Haematology Flashcards
Which anticoagulant is teratogenic
Warfarin
- especially if taken week 6-12 pregnancy
Heparin doesnt cross the placenta
Aspirin in high doses can cause premature closure of ductus arteriosus
Thalassemia
imbalance between alpha and beta globin chain production ie problem with quantity of globin
alpha - less alpha globin (normal= 4 genes); beta - less beta globin (normal = 2 genes)
Alpha characterised by increased Hb Barts (tetramer of gamma Hb)
Beta characterised by elevated A2 (alpha + delta)
Alpha thalassemia
1-4 gene deletions
1 gene deletion: clinically silent
2 gene deletion: normal or mild anemia
Moderate Barts (5-10%)
2 gene deletion + constant spring: mod -severe anemia
B0 thalassemia
No beta globin produced by that allele
If homozygous= no beta chains at all
unable to make HbA (only HbF/HbA2)–> severe anemia, transfusion dependant, haemochromatosis –> death
B+ thalassemia
B+/B+
B+= Reduced amount of normal beta globin
Moderate anemia, may be transfusion dependant
Less severe than B0
Produce up to 50% HbF, >4% HbA2, HbA ~50%
Beta thalassemia major
B0/B0, B0/B+, B+/B+ or compound heterozygote with HbE
progressive haemolytic anemia from ~6 months (when HbA is supposed to predominate), transfusion dependant from early age (<2 years)
clinical/phenotypical diagnosis
A globin tetramers form and appear as red cell inclusions; very unstable, reduce red cell survival –> anemia, increased (but ineffective) erythropoesis with early erythroid precursos death in BM (inappropriately low reticulocyte count) + compensatory massive BM expansion with thalassemic facies + maxilla hyperpasia/frontal bossing/HSM
HbF (alpha + gamma) >90%,HbA2 (alpha + delta) >5% no or very little HbA
Can be diagnosed at birth as no /very little HbA (only HbF)- normally 20% HbA at birth
beta thalassemia intermedia
less severe phenotype
Mod anemia but not transfusion dependant in childhood; may only be transfusion dependant during infection/pregnancy
usually B+/B+ or B0/B+
HbF up to ~60%, HbA up to ~40%, HbA2 >4%
B thal minor
AKA beta thal trait
Carrier
Mutation in only one beta globin gene
- either B+/B or B0/B
- only need one notmal gene to produce enough beta globin
Asymptomatic or mild microcytosis +/- anemia
Slightly elevated HbA2 3-7% HbF 1-3%, HbA >90%
Alpha 0 mutation
no alpha chains produced from that gene
Alpha + mutation
reduced alpha chains produced from that gene
major difference between sickle cell anemia and thalassemia
sickle cell- quality of globin produced
thalassemia - quantity of globin produced
What is Bart haemaglobin
Tetramer of gamma chains
Occurs in alpha thalassemia due to excess gamma chains when alpha chains cant be produced to form normal fetal haemaglobin
After birth this becomes HbH (tetramer of beta globins) when gamma chains stop being produced
What is HbH?
Tetramer of beta globins
Due to no alpha chains in alpha thalassemia
Complications of thalassemia
Anemia - can lead to high output heart failure, FTT
Skeletal abnormalities from BM enlargement
Iron overload from transfusions- toxicity in various organs, hypogonadism, hypothyroidism, insulin resistance growth impairment
Complications of hemolysis: jaundice, pigment gallstones
Hepatosplenomegaly (extramedullary hematopeisis in liver and spleen, hepatic iron deposition, hemolysis)
Hypersplenism –> pancytopenia
Liver fibrosis and cirrhosis
Venous thrombosis
Osteopenia/osteoporosis /bone pain
HbH disease
3 alpha chains affected
usually have symptomatic anemia at birth
May have pigment gallstones
HbH up to 30%, HbA2 up to 4%
Newborn screening for haemaglobinopathies
Normal adult and neonate haemaglobin studies
Adult: HbA 96-98%, HbA2 2-3%, HbF <1%
Neonate: HbF 80%, HbA 20%, HbA2 0%
Haemaglobin studies in beta thal trait
Elevated HbA2 >3.5%, HbF 1-4% (ie both slightly eleveated compared to normal) HbA 92-95%
Haemaglobin studies in beta thal major
Very low or no HbA, only HbF (95-98%), HbA2 (2-5%
this is detectable from birth (should have 20% HbA at birth >36 weeks)
*consider b thalassemia intermedia or major in a bub with <5% HbA (if born >36 weeks)
The absence of HbA (even at birth) is pathomenmonic for beta thal major
Hb Barts in newborns haemaglobin studies
In all newborns with α-thalassaemia the non functional abnormal fraction Hb Bart’s will always be detected. To some extent, the amount of Hb Bart’s correlates with the number of defective α-globin genes. A simple mild condition with a single gene defect (-α/αα) will present with very little Hb Bart’s (1-4%), while in samples with two defective α-genes, either in cis (–/αα) or in trans (-α/-α), the Hb Bart’s will rise to 5-15%, reaching 25% and higher in HbH disease with 3 defective α-genes (–/-α) (13-15).
