Haematology Flashcards
Acquired thrombocytopaenia
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
Alpha thalassemia
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
Anaemia
Anaemia chronic disease
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
Anti-phospholipid antibodies
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
Aplastic anaemia
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
Autoimmune thrombocytopaenia
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
Bernard Soulier
aka. hemorrhagiparous thrombocytic dystrophy
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
Bernard Soulier syndrome
pathogenesis: absence of vWF receptor (GpIb complex) on platelet membrane
diagnosis: thrombocytopaenia, large platelets, prolonged bleeding time >20mins
Blackfan-diamond anaemia
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
Cell morphology
Clotting factors half lives
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
Clotting times
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
Coagulation cascade
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
Coagulation cascade
Coagulation tests
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
Cold agglutinin haemolytic anaemia
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)
Concomitant alpha and beta thalassemia
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
Congenital abnormalities of platelet function
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
Congenital Amegakaryocytic Thrombocytopaenia
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
Congenital thrombocytoapaenia
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
Diagnosis/Clinical features of haemophilia
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
Diamond-Blackfan Anaemia
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
DIC
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)
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
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
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
Factor V deficiency
(parahaemophilia)
genetics: AR
clinical: mild bleeding, menorrhagia
treatment: FFP
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
Factor X deficiency
genetics: rare, autosomal
associations: amyloidosis due to absorption of factor X on amyloid protein
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
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
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%
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
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
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
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%)
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
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
Heinz Bodies
pathogenesis: precipitated Hb
causes: G6PD
Hereditary elliptocytosis
genetics: RARE
clinical: similar to spherocytosis
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
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
Howell Jolly-Bodies
pathogenesis: contain nuclear remnants
causes:
- post spleenectomy
- megaloblastic anaemia
- iron deficiency anaemia
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
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
Iron Physiology
source:
- iron absorbed duodenum
- released RBC/monocytes/macrophages
location:
- haemoglobin, myoglobin, ferritin, haemosiderin, enzyme bound
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
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
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
Normal haemoglobin
structure: tetramer with 2 pairs of globin chains
distribution:
- HbF (α2γ2):
- HbA2 (α2d2):
- HbA (α2β2): >95%
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
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
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
Prothrombin (FII) deficiency
diagnosis: prolonged PT/PTT
clinical: mucocutaneous, traumatic bleeding
treatment: FFP, prothrombin complex concentrates
Prothrombin gene mutation
incidence: 2%
genetics: mutation 20210
pathophysiology: increased prothrombin synthesis
clinical:
- 3x risk of thrombis
- increased risk with OCP/pregnancy
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)
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
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
Spherocytes
definition: sphere shaped and not biconcave red blood cells
causes: hereditary spherocytosis, AIHA
Target cells
pathogenesis: increased SA to volume
causes:
- post spleenectomy/non-functioning spleen
- liver diisease
- thalassaemias
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
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
Thrombocytopaenia and Absent Radii
TAR
genetic: 1q21.1
clinical: absent radius and thrombocytopaenia
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
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
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
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
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
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
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
Haemolytic Anaemia
