Haematology Flashcards
1
Q
Acquired thrombocytopaenia
A
liver disease: portal HTN with splenic sequestration, decrease thrombopoeitin
uraemia: platelet dysfunction
DM: platelet dysfunction (increased activity with thromboses)
drug induced Ab/BM suppression
- usually drug induced Ab destroy platelet but also BM suppression
- common: quinidine, penicillin, digoxin, anti-epileptics, heparin
drug preventing aggregation:
- aspirin: irreversible COX inhibition
- NSAIDs: reversible COX inhibition
- clopidogrel: prevents platelet aggregation
2
Q
Alpha thalassemia
A
genetics: 4 genes on chromosome 16
pathophysiology: decreased alpha increases other chains
- decreased HbA, HbA2, HbF
- b4 (HbH)
- g4 (Barts Hb)
- overtime Bart’s Hb is replaced with HbH
clinical (see chart)
treatment: folate, transfusion, iron chelation, splenectomy
3
Q
Anaemia
A
4
Q
Anaemia chronic disease
A
pathogenesis:
- decreased lifespan RBCs and relative BM failure
- decrease iron availability as trapped in macrophages
diagnosis:
- low serum iron, high ferritin, normal binding capacity
- normocytic, normochromic anaemia
5
Q
Anti-phospholipid antibodies
A
types: anti-cardiolipin antibodies, lupus anticoagulant
diagnosis: prolonged APTT, does not correct on mixing
- DOES correct with adding phospholipid
clinical: risk of clotting, not bleeding
- children post viral illness, older with AI (SLE, ITP, Addison’s, RF)
- must be present >3 months to increase risk of clotting
- arterial/venous thrombosis, recurrent miscarriage
6
Q
Aplastic anaemia
A
definition: pancytopaenia with hypocellular/hypoplastic bone marrow (replaced by fat)
causes
acquired :
- idiopathic 80%
- other: drugs, radiation, virus, PNH, pregnancy
hereditary: Fanconi (most common), Schwachmann Diamond, Dyskeratosis Congenita
7
Q
Autoimmune thrombocytopaenia
A
pathophysiology: maternal Ab against both maternal/foetal platelets
- associated materal ITP/SLE
clinical: low maternal platelets
- neonatal thrombocytopaenia (20-50 with nadir days 2-5)
- neonatal petechiae/bruising/bleeding
management: monitor, transfusion, IVIG, methylpred, materanl IVIG/pred
8
Q
Bernard Soulier
aka. hemorrhagiparous thrombocytic dystrophy
A
prevalence: 1/1,000,000
genetic: AR
pathogenesis: deficiency of glycoprotein Ib (Gb1b) the receptor for vWF
diagnosis: thrombocytopaenia, increased megakaryocytes, decreased GpIb/V/IX
clinical: bleeding gyms, bruising, bleeding with minimal trauma
9
Q
Bernard Soulier syndrome
A
pathogenesis: absence of vWF receptor (GpIb complex) on platelet membrane
diagnosis: thrombocytopaenia, large platelets, prolonged bleeding time >20mins
10
Q
Blackfan-diamond anaemia
A
definition: congenital pure red cell aplasia
pathophysiology: ineffective erythropoiesis
genetics: AD
clinical: presents infancy
- progressive normochromic/macroocytic anaemia, reticulocytopaenia
- normal cellularity BM
associations:
congenital malformations (50%)
- craniofacial, eye, neck, cardiac, thumb, GUT
growth retardation 30%
treatment:
- corticosteroids (40% steroid dependent)
- blood transfusions (40% transfusion dependent)
prognosis: 20% go into remission
complications: hemosiderosis requiring Fe chelation
11
Q
Cell morphology
A
12
Q
Clotting factors half lives
A
Factor VII 2-4 hours
Factor VIII 12 hours
Factor IX 24 hours
Factor X 30 hours
Prothrombin 3.5 days
Fibrinogen 2-4 days
Factor XIII 5-7 days
13
Q
Clotting times
A
reptilase time: conversion of fibrinogen to fibrin (heparin fx)
bleeding time: interaction platelet with BV wall (normal<3 mins)
D-dimer: breakdown products of fibrinogen
14
Q
Coagulation cascade
A
Primary hemostasis: initial immediate platelet plug