Can a B thalassemia carrier be detected at birth?
Only intermedia or major can be detected by measuring HbA levels
HbA2 is not significantly expressed until 1 year of age to be used as a diagnostic parameter
Carriers would have HbA««20% but there is wide variation of “normal” so not really able to diagnose until later
haemaglobin studies in beta thal intermedia
HbA 10-30%
HbF 70-90%
HbA2 2-5%
co inheritance of alpha trait with homozygous beta thal major leads to…
reduction in alpha globin synthesis reduces burden of alpha globin inclusions so improves the phenotype
can change tranfusion dependant thal major to non transfusio dependant thal intermedia
what infections are increased in thalassemia major
Yersinia enterocolitica - iron loving, iron chelation makes it even more available
Listeria
Salmonella
how do you reduce the risk of iron overload in transfusion dependant thalassemia
Chelation with desferrioamine (subcut/IV)- ototoxicity, retinal changes, cataracts, GI side effects, yersinia infections)
Desferasirx - oral tds (a/e- GI, renal)
Deferiprone - oral tds (A/e- agranulocytosis, deranged LFTs, arthralgia, arthropathy
Differentiating iron deficiency from thalassemia minor
iron def - low retics, low RBC count, low ferritin
thalassemia - normal or slightly increased retics, high RBC
Iron studies in thalassemia- elevated ferritin and transferrin saturation (even without transfusion )
Low ferritin is only seen in thalassemia if there is a concomitant iron deficiency
Film in thalassemia: nucleated RBC, target cells, anisopoikolocytosis
how does iron def interfere with the diagnosis of beta thal minor
reduces the amount of HbA2 which is the main diagnostic feature in beta thal minor
Haemaglobin constant spring
The most common non-deletional alpha globin variant is hemoglobin Constant Spring.
In contrast to beta thalassemias, in which beta+ variants tend to be less severe, some alpha+ alleles such as Hb Constant Spring can actually aggravate severity. This is because the common alpha+ alleles encode alpha chains that, when combined with beta chains, create highly unstable hemoglobins that precipitate, adding to the burden of inclusion bodies in the developing and circulating RBCs.
1 alpha globin deletion leads to ..
silent carrier
maybe microcytosis
can only be detected on genetic analysis
2 gene deletion /mutation in apha globin gene leads to..
