1
Q
Tranexamic acid
A
TXA is an antifibrinolytic that works to counteract the degrading effects that plasmin has on fibrin, thereby preserving stabilised fibrin to participate in the clotting process for longer
2
Q
Cryoprecipitate
A
Cryoprecipitate contains mostly fibrinogen, factor 8, factor 13 and von Willebrand factor
3
Q
Disorders of red cell production (cause Anaemia)
A
haematinic def (iron, b12, folate) marrow failure marrow replacement anaemia of chronic disease ineffective erythropoeisis dyserythropoeisis
4
Q
Disorders of haemolysis (increased destruction RBC)
A
- Immune
- autoimmune (AIHA - warm IgG, cold IgM)
- alloimmune ( HDN) - DAT+ve
- -> DAT to distiguish - non-immune
- inherited haemaglobinopathies (sickle, thalassemia)
- inherited RCC membrane disorders - spherocytosis
- inherited RCC metabolism disorders - G6PD
- infection –> malaria
- physical damage –> MAHA, thermal, cardiac defects
5
Q
MAHA
A
microangiopathic haemolytic anaemia –> caused by PHYSICAL damage.
NOT inherited and NOT immune mediated
associated with DIC and sepsis
HUS, TTP, SLE,
malignancy, post total body irradiation, post transplant, drugs –>calcineurin inhibitors such as tacrolimus and cyclosporin); Sirolimus; mitomycin C; clopidogrel
Presence of fragmented RCC (shistocytes) and anaemia
6
Q
Haemolytic anaemia
A
Lots of causes (see disorders of haemolysis)
Most common are: ABO/resus incompatibility post viral hereditary spherocytosis HUS Can be associated with autoimmune phenomena (SLE) or immunodeficiency (SCID)
Can get: macrocytosis Raised reticulocytes Raised bili (more so in chronic) Raised LDH (break down) schistocytes polychromasia Need to do DAT to see if autoimmune
Treatment:
- support with folic acid
- avoid T/F as hard to provide compatible blood
- Warm(rather than cold agglutinan) antibody mediated autoimmune haemolytic anaemia responds to steroids
- treat underlying disease
- if can’t treat underlying disease AIHA may be refractory to Rx
7
Q
Evan’s syndrome
A
Rare autoimmune disorder
- autoimmune haemolytic anaemia (DAT +ve)
- immune thrombocytopenia
8
Q
Hereditary spherocytosis
A
Autosomal dominant (3/4 have family Hx) disorder RBC membrane which leads to spherocytes and haemolysis. More common Northern European
presentation heterogeneous
deficiency or dysfunction of RCC cytoskeleton (spectrin, ankyrin or band 3)
Present - neonatal jaundice
Mild/ mod haemolytic anaemia (low Hb, high retics, raised bile and LDH) DAT -VE
SPLENOMEGALY almost always
can get gallstones in chronic disease
Low hb, raised retics
spherocytes and polychromasia
DAT NEGATIVE ( if +ve think SLE )
Raised bilirubin and LDH
Ix:
Eosin-5-maleimide (EMA) binding –> esp if no Fhx
-LOW result confirms Dx
Osmotic fragility (no longer used
Rx:
- Folic acid, T/F
- Splenectomy if transfusion dependent (increased risk of encapsulated bacteria and VTE)
- Cholecystectomy if sx gallstones at same time
9
Q
Congenital TTP
A
Autosomal recessive
Defect in ADAMTS13 gene
ADAMTS13 gene processes a large protein called von Willebrand factor. It helps to prevent uneccesary clotting
Usually occurs in infancy and childhood but can occur when a woman is pregnant
Clotting in small blood vessels
fever and puprura/petechiae
Clinical (FAT RN)
- Fever
- MAHA
- Low platlets
- Renal impairment
- CNS (neuro)
Haemolytic anaemia - schistocytes Low Hb, Low Plt, Raised LDH and bilirubin Raised creatinine/proteinuria Coags normal
Rx: plasma exchange +/- immunosuppression
10
Q
Beta thalassemia major
Note (intermedia, homozygous but less severe)
Note (minor –> genetic counsellor as a carrier)
A
Mutation of HBB gene on chromo 11
Autosomal recessive
No beta chains
Jaundice, fatigue, frotal bossing, gallstones, splenomegaly, maxillary hyperplaisa, dental malocclusion
Raised HbA2 (because can't make B chains) Mildly raised HbF
Ix:
Haemaglobin electrophoresis
Hb A2 and HbF measurement
Antenatal:
CVS, sequence B globulin chains
Rx:
- T/F dependent –> TF if <90. Hypertransfuse aim Hb>100 pre next TF
- iron chelation (as risk of iron overload). 3 drugs:
- deferoxamine –> SC over 8 hours, feel unwell. increased risk of cataracts
- Deferipone –> increased risk agranulocytosis
- Deferasirox –> increased risk of renal impairment - Transplant –> matched sibling. done first 10-12 years
Risk of Fe toxicity: Diabetes arthritis heart depositions--> arrythymias, CHF cirrhosis of liver
11
Q
Alpha thalassemia
A
AR
Defect chromo 16p
Jaundice, fatigue, frotal bossing, gallstones, splenomegaly
Common in SE asian population
Haemaglobin electrophoresis
- beta chains in aduts
- gamma chains in neonates
Haemoglobin BARTS (gamma x 4 chain) = only gamma chains if no HA2 (results in death in neonate as poor affinity 02
HbH (beta x 4 chain)
12
Q
chronic benign neutropenia
A
1:100,000 assoc with minor infections less than 4 years old (90% occur <14 months) \+ve anti-neutrophil autoantibodies 95% remission 7-24 months
13
Q
Sickle cell
A
AR, abnormality in B chain SS (Ch11)
HbS and HbA = trait ; HbSS = disease
less severe if also inherited a thalassemia trait
Result of single base pair change, thiamine for adenine in globin chain. Missense mutation (GAG to GTC) causing substitution of a valine for glutamic acid on HbS molecule on beta globulin surface
Issues are
- vasoccclusive crises (dactylitis, AVN hip, priapism, stroke, splenic infarct) Rx O2, morphine, IVF, T/F
- Acute chest syndrome
- aplastic, haemolysis(intravasc and extravasc) and
- sequestration
Rx:
splenectomy (need vaccine and penicillin prophy)
Avoid precipitants
Rare TF ; need iron chelation if freq TF (iron >100mg/kg = 20-30units)
Hydroxyurea ameliorates disease by increasing HbF
Risk of proliferative retinopathy (HbSC disease)
14
Q
Schwachman diamond syndrome
A
mutation SBDS gene (Ch7), AR
Shwachman-Diamond syndrome is the second most common cause of inherited pancreatic insufficiency after cystic fibrosis and the third most common inherited bone marrow failure syndrome after Fanconi anemia and Diamond-Blackfan anemia.