Secondary haemostasis: via intrinsic/extrinsic cascade with fibrin
Intrinsic (Contact): Factors 8, 9, 11, 12
Extrinsic (Tissue Factor): Factor 7
Common pathway: Factors 2, 5, 10, Fibrinogen
Cofactors:
- calcium: for every step except 11/12
- phospholipids: create factor III
- vitamin K: produce 2, 7, 9, 10, protein S, protein C, protein Z
Regulators:
- protein S: cofactor for protein C
- protein C: inactivates 5a and 8a
- antithrombin III: inactivates thrombin and Xa
- heparin (mast cells): accelerates antithrombin 1000x
- tissue factor pathway inhibitor (TFPI): limits activation of X
- plasmin: digests fibrin clots
15
Q
Coagulation cascade
A
16
Q
Coagulation tests
A
PT/INR: extrinsic/common pathway
- normal: PT < 18 secs, INR <2 secs
- disorders: vit K def, factor VII def, warfarin, DIC
APTT: intrinsic/common pathway
- normal: <70 secs
- disorders: factor 8, 9, 11, 12 deficiencies (<40%), herparin, lupus anticoag
- mixing studies: corrects if factor deficiency
PT/APTT prolonged
- disorders: prothrombin, V, X, fibrinogen, liver disease, vit K def, herparin + warfarin, DIC
Fibrinogen:
- normal: <17 secs
- low: liver, DIC, fibrinogen def, thrombolytic therapy
- high: acute phase reactant, malignancy, OCP
17
Q
Cold agglutinin haemolytic anaemia
A
pathogenesis: intravascular haemolysis with anaemia/hemoglobinuria due to high titer of cold antibodies (IgM)
clinical: anaemia, haemoglobinuria, dark urine, less splenomegally than warm
film: RBC agglutination into irregular clumps
treatment: avoid cold, cytotoxic agents, IVIG, plasmaphoresis (only lasts 5 days)
18
Q
Concomitant alpha and beta thalassemia
A
presence of alpha trait lessens severity of beta thalassemia
- reduction in alpha globin synthesis reduces the burder of alpha globin inclusions without affection haemoglobin made
19
Q
Congenital abnormalities of platelet function
A
Bernard-Soulier:
- AR defect in glycoprotein receptor on platelet for binding vWF
- severe thrombocytopaenia, giant platelets, poor aggregation, bleeding
Glanzmann thrombasthaenia
- AR defect in fibrinogen receptor causing platelet dysfunction preventing aggregation
- normal platelet count
- mucocutaneous bleeding
Grey platelet syndrome
- absence of platelet alpha granules causing them to look grey
- defective platelet activation/aggregation
Wiskott-Aldrich
- XLR immunodeficiency, thrombocytopaenia, eczema
20
Q
Congenital Amegakaryocytic Thrombocytopaenia
A
genetic: rare, AR
pathophysiology: myeloproliferative leukaemia virus oncogene that encodes thrombopoitein and is needed for platelet production
clinical: neonatal thrombocytopaenia, bleeding into skin/mucosa/GI
- pancytopaenia later in childhood
treatment: BMT, limit transfusion
21
Q
Congenital thrombocytoapaenia
A
Congenital amegakaryocytic thrombocytopaenia (CAMV)
- megakaryocytes absent in BM due to receptor defect
- pancytopaenia develops
- treatmentL BMT
Thrombocytopaenia-Absent Radius (TAR) syndrome
- thrombocytopaenia, hypereosinophilia, absent radius, bilat DDH, limb shortening
- associated cow’s milk intolerance 50%
- remits in 1st year of life
22
Q
Diagnosis/Clinical features of haemophilia
A
diagnosis: prolonged APTT (intrinsic pathway)
- corrects on mixing studies unless high inhibitor titres
clinical: usually presents <1yr
- 2% intracranial haemorrhage
- 30% bleeding post circumcision
- haemarthroses: ankle 1st
23
Q
Diamond-Blackfan Anaemia
A
definition: congenital erythroid aplasia
clinical: present in infancy
- progressive normochronic/macrocytic anaemia
- reticulocytopaenia
- normal BM/WCC/platelets
- 50% assoc congenital abnormalieis
