema, infant-onset
Clinical features of TAR syndrome and classic age of presentation
Severe thrombocytopaenia at birth or in the first week (tends to freq remit over first few years of life)
Bilateral absent radii - Thumbs ALWAYS present
- 50% have leg involvement: patella, hip, knee dislocations, tibial torsion
Congenital heart disease in 1/3 of patients
CMPI (present in 50-100%)
Clinical features of Congeintal amegakaryocytic thrombocytopaenia (CAMT)
Type of congenital thrombocytopaenic disorder due to mutation in stem cell TPO receptor (MPL)
CAMT is usually diagnosed anywhere from birth to nine months but often in a child’s first month of life. There are two forms of the disease:
Group I CAMT—severe, persistent thrombocytopenia (low platelet count) and early onset of pancytopenia (low red and white blood cell count) around ~1 yo
Group II CAMT—temporary increase in platelets early in life, with possible later development of pancytopenia. BM failure 3-6yo.
Presents: petechiae and purpura +/- IC/pulm/GI etc bleeding without other physical abnormalities
Results in thrombocytopaenia with subsequent aplastic anaemia + BM failure
Diagnosis - BM biopsy: reduced megakaryocytes -> genetic analysis for c-MPL
Tx
- Bone marrow transplant is definitive tx
+/- Need for regular plt transfusions
Iron sources
Factors
Enhancing absorption
Decreasing absorption
Iron sources
- Heme iron in red meat
- Non heme iron from other non-meat
- Enhanced by gastric acid, vit C, breast milk
- Decreased by cow milk protein, egg white, bran, Ca, Zn, lead
What is the difference between
- iron depletion
- iron deficiency
- iron deficiency anaemia
Depletion: Low ferritin, normal MCV/MCH/Hb
Deficiency: Low ferritin, Low MCV+/- MCH, normal Hb
Deficiency anaemia: Low ferritin, low Hb
Causes of iron deficiency
Neonatal period
Vs Infancy
Vs Older kids/teens
Neonatal
- maternal iron deficiency
- prematurity (lower iron stores and require more to grow)
- perinatal haemorrhagic event
Infancy
- Dietary
- Cow’s milk under 1 yo (human milk 2-3x better absorbed)
- Delayed introduction of solids
- Lack of iron supplementation in breast fed babies
- Use of low iron formula
- Malabsorptive disease (coeliac; Fe2+ absorption in duodenum and jejunum)
- Blood loss
- Oesophagitis
- Meckel’s diverticulum
- CMPI
Older kids/teens
- Dietary
- Excessive cow’s mlk (>500ml/day)
- Insufficient iron-containing foods
- Malabsorption (coeliec, IBD)
- Blood loss (menstrual urinary losses, worms, bleeding disorder, hereditary haemorrhagic telangiectasis, peptic ulcer)
Ix
- FBE, iron studies, film
- Coeliac screen
- ?haematuria ?menorrhagia ?scopes ?meckel scan ?hook worm
Iron defieincy changes to FBE and iron studies
- MCV
- RDW
- Plt
- Ferritin
- Transferrin receptors and saturation
- MCV low
- HYPOCHROMIC red cells (white bit central to RBC is =/> 1/2 of RBC diameter)
- RDW high
- Plt moderately high (or normal)
- Ferritin low (not always depending on bg state of inflammation)
- Transferrin receptors high (note - not affected by inflammation)
- Transferrin saturation low
- Pencil cells on blood film
Causes of B12 deficiency anaemia
Reduced intake
- breastmilk fed mubs to vitB12 deficient mothers
- vegan diet
Impaired absorption
- Gastric anomalies (incl Pernicious anaemia, hereditary IF deficiency, Gastrectomy/bariatric surgery, Gastritis, autoimmune atrophic gastritis)
- Small bowel disease (Malabsorption, IBD, coeliac, bacterial overgrowth, tapeworm, ileal resection/bypass)
Pancreatic disease
Drugs which impair absorption
- Neomycin
- Metformin
- PPIs, H2 antagonists
Impaired transport
- inherited Transcobalamin II deficiency (cannot absorb or transport B12)
B12 deficiency
- Changes on blood film
- What inv confirms diagnosis?
