Anaemias Flashcards
Numerical definition of anaemia in men and women
Men = Hb under 135g/L, Women = Hb under 115g/L
Causes of anaemia (3 groups)
Reduced production of RBCs, increased loss of RBCs (haemolytic anaemias), increased plasma volume
4 causes of Microcytic Anaemias
FAST: Fe Deficiency anaemia, Anaemia of chronic disease, Sideroblastic anaemia, Thalassaemia (in the absence of anaemia)
7 causes of Normocytic Anaemias
Acute blood loss, ACD, Bone Marrow Failure, Renal failure, Hypothyroidism, Haemolysis, Pregnancy
7 causes of Macrocytic Anaemias
FATRBC: Foetus (Pregnancy), Antifolates (e.g. Phenytoin), Thyroid (hypothyroidism), Reticulocytosis, B12 or folate deficiency, Cirrhosis (Alcohol xs or liver disease), Myelodysplastic syndromes
Clinical signs of Iron Deficiency Anaemia
Hands: koilonychia, brittle nails
Face: atrophic glossitis, angular cheilosis, brittle hair
Chest: ejection systolic murmur ( due to turbulent flow in severe Anaemia)
Plummer Vinson syndrome = IDA + post-cricoid webs +
Typical IDA Blood Film
Microcytic, hypochromic, anisocytosis, poikilocytosis, pencil cells
Causes of IDA
Blood Loss: GI loss
Increased Utilisation: Pregnancy, Growth
Decreased Intake: Prematurity, Infants/children/elderly
Decreased Absorption: Coeliac, Post-gastric surgery
Intravascular haemolysis: Microaniopathic, Haemolytic anaemia, PNH
Treatment of IDA
Treat the cause! Oral iron (SE: nausea, abdominal discomfort, diarrhea/constipation, black stools)
Explain the mechanism behind Anaemia of Chronic Disease (How does chronic disease causes anaemia?)
Cytokine driven inhibition of RBC production:
-Inflammatory markers (IFN, TNF, IL1) reduce EPO receptor production by kidneys.
IL6 and LPS stimulate the liver to make hepcidin which decreased iron absorption from gut by inhibiting transferrin, and also causes iron accumulation in macrophages
What are the causes of ACD?
Chronic Infection (TB, Osteomyelitis etc.), Vasculitis, Rheumatoid Arthritis, Malignancy
Is the ferritin level (intracellular protein iron store) low or high in ACD and why?
Is it low or high in IDA?
ACD: high, because Fe is sequestered into macrophages to deprive invading bacteria of Fe
IDA: low
Mechanism underlying Sideroblastic Anaemia
Ineffective erythropoiesis: Iron loading (bone marrow) causing haemosiderosis. Can lead to endocrine, liver, and cardiac damage due to iron deposition
Causes of Sideroblastic anaemia
Myelodysplastic disorders, following chemotherapy, irradiation, alcohol XS, lead XS, anti-TB drugs, myeloproliferative disease
How is Sideroblastic Anaemia diagnosed?
Ring sideroblasts seen in the marrow (erythroid precursors with iron deposited in mitochondria in a ring around the nucleus)
Treatment of Sideroblastic anaemia
Remove the cause and Pyridoxine (vit B6 promotes RBC production)
Will Iron, TIBC and Ferritin be high, normal, or low in:
Iron Deficiency Anaemia?
Iron - Low
TIBC - High
Ferritin - Low
What does a megaloblastic blood film look like?
Hypersegmented polymorphs, leucopenia, macrocytosis, anaemia, thrombocytopenia
What are the megaloblastic causes of macrocytosis?
B12 deficiency, folate deficiency, cytotoxic drugs
What are the non megaloblastic causes of macrocytosis?
Alcohol (most common cause of macrocytosis without anaemia), reticulocytosis, liver disease, hypothyroidism, pregnancy.
What haematolgical diseases are associated with a macrocytic blood film?
Myelodysplasia, myeloma, myeloproliferative disorders, aplastic anaemia`
Why might someone have a Vit B12 deficiency?
- Dietary (found in meat and dairy products)
- Malabsorption in stomach: IF is produced by gastric parietal cells and needed for B12 to be absorbed later, could be lacking due to pernicious anaemia or post gastrectomy
- Malabsorption in terminal ileum: ileal resection, crohn’s disase, bacgterial overgrowth, tropical sprue and tapeworms
What are the clinical features of B12 deficiency?
