Haemolytic Anaemia Flashcards
Normal red cell life cycle
Early erythroid –> late erythroid –> polychromatic cells –> mature red cells
Nuclear and cytoplasmic pathways
Senescence (extravascular haemolysis at the spleen into iron, globin and protoporphyrin/bilirubin) – fine balance between production and destruction
Haemolytic anaemia general features
Increased break down of RBC > compensatory production
General features of HA
- increased red cell breakdown and shortened RBC life span
- -> anaemia, hyperbilirubinaemia, pigment gallstones, increased LDH, splenomegaly, aplastic crises with parvovirus B19 infection
- increased red cell production
- -> reticulocytosis, polychromasia, BM erythroid hyperplasia, folate deficiency
Classifications of HA: Extravasular vs Intravascular
Extravascular
- breakdown in RE system, resembling normal RBC clearance but at an increased rate
Intravascular
- breakdown in circulation with direct release of Hb
- haemoglobinaemia, haemoglobinuria
- haemosiderinuria (Fe release from Hb)
- reduced haptoglobin (proteins that bind free Hb in plasma to “clean up”)
Classifications of HA: Intrinsic red cell defect vs Extracorpuscular factors
Intrinsic red cell defect (usually inherited)
- membrane: hereditary spherocytosis, elliptocytosis
- enzyme: G6PD or pyruvate kinase deficiency
- Hb: Hb variants
Extracorpuscular factors (acquired)
- immune: auto/alloimmune
- non-immune: red cell fragmentation syndromes, infection, chemicals/drugs/physical agents, secondary to systemic diseases
- PNH (acquired intrinsic red cell defect)
Intrinsic red cell defect: membrane - hereditary spherocytosis (inheritance pattern, pathogenesis, clinical features, diagnosis, treatment)
Proteins in the membrane essential for maintaining integrity of the RBC and allow them to deform and squeeze through microcirculation
Hereditary Spherocytosis
- AD, variable expression, can be due to germline de novo mutation
- defects in proteins involved in the vertical interactions between membrane skeleton and lipid bilayer –> lose biconcave shape and increased fragility
- clinical features: splenomegaly and gallstones common, increased MCHC, spherocytes (loss of central pallor) +/- polychromasia
Diagnosis:
- osmotic fragility test (historically)
- FLOW CYTOMETRY for eosin-maleimide (EMA) binding to red cells –> lower fluorescence due to less membrane protein expression and reduced SA:Vol in spherocytes
- negative direct coombe’s test (r/o AIHA)
Treatment:
- folate replacement
- monitor growth and development
- splenectomy/cholecystectomy depending on symptoms
Intrinsic red cell defect: membrane - other defects
Hereditary elliptocytosis
- elliptocytes on blood film
- milder than HS
SE asian ovalocytosis
- Band 3 protein defect
- ovalocytes and stomatocytes (advantage in malaria resistance)
- mostly asymptomatic
Intrinsic red cell defect: enzyme - G6PD deficiency (pathophysiology, inheritance, clinical features, precipitating factors, diagnosis, treatment, prevention)
Normal function: reduction of NADP to NADPH for production of reduced glutathione for anti-oxidation
- deficient G6PD increases RBC susceptibility to oxidant stress e.g. fava beans, mothballs (napthalene), drugs (antimalarials, septrin, nitrofurantoin, HD aspirin)
X linked recessive, affecting males
Female carriers have advantage of malaria resistance
Clinical features:
- usually asymptomatic unless exposed to oxidant stress –> acute intravascular HA
- neonatal jaundice
Diagnosis:
- blood smear: polychromasia, reticulocytosis, “bite” cells, HEINZ BODIES (denatured Hb; ring-like)
- G6PD assay (falsely normal during acute haemolysis as G6PD levels higher in reticulocytes)
Treatment:
- stop offending drugs and treat infections
- maintain urine output to prevent renal toxicity of free Hb
Routine antenatal screening in HK
Intrinsic red cell defect: Hb
Refer to other set of flashcards
Extracorpuscular factors: immune - types
Autoimmune (AIHA)
- Ab against own RBC
- POSITIVE DIRECT COOMBE’S TEST
- cold and warm types
Alloimmune HA
- mainly concerning transfusion and transplantation (Ab of one individual reacts with another’s RBC)
- also related to haemolytic disease of newborn (RhD alloimmunisation)
Direct and Indirect Coombe’s test
Direct
- test for RBC coated with Ab
- add anti-human globulin (anti-IgG and anti-C3d) to patient’s blood and check for agglutination
Indirect
- for pretransfusion testing for Ab in plasma
- add test RBCs and anti-human globulin and check for agglutination
Warm AIHA - pathogenesis, clinical features, causes, treatment and support
Pathogenesis: autoimmune IgG Ab
- IgG coated RBC taken up by macrophages in RE system (spleen) and part of coated membrane lost –> red cells come progressive spherical
Clinical features:
- splenomegaly
- features of extravascular HA
- spherocytosis (c.f. distinguish from HS by DCT)
- DCT positive (anti-IgG)
- Evan’s syndrome when a/w ITP
Causes:
- idiopathic, SLE, lymphoma, CLL, drugs (e.g. methyldopa)
Treatment:
- remove underlying cause e.g. stop drugs, treat AI disease, treat lymphoma (mostly idiopathic)
- steroid
- if steroid ineffective: splenectomy, monoclonal Ab (rituximab anti-CD20), other immunosuppressants
Supportive treatment:
- folic acid
- blood transfusion if severe symptomatic anaemia
Cold AIHA - pathogenesis, clinical features, lab findings, causes, treatment
Pathogenesis: autoimmune IgM Ab (anti-C3d) which is highly efficient at fixing complement
- mostly against I antigen on RBC
Clinical features:
- chronic HA aggravated by cold
- intravascular haemolysis
- acrocyanosis of fingers, toes, nose, ears
Lab findings
- less marked spherocytosis
- red cell agglutination in cold
- DCT positive (anti-C3d)
Causes:
- idiopathic, lymphoma, infections (Mycoplasma pneumonia, infectious mononucleosis)
- paroxysmal cold haemoglobinuria
Treatment:
- keep warm
- treat underlying cause
- Rituximab
- splenectomy/steroids not useful
Paroxysmal cold haemoglobinuria
Rare
Intravascular haemolysis after exposure to cold then warm temp due to anti-P IgG Ab
Donath-Landsteiner test
A/w malignancies, viral infections, syphilis
Extracorpuscular factors: non-immune - causes, main features
Red cell fragmentation syndromes
- caused by altered blood flow follow cardiac surgery or AVM or pathological small blood vessels i.e.g Microangiopathic HA – SCHISTOCYTES + HA
- ABNORMAL THROMBOSIS at inappropriate sites
Red cell fragmentation: TTP - pathogenesis, clinical features, coagulation time, diagnosis, associations
Thrombotic thrombocytopenic purpura
Pathogenesis: ADAMTS13 deficiency = increase HMW vWF which are more thrombogenic –> clot formation at random sites
Rapidly fatal emergency!
Clinical features:
- classical pentad (fever, MHA, thrombocytopenia, renal impairment, fluctuating neurological signs)
- normal coagulation time
- haemolysis features
- markedly reduced ADAMTS13 activity
Difficult diagnosis:
- ADAMTS13 activity not widely available for testing
- often full pentad not present
- must be on DDx when there is MHA and thrombocytopenia!! (other DDx are DIC and HUS)
Associated with drugs, malignancies, infections, pregnancy, autoimmune diseases