- What is mx of B12 clinical deficiency
Hypersegmented neutrophils
Oval macrocytes
Macrocytic anaemia - large, darkly coloured RBCs
Low Active B12 or Elevated serum methylmalonic acid level confirms diagnosis (NOT total B12)
Mx
- Infants + older pts with neurological sx: replacement with IM B12
- Older children/low risk: oral replacement
Transcobalamin II deficiency
What is it?
Presentation
Diagnosis
Tx
failure to absorb and transport B12
Manifests first week of life – FTT, diarrhoea, vomiting, glossitis, neurologic abnormalities + megaloblastic anaemia
Diagnosis
o Severe megaloblastic anaemia
o Normal serum B12 and folate levels BUT LOW ACTIVE B12
o No evidence of any other inborn errors of metabolism
Treatment
o Large parenteral doses of B12 – ‘overcomes’ transcobalamin deficiency
o Death in infancy if untreated
Causes of folate deficiency
Incr requirements
- Pregnancy
- Accelerated growth after birth w incr demands
- Haemolysis
Inadequate dietary intake
- malnutrition
Decr absorption
- Chronic diarrhoea
- Diffuse inflammatory disease
- Coeliac
- Prev intestinal surgery
- Some anticonvulsants (phenytoin, primione, phenobarbital)
- Alcohol overuse
Disorders of folate metabolism/transport
- Hereditary folate malabsorption
- Enzyme deficiencies
- Drugs (methotrexate, primethamine, trimethoprim)
Clinical manifestations of folate def
a. Irritability (older – depression, dementia, psychosis)
b. Chronic diarrhea
c. Poor weight gain
d. Advanced – haemorrhages from thrombocytopaenia
Folate def
Ft on blood film and FBE
FBE = macrocytic anaemia, low reticulocytes +/- neutropaenia +/- thrombocytopaenia
i. Note: acute folate deficiency not macrocytic
Film = nucleated RBC with megaloblastic morphology, variation in RBC size/shape, neutrophils large some with hypersegmented nuclei
Serum folic acids levels = < 3ng/ml (normal 5-20ng/ml)
RBC folate= is a better indicator of chronic deficiency (normal 150-600ng/ml)
Tx folate def
Note - must exclude Vit B12 deficiency before treating (levels should be normal/elevated)
Folic acid – oral or parenteral for 3-4 weeks, 0.5-0.1mg/day as treatment then multivitamin as maintenance
What supplement do pregnant women receive for prevention of nuchal tube defects (spina bifida)?
folate
Blood supply to and from spleen
Is spleen intra or extra peritonitic?
Splenic artery (frmo celiac trunk off abdominal artery
Splenic vein -> portal vein
Intraperitonitic
Major components of hte spleen (x3)
- Lymphoid compartment (white pulp) = immune fxn, stores WBCs
- periarterial lymphatic sheaths of T lymphocytes with embed germinal centres containing B lymphocytes - Filtering system (red pulp, 75%) = destroys and filters old and unhealthy RBCs, recycles heme, plt reservoir
- skeleton of fixed reticular cells, mobile macrophages, partially collapsed endothelial passages (cords of Billroth), and splenic sinuses. - Marginal zone separates the red pulp from the white pulp = rich in dendritic APCs
- Splenic capsule = smooth muscle and contracts in response to epinephrine
Functions of spleen
- Fetal haematopoiesis (first 3-6mo of fetal life although liver more so)
- Reservoir
- Factor VIII and plt are sequestrated in spleen for release when ‘stressed’ (adrenaline) - Filtering old/damaged/abnormal RBCs
- Host defence (largest lymphoid organ in body)
- Dendritic cell from periphery brings Ag (Ag-presenting cell) and present it to T cells in white pulp of spleen -> activate T cells -> T cells activate B cells to become plasma cells -> plasma cells produce Abs +++ against Ag that was initially presented (IgM or IgG)
- macrophages in white pulp pick up viruses that travel to spleen -> activate T cells -> … etc (same as above)
- encapsulated bacteria
Definition of splenomegaly in kids
Causes of splenomegaly
>2 cm below the left costal margin = abnormal
- CHF
- Cirrhosis -> portal HTN
- Thrombosis of portal or splenic vein
- Malignancy (leukaemia, lymphoma, Hodgkin, mets)
- Infections
- Extra-medullary haumatopoeisis (myelofibrosis etc)
- Autoimmune and inflammatory conditions (SLE, RA, serum sickness)
- Haematological (sickle cell, haemolytic anaemia)
- Infiltrative (sarcoid, amyloid etc)
Asplenia
- causes
- complications/risks assoc w asplenia
- Blood film feature
Congenital absence
Splenectomy
Infarct of spleen (sickle cell can cause this)
Infiltration (amyloid, sarcoid)
Functional
- prematurity
- malaria
- post-radiation
- overwhelming of reticuloendothelial function (Severe hemolytic anaemia)
Decr splenic function leads to incr risk of infection (polysarrcharide encapsulated eg: Streptococcus pneumoniae, Haemophilus influenzae, and N. meningococcus)
AND incr risk of thromboembolic disease (loss of filtration of abnormal RBCs -> clots)
Blood film feature : howell-jolly bodies
Mx of asplenia and infective complications (what abx to use?)
