Red Blood Cells Flashcards
What is anaemia
Reduction in red cells or their haemoglobin. Theres multiple aetiologies.
Red cell production in marrow.
Haemocytoblast - committed cell (proerythroblast)
Developmental - early erythroblast - late erythroblast - noroblast - reticulocyte - erythrocyte (no nucelus)
Substances required for red cell production
Metals: Iron, copper, cobalt, manganese
Vitamins: B12, folic acid, thiamine, Vit.B6, C,E
Amino acids
Hormones: Erythropoietin (made in the kidneys), GM-CSF, androgens, thyroxine, SCF
Red cell breakdown
Normal life span is 120 days. They are normally removed from the circulation and replaced. Magrophages of the reticuloendothelial system (liver and the spleen) breakdown. Globin is re-utlised. The haem is broken down into bilirubin and iron. It is then conjugated in the liver and comes out in the bile and stercobiligin in the stool.
The Red Blood Cell
Biconcave disk, larger surface area for gas transfer and is able to squeeze through small spaces. Contains membrane, enzymes, haemglobin.
Genetic defects in congenital anaemias
Red cell membane, metabolic pathways, haemoglobin. These reduce red cell survival and result in haemolysis. The carrier states are often silent (autosomal recessive).
Red cell membrane
Bilipid layer, intrinsic proteins that help maintain the structure of the cell. Skeletal proteins inside to keep the cell flexible.
Defects in red cell membrane.
Defects in skeletal protiens leading to increased cell destruction. Mutations in Ankyrin, band 3 and spectrin.
Hereditary Spherocytosis
Defects in structural protein resulting in red cells being spherical. These are then removed from circulation by spleen. Leads to anaemia. The most common are autosomal dominant.
Clinical presentation of Herediatry spherocytosis
Anaemia
Jaundice (neonatal)
Splenomegaly
Pigment gallstones (due to increased haemolysis and bilirubin)
Treatment of Hereditary Spherocytosis
Folic acid (increased requirement)
Transfusion (if severe)
Splenectomy (remove the site of production)
Other rare membrane disorders (for information, don’t need to know)
Hereditary Elliptocytosis (ellipotcytes, look like rods) Hereditary Pyropoikilocytosis (cells look an utter mess) South East Asian Ovalocytosis
Red cell enzymes
Glycolysis (production of ADP provides energy for the cell)
Pentose Phosphate Shunt (Protects from oxidative damage)
GLUCOSE 6-PHOSPHATE DEHYDROGENASE
PYRUVATE KINASE
Glucose 6 Phosphate dehydrogenase
Protects red cell proteins (Haemoglobin) from oxidative damage
Produces NADPH - Vital for reduction of glutathione
Reduced glutathione scavenges and detoxifies reactive oxygen species
More likely to break down as a result
G6PD Deficiency
Commonest disease causing enzymopathy in the world
Results in the cells vulnerable to oxidative damage.
X-Linked
Bite cells
Blister cells under the microscope.
Clinical Presentation of G6PD deficiency
Neonatal Jaundice Splenomegaly Pigment Gallstones Intravascular haemolysis Haemoglobinuria
Only really when exposed to infection, acute illness, drugs etc do symptoms occur
Drugs precipitating Haemolysis in G6PD deficiency
Antimalarials
Antibacterials
Analgesics
Antihelminthics
Pyruvate Kinase Deficiency
Reduced ATP, increased 2,3-DPG, cells rigid.
Anaemia, jaundice, gallstones.
Function of haemoglobin
To carry oxygen and facilitate oxygen delivery to the tissues.
Bohr Effect
Acidosis
Hyperthermia
Hypercapnia
Haemoglobin give up oxygen
Normal Adult Haemoglobin
2 Alpha Chains (4 alpha chain genes)
2 Beta Chains (1 beta gene)
HbA (alphaalphabetabeta)
Haemoglobinopathies
Inherited abnormalities of haemoglobin syntesis.