- Exocrine pancreatic insufficiency with malnutrition and poor growth (low faecal elastase)
- metaphyseal abnorm (short stature, skeletal dysplasia)
- Neutropenia - > bone marrow failure
- Neutropenia/neutrophil migration defect (can have cyclical neutropenia–> Recurrent bacterial infections of the upper respiratory tract, otitis media, sinusitis, pneumonia, osteomyelitis, bacteremia, skin infections, aphthous stomatitis, fungal dermatitis, and paronychia are common
Risk AML and MDS
high risk AML with GCSF
15
Q
Congenital neutropenia
A
signficant infection hx - pneumonia, abscess, gingivitis
elevated monocytes or eosinophils (+ low neu)
Multigene disorder >50% mutation in neutrophil elastane gene (ELANE)
Kostman's syndrome --> AR form of CN -assoc with cognitive defects and seizures HAX1 mutation - early onset and severe infections -may need high levels gcsf
Rx
GCSF
HSCT
RISK MDS/AML later life
16
Q
DDAVP
A
promotes release of vWF through releasing endogenous factor VIII
Used in treatment of mild haemophilia A and thrombocytopenia and VWD
17
Q
Fanconi anaemia
A
AR ; multiple genes, very rarely is X-linked
Increased risk Ashkenazi jews
Most common inherited BM failure syndrome
Defect in DNA repair
Median age presentation age 7
Clinical BM failure - Cytopenias (macrocytosis) Skin - CAL spots Short stature Skeletal problem - abnormal thumbs/absent radii Genitourinary defects 25% have no associated features Risk malignancy (AML, MDS, solid tumours)
- Most common congenital bone marrow failure syndrome (2nd is Diamond black, 3rd is Schwachmann diamond)
- Type of chromosomal breakage syndrome (along with telangectasia ataxia)
- Significant increased risk of leukaemia esp AML(1/3 by 40)
- significant increased risk of head/CNS, neck, GI, genital (1/4 solid tumour by 40)
Dysmorphic features:
- ABNORMAL THUMBS
- ABSENT RADII
- cafe au lai spots
- strabismus
- low set ears
- hearing loss
- short
- triangular facies,
- microcephaly
- -abnormal kidneys, decreased fertility
Ix:
Chromosomal breakage studies
18
Q
Acute splenic sequestration crisis
A
Splenic sequestration occurs primarily in infants, as early as five weeks old. Approximately 30% children with sickle cell anaemia will have splenic sequestration.
This presents as engorgement of the spleen, a rapid increase spleen size, hypovolaemia and a decreased haemoglobin. Reticulocytosis may be present
It is often precipitated by URTI, bacteraemia, viral infection.
The treatment is to stabilise haemodynamically, and then carry out a prophylactic splenectomy after the first event.
19
Q
Diamond Blackfan anaemia
A
- Rare congential marrow failure syndrome that presents in early infancy (90% <1year, median age 2-3months)
- Normocytic/macrocytic anaemia with low retics
- Absent erythroid progenitors in BMA
- Most autosomal dominant inheritance, assoc mutations in RPS19 gene
- Profound anaemia by 2-6mo age
- 50% have assoc congenital anomalies
o Craniofacial (50% - hypertelorism, high arch palapte, snub nose
o Skeletal abnorm 30%; Thumb abnormalities (triphalangeal thumb)
o Genitourinary problems – 30%
o Cardiac problems
o Opthalmological problems
o Short stature common - RBC: Macrocytic anaemia, Elevated HbF; Increased ADA(adenosine deaminase), Low Retics
- Increased ADA activity (helps distinguish from transient eryroblastemia childhood)
- NB outrule Parvovirus
Treatment: Steroids – 80%respond, chronic transfusion Tx; HSCT
- Assoc with increased risk MDS, AML
20
Q
Target cells and tear drop cells are consistent with?
A
Thalassaemia trait
21
Q
What is haemoglobin made up of and how is it made?
A
4 globin chains + haem Fetal (HbF) = a2 + y2 Adult(HbA) = a2 + b2 Haem is developed in the mitochondria of developing erythroblasts. Haem = porphyrin (from Vit B6) + iron. 90% of EPO comes from kidney.
Adult HbA: 1 pair alpha and 1 pair beta (a2b2), at term 30% total Hb, by 6mo >95%
HbA2(2alpha, 2 delta) – at birth <1%, by 12mo age, normal ratio 2-3% ; Normal ratio HbA to HbA2 = 30:1
Increased levels in beta thalassemia and megaloblastic anaemia ;
Reduced in IDA and alpha thalassemia
Fetal HbF: a2y2(2 alpha, 2 gamma), at birth represents 70% total Hb, by 12mo only trace present, <2%
Elevated HbF is seen in beta thalassemia, sickle cell, haemolytic anaemia, leukaemia and aplastic anaemia
Fetal RBC life span 60-90days, Adult RBC lifespan 120days
22
Q
Which factors shift the oxygen dissociation curve to the left?