a. Register with Spleen Australia
b. Education
c. Vaccination
- pneumococcal (addit booster)
- meningococcal quadrivalent + B
- haemophilus
- annual flu
d. Antibiotic prophylaxis
- Prophylaxis with Oral amoxicillin 20 mg/kg daily or Oral phenoxymethylpenicillin (penicillin V)
e. Rapid treatment of infections
- Emergency abx - augmentin
- Sepsis - IV cefotax or ceftriaxone +/- vanc
What is the average lifespan for normal human RBC and plts in circulation?
RBC = 120 days plt = 10 days
What things do
1. FFP
2. Cryoprecipitate
Replace in blood?
- FFP contains all coagulation factors and other proteins in original unit of blood
- Note - cryo is derived from FFP. Contains fibrinogen, factor 8, factor 13, vWF
What is the biggest risk of plt transfusion?
Why is this?
Bacterial contamination -> sepsis (second biggest risk of blood product infusions secondary to ABO incompatibility)
This is because plts are stored at room temp
Presentation G6PD
Diagnostic ix of choice?
Findings on blood film
X-linked recessive condition of G6PD enzyme deficiency
Presentation
- Neonatal jaundice (rarely w anaemia), days 2-3 of life
- Episodic haemolytic anaemia w classic precipitants that cause oxidative stress (sepsis, drugs like antimalarials, bactrim, moth balls, fava beans)
Ix: macrocytic anaemia w reticulocytosis during crisis, haemoglobinuria (intravascular haemolysis)
Diagnostic is G6PD red cell enzyme levels (low)
Blood film
- Blister/bite cells
- Heinz bodies
What is link between G6PD and malaria
Advantage of resistance to falciparum malaria in heterozygous females
What is the biggest risk of plt transfusion?
Bacterial contamination (second biggest risk of blood product infusions secondary to ABO incompatibility)
How many mg iron in 1 unit of pRBC
200mg
Methaemoglobinaemia
Functional anaemia
-> Hb therefore contains Fe in oxidised form Fe3+ (ferric) rather than Fe2+ (ferrous)
Causes
- Hereditary deficiency in cytochrome b5 reductase (enzyme in RBCs)
- Drug reaction oxidising the Iron
Main risk factors (conditions ) for iron overload
Beta thalassaemia
Sickle cell anaemia (if sustained transfusions)
Diamond Blackfan anaemia (lot of transfusions)
MDS (quite a few transfusions)
Complications/presentations of Sickle cell anaemia
Ft on blood film
Vaso-occlusive cx
-> Lung blood vessels
= Acute chest syndrome (50% of pts w SCA)
-> Bones of hands and feet = dactylitis
-> Other bones (most common)
= bone/joint infx (if septic, think salmonella!)
= pain crisis
= avascular necrosis (hip/head of femur)
-> Spleen
= Infarct
= Splenic sequestration (leads to anaemia, thrombocytoaenia and splenomegaly) -> hypovolaemic shock
= Auto-splenectomy from fibrosis
= Susceptible to encapsulated bacteria (strep pneum, H infl, N men, salmonella)
-> Cerebral vasculature
= stroke (5-10% of pts w SCA) - do NOT give tPA, will cause them to bleed! Silent infarcts can cause poor school performance (high TCD = higher risk of stroke; give transfusion or hydroxyurea to prevent this)
= moya-moya
-> Renal papilae
= necrosis -> hematuria, proteinura, AKI
-> Penis
= priapism (prolongued/painful erection)
Triggers:
- PARVOVIRUS infx
- Infection
- Cold
- Hypoxia
- Dehydration
Neonatal allo-immune thrombocytopaenia
What is it?