- increased risk of malignancies: AML, myelodysplastic sx, solid tumours
diagnostic criteria:
- age<1
- macrocytic anemia
- reticulocytopaenia
- normal marrow
treatment: steroids, bloods transfusion, HCT
24
Q
DIC
A
mechanism: widespread consumption of clotting factors, platelets and anticoagulation proteins producing
- widespread fibrin clots with ischaemia and necrosis
- haemorrhagic state
- microangiopathic haemolytic anaemia
trigger: any systemic disease associated with hypoxia, acidosis, tisse necrosis, shock
diagnosis: increased INR/APTT/TT, decrease platelets/Hb/fibrinogen
association: overtbleeding
treatment: cause, correct acidosis/hypoxia, blood products (FFP)
25
Disorder of fibrinogen
**source:** made in liver
**function:** formation of fibrin clot, supports platelet aggregation
- fibrin clot is template for thrombin or fibrinolysis
**diagnosis:** abnormal APTT/INR as in final p/w
- corrects with mixing
**types:**
_dysfibrinogenaemia:_abnormal fibrinogen molecules
- congenital or acquired (liver disease)
_afibrinogaemia/hypofibrinogaemia_
- mild bleeding
26
Dyskeratosis Congenita
**genetics (3 mechanisms):** X linked, AR, AD
- multiple genes
**clinical: BM failure with ectodermal abnormalities**
- hyperpigmented rash over face/neck/trunk
- nail dystrophy
- mucosal leukoplakia
- increased risk of malignancies
**diagnosis:** genetic testing, telomere length analysis
**management:** androgens, BMT
27
Factor half lives
Factor VII: 2-4 hours
Factor VIII: 12 hours
Factor IX: 24 hours
Factor I/II: 2-4 days
Factor XIII: 5 days
\*\*Factors involved in clot formation have longer half lives
28
Factor V deficiency
| (parahaemophilia)
**genetics:** AR
**clinical:** mild bleeding, menorrhagia
**treatment:** FFP
29
Factor V Leiden mutation
**incidence:**
- 6% heterozygotes: 5x risk thrombus
- homozygotes: 100x risk thrombus
- increased risk with OCP
**pathophysiology:** mutation in factor V that prevents it being inhibited by activated protein C
30
Factor X deficiency
**genetics:** rare, autosomal
**associations:** amyloidosis due to absorption of factor X on amyloid protein
31
Factor XII deficiency
**genetic:** AR, rare
**diagnosis:** APTT prolonged, PT normal
**clinical:** delayed separation of umbilical cord, delayed bleeding of umbilical stump, ICH, poor wound healing
32
Factor XIII deficiency
F13D
**function:** cross-links fibrin clot
**pathophysiology:** unstable clot
**clinical:** delayed bruise/bleed, poor wound healing
**treatment:** FFP/cryoprecipitate, recombinant factor XIII
33
Fanconi anaemia
**incidence:** heterozygote 1/300, consanguinity 10%, assoc affected siblings
**genetic:** AR, 15 different FA genes
- FA-A 65% chromosome 16
- FA-C/FA-G 10% each
**pathophysiology:** protein involved in DNA repair
**clinical:**
- diagnosis 6-9 years
_congenital malformations 60-70%_
- short stature 50%
- hyperpigmented spots/cafe au lait
- abnormality of thumbs: bifid/hypoplastic
- radial hypoplasia/absent radius
- facies: microcephaly, small eyes, epicanthic folds, abnormal ears
- hypogonadism
- DD
- hypospadias, cryptorchidism, phimosis
**associations:** malignancies (myelodysplastic syndrome, AML, SCC, Wilm's tumour), endocrine/opthalmological/renal/GI/CVS issues
**diagnosis:** BM failure in 1st decade
- thrombocytopaenia, anaemia (macrocytic, increased HbF), leukopaenia, increased AFP
- chromosome breakage studies (add mitomycin C/diepoxybutane)
**management:** BMT, androgens (improve anaemia\>thrombocytopaenia\>neutropaenia) in 50%, GCSF, transfusions
**prognosis by 40yrs:**
- BM failure 90%, haem malignancy 30%, non haem malignancy 30%, mortality 80%
34
G6PD