A
Shift to left = increased affinity for oxygen
Alkalosis, low CO2, low temp, low 2,3 DPG, HbF
23
Q
Which factors shift the oxygen dissociation curve to the right?
A
Shift to right = decreased affinity for oxygen
Acidosis, hight CO2, high temp, high 2,3 DPG, Hb S, exercise
i.e. shifts to right when tissues need more oxygen
“Right Raised Reduced affinity”
24
Q
What is Hb Barts?
A
4 x fetal gamma chains due to 4 x alpha deletions
25
Describe the types and consequences of alpha thalassaemia
1 alpha missing - silent carrier, normal FBC
2 missing - alpha thalassaemia trait: mild anaemia
3 missing - HbH disease/alpha thalassaemia intermedia: mod anaemia, mild haemolysis, not transfusion dependant, HSM and skeletal changes
4 missing - Hb Barts: hydrops fetalis, newborn death due to severe anaemia, congestive heart failure. Can do IU transfusions and then BMT postnatally
BF: hypochromic, microcytic, target cells, golf-ball like
- Leads to excess b or y chains, abnormal O2 dissociation curves
26
Describe the types and consequences of beta thalassaemia
- Autosomal recessive, B+ (partial function), Bo (no function)
- Minor- B/Bo or B/B+. Mild microcytic anaemia, no Tx
- Intermedia - B+/B+ or B+/Bo. Mod haemolysis, mod-severe anaemia, not transfusion dependant, splenomegaly
- Major - Bo/Bo. Severe haemolysis from 3-6m life (after HbF decreases) transfusion-dependent, HSM, iron overload, bony deformities, "hair on end" skull x-ray, may need splenectomy
- Inc HbA2% (>3.5% in minor) and HbF%, inc RBC distribution width
- BF: microcytic hypochromic, target cells
- High Fe, transferrin, ferritin
27
Management of thalassaemia
If Hb <60 for ?3/12 then need regular transfusions
Iron chelation therapy (deferiprone or deferasirox)
May requite BMT, splenectomy
Gene therapy in future
28
What is Bernard Soulier Syndrome?
- AR disorder
- Absence or severe deficiency of the VWF receptor (GPIb complex) on the platelet membrane
- Extremely large platelets and thrombocytopenia, prolonged bleeding time
- Defect in ristocetin induced agglutination, but platelets will agglutinate in response to other agonists (collagen, ADP)
29
Intra vs extravascular haemolysis
- Intra: higher LDH and haemoglobinuria, low hapto (HUS, DIC, transfusion reaction, PNH, prosthetic valve hemolysis)
- Extra: higher bilirubin, lower LDH, low hapto (alloimmune haemolysis, thalassaemia, inc RBC turnover).
30
What are schistocytes?
Schistocytes are seen in microangiopathic haemolytic anaemia (such as haemolytic uraemia syndrome). They are caused by damage in the vessels. Schistocytes are always an abnormal finding on a blood film.
31
Causes of macrocytosis
B12/folate deficiency
Newborn
Hypothyroidism
Down syndrome
Massive reticulocytosis (recticulocytes are larger than RBC)
Liver disease
Megaloblastic anaemia - nutritional, IEOM, drug e.g. azathioprine
Folate/B12 have associated hyperhsegmented neutrophils
32
Inherited causes of thrombophilia
- Factor V Leiden mutation - activated protein C resistance
- Protein S, protein C deficiency - AD, infants with homozygous protein C def present like DIC, can cause purpura fulminans and blindness. FFP only source of protein C. When out of neonatal period, use warfarin
- Prothrombin gene mutation - inc prothrombin levels
33
Acquired causes of thrombophilia
- Central line e.g. neonates - renal vein thrombosis
- Trauma, surgery, nephrotic syndrome, malignancy
- Lupus anticoagulant (in APTT) e.g. SLE, antiphospholipid syndrome
34
Describe vWD
common 1/1000, VWF gene on Ch12
VWF binds platelets together (binds gp1b) ;
- deficiency - mucosal bleeding
also has intmportant role in factor 8 activity (binds and carries factor 8 which protects it from Protein c and S)
- Deficiency similar presentations to Haemophilia
Blood group O have low VWF
Stress, pregnancy and exercise increase VWF
Elevated APTT (may be normal in T1)
- F8 decr, vWF decr,
- bleeding time N or inc
- plt count N (except 2b)
- ristocetin cofactor activity decr (c.f. normal in Haemophilia A)
Inx VWF levels and activity (risoscetin cofactor assay)
- T1: AD, 70%, partial def of vWF (reduced production), responds to DDAVP
- T2: abnormal vWF function, AD
2b has low platelets
2N has low factor 8 (similar to Haemophilia)
- T3: complete absence, AR, present similarly to Haemophilia A (DDAVP not helpful)
type 2n and type 3 can have severe bleeds
- Tx:
DDAVP (increased VWF)
tranexamic acid (for bleeding)
type2n+3 require plasma-derived factor 8 concentrate (recombinant factor contains no vWF)
35
Describe Vit K deficiency of infancy
- Early, within 24 hrs, maternal warfarin or anticonvulsants
- Classic, 1-7d, idiopathic or BF babies
- Late, >8d, peaks several weeks, idiopathic or due to BFing, malabsorption, diarrhoea
- APTT inc, PT inc, plt + fibrinogen N. PT prolonged only when <50% prothrombin
- Tx: IV Vit K, works within 20 min, don't given IM. FFP +/- transfusion
36
Presentation of F13 deficiency
Delayed bleeding from umbilicus/cord in up to 80%.