Inheritance and pathophys
Clinical ft
Ix
NAIT occurs when fetal platelets contain an antigen inherited from the father (most commonly human platelet antigen [HPA]-1a) that the mother lacks.
The mother forms immunoglobulin G (IgG) class antiplatelet antibodies against the “foreign” antigen, which cross the placenta and destroy fetal and neonatal platelets that express the paternal antigen
Clinical ft
Maternal history of previously affected pregnancies
Neonate otherwise look well, but may develop thrombocytopenia, petechiae, bruising, and bleeding may be observed. The most serious complication is intracranial haemorrhage.
Ix
Platelets – moderate to severe thrombocytopaenia
Maternal antiplatelet alloantibody – maternal alloantibodies directed against the father’s platelets
Platelet Ag typing of mother and father’s platelets – to confirm Dx
CNS imaging – CrUSS + MRI
- Blister/bite cells
- Heinz bodies
On blood film = ?
G6PD deficiency
Bernard-Soulier disease
- what is it
- what causes it
- what is inheritance pattern
- clinical features
- Severe congenital platelet function disorder
- Absence or severe deficiency of VWF receptor on platelet membrane
- Inherited autosomal recessive
- Features: Giant platelets and prolonged bleeding time (> 20 mins); sometimes have thrombocytopaenia (not always as is a function disorder)
Howel jolly bodies on blood film = ?
Post splenectomy or hyposplenism
PT - what is this used to measure and in what diseases is it abnormal?
PT = prothrombin time
May be expressed as INR
Measure of extrinsic and common pathways (factors 5, 7, 10, PT, fibrinogen)
Prologued = liver disease, vitamin K dependent clotting factor deficiency (inadequate dietary intake, CF, coelic disease, haemmhoragic disease of newborn)
Used to monitor Warfarin therapy
Physiological adjustment to anaemia
- Incr Cardiac output -> incr blood/oxygen delivery to tissues
- Incr concentration of RBC 2,3 DPG
- > Right shift O2 dissociation curve
- > Decr affinity of Hb for O2 -> more complete t/f of O2 to tissues
haemoglobinuria - what does this indicate and what are possible causes?
Indicates INTRAVASCULAR haemolysis
-> If freshly collected urine from a patient with hematuria is centrifuged, red blood cells settle at the bottom of the tube, leaving a clear yellow urine supernatant. If the red color is due to hemoglobinuria, the urine sample remains clear red after centrifugation
Causes
- G6PD deficiency
- Sickle cell anaemia
- Pyruvate Kinase deficiency
- Paroxysmal nocturnal haemoglobinuria
- Transfusion reaction
- Warm or cold Ab
- Malaria
- Drug induced haemolysis
- Severe burns
Pyruvate Kinase deficiency
- what is it?
- sx
- ix
- mx
AR condition resulting in deficiency of pyruvate kinase enzyme resulting in rigid abnormal RBCs which are prematurely destroyed via autohaemolysis
Sx: mild sx of anaemia due to compensatory incr in 2,3DPG which helps with O2 offloading into tissues
- Jaundice
- Splenomegaly
- Gallstones
Ix
- Macrocytic anaemia with reticulocytosis
- FIlm: Echinocyte/Burr/Prickle cell, poikilocytes (abnormal shape), anisocytosis (uneven sizes), reticulocytes
- Diagnosis via RBC enzyme assay of PK levels (low)
Mx (same as hereditary spherocytosis)
- Transfusions as necessary
- Splenectomy if necessary (>6yo)
- Folic acid supplementation
What is Paroxysmal nocturnal haemoglobinuria
Pathophys
Clinical ft
Ix
Mx
Risk with progression of disease?
Is an acquired defect of RBC (+/- plt and WBC) that makes them susceptible to destruction by the complement-mediated lysis
Pathophys
- Acquired mutation in the PIGA (phosphatidylinositol glycan anchor biosynthesis, class A) gene in a self-renewing haematopoietic stem cell, followed by clonal expansion.