**G6PD** :1st enzyme in hexose monophosphate pathway (5% RBC metabolism)
- reduces NADP to NADPH for reduction of glutathione
- absence of reduced glutathione causes accumulation of oxidants and intracellular precipitation of Hb
**genetics:** XLR
- female heterozygotes protected against malaria
- 3 mutations: A (africa 15%), B (Med/Asian 5-40%), D (China 5%)
**clinical:** neonatal onset jaundice OR acute haemolytic episode
- triggers: fava beans, napthalene, medications, illness
**diagnosis:**
- heinz bodies seen under blue stain: removed 1-4 days
- haemolysis (bite cells)
- direct enzyme activity: \<10% normal
**management:** avoid precipitants, supportive during episodes
35
Glanzmann Thrombasthenia
**prevalence:** RARE
**genetic:** AR or AI
**pathogenesis:** platelets contain defective GpIIb/IIIa which is the receptor for fibrinogen preventing crosslinking of platelets
**clinical:** bruising, epistaxis, GI bleed, post-op bleeding
**diagnosis:** bleeding time significantly prolonged
36
Haemolytic anaemia
- categories-
**INTRINSIC**
- enzyme defects: G6PD, pyruvate kinase def
- haemoglobinopathies: sickle cell, thalassemias
- membrane defects: hereditary spherocytosis, elliptocytosis
**EXTRINSIC**
- autoimmune haemolytic anaemias: warm reactive/cold reactive
- liver disease: cirrhosis, hypersplenism
- oxidant agents: nitrates, dapsone, aniline dyes
- microangiopathies: HUS, DIC, artificial heart valves, Kasabach Merritt
- paroxysmal cold haemoglobinuria
- paroxysmal nocturnal haemoglobinuria
37
Haemophilia
**cause:** reduced factor VIII/IX causing delay in thrombin and fibrin clot
**genetics:** X-linked recessive, spontaneous mutations 1/3
**both types identical clinical picture:**
haemophilia A (85%): 1/5000, most reduced levels of protein (5-10% dysfunctional protein)
- most common mutation internal inversion within the FVIII gene
haemophilia B (10-15%): 1/25,000, 50% reduced protein, 50% dysfunctional protein
**severity: based on % of factor in the plasma**
- \<1% severe with spontaneous bleeding
- 1-5% moderate with bleeding in minor trauma
- \>5% mild bleeding in significant trauma
_(normal haemostatic level for both factors in 30%)_
38
Haemophilia management
**MANAGEMENT**
**_F__actor replac__ements with bleeds: treat early and enough_**
- factor levels 50% for mild/mod bleeds, 100% for life threatening
- treat for 14 days in major bleeds
**_Factor VIII_**
- half life 6 hours for first dose
- repeat doses 12 hourly if necessary
- 1u/kg raises FVIII by 2%
**_Prophylactic factor replacement: 2-3 days to maintain 1-2%_**
- severe haemophilia: prevents joint deformities
**_DDAVP_**
- mild haem A: causes endogenous FVIII to be released from endo stores
**_Supportive_**
- avoid contact sports
- blood products: cryo (FVIII, fibrinogen), FFP (FIX)
- screen for hepB, hepC, HIV
**_Complications_**
- arthropathy: bleed into joint space with inflammatory changes to synovium and increased bleeding risk
- inhibitors: 30% in Haem A, need to desensitize if high
- failed desensitization: FVIIa or activated prothrombin complex to bypass inhibitor
39
Hepcidin
**function:** inhibits Fe absorption in small intestine/placenta and decreases release from macrophages
**release:** acute phase reactant (induced by IL-6)
- increases with inflammation, malignancy, infection
- decreases Fe in inflammation
**diagnosis:** assays not available
40
Heinz Bodies
**pathogenesis:** precipitated Hb
**causes:** G6PD
41
Hereditary elliptocytosis
**genetics:** RARE
**clinical:** similar to spherocytosis
42
Hereditary spherocytosis
