Haem Flashcards
Tranexamic acid
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
Cryoprecipitate
Cryoprecipitate contains mostly fibrinogen, factor 8, factor 13 and von Willebrand factor
Disorders of red cell production (cause Anaemia)
haematinic def (iron, b12, folate) marrow failure marrow replacement anaemia of chronic disease ineffective erythropoeisis dyserythropoeisis
Disorders of haemolysis (increased destruction RBC)
- 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
MAHA
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
Haemolytic anaemia
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
Evan’s syndrome
Rare autoimmune disorder
- autoimmune haemolytic anaemia (DAT +ve)
- immune thrombocytopenia
Hereditary spherocytosis
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
Congenital TTP
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
Beta thalassemia major
Note (intermedia, homozygous but less severe)
Note (minor –> genetic counsellor as a carrier)
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
Alpha thalassemia
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)
chronic benign neutropenia
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
Sickle cell
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)
Schwachman diamond syndrome
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
Congenital neutropenia
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
DDAVP
promotes release of vWF through releasing endogenous factor VIII
Used in treatment of mild haemophilia A and thrombocytopenia and VWD
Fanconi anaemia
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
Acute splenic sequestration crisis
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.
Diamond Blackfan anaemia
- 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
Target cells and tear drop cells are consistent with?
Thalassaemia trait
What is haemoglobin made up of and how is it made?
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
Which factors shift the oxygen dissociation curve to the left?
Shift to left = increased affinity for oxygen
Alkalosis, low CO2, low temp, low 2,3 DPG, HbF
Which factors shift the oxygen dissociation curve to the right?
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”
What is Hb Barts?
4 x fetal gamma chains due to 4 x alpha deletions
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
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
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
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)
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).
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.
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
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
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
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)
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
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
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
Natural anticoagulants
Antithrombin III - most potent inhibitor, heparin potentiates its effect
Protein C - inhibits 5a, 8a, promotes fibrinolysis. Protein S enhances protein C action