- The PIGA protein is involved in the initial step of the glycosylphosphatidylinositol (GPI) anchor synthesis, a glycolipid that links several cell surface proteins to the plasma membrane of haematopoietic cells.
Clinical features
- Haemolysis
- Dark urine (haemoglobin and haemosiderinuria)
- Thrombosis (main cause of mortality)
Ix
- Bone Marrow flow cytometry
- Ham’s test (the old test): red cell lysis occurs at low pH (complement activation at low ph)
Mx
- Eculizumab (inhibits C5)
- HSCT
- Prophylactic anticoagulation (if not on aculizumab)
Risk of progression to leukaemia or aplastic anaemia
Causes of aplastic anaemia
Typical Ix findings
CAUSES
- Congenital
- Fanconi anaemia (most common; crytorchdism, short stature, limb abnormalities, cafe au lait spots, 25% low IQ)
- Dyskeratosis congenita (nail dystrophy, mucosal leukoplakia, reticular pigmentation (lace-like pattern) of skin creases, premature ageing. may p/w liver or lung fibrosis)
- Diamond-blackfan anaemia (pure red cell aplasia)
- Shwachman syndrome (pancreatic insufficiency, short stature, FTT)
- Congenital amegakaryocytic thrombocytopenia (CAMT) - Acquired Aplastic Anaemia = 70% Idiopathic (MOST COMMON)
- HSCT best treatment - Secondary
- Drugs (chemo)
- Infx (viral hepatitis, measles, EBV, PARVOVIRUS, Tb)
- Malignancy (ALL prodrome)
- Radiation
- pregnancy
Ix
- FBE: normochromic macrocytic (or normocytic) anaemia
- LOW retics
- Leucopenia (particularly Neuts)
- Thrombocytopenia
*Definitive diagnosis via Trephine bone marrow bx (dry tap) = hypoplasia, replacement with fat cells*
A child with Sickle cell anaemia presents with fever, what are your top ddx for pathogens?
A fever in child w SSA is a medical emergency (high risk of septicaemia, meningitis, pneumonia, OM, particularly if <3yo)
Viral : Parvovirus
Bacterial: encapsulated (strep pneum, H infl, N men, salmonella)
IF SA/OM - think Salmonella!
Long term consequences of sickle cell anaemia
FTT
Aseptic necrosis of hip
Pigment gallstones sec to haemolysis
Priapism (persistent painful erection)
Renal failure
CCF
Proliferative retinopathy
Leg ulcers
Splenomegaly in infancy -> autosplenectomy
Bleeding time - what is this used to measure and in what diseases is it abnormal?
Used to measure platelet plug formation
Prolonged in platelet disorders: thrombocytopaenia, platelet function disorders, vWD
APTT - what is this used to measure and in what diseases is it abnormal?
Measure of intrinsic and common pathway (factors 5, 8, 9, 10, 11 ,12, PT, fibrinogen)
Used to monitor heparin therapy
Ddx thrombocytopaenia
Decr production
- Infection
- Drugs
- Wiskott Aldrich syndrome
- Aplastic anaemias /BM failure
- Malignancy and infiltration
Incr consumption or destruction
- ITP
- TTP
- Drug induced
- Post-infectious (malaria)
- NAIT (maternal anti-plt Ab)
- Post-transfusion (Pl Ab)
- SLE
- DIC
- HUS
Splenic sequestration
What is Polycythaemia?
Causes
Clinical features
Tx
Increased Hb and HCT > ULN
Relative
- hypovolaemia w decr circulating blood vol: dehydration
- Stress polycythaemia
Causes
- Compensatory: cyanotic heart disease, lung disease, central hypoventilation, high altitude
- other: renal disease, adrenal disease, tumour, IUGR, twin-twin transfusion, infant of diabetic mother
Clinical features
- headaches
- haemmhorage
- thrombosis
Tx
- Treat cause
- venesection rarely necessary
What is this?
Sickle cell anaemia
Blood film features: sickled cells, target cells, howell jolly bodies
What is this condition?
Iron deficiency anaemia
Features
- Microcytic and hypochromic red blood cells
- Secondary thrombocytosis which differentiates it from beta thalalassaemia
- Unlike thalassemia: you usually DON’T have target cells, and anisocytosis (abnormal variation in the size of RBC) and poikilocytosis (abnormally shaped RBC) are not marked
What is this condition?