**incidence:** 1/5000
**genetics:** autosomal dominant
**pathophysiology:** abnormality of spectrin OR ankyrin (components of cytoskeleton for RBC shape)
- spherocytes less deformable and destroyed by the spleen
**clinical:** variable severity
- haemolytic disease of newborn, medullary expansion of bones, splenomegally, bilirubin gallstones, risk aplastia crisis
**diagnosis:** high retics/bilirubin, low haptoglobin
**film:** small hyperchromic spherocytes
**management:** splenectomy (Hb \<100, retics \>10%) age 5-6 yrs, folate
43
Transfusion risk
**Haemolysis**
- acute: ABO incompatibility
- delayed
**Infection:** bacterial \> viral
bacteria: skin (staph/strep), storage (yersinia)
- rRBC out of fridge max 4 hours
- platelets MOST risk: stored at room temp 5 days
**viral:**
- HIV 1/9 million
- HCV 1/3 million
- HBV 1/1 million
- HTLV 1/1 million
In Australia testing for HIV/HBV/HCV/HTLV/syphillus
44
Howell Jolly-Bodies
**pathogenesis:** contain nuclear remnants
**causes:**
- post spleenectomy
- megaloblastic anaemia
- iron deficiency anaemia
45
Idiopathic Thrombocytopaenic Purpura
ITP
**incidence:** 3/100,000 per year
**pathophysiology:** acquired transient immune mediated thrombocytopaenia
- autoAb (IgG) bind platelet mem Ag esp glycoprotein IIb/IIIa complex
- preceding history of infection
**clinical:** platelets
- _acute_: platelets return to normal within 6 months
- _chronic_: 15% of acute \>6months, older children, assoc atypical presentations, assoc underlying AI disorder
- petechiae/purpura/bruising
- mucosal/conjunctival/retinal haemorrhage
- ICH (0.1-1%, platelets
**treatment if NOT bleeding:** conservation
**treatment if bleeding:**
- IVIG (binds Fc prolonging survival, increase 24hrs, 85% respond),
- steroids: improve vasc integrity, decreased Ab affinity, most respond
- transfusion: half life can be 10mins, only life threatening bleed
46
Iron deficiency Anaemia
**incidence:** most common nutritional deficiency
- most common in toddlers: 12-36 mths 9% deficient, 3% anaemia
**pathophysiology:** 75% Fe bound to Hb/myoglobin
- hard to maintain stores rapid growth in infancy
- 30% iron from diet
**etiology:** insufficient intake, decreased absorption, blood loss
clinical: pallor, irritability, tachycardia, cardiomegally, decreased exercise tolerance, pica, splenomegally (15%), brittle nails, blue sclera, angular stomatitis
**associations:** increased breath holding, long term neurodev. impact, increased thrombosis
**diagnosis:** low total Fe/ferritin/transferrin, high TIBC/RDW
**film:** eliptogenic RBCs
**BM:** hypercellular, erythroid hyperplasia
management: 6mg/kg elemental iron/day 45mins before meals
**outcome:** increased Hb by 10 in 4 weeks
47
Iron Physiology
**source:**
- iron absorbed duodenum
- released RBC/monocytes/macrophages
**location:**
- haemoglobin, myoglobin, ferritin, haemosiderin, enzyme bound
48
Lupus anticoagulant
**definition:** antibody against phospholipid and other factors
**effect:** prolongs APTT and does not correct on mixing studies
**risks:** paradoxical risk of CLOTTING if presents \> 3 months
**etiology:**
- post viral in children
- autoimmune in adults
49
Methaemoglobinaemia
**etiology:** congenital or acquired
**pathophysiology:**
- Fe2+ bound to Hb and Fe3+ when released
- Fe3+ binds water to produce MetHb
- cytochrome 5b breaks down MetHb
- metHb occurs when _NADH-cytochrome 5b reductase deficient_
OR
_- toxic substances:_ medications (NO, metoclopramide, sulfonamides), medical condictions (GI infection, SS pain crisis), pesticides
**clinical:**
- poor oxygen carrying capacity
- cyanosis \>15%, death \>70% metHb
50
Neonatal alloimmune thrombocytopaenic purpura