AR. Decr F13 level. Clots lyse in 5M urea solubility test.
Causes inability to cross-link fibrinogen. Lifelong risk ICH. Tx: fibrogammin.
Abnormalities of fibrinogen also present as cord oozing
37
Describe haemophilia A
- X-linked, 30% new mutations
- Carriers have variable F8 levels
- Neonate - IVH, haematoma, excessive bleeding
- Inc APTT, N PT + bleeding time, F8 decr
- Mild: DDAVP (releases vWF from endothelial cells, incr FVIII)
- Tranexamic acid for mucosal bleeds
- Mod+severe: recombinant F8, up to 20% develop inhibitors (low titre give inc doses F8. High titre use F7a to bypass)
- Mild 5-50% F8, mid 1-5%, severe <1%
Treatment
Prophylactic recombinant factor VIII infusions (usually 2-3 times per week)
Recombinant factor VIII pre op or post injury
DDAVP in mild disease - this raises the patient's own factor VIII levels
Tranexamic acid can be given with DDAVP
However, giving factor VIII in a patient with a high titre inhibitor will not increase factor VIII levels.
Factor VIIa activates haemostasis by combining with tissue factor and is able to achieve haemostasis by generating thrombin by directly activating Factor X and bypassing the need for Factor VIII or Factor IX, thus being useful even in patients with inhibitors to Factor VIII or Factor IX
38
Natural anticoagulants
Antithrombin III - most potent inhibitor, heparin potentiates its effect
Protein C - inhibits 5a, 8a, promotes fibrinolysis. Protein S enhances protein C action
39
Prothrombin time measures?
Extrinsic pathway + common pathway
| Factor 7, 5, 10, 2
40
APTT measures?
Intrinsic pathway + common pathway
| Factor 8, 9, 11, 12, 5, 10, 2
41
Howell-Jolly bodies
Hyposplenism
| nuclear remnants in RBC that haven't been removed as spleen is not working
42
What drugs can cause thrombocytopenia?
```
Sodium valproate
Phenytoin
Carbamazepine
Cotrimoxazole
Rifampicin
Heparin
```
43
Causes of low platelets in neonate
Alloimmune (NAIT) - maternal antibodies to father's platelet antigen. HPA1 most common (85%). Can occur in firstborn. If plts <20 urgent transfuse due to risk ICH first few days life +/- IVIG
If have ICH high risk recurrence in subsequent pregnancy
Isoimmune (ITP) - mother will have low platelets
Sepsis
TORCH infection
44
Causes of thrombocytopenia?
Impaired production - thrombocytopenia + absent radius syndrome, Fanconi anaemia, Wiskott-Aldrich, aplastic anaemia
- Decreased survival
- Immune mediated: ITP, NAIT, SLE, drug-induced, malignancy
- Non immune mediated: DIC, HUS, TTP, cyanotic CHD, Kasabach-Merrit
45
Most commonly implicated antigen in NAIT?
In Caucasian women it is Human Platelet Antigen 1a (HPA1a) which accounts for 85% of cases.
3% population negative.
There are over 20 platelet antigens implicated in NAIT.
In Caucasian women, more than 85% of cases can be attributed to HPA1a.
HPA5b is the second most frequently implicated antigen in Caucasian women.
In Asian women, the HP4a system is most commonly implicated.
46
Is beta thalassaemia associated with hydrops?
Not associated with fetal hydrops, as fetal haemoglobin (α2γ2) compensates
47
Describe autoimmune haemolytic anaemia
- Acute, self-limiting, often presents post virus (EBV, mycoplasma)
- DAT/Coombs +ve, low Hb, high retics
- Jaundice, splenomegaly, anaemia
- Causes: infections, drugs (penicillin, quinidine), SLE/RA, lymphoprolif disease (Hodgkin's)
- Tx: supportive with folic acid, occ steroids, splenectomy, transfusions (but haemolyse), occ rituximab
48
Causes of polycythaemia
- Primary (rare in childhood) - familial or congenital, polycythaemia vera
- Secondary - heart disease (ToF, CHD), lung disease, high altitude, congenital methaemoglobinaemia, neonates, delayed cord clamping. All are a response to hypoxia with increased EPO production
49
Describe the mechanism of sickle-cell disease
- Single base mutation A->T which changes valine to glutamic acid on B-globin chain
- HbS is insoluble, forms crystals when exposed to low O2 tensions.
- Shifts O2 dissociation curve to right
- Presents >6m age when HbF-> HbA
- Sickle cell trait usually asymptomatic as long as well-oxygenated
50
Risks of sickle-cell disease
- Crisis: vaso-occlusion with ischaemia-reperfusion injury
- Haemolytic anaemia
- Above precipitated by infection, acidosis, dehydration, deoxygenation
- Infection risk: pneumococci, haemophilus, salmonella (due to impaired splenic function, defective complement activation, tissue ischaemia, micronutrient deficiencies)
- Stroke - progressive vasculopathy, moyamoya-like syndrome, acute IH when older, cognitive defects due to silent brain infarcts
- Aplastic crisis, often associated with parvovirus
- Acute chest syndrome - pulmonary infiltrate, infection, embolism, vaso-occlusion
51
Management of sickle-cell disease
- Penicillin prophylaxis + conjugate vaccines
- Hydroxyurea - increases HbF concentration
- RBC transfusions - decr HbS synthesis
- BMT is curative (inc morbidity and mortality)
- Opiates for acute pain in crisis
52
What are the causes of asplenia?