Hereditary spherocytosis
In microscopical blood smear evaluation, spherocytic red blood cells appear as smaller round cells lacking the normal central pale area due to the absence of a normal biconcave shape.
Presentation: The classic triad in a child is of jaundice, anemia, and splenomegaly. The most common finding in neonates is jaundice.
What is this condition?
Thalasseaemia
Features
Microcytic and hypochromic red blood cells
- Target cells
- Anisocytosis (abnormal variation in the size of RBC)
- Poikilocytosis (abnormally shaped RBC - tear drop cells)
- Erythroblasts (nucleated RBC precursor)
What is this condition?
- bite cells
- blister cells
- heinz bodies
- target cells
- reticulocytes
What is this condition?
Megloblastic anaemia secondary to B12 deficiency
- macrocytic (large oval) RBCs
- hypersegmented neutrophils
what are anti-folate drugs?
- anti-folate drugs: MTX, phenytoin, trimethoprim
Who to give anti-D injections to in pregnancy?
RhD negative women
Prevention of Rh disease of the newborn
Glanzmann thrombasthenia
What is it/cause
Presentation
Diagnosis
Tx
- Rare AR bleeding syndrome affecting the megakaryocyte lineage
- Caused by lack of platelet aggregation (normal plt count)
- Deficient/abnormal GP2b/3a receptor (receptor for fibrinogen, mediates plt aggregation)
- Presentation is variable
- Mostly assoc w mucosal bleeding (purpura, epistaxis, gingival hemorrhage) and menorrhagia
- Severe forms can have potentially fatal hemorrhages
- In most cases, bleeding symptoms manifest rapidly after birth
- Diagnosis
- Normal plt count and morphology with prolongued bleeding time (normal APTT, INR)
-
Light transmission aggregometry is widely accepted as the gold standard
- Centrifuged platelet-rich plasma samples are monitored before and after the addition of an agonist (ADP, collagen, epinephrine, arachidonic acid, ristocetin, thrombin receptor activating peptide, and thromboxane A2 mimetic), assessing shape change, lag phase, percent of aggregation, slope of aggregation, and deaggregation. This test is highly specific for GT, as platelet aggregation fails to occur with any agonist, except ristocetin, where the reaction is preserved.
- Or PFA (plt functino analyser) or Flow cytometry
- Tx
- HLA-matched platelet transfusion when necessary
- Recombinant factor VIIa
this blood film + easy bruising; grey hairs, pale eyes and skin and frequent pyogenic infecitons =?
What are the other features and ix findings characteristic of this condition?
Chédiak-Higashi syndrome (CHS)
Diagnosis is made by recognition of the characteristic giant granules in neutrophils, eosinophils, and granulocytes on blood film
Other laboratory findings include neutropenia and hypergammaglobulinemia
partial oculocutaneous albinism, frequent pyogenic infections, silvery hair, photophobia, nystagmus and hepatosplenomegaly.
Aicardi syndrome
X-linked DOMINANT (Males don’t survive)
Classic triad
- Seizures
- Agenesis of the corpus callosum
- Chorioretinal lacunae
+ optic nerve coloboma and microphthalmia
what form is iron in when it is incorperated into Hb?
Fe 2+ (ferrous)
HbA
HbA2
HbF
HbE
HbA2 elevated in beta thal
How does HbS affect the o2 saturation curve?
Right shift - reduced affinity for O2
How does HbH affect the o2 saturation curve?
Left shift - INCREASED affinity for O2
HbE
What is this and what clinical disease states can it result in?
Structural variant of beta globin gene (G -> A substitution) common in SE Asia
HbE trait and Homozygous HbE is not clinically signigicant
HbE/beta thal is much more severe phenotype (transfusion dependent disease)
- ie inherited HbE from one parent and beta thal from other parent
HbE/S - mild sickle cell
which thalassaemias are transfusion dependent?
Regular lifelong transfusions required for survival
- Beta thal major (beta 0 x2)
- HbE/beta thal
- Hb Bart hydrops (alpha thal major)
Only when unwell/pregnant/surgeries or intermittently
- Beta thal intermidia
- HbH (alpha thal intermidia)
for which thalassaemias are transfusions NOT required?
alpha thal trait
beta thal minor
