Haemolytic Anaemia Flashcards
Anaemia vs haemolytic anaemia
Anemia = ↓ Hb for age/gender HA = anaemia due to ↓ RBC survival
RBC life cycle - brief
RBC prod needs = iron, B12, folate, globin chains, protoporphyrins (carry heme),
loose nucleus on the way out from BM – into circulation live for 120 days
changes on CM identified by macrophages in liver and spleen which remove those RBCs
Mature RBC - metabolic pathways
Glycolytic pathway, hexose monophosphate shunt
Haemolysis - effect
Haemolysis = shortened RBC survival,
BM compensates w/increased RBC production
= ↑ young cells in circulation
= reticulocytosis +/- nucleated RBC
What is compensated haemolysis
RBC production able to compensate for decreased RBC life span = normal Hb
What is incompletely compensated haemolysis
RBC production unable to keep up with decreased RBC life span = decreased Hb
Clinical findings of haemolytic anaemia
Jaundice = unconjugated bilirubin
Pallor/fatigue
Splenomegaly, increased bilirubin
Dark urine
Haemolytic crisis - define
Increased anaemia and jaundice with infections/precipitants
Aplastic crisis - define
Anaemia, reticulocytopenia with parvovirus infection = rash/red cheeks, infects BM
Chronica haemolytic anaemia - clinical findings
Gallstones – pigment Splenomegaly Leg ulcers - free Hb scavenges NO Folate deficiency (increased use) = acute hemolysis = more folate to make more RBCs
Haemolytic anaemia laboratory findings
Increased reticulocyte count = HAs unless they have parvovirus or other reason they cant make RBCs
Increased unconjugated bilirubin
Increased LDH (lactate dehydrogenase) = from haemolysed RBCs
Low serum haptoglobin = protein that binds free haemoglobin
Increased urobilinogen
Increased urinary hemosiderin = iron from Hb that gets picked up by epithelial cells in urinary tract
Abnormal blood film
Blood film for haemolytic anaemia
Reticulocytes - (Supravital stain)
Polychromasia
Nucleated RBC
Classifying Haemolytic Anaemias
If looking at inheritance:
Inherited = Hereditary spherocytosis
Acquired = Paroxysmal nocturnal haemoglobinuria
If looking at site of RBC destruction:
Intravascular = Thrombotic thrombocytopenic purpura
Extravascular = Autoimmune haemolysis
If looking at origin of RBC damage:
Intrinsic = G6PD deficiency
Extrinsic = Delayed haemolytic transfusion reaction
Describe RBC destruction
If extravascular (in macrophages) = into globin (broken into AAs) + iron (circulation, binds transferrin) + protoporphyrin
→ bilirubin (CO released as expired air)
→ bilirubin → (in peripheral blood) bilirubin - UC
→ bilirubin glucuronides through liver
→ stercobilinogen (faeces) → urobilinogen (urine)
Intravascular = RBC into haemoglobinaemia then methaemalbuminaemia then haemoglobinuria then haemosiderinuria
Vertical interaction function and defects in it
Stabilize lipid membrane:
Spectrin-ankyrin-band 3 interactions, Spectrin-protein 4.1R–junctional complex linkages
Skeletal proteins/-ve proteins of inner LBL
Spectrin, band 3, protein 4.2 + ankyrin = hereditary spherocytosis
Horizontal interaction function and defects in it
Support structural integrity of the red cell, including after exposure to shearing:
(involving the spectrin heterodimer associations)
Protein 4.1 + glycophorin C + spectrin – HPP = hereditary elliptocytosis
What is hereditary spherocytosis and its effects
Common hereditary haemolytic anemia
Inherited in autosomal dominant fashion (75%)
Defects in proteins involved in vertical interactions between the membrane skeleton and the lipid bilayer
Decreased membrane deformability
Bone marrow makes biconcave RBC, but as membrane is lost, the RBC become spherical
Hereditary spherocytosis vs AI haemolysis distinction
No central pallor = same look as AI haemolysis
DAT (test) = look for AB on red cell +ve in AIH and –ve in spherocytosis
Clinical features of hereditary spherocytosis
Asymptomatic to severe haemolysis
Neonatal jaundice
Jaundice, splenomegaly, pigment gallstones
Reduced eosin-5-maleimide (EMA) binding – binds to band 3
Positive family history
Negative direct antibody test
Management of hereditary spherocytosis
Monitor, Folic acid, Transfusion, Splenectomy – not in small children = important for immunity
RBC metabolic pathways
Glycolysis –energy- ATP
Na/K pump
3 Na+ out 2 K+ in
ATP to ADP+Pi
HMS – reducing power -NADPH/GSH
Rapoport Luebering shunt –
2,3 Bi-PhosphoGlycerate (2,3 BPG) – modulates O2 binding to Haemoglobin
Role of the HMP shunt
Generates reduced glutathione
Protects the cell from oxidative stress
Effects of oxidative stress
Oxidation of Hb by oxidant radicals
Resulting denatured Hb aggregates & forms Heinz bodies – bind to membrane