incidence: 1/5000
**pathophysiology:** maternal Ab against foetal plts that contain paternal Ags (HPA)
- most non-HPA1a mother and HPA1a foetus: 75% anti-HPA1a, 16% Anti-HPA5b, 4% Anti-HPA15b
- form in 1st trimester causing foetal/neonatal thrombocytopaenia
**clinical:**
- petechiae/purpura in days
- higher risk of haemorrhage than ITP: ICH 14%
- platelets fall in days and rise by 4 weeks
**diagnosis:** low platelets, normal coags, platelet typing neonate/mother
**treatment:** IVIG to mother from 2nd trimester onwards, monitor plt count via umbi line sampling, LSCS, platelet transfusion, neonate IVIG, methylpred
**prognosis:** subsequent pregnancies more severe
51
Normal haemoglobin
**structure:** tetramer with 2 pairs of globin chains
**distribution:**
- HbF (α2γ2):
- HbA2 (α2d2):
- HbA (α2β2): \>95%
52
Paroxysmal cold haemoglobinuria
**incidence:** RARE, assoc cold antibody anti-P
**pathophysiology:** intravascular haemolysis assoc with low temps
- post viral in children
- does NOT cause agglutination like IgM positive does
**clinical:** similar to warmAb, 7-10 days post febrile illness and persists for 6-12 weeks
- haemoglobinuria mins-hrs post cold exposure
**diagnosis:** jaundice, reticulocytosis, haemosiderinuria, bilirubinaemia, reduced haptoglobin/complement, DAT positive
53
Paroxysmal nocturnal haemoglobinuria
**pathophysiology:** RBC membrane defect in GPI anchor causing increased sensitivity to complement
**clinical:** marrow failure 60%, haemolytic anaemia, haemoglobinuria (nocturnal/morning), hypercoagulable state, decreased haematopoesis
**associations:** AML, myelodysplasia
**diagnosis:** flow cytometry to detect absent GPI
**management:** steroids for acute haemolysis, anticoagulants for thrombosis, Fe therapy, splenectomy NOT useful, androgens/EPO/GH, BMT
**prognosis:** 80% 5yr survival, mortality due to thombosis/pancytopaenia
54
Protein C/S deficiency
**incidence:** 1%
**clinical:**
- homozygous protein C def: purpura fulminans in neonate
**pathophysiology:**
type 1: quantitative
type 2: qualitative
**treatment:** FFP
- once \>1 month: warfarin + FFP/protein C
55
Prothrombin (FII) deficiency
**diagnosis:** prolonged PT/PTT
**clinical:** mucocutaneous, traumatic bleeding
**treatment:** FFP, prothrombin complex concentrates
56
Prothrombin gene mutation
**incidence:** 2%
**genetics:** mutation 20210
**pathophysiology:** increased prothrombin synthesis
**clinical:**
- 3x risk of thrombis
- increased risk with OCP/pregnancy
57
Pyruvate kinase deficiency
**genetics:** autosomal recessive
**pathophysiology:** decreased activity pyruvate kinase depleting RBCs of ATP
- secondary elevation of 2,3-DPG
**clinical:** mild to severe anaemia with pallor, icterus, splenomegally
**film:** polychromatophilic/spiculated erythrocytes
**treatment:** exchange transfusion, transfusions, splenectomy (not curative)
58
Sickle cell disease
**incidence:** 1/2500
**pathophysiology:**
- single base pair change at the β globin gene
- poorly soluble when not carrying O2 and susceptible to polymerization resulting in elongated shape and sickling
- sickle cells increase blood viscosity (Hct\>30%) and adherence
**clinical:**
- **S**: stroke (20% by 18), swelling, splenic sequestration, asplenic
- **I**: infections, infarction: bone infection SALMONELLA
- **C**: cardiac, chest, chronic haemolysis, crises
- **K**: kidney problems
- **L**: liver disease, lung problems
- **E**: erections, eye problems
**diagnosis:** anaemia with retics, high SBR/LDH, low haptoglobin
- DNA testing, Hb electrophoresis