Glossitis, angular cheilosis, irritability, depression, psychosis, dementia, paraesthesiae, peripheral neuropathy (loss of vibration and proprioception first, absent ankle reflex, spastic paraperesis, SACD of spinal cord)
What is pernicious anaemia?
Autoimmune atrophic gastritis: achlorhydria and lack of gastric intrinsic factor.
Most common cause of macrocytic anaemia in Western countries
What are the specific tests for Pernicious anaemia?
Parietal cell antibodies (90%), IF antibodies (50%), Schilling test (outdated)
What is the treatment for Vit B12 deficiency?
Replenish stores with IM hydroxocobalamin
What are the causes of folate deficiency?
Poor diet
Increased demand: pregnancy or increased cell turnover (haemolysis, malignancy, inflammatory disease, renal dialysis)
Malabsorption: coeliac disease, tropical sprue
Drugs: alcohol, anti-epileptics, methotrexate, trimethoprim
When should folic acid not be given in a macrocytic anaemia?
When the cause of anaemia is not known, as folic acid will exacerbate the neuropathy of B12 deficiency
Causes of Inherited Haemolytic Anaemias
Membrane defect: hereditary spherocytosis, hereditary elliptocytosis
Enzyme defect: G6PD deficiency, PKD
Haemoglobinopathies: Sickle cell disease, thalassaemias
Causes of acquired Haemolytic anaemias
Immune: Autoimmune, alloimmune (haemolytic transfusion reactions
Non-immune: Mechanical (metal valves, trauma), PNH, MAHA, Infections, Drugs
Hereditary Spherocytosis:
Genetics
Diagnosis
Treatment
Genetics: Autosomal dominant (25% recessive or de novo)
Diagnosis: spherocytes, increased osmotic fragility (lysis in hypotonic solutions), -ve DAT (not AI Ab mediated), flow cytometry
Treatment: Splenectomy, Folic acid
What membrane protein deficiency is seen in hereditary spherocytosis?
Spectrin or ankyrin deficiency
What are people with hereditary spherocytosis more susceptible to?
Parvovirus B19 + Gallstones
Herditary Elliptocytosis:
Genetic Inheritance
Protein mutation
Severity
Inheritance: Autosomal Dominant, except for Hereditary Pyropoikilocytosis which is AR
Spectrin mutation
Severity ranges from hydrops foetalis to asymptomatic
What is the genetic inheritance of G6PD and in what populations is it most prevalent?
X linked
African, Mediterranean, Middle Eastern (areas of malarial endemicity
How are G6PD attacks characterized?
Rapid anaemia and jaundice (with dark urine)
Blood: Bite cells and Heinz bodies
What often precipitates a G6PD attack and why (mechanism)?
Oxidants: G6PD helps RBCs make glutathione which protects them from oxidant damage
Oxidants incl: Drugs e.g. Primaquine, Sulfonamides, Aspirin (usually 2-3 days after starting), Broad beans (within 24h of ingestion), acute stressors, moth balls, acute infection
How is G6PD diagnosed and what is the treatment?
Diagnosis: Enzyme assay 2-3 months after a crisis (N.B young RBCs may have sufficient enzyme so results may appear normal)
Treatment: avoid precipitants, transfuse if severe, genetic screening (rare subtypes give chronic haemolysis for which splenectomy is a good treatment)
Pyruvate Kinase Deficiency:
Inheritance Pattern, Clinical features, Treatment
Inheritance: Autosomal recessive (though AD has also been observed)
Clinical Features: severe neonatal jaundice, splenomegaly, haemolytic anaemia
Treatment: normally no treatment required, but can do splenectomy or blood transfusion
What is the inheritance pattern of Sickle Cell disease and what mutation(s) is present?
Autosomal Recessive
Single base mutation: GAG –> GTG, Glu –> Val at codon 6 of Beta chain, HbA –> HbS
What is the difference between Sickle Cell anaemia and Sickle cell Trait?
Sickle Cell Anaemia: HbSS - severe
Sickle Cell Trait: HbAS - usually asymptomatic
What is Sickle-Hb C disease?
HbSC: one HbS inherited from one parent, and one HbC (defective b chain) inherited from another
What is Sickle Beta thalassaemia?