Oxidised membrane proteins – reduced RBC deformability
What is G6PD, its spread, clinical features
Hereditary, X-linked disorder
Common in African, Asian, Mediterranean and Middle Eastern populations
Mild in African (type A), more severe in Mediterraneans (type B)
Clinical features range from asymptomatic to acute episodes to chronic haemolysis
G6PD oxidative precipitants
Infections Fava/ broad beans Many drugs e.g.: Dapsone Nitrofurantoin Ciprofloxacin Primaquine
G6PD features
Haemolysis Film: - Bite cells - Blister cells & ghost cells - Heinz bodies (methylene blue) Reduced G6PD activity on enzyme assay: - May be falsely normal if reticulocytosis
Oxidative haemolysis definition
Destruction of circulating human erythrocytes exposed to oxidant stress
Pyruvate Kinase Deficiency - cause and effects
PK required to generate ATP Essential for membrane cation pumps (deformability) Autosomal recessive Chronic anaemia - Mild to transfusion dependent - Improves with splenectomy
Hb structure
Hb structure = Haem (Fe2+ + protoporphyrin IX) + globin (2ɑ + 2β)
HbA = ɑ2β2, HbA2 = ɑ2δ2 + HbF = ɑ2γ2
Quantitative - thalassaemias = define
Production increased/ decreased amount of a globin chain (structurally normal)
Qualitative – variant haemoglobins = define
Production of a structurally abnormal globin chain
HbS - ↓solubility, polymerisation
Hb Koln - ↓stability, Heinz body formation
HbC - ↓solubility, crystallisation
Thalassaemias - define
Imbalanced alpha and beta chain production
Effect of excess unpaired globin chains
Excess unpaired globin chains are unstable
- Precipitate and damage RBC and their precursors
- Ineffective erythropoiesis in bone marrow
- Haemolytic anaemia
Beta thalassaemias - chance
Autosomal recessive = ¼ chance
Diagnosis of thalassaemia trait
Asymptomatic Microcytic hypochromic anaemia Low Hb, MCV, MCH Increased RBC Often confused with Fe deficiency HbA2 increased in b-thal trait –(diagnostic) a-thal trait often by exclusion globin chain synthesis (rarely done now) DNA studies (expensive)
Beta Thalassaemia Major effect if not transfused
Transfusion dependent in 1st year of life
If not transfused = Failure to thrive, Progressive hepatosplenomegaly, Bone marrow expansion – skeletal abnormalities, Death in 1st 5 years of life from anaemia
Side effects of transfusion
Side effects of transfusion = Iron overload, Endocrinopathies, Heart failure, Liver cirrhosis
Sickle cell disease cause
Sickle cell = Point mutation in the β globin gene: glutamic acid → valine = Insoluble haemoglobin tetramer when deoxygenated → polymerisation = “Sickle” shaped cells
Clinically significant sickling syndromes
Clinically significant sickling syndromes: HbSS HbSC HbS-D Punjab HbS- O Arab HbS- β thalassaemia
SCD acute complications
Stroke: ischaemic & haemorrhagic Cholecystitis Hepatic sequestration Dactylitis Bone pain & infarcts Osteomyelitis Leg ulcers Aplastic crisis Priapism Haematuria: papillary necrosis Splenic sequestration Chest syndrome Retinal detachment Vitreous haemorrhage
SCD chronic complications
Silent infarcts Pulmonary hypertension Chronic lung disease, bronchiectasis Erectile dysfunction Azoospermia Chronic pain syndromes Delayed puberty Leg ulcers Avascular necrosis Chronic renal failure Retinopathy, visual loss Moya-moya
Clinical features of SCD
Painful crises Aplastic crises Infections Acute sickling: - Chest syndrome - Splenic sequestration - Stroke Chronic sickling effects: - Renal failure - Avascular necrosis bone
Laboratory features of SCD
Anaemia - Hb often 65-85 Reticulocytosis Increased NRBC Raised bilirubin Low creatinine
SCD diagnosis
Diagnosis = Solubility test, Expose blood to reducing agent, Hb S precipitated, Positive in trait and disease
Or electrophoresis to look at structure
Autoimmune haemolysis - features
Idiopathic - cause unknown
- Usually warm
- Rare cause of hemolysis precipitated by antibodies directed against blood group antigens, most commonly IgG + react with proteins on the surface of RBC at normal body temp (warm agglutinins) (IgM as well)
Drug-mediated
Cancer associated
- LPDs (Lymphoproliferative disorders)q
Alloimmune haemolysis - features
Transplacental transfer:
Haemolytic disease of the newborn:
- D, c, L
ABO incompatability
Transfusion related: Acute haemolytic transfusion reaction - ABO Delayed haemolytic transfusion reaction - E.g Rh groups, Duffy
Non-immune acquired haemolysis - causes
Paroxysmal nocturnal haemoglobinuria
Fragmentation haemolysis:
- Mechanical
- Microangiopathic haemolysis
- Disseminated intravascular coagulation
- Thrombotic thrombocytopenic purpura
Other:
Severe burns
Some infections: e.g. malaria