**film:** sickled cells, Howell-Jolly bodies, target cells
mangement: prophylactic penicillin/fluvax, folic acid, hydroxyurea (decreases HbS), chronic transfusion (HbS
59
Sideroblastic anaemia
**pathophysiology:** defect in synthesis of haem within RBC precursors
- decreased d-ALA or ferrochelatase and decreased incorporation of Fe into porphyrin ring
- causes accumulation of Fe in mitochondria of nucleated RBCs (sideroblasts)
**causes:**
- _hereditary:_ XLR (presents late childhood, splenomegally), AR, Pearson syndrome (refractory, pancreatic dysfunction)
- _acquired:_ pure sideroblastic anaemia, malignancy, chronic inflammation, drugs (EtOH, isoniaxid, chloramphenicol, lead), nutrition (low copper/folic acid, high zinc), hypothermia, uremia, hyperthyroidism
**diagnosis:** high serum iron/ferritin, low transferrin
**film:** micro/macrocytic RBCs, high RDW, basophilic stippling, low retic count
**BM:** ring sideroblasts
**treatment:** cause, supportive, transfusions, vit B6
60
Spherocytes
**definition:** sphere shaped and not biconcave red blood cells
**causes:** hereditary spherocytosis, AIHA
61
Target cells
**pathogenesis:** increased SA to volume
**causes:**
- post spleenectomy/non-functioning spleen
- liver diisease
- thalassaemias
62
Thalassemia
**genetics:** 2 genes on chromosome 11
- \>200 mutations producing decreased production
**types:**
- β thalassaemia major: complete absence of β globin (β0/β0)
- β thalassaemia minor: partial absence of β globin (β+/β) or (β0/β)
**clinical (see chart)**
- increased HbF and HbA2
**treatment:**
- folate, blood transfusions 4-6 weeks (Hb\>100), hep B vaccine, iron chelation (from 4yrs), splenectomy, BMT
63
Thrombocytopaenia
**increased destruction:**
- immune: autoimmune, alloimmune, drug induced
- peripheral consumption: hypersplenism, infection, DIC, Kasabach-Merritt syndrome, drug toxicity
- procedure related
**decreased production:**
- congenital thrombocytopaenias
- maternal PET
- infections: viral, bacterial, fungal
- drug toxicity
- trisomies 13, 18, 21, Turner's syndrome
**impaired function:**
- uraemia
- congenital forms
64
Thrombocytopaenia and Absent Radii
TAR
**genetic:** 1q21.1
**clinical:** absent radius and thrombocytopaenia
65
Thrombotic thrombocytopaenic pupura
**incidence:** 0.3/100,000, 10-40yrs, F\>M
**risk factors:** pregnancy, OCP, metastases, HIV, vasculitis, SLE, drugs
**pathophysiology:** excess ultra high molecular weight vWF from deficient activity of ADAMTS13
- ADAMTS13: metalloproteinase in plasma cleaves UHMvWF secreted by endo cells to yield multimers
- accumulation UHMvWF causes platelet adhesion/aggregation
**forms:**
acquired: inhibitory Ab blocks ADAMST13 activity
hereditary: AR recessive deficiency ADAMTS13 (Upshaw-Schulman)
**PENTAD:**
- microangiopathic haemolytic anaemia: schistocytes
- thrombocytopaenia
- neurological: plt\<30, diffuse/focal symptoms
- acute renal failure
- fever
**diagnosis:** usually clinical, also hyaline thrombi in BV wall, DAT neg
**film:** schistocytes, polychromasia, nucleared RBCs
**management:** remove UHMvWF, decreased ADAMST13 inhibitor, increased ADAMST13, plasma exchange, FFP, steroids
**complications:** haemorrhage, RF, stroke, coma, CHF, death
**prognosis:** estimated degree anaemia/thrombocytopaenia/LDH
- mortality \>90% if untreated
- 1/3 of patients relapse
66
Transient Erythroblastopaenia of Childhood
(TEC)
**definition:** transient/temporary red cell aplasia
**pathophysiology:** decreased RBC production
**clinical:** self limited anaemia in previously healthy child
- reticulocytopaenia
- 2 month course with remission
67
Transient erythroblastopaenia of childhood
TEC