HbS/Beta: one HbS from one parent, Beta thalassaemia trait/BO from other. Sickle BO is similar in severity to HbSS.
When does Sickle Cell Anaemia manifest? Why?
3-6 months, coincides with decreasing foetal Hb (HbF)
Explain basic Sickle Cell Anaemia Pathophysiology (i.e why does sickling occur and what does the sickling cause?)
Low O2 tension promotes HbS polymerization, which leads to sickling. Repeated episodes of sickling damage the cell membrane and decrease the cell’s elasticity. Rigid RBCs can then block small capillaries –> vaso occlusion and infarction. Decreased elasticity also makes cells more likely to haemolyze.
What are the clinical features of increased haemolysis seen in Sickle Cell Disease
Anaemia (60-80g/L), Splenomegaly, Folate deficiency, Gallstones, Aplastic crisis (Parovirus B19)
What are the clinical features of the vaso-occlusion and infarction present in Sickle Cell disease?
SICKLED:
Stroke, Infections (hyposplenism, CKD), Crises (splenic sequestration, chest pain), Kidney (papillary necrosis, nephrotic syndrome), Liver (gallstones), Eyes (retinopathy), Dactilitis (impaired growth), mesenteric ischemia, Priapism
How do symptoms change in Sickle Cell Anaemia as the age of onset increases? Group into child, teens, adults.
Child: Strokes, splenomegaly + splenic crises, dactylitis
Teens: impaired growth, gallstones, psych, priapism
Adult: hyposplenism, CKD, retinopathy, pulmonary HTN
How is Sickle Cell Anaemia diagnosed?
Blood film: sickle cells and target cells
Sickle solubility test, Hb electrophoresis, Guthrie test (birth) to aid prompt pneumococcal prophylaxis
How do you treat Sickle Cell Anaemia?
Analgesia in painful crises, Folic acid, Penicillin V, pneumovax, HIB vaccine, Hydroxycarbamide, carotid Doppler monitoring in early childhood with prophylactic exchange transfusion if turbulent carotid flow.
How is Beta Thalassaemia diagnosed and treated?
Diagnosis: Hb electrophoresis (Guthrie at birth)
Treatment: blood transfusions and desferrioxamine to stop iron overload, folic acid
What are the symptoms seen in the 3 forms of Beta Thalassaemia (minor, intermediate, major)?
Minor: Asymptomatic carrier, mild anaemia, reduced MCV
Intermedia: Moderate anaemia, splenomegaly, gallstones, bony deformity (skull bossing, maxillary hypertrophy, hairs on end of skull xray)
Major: 3-6mnths severe anaemia, FTT, hepatosplenomegaly (extramedullary erythropoiesis), bony deformity, heart failure
Genetic mutations and basic pathophysiology of Beta Thalassaemia?
Point mutations on HBB gene (Ch 11), can be deletional or non deletional mutation. Causes a decrease in B chain synthesis, and an excess in alpha chains, preventing the RBCs to function properly.
B thal Major, always involves a deletional mutation on both alleles.
How many genes (in a diploid cell) are involved in alpha chain synthesis? What happens to these genes in alpha thalassaemia?
4 alpha chains, deleted in alpha thalassaemia, severity of the disease depends on how many genes are deleted.
What are the 3 different forms/severities of alpha thalassaemia, and how do they present?
a-thalassaemia trait (1/2 genes deleted): asymptomatic, mild anaemia HbH disease (3 deleted): moderate anaemia, splenomegaly Hydrops Foetalis (4 deleted): incompatible with life
How are Immune Acquired Haemolytic Anaemias differentiated from Non Immune AHA’s, and how can the Immune group be further subdivided?
Immune = +ve DAT/Coombs Test
Non Immune = -ve DAT Test
Immune Subdivisions: Autoimmune (warm or cold), Alloimmune (haemolytic transfusion reactions)
What are th 3 Autoimmune Acquired Haemolytic Anaemias, which is the most common?