Surgical resection
Autosplenectomy (infarct e.g. sickle-cell)
Congenital asplenia syndromes
Iatrogenic/treatment for diseases (ITP, spherocytosis, thalassaemia)
53
Describe transient erythroblastopenia of childhood
Pure red blood cell defect: low Hb, low retics, normal MCV
6m - 5y/o
Due to viral illness, spontaneous recovery
Expectant transfusion for symptomatic anaemia
54
Causes of anaemia
- Decreased substrate (Fe, B12, folate)
- Abnormal production (aplastic BM, malignancy, drugs, liver/renal disease, haemoglobinopathies)
- Increased destruction (haemolysis, congenital, autoimmune, infection, hypersplenism)
55
Causes of aplastic anaemia
- Constitutional: Fanconi anaemia, Dyskeratosis congenita, Schwachman-Diamond syndrome
- Acquired: idiopathic, drugs (acetazolamide, chloramphenicol), infections (EBV, parvovirus, viral hepatitis), toxins (glues), paroxysmal nocturnal haemoglobinuria
- Tx: HSCT or immunosuppression (cyclosporin)
56
What are the causes of microcytic anaemia?
Iron deficiency
Thalassaemia (beta or alpha)
Lead poisoning
Sideroblastic anaemia (iron present but cannot be utilised to make Hb)
Anaemia of chronic disease (infection, malignancy) - can be normocytic
57
Describe Fanconi Anaemia
- AR, mean onset age 8y. Defect in DNA-repair, increased chromosomal breakage.
- Marrow aplasia - all lines affected. Macrocytic anaemia
- Microcephaly, absent thumbs + radii, cafe au-lait, short stature, cutaneous hyperpigmentation, decreased fertility (hypogonad), develop delay
- Increased risk AML (1/3) and solid tumours (1/4) by 40
- Tx: androgens (inc RBC synthesis), steroids, HSCT
58
Describe Dyskeratosis Congenita
- X-linked recessive, mean age 10 for skin, 17 for anaemia
- Associated with short telomeres (repair regions), similar to premature ageing
Triad
Dystrophic nails
Oral leukoplakia
Reticular pigmentation = ectodermal dysplasia
- Pancytopenia, hyperpigmentation, dystrophic nails, oral leukoplakia, pulmonary and liver fibrosis
- Tx: androgens (inc RBC synthesis), splenectomy, HSCT
- Inc risk oral, nasopharyngeal, GI and vulvul cancers
Increase risk AML
59
Describe Shwachman-Diamond Syndrome
- Neutropenia +/- anaemia + thrombocytopenia
- Exocrine pancreatic insufficiency
- Skeletal abnormalities (esp hip and knee)
- Short stature
- Can progress to marrow aplasia or AML
60
Diamond-Blackfan Syndrome
inherited defect in ribosomal proteins (RPS gene in 50%)
- Newborn, 90% present <1yo. (median age 2-3mo) AR
- Pure RBC aplasia, elevated HbF, inc RBC adenosine deaminase activity
- Macrocytic, absent red cell precursors in marrow
- Short stature, webbed neck, cleft lip,
- triphalangeal thumb
- Late onset leukaemia
Assoc malignancies
- acute myelogenous leukemia
- myelodysplastic syndrome
- female genital Ca
- osteosarcoma
- Tx: steroids (80% respond, 20% remit), transfusion, HSCT
61
Describe G6PD deficiency
- X-linked recessive,
Mediterranean (more severe)
African
Protective against falciparum malaria
- Usually asymptomatic or prolonged jaundice
- Acute haemolysis triggered by meds (aspirin, antimalarials, cotrimox, nitrofurantoin), infections, acidosis, fava beans
- Decr NADPH (may be normal in acute haemolysis) - needed for glutathione reduction to neutralise free radicals,
- low Hb, high retics, high bili
- Tx: supportive (hydration, transfusion)
Heinz bodies + bite cells on blood film (bite cells are where the Heinz body has been "bitten" out/phagocytosed by splenic macrophages)
The amount of G6PD enzymatic activity depends on the age of the RBC. Older RBCs have the least, and reticulocytes have the most. In an acute hemolytic episode, the older cells are destroyed first; younger ones may remain, and reticulocytes may increase. If erythrocytic G6PD levels are measured at this point, the result may be misleadingly near or above the normal range. If clinical suspicions remain, repeating the test when the reticulocyte count is reduced will give a more accurate measurement.
62
Describe pyruvate kinase deficiency
- Low PK level leads to low ATP which impairs RBC survival
- Tolerate low Hb due to inc in 2,3DPG and shift O2 curve to R - increased O2 availability
- AR
- Haemolysis secondary to infections e.g. parvovirus, not aggravated by stress
- Splenectomy to stop RBC destruction
- Can get chronic haemolytic anaemia, unconjugated jaundice
63
Causes of DAT/Coombs+ve
ABO incompatibility/ haemolytic disease of newborn
AIHA
Drug-induced HA
Haemolytic transfusion reactions
64
TAR syndrome
```
Thrombocytopenia
Absent Radii (bilateral aplasia of radii + other digit abnormalities)
- Thumbs are persevered (vs Fanconi)
- can get lower limb anomalies
- increased risk CMPTA
- Bleeding in first year worst, risk ICH
```
65
Glanzmann thrombasthenia
AR disorder of GPIIb/IIIa (mediator platelet aggregation)
| Normal platelet number but poor function
66
Microcytic anaemia
TAILS
```
Thalassemia (alpha or beta)
Anaemic chronic disease
IDA
Lead poisoning (secondary to reduced iron)
Sideroblastic anaemia
```
67
Where are the main sites and stages of haematopoesis in embryonic/foetal life?