**pathophysiology:** transient cessation of erythropoiesis
**incidence:** children 1-4 years, M\>F
**etiology:**?viral serum inhibitors against RBCs, ?inherited response to environmental stimuli
**clinical:** anaemia 6-8g/dL, mild neutropaenia
- lasts 1-2 months before complete recovery
**treatment:** DO NOT respond to steroids
68
Vitamin K deficiency bleeding
- haemorrhagic disease of the newborn-
- consider child \< 9 months with bruising/bleeding
**vitamin K:** group of compounds with a common, structure, fat soluble
- K1: diet fortified foods, green leafy veg, legumes
- K2: intestinal bacteria
- limited stores/half life
- deficiency after 4 days no intake
**vitamin K dep factors:** 2, 7, 9, 10, protein C, protein S
**pathophysiology:**
- Vit K dep factors low at birth and drop further 48-72 hrs w/o vit K
- returns to normal levels 7-10 days
**deficiency:** vit K low in breast milk and neonates absent bacterial flora
**clinical:**
_early onset (\<24hr): rare and life threatening_
- bleed: cranial, GI, umbilicus
- cause: maternal phenytoin, warfarin, rifampicin, isoniazid, inherited coagulopathy
- prevention: vit K birth
_classic disease (2-7 days): 2% if vit K not given_
- bleed: GI, umbi, ENT, IC, cutaneous, injection, circumcision
- cause: Vit K def, BF
- prevention: vit K birth
_late onset (1-6 months): primary disease_
- bleed: IC\*\*, cutaneous, GI, ENT, injection
- cause: cholestatis, malabsorption
- treat: high dose vit K
**diagnosis:** prolonged INR/APTT, low 2, 7, 9,10
**management:** IV vit K (onset 4-6 hrs), FFP/whole blood
69
Von Willebrand Disease
**incidence:** most common bleeding disorder, 1-2% population
**genetics:** AD, chromosome 12
**levels:** vary age, stress
**pathophysiology:** vWF large glycoprotein made by megakaryocyte/endo cells
function as adhesive protein:
- _platelets:_ vWF binds subendothelium at site of damage, changes confirmation to allow platelet binding through glycoprotein receptor causing activation
- _factor VIII_: vWF carrier protein for FVIII
**clinical:**
_type 1/2_: mucocutaenous bleeding childhood/adolescence
- bruising, epistaxis, menorrhagia, postop haemorrhage
_type 3:_ present earlier with more severe bleeding
**classification:**
- type 1: quantitatively reduced but not absent (80%)
- type 2: qualitatively abnormal
- type 3: quantitatively absent (severe)
**diagnosis:**
- coags (normal OR abnormal): increase APTT (FVIII)/bleeding
- vWF Ag levels/structure
- vWF activity (ristocetin cofactor activity)
- decreased FVIII activity
**treatment:**
- avoid aspirin, NSAIDS, alcohol, antihistamines
- desmopressin: release vWF from endothelium (type 1)
- replacement therapy: plasma derived vWF)
**complications:** bleeding is rare
70
Warfarin
**mechanism**: inhibits clotting factors II, VII, IX, X, protein C/S
**half life:** 40 hours
**increased effect (drugs induce cP450)**
- carbamazepine, phenytoin, phenobarb, rifampicin, OCP
**decreased effect (drugs INHIBIT cP450)**
- isoniazid, fluconazole, CCB, erythromycin
71
Warm reactive haemolytic anaemia
**pathophysiology:** circulating Ab against own RBCs
- etiology unknown ?viral ?drug induced
**clinically 2 patterns:**
_primary AIHA: fulminant presentation_
- acute onset pallor, jaundice, hemoglobinura preceded by RTI
- splenomegally
- responsive to CS with low mortality and complete remission
_secondary AIHI: related to SLE/lymphoma_
- chronic disease course with significant mortality
**diagnosis:** Hb\<60, spherocytosis/polychromasia, reticulocytosis, nucleated RBCs, leukocytosis, Ig Ab positive, DAT positive
**treatment:** transfusion, prednisone, splenectomy, immunosuppression
72
Haemolytic Anaemia