Warm (WAIHA), Cold Agglutinin Disease, Paroxysmal Cold Haemoglobinuria)
Most Common = WAIHA
Warm AIHA:
Features (Temp, Ig, Coombs Test, Blood Film)
Causes
Management
Features: 37C, IgG, +ve DAT, Spherocytes on blood film
Causes: mainly primary idiopathic, Lymphoma, CLL, SLE, methyldopa
Management: Steroids, Splenectomy, Immunosupression
Cold Agglutin Disease:
Features (Temp, Ig, Coombs Test)
Causes
Management
Features: under 37C, IgM, +ve DAT
Causes: Primary Idiopathic, Lymphoma, Infections (EBV, mycoplasma)
Management: treat underlying condition, avoid the cold, Chlorambuicil (chemo)
Pathogenesis of PCH
Polyclonal IgG autoantibody (Donath Landsteiner antibodies) bind to RBC surface antigens in the cold. When th blood returns to the warmer central circulation, the RBCs are lysed with complement, causing intravascular haemolysis. Haemoglobinuria and anaemia can then occur.
What is the cause of PCH and how is it managed?
Cause: Triggered by an infection, mostly viral: measles, EBV, VZV, CMV; and some bacterial: syphilis, haemophilus influenzae, mycoplasma pneumoniae.
Acute PCH tends to be transient and self limiting. Chronic PCH (associated with syphillis) resolves after the syphilis is treated with antibiotics.
What is Paroxysmal Nocturnal Haemoglobinuria? Explain the Pathophysiology.
Non Immune Acquired Haemolytic Anaemia.
Acquired loss of protective surface GPI markers on RBCs (platelets and neutrophils) causes complement mediated lysis and so chronic intravascular haemolysis (especially at night)
How does Paroxysmal Nocturnal Haemoglobinuria present and how is it diagnosed?
Presentation: Morning Haemoglobinuria, thrombosis (+ Budd Chiari Syndrome - hepatic venous thrombosis)
Diagnosis: immunophenotype shows altered GPI, Ham’s test +ve (in vitro acid induced lysis), will also have a -ve DAT test, though this is not diagnostic.
How is Paroxysmal Nocturnal Haemoglobinuria treated?
Iron/folate supplements, prophylactic vaccines/antibiotics. Eculizumab (monoclonal antibodies - expensive)
How does Ecluziumab work in treating Paroxysmal Nocturnal Haemoglobinuria?
Prevents complement from binding to RBCs ad thus stops lysis of RBCs
What is Micropangiopathic Haemolytic Anaemia (MAHA)? Brief Pathophysiology.
Subgroup of haemolytic anaemia caused by factor in the small blood vessels. Anaemia + Schistocytes.
When the endothelial layer of small vessels is damaged, a fibrin/platelet mesh will be deposited. As red blood cells travel through these damaged vessels, they are forced through the mesh, and become fragmented (mechanical intravascular haemolysis)
What diseases are associated with MAHA?
Haemolytic uraemic Syndrome, DIC, TTP, malignant HTN (Adenocarcinoma!), Pre-eclampsia, Rx eg to plasma exchange.
What Haemolytic Uraemic Syndrome? What is the main cause?
Disease characterized by haemolytic anaemia, acute kidney failure, and a low platelet count. Predominantly affects children and elderly.
Most often caused by E.Coli (toxin damages endothelial cells), and so preceded by severe diarrhea.
What is the classic pentad of symptoms seen in TTP?
Thrombocytopenia, Microangiopathc haemolytic anaemia, Neurological symptoms (hallucinations, odd behaviour, delirium, headaches), Kidney failure, Fever
How does Autoimmune TTP cause MAHA? (basic)
In Autoimmune TTP, the enzyme which breaks down vWF is inhibited –> vWF becomes more abundant –> coagulation becomes more active (particularly in microvasculature where vWF is most active) –> Aggregation of platelets and formation of clots cause shearing of RBCs.
Will Iron, TIBC and Ferritin be high, normal, or low in:
Anaemia of Chronic Disease?
Iron - low
TIBC - low
Ferritin - high
Will Iron, TIBC and Ferritin be high, normal, or low in:
Chronic Haemolysis?
Iron - high
TIBC - low
Ferritin - high
Will Iron, TIBC and Ferritin be high, normal, or low in:
Haemochronatosis?
Iron - high
TIBC - low (or N)
Ferritin - high
Will Iron, TIBC and Ferritin be high, normal, or low in:
Pregnancy?
Iron - high
TIBC - high
Ferritin - normal
Will Iron, TIBC and Ferritin be high, normal, or low in:
Sideroblastic Anaemia?
Iron - high
TIBC - Normal
Ferritin - high