- Mesoblastic stage → occurs in extra-embryonic structures e.g. yolk sac/placenta from 2-12/40
- Hepatic stage → predominant blood production site from 6-24/40, ↓ in 2nd trimester, 85% erythroid (no neutrophils)
- Myeloid stage from 24/40 onwards, 40% erythroid (15% neutrophils)
68
What cancer do you worry about with bone marrow failure syndromes?
AML for all of them
Fanconi anaemia & dyskeratosis congenita give you SCC
Diamond-Blackfan - sarcoma
69
What is the typical presentation of LCH?
- Presents with osteolytic bone lesions +/- multi-organ involvement
- LCH cells can infiltrate most body tissues (except kidney and heart)
Histiocyte markers CD1a, S100, and CD207
(langerin)
Birbeck granule – a tennis racket shaped granule in the cytoplasm of cells on electron microscopy
70
Changes in blood constituents from fetal life to neonate
Red cells - higher MCV and MCH but lower Hb and Hct 22/40 - at term, MCV/MCH lower and Hb/Hct higher
Platelets - same size, but numbers gradually increase from 22/40
Neutrophils - none before 2nd trimester and scarce in blood until 3rd. Lots of progenitor cells in blood.
71
What is the life span of:
- neutrophils?
- platelets?
- red blood cells?
- neutrophils 6-8hrs
- platelets 10 days
- red cells 120 days
72
Cyclical Neutropenia
Cycles of neutropenia every 3 weeks with symptoms neutropenia (fever, skin/oropharynx infection, mucositis, cervical LN)
Affected individuals are generally well between episodes. Individuals usually present within the first year of life, and symptoms generally improve in adulthood
Assoc with pathological variants ELANE gene mutation
FBC 2-3x per week for 8 weeks
Rx G-CSF
73
Vitamin K dependent factors
Factors 2,7,9,10
| Protein C and Protein S
74
Haemophilia
```
Hameophilia A = Factor 8 deficiency (85%)
Haemophilia B(Christmas) = Factor 9 deficiency (15%)
```
1/5000 males
Both X linked recessive, 1/3 new mutations
Both increased APTT (normal PT)
Manifests as bleeding
Toddlers - haemarthrosis ; often same joints which leads to destruction of joints over time
Test for factor deficiency and inhibitors
Severe disease associated with inhibitors to factors (reduced efficacy of factor replacement, risk anaphylaxis with factor replacement)
* Severe: <1% factor VIII or IX activity; spontaneous bleeding common; bleeding often involves joints, soft tissue, brain (intracranial hemorrhages in neonates), postcircumcision; most common type (50% to 70% of cases).
* Moderate: 1% to 5% factor VIII or IX activity; bleeding after minor trauma, but not usually spontaneous; may involve joints and soft tissue, but less commonly central nervous system (CNS) or postcircumcision; least common type (10% of cases)
* Mild: 6% to 30% factor VIII or IX activity; bleeding only after major trauma or surgery; joint and soft tissue involvement, but uncommon after circumcision; more common than moderate type (30% to 40% of cases)
```
Rx Replace factors
Consider DDAVP in mild factor 8 def (increases VWF release - factor 8 needs VWF to function)
Tranexamic acid (reduces plasminogen to plasmin - increases clot stability)
```
The half-lives for the first doses of factors VIII and IX are 6 to 8 hours and 4 to 6 hours, respectively. With subsequent doses, factor VIII has a half-life of 8 to 12 hours, whereas factor IX has a half-life
of 18 to 24 hours. Thus, for serious bleeding, the second dose of factor VIII should be given 6 to 8 hours after the first, whereas the second dose of factor IX should be given 4 to 6 hours after the first. Subsequent doses are usually given every 12 hours for factor VIII replacement and every 24 hours for factor
IX replacement, but the measurement of actual factor levels may be necessary to guide therapy in life-threatening situations.
75
Thrombosis and elevated APTT(doesn't correct with mixing)
antiphospholipid antibodies
- APTT doesn't correct with normal plasma but corrects with addition phospholipid
APL syndrome
Secondary: SLE, Addisons, ITP, Rhem fever
76
Spleen function
- Produces RBC from 3-6mo fetal life
- Remove young RBC membranes
- Remove old/damaged RBC
- Remove intracytoplasmic lesions from RBC without lysis (ICL = Howell jolly bodies - seen post splenectomy)
Immune function - destroy encapsulated bacteria and parasite infected RBC
77
SPLENOMEGALY
Infection
- Viral EBV, CMV
- Bacterial - IE, sepsis
- Parasitic - malaria, toxo
Immune
- SLE, RA
Haem
- Haemalytic anaemia (Hypersplenism)
- extramedually erythropoeiesis (thalassemia)
Malignant
- Leukaemia/lymphoma
Metabolic
- Gaucher, Nieman pick
Portal hypertension
- CLD - Wilsons, HCC
- Budd chiari
78
Transient Erythroblastopaenia of childhood
- Most common acquired red cell aplasia in children
- Severe transient anaemia in children 6mo-3years; most >12mo, <10%occurs >3yrs
- Moderate to severe normocytic anaemia with reduced Retics;
Virtually all recover by 1-2months, rarely requires transfusion
79
Megaloblastic Anaemia
- caused by impaired DNA synthesis
– deficiency of folic acid, Vitamin B12(cobalamin), rare IEM
- Blood film: large, oval RBC, High MCV, hypersegmented Neutrophils
Folic acid deficiency – rare, peak incidence 4-7months ;
Causes: inadequate intake (Dietary - mothers; premature/ill infants or hemolytic disorders have increased folate requirements ; Goats milk low in folate) ; Malabsorption (diarrhea, coeliac), medications (anticonvulsants – phenytoin/phenobarb impair folate asboprtion), IEM
Clinical: Anaemia, FTT, irritability, neurological complications, infections
Lab: Anaemia, High MCV, low retics, megaloblastic blood film, increased LDH. Marrow – hypercellular
Treatment – supplementation, hematological response within 72hrs ; treating folate def can exacerbare neurological abnormalities if has B12 def ; high dose supp x 4 weeks then maintenance
B12 Deficiency
-in young infants born to mothers with low B12 stores – clincal signs of B12 def appear by 6-18mo of life
Causes: Inadequate intake (Low maternal supply – pernicious anaemia, coeliac, H.pylori, IBD, pancreatic insuff, PPIs, vegetarian diet), Impaired absorption (gut/pancreatic pathology, post surgery), hereditary causes, Pernicious anaemia (early adults)
Clinical: Anaemia, FTT, glossitis, Neuro ( seizures, paraesthesia, sensory, hypotonia, devel. Delay).