alpha thalassemia trait
microcytosis +/- silent carrier
Slightly elevated Hb barts in newborn period; otherwise electrophoresis is normal
3 gene alpha globin mutation leads to
HbH disease
can be deletional or non deletional (more severe- constant spring)
Moderate haemolytic/microcytic anemia
Electrophoresis: Elevated HbH (up to 30%), elevated HbA2 ~4%
HbH has virtually no oxygen transport capacity and is insoluable, so precipitates out of RBC leading to haemolytic anemia
2 alpha deletions + constant spring mutation (compound heterozygote) leads to a more severe anemia with more frequent hemolytic events and earlier mean age at first transfusion
4 gene deletion of alpha globin leads to
severe hemolytic anemia in utero–> hydrops fetalis
Only Hb is Hb barts (tetramer of gamma chains)
only survive with exchange transfusions
when do you see Hb Barts
elevated in all newborns with alpha thalassemia mutations (carriers/trait/HbH)
How do you diagnose alpha thalassemia
alpha trait/minor- only by DNA testing
Electropheresis can show Hb Barts or HbH in a neonate with alpha thal
Hb Barts of 20-40% within 2 days of birth is a hallmark of HbH disease in newborn
Low levels of Hb Barts (3-8%) or no Hb Barts is diagnostic of alpha thal minor
If above findings are present, need to do gene analysis
Fanconi anemia
AR
Bone marrow failure
Increased chromosomal breakage, poor DNA repair
Pancytopenia
Skin- hyperpigmentation, cafe au lait
Short stature
Thumb/radia abnormalities
Genital problems
(ddx diamond blackfan anemia- usually red cell aplasia)
Dyskeratosis congenita
bone marrow failure syndrome
short telomeres (defect in telomere maintenance)
diagnosed by telemere length analysis
Triad: lacy skin pigmentation, dystrophic nails, oral leukoplakia
Schwachman -Diamond syndrome
Bone marrow failure syndrome
Triad: exocrine pancreatic insufficinecy, neutropenia, metaphyseal dyspasia
Risk increased with monosomy 7
heinz bodies are seen in
G6PD deficinecy - oxidative stress leading to denatured haemaglobin
Alpha thalassemia (excess of beta chains precipitating as HbH)
Hyposplenism eg sickle cell anemia
haemolytic uremic syndrome presentation
triad of microangiopathic haemolytic anemia, thrombocytopaenia and acute kidney injury with concurrent gastroenteritis is suggestive of shiga-toxin producing E. Coli
MoA hydroxyurea
Increased HbF production
shift in gene expression at the beta globin gene locus, leading to a relative increase in gamma globin gene expression and hence increases production of HbF (2 alpha and 2 gamma chains) with relative reduction in HbS. Reduction in HbS leads to increased RBC lifespan, reduced haemolysis and reduced microvascular adhesion, improving microcirculation.
Evans syndrome
Autoimmune haemolytic anemia + thrombocytopenia
HbSC
clinically significant sickle cell variant syndrome. It is less severe than sickle cell disease, and more severe than sickle cell trait. Patients will HbSC are at the same risk of life threatening crises as (painful episides, strokes), lower risk bacterial infection, patients with HbSS but these occur less frequently with milder clinical severity.
sickle cell anemia
homozygous Hb SS (both beta globin alleles have the sickle cell mutation.)
Hb S 85-95% of total Hb
sickle cell disease
either sickle cell anemia (homozygote) or compound heterozygote with beta thal or Hb C/D/E
>50% HbS
Hb studies in HbSS
HbA = 0
HbF 5-15%
HbS 85-95%
HbA2 <3.5%
Neonate: FS
Hb studies in sickle B0 thal
HbA= 0
HbF 2-15%
HbS80-90%
HbA2 >3.5 (rememeber beta thal has elevated HbA2!)
Neonate: FS
Hb studies in sickle B+ thal
HbA 3-30%
HbF 2-10%
HbS 60-90%
HbA2 >3.5 %
Neonates: FS or FSA
Hb studies in HbSC
HbA = 0
Hb F 1-5%
HbS 45-50%
HbC 45-50%
HbA2 <3.5
what is the most common cause death in sickle cell disease
infection
Almost all patients become functionally asplenic by age 5 years and are at risk for severe infection and sepsis (particularly by encapsulated organisms).
Low threshold for antibiotics if any hint infection
Penicillin prophylaxis at diagnosis/by 2 months of age until at least 5 years
* All sickle cell patients should be treated as if they are functionally asplenic and at risk from invasive disease with encapsulated organisms * If pain is also present treat concurrently as VOC * If cough or dyspnoea also present look and treat for acute chest syndrome (see below) * Commence antibiotics without delay if febrile or toxic: o Cefotaxime IV 50mg/kg (max 2g/dose) every 6 hours OR Ceftriaxone IV 100mg/kg (max 4g/day) once daily.