80
Post splenectomy
Howell jolly bodies on FBC
Risk overwhelming post splenectomy sepsis, increased risk <5years
Risk encapsulated organisms - Pneumococcus, Meningococcus, haemophilus
Prevention with vaccines and penicillin v prophylaxis
81
DIC
```
Low platelets
Elevated PT and APTT
Low fibrinogen
Elevated d-dimer
Fragmented cells, burr cells and helmet cells on microscopy
```
Widespread activation of coagulation cascade with microvascular thrombosis and consumption of coagulation factors leading to bleeding
Causes
-sepsis
82
Thrombocytopenia causes
1. Decreased production
- Congenital syndromes:
Congenital megakaryocytic thrombocytopenia (severe, present at birth, rare AR ; Rx HSCT, risk MDS)
TAR syndrome (AR - b/l absent radii, normal thumbs vs falcon ; 1/3 CHD (asd/tof), increase risk CMPTA
Pancytopenia - trisomy 13/18, fanconi
```
-Acquired
Drugs- NSAIDs (cox inhibitor), aspirin, valproat, high dose penicillin
Malignancy / BM infiltration
Aplastic anaemia
Liver/renal failure
```
2. Increased destruction
-Neonatal
NAIT (alloimmune - HPA-1a and HPA-5a)
Neonatal autoimmune ITP
-WAS - immune, eczema, small platelets (XL WASP gene mutation ; Rx HSCT)
```
- Acquired:
Infection (TORCH)
Immune - ITP, AIHA, SLE
Non immune - MAHA, TTP, DIC
Drug induced - within 1-2 weeks after starting medication
```
3. Functional disorders
- Bernard soulier (absent gp1b receptor, AR)
- Glanzmann thrombasthenia (mutation gIb/IIA) may have normal platelets
- May hegglin anomaly (MHY9 gene mutation, AD) - large platelets with dole bodies; nephritis, HL, glaucoma
4. Sequestration
Hypersplenism - Portal HTN, Gaucher
Kasabach Meritt
83
Kasabach-Merritt syndrome
Kasabach-Merritt syndrome is characterised by the combination of:
- A rapidly growing vascular tumour
- Thrombocytopenia (low platelets)
- Microangiopathic haemolytic anaemia (destruction of red blood cells)
- Consumptive coagulopathy (impaired clotting).
Causes:
- KHE
- Tufted angiomas
84
Neonatal thrombocytopenia
```
Fetal:
Alloimmune
Congenital infection
Anueploidy (eg trisomy 18,13,21)
Autoimmune
Severe Rh disease
Congenital (e.g. Wiskott-Aldrich)
```
```
Early onset (< 72hrs):
Placental insufficiency (PET, IUGR)
Perinatal infection
Alloimmune condition
Autoimmune condition (e.g. ITP, SLE)
Congenital infection (TORCH)
Thrombosis (renal vein, aortic)
Bone marrow replacement (congenital leukaemia)
Kasabach-Merritt syndrome
Metabolic disease
Congenital/inherited
```
```
Late onset:
Late onset sepsis
NEC
Congenital infection
Autoimmune
Kasabach-Merritt syndrome
Metabolic disease
Congenital/inherited
```
85
Bone marrow failure syndromes
Fanconi anaemia (mean 7years ; 75% other features - short stature, skeletal, GI/GU)
Diamond Blackfan (mostly erythroid progenitors, present in 1st year life)
Schwachman diamond (pancreatic insufficiency)
Dyskeratosis congenita
Severe congenital neutropenia (Kostmann)
86
Aplastic anaemia
```
80% idiopathic
Acquired
- Drugs (chemo, AEDs, NSAIDs, chloramphenicol)
- Infection (HIV, EBV, parvovirus)
- Leukaemia
- PNH
```
Severe - hypo cellular marrow <30% and drop in 2+ cell lines (Plat <20, ANC <0.5, Retics <1%)
Poor prognosis without treatment
Rx HSCT (donor sibling HLA matched)
If no sibling immune suppression with ATG and cyclosporin
Inx
- FBC and film ; Reticulocyte count
- HBF (only useful if pre-transfusion)
- Blood group and antibody screen
- Biochemistry including liver function
- Bone marrow aspirate and trephine with cytogenetics
- Immunoglobulins and autoantibody screen
- Tissue typing patient and family
- Chromosomal fragility testing
- Flow - FISH for telomere length
Other genetic testing dependent on clinical presentation
87
Splenomegaly and anaemia
```
Anemia-causing splenomegaly
• Membrane disorders
• Hemoglobinopathies
• Enzyme abnormalities
• Immune hemolytic anemia
```
```
Splenomegaly-causing anemia
• Cirrhotic liver disease
• Cavernous transformation of portal vessels
• Storage diseases
• Persistent viral infections
```
88
Methemoglobinemia
Consider if cyanosis and no signs cardiac/resp disease.
Methemoglobin is produced by the oxidation of ferrous iron in hemoglobin into ferric iron. Methemoglobin cannot transport oxygen. Normally, it constitutes <2% of circulating hemoglobin.
```
Oxidant toxins (e.g., antimalarial drugs, nitrates in food
or well water) can dramatically increase the concentration.
```
Infants at higher risk
- lower levels cytochrome b5 (antioxidant)
- gut more alkaline (nitrates converted to nitrates which are oxidants)
- Counter teething preparations with benzocaine, and metoclopramide for gastroesophageal reflux
Patients with cyanosis as a result of methemoglobinemia can have normal oxygen saturation as measured by pulse oximetry because the oximeter operates by measuring only hemoglobin that is available for saturation
Rx Methlyene blue ;
if treatment failure ? G6PD def - exchange tf
89
Thrombophilia
Factor V Leiden (activated protein C resistance) - most common
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
All of these inherited in AD fashion ; Factor V Leiden has incomplete penetrance
• Factor V Leiden: This is an abnormal factor V protein that is resistant to the normal antithrombotic effect of activated protein C.
• Protein C deficiency: Protein C inactivates factors V and VIII and stimulates fibrinolysis.
• Protein S deficiency: Protein S serves as a cofactor for the activity of protein C.
• Antithrombin III deficiency: Antithrombin III is involved in the inhibition of thrombin; factor X; and,
to a lesser extent, factor IX.
• Prothrombin variation: Mutation at gene position 20210 increases prothrombin levels possibly
through decreased mRNA degradation.
• Hyperhomocysteinemia: Often the result of a mutation of the MTHFR gene. Those with
predisposition to hyperhomocystenemia due to thermolabile MTHFR variants benefit from folate
supplementation, sometimes with vitamins B6 and B12 in addition.
• Antiphospholipid antibodies: These are passed from mother to infant prenatally. They can also be
acquired, often in adolescence in the presence of systemic autoimmune diseases such as SLE. (Elevated APTT)
Rare in childhood, only indication for testing for Protein C / S def is neonatal purport fulminans
Present with DVTs
RF Thrombosis
- CVL most common
- Sepsis
- Immobility, malignancy, surgery, TPN, renal disease
90
Infection in patients with frequent transfusions and iron overload ( such as T/F dependent beta thal) with gastro/fever/RLQ pain
Yersinia enterocolitica is a gram-negative coccobacilli that causes acute febrile gastroenteritis or pseudoappendicitis syndrome. It may be indistinguishable clinically from other causes of diarrhoeal illnesses (diarrhoea, abdo pain, fever plus nausea and vomiting), however in some cases pain is localised to right lower quadrant. Bloody diarrhoea is more common in children than adults. It can also cause pseudoappendicitis but at surgery, findings are of inflammation around appendix and terminal ileum and mesenteric nodes, appendix itself is generally normal. Yersinia septicaemia can occur during acute infection, particularly among infants and individuals with impaired immunity or iron-overload states.
Antimicrobial treatment is NOT recommended for acute, uncomplicated yersiniosis. The most common post-infectious sequelae are erythema nodosum and reactive arthritis (associated with HLA B27).
91
Drugs interacting with Warfarin
Almost all antibiotics can potentiate the effects of warfarin by inhibiting intestinal flora that produce vitamin K. Inhibition of the hepatic metabolism of warfarin is another possible mechanism for increased bleeding.
Drugs that inhibit warfarin's metabolism include ciprofloxacin, clarithromycin, erythromycin, metronidazole and trimethoprim-sulfamethoxazole
Carbamazepine, oral contraceptive, and vitamin K decrease the INR.
92
FFP indications
1. Disseminated Intravascular Coagulation (DIC) complicated by bleeding
2. Massive Transfusion Protocol
3. FFP should be considered with an INR >2 depending on the underlying cause and clinical condition of the infant
4. Vitamin K deficiency with bleeding
5. Liver disease in the presence of bleeding and abnormal coagulation or as a prophylaxis
Dose 10-15ml/kg
93
Chediak Hegsahi
autosomal recessive disease with a defect in phagocytosis due to a mutation of a lysosomal trafficking regulator protein.
Microtubules do not form normally and neutrophils do not respond to chemotactic stimuli.
Giant lysosomal granules, which fail to function properly, are evident in a peripheral smear.
Associated features include partial albinism, peripheral neuropathy, and a susceptibility to recurrent pyogenic infections.
94
Clotting factor not produced in liver
```
Factor 8 (elevated in liver F as cause of bleeding)
Rx Vit K, FFP or cryo
```
95
Ddx severe bleeding in infant
```
Haemophilia
Thrombocytopenia
Platelet function disorder - Bernard Soulier, Glanzmann thrombasthenia
VWD (type 3)
Vitamin K deficiency
```
96
Response to iron therapy in IDA
- 12-24 hours = subjective improvement, less irritable, improved appetite
- 72hours - reticulocytosis
- 7-10days increase in Hb (should rise by 10g/L per month)
- 1-3 months repletion of iron stores
If not responding to oral iron
- poor compliance
- malabsorption
- blood loss
- alternative diagnosis - chronic disease, thalassemia, b12/folate def, lead
Paeds
flashcards
Decks in class (25)
# Cards
-
Resp99
-
Neonate166
-
Immunology37
-
Cardiac20
-
Gen Paed38
-
Renal91
-
Short cases108
-
Endocrine98
-
Haem96
-
Oncology97
-
Infectious Disease122
-
Statistics36
-
Cardiology187
-
Emergency Medicine129
-
Rheumatology/dermatology64
-
Genetics229
-
Metabolic124
-
Gastroenterology235
-
Cardiology COPY157
-
Neurology267
-
Derm16
-
Nephrology219
-
Psych AND Adolescent25
-
Pharmacology56
-
Pharmacology COPY145