Reduced or absent globin chain production (Thalassaemia)
Point Mutations leading to structurally abnormal globin chain (HbS Sickle Cell anaemia)
Inheritance of Haemoglobinopathies
Autosomal Recessive Inheritance.
Sickle Haemoglobin
2 alpha chains
2 abnormal sickle beta chains.
When it is deoxygenated it crystallises and changes the shape to become a rigid abnormally shaped cell.
Consequences of HbS Polymerisation in Sickle Cell dDisease
Red cell injury, cation loss, dehydration resulting in haemolysis of the red cells.
Endothelial activation
Promotion of inflammation
Coagulation activation
Dysregulation of vasomotor tone by vasodilator mediators (NO) ALL RESULTING in VASO-OCCLUSION
Sickle Cell Disease Clinical Presentation
Painful Vaso-Occlusive Crises (bone pain)
Chest crises
Stroke
Increased infection risk (hyposplenism due to autoinfarction)
Chronic haemolytic anaemia (gallstones, aplastic crisis)
Sequestration Crises (when blood pools in the liver or spleen resulting in redution in blood volume)
Sickle Cell Painful Crises
Severe pain which often requires Opiates (30 minutes of presentation), hydration, oxygen, consider antibiotics (crises triggered by infection)
Sickle Cell Chest Crises Presentation
Chest Pain
Fever
Worsening hypoxia
Infiltrates on CXRay
Chest Crises Treatment
Respiratory support Antibiotics IV fluids Analgesia Transfusion - top up or exchange target HbS <30%.
Life long prophylaxis of Sickle Cell Disease
Vaccination
Penicillin prophylaxis
Folic Acid
Other management of Sickle Cell Disease
Blood transfusion
Hydroxycarbamide
Bone marrow transplantation
Gene Therapy
Thalassaemias
Reduced or absent globin chain production. Mutations or deletions in genes. Chain imbalance results in chronic haemolysis and anaemia.
Homoygous alpha zero thalassaemia (alpha0/alpha0)
No alpha chains Hydrops Fetalis (incompatible with life)
Thalassaemia Major
No beta chains
Transfusion dependent anaemia
Thalassaemia Minor
“trait” or carrier state
Hypochromic microcytic red cell indices
Presentation of Beta Thalassaemia Major
Severe anaemia presenting at 3-6 months. There is an expansion of ineffective bone marrow, bony deformities (marrow expansion) splenomegaly, growth retardation
Life expectancy of untreated Beta Thalassaemia Major
<10 years
Treatment of Beta Thalassaemia Major
Chronic transfusion support - 4-6 weekly.
Normal growth and development but Iron Overloading, Iron collaters which remove the iron.
Iron Chelation Therapy
s/c desferrioxamine infusions (desferal) Oral deferasirox (exjade)
Rare Defects in Haem Synthesis
Defects in mitochondrial steps of Haem Synthesis resulting in sideroblastic anaemia. ALA Synthase mutations, X-linked.
Factors influencing normal haemoglobin
Age Sex Ethic Origin Time of day sample taken Time to analysis
Haemoglobin Male 12-70
(140-180)
Haemoglobin Male >70
116-156
Haemoglobin Female 12-70
120-160
Haemoglobin Female >70
108-143
General features of anaemia
Tiredness/Breathlessness Breathlessness Swelling of Ankles (due to heart failure) Dizziness (hyperdynamic blood flow) Chest Pain (reduce cardiac blood flow)
Red Cell Indices
Automated measurement of red cell size and haemoglobin content.
MCV = mean cell volume (cell size)
MCH = mean cell haemoglobin
Descriptions of anaemia Hypochromic Microcytic
Small pale cells. Do serum ferritin (measure of the bodies iron stores). Commonest cause is iron deficiency.
Descriptions of anaemia Normochromic Normocytic
Normal colour (haemoglobin normal) and normal size. Do reticulocyte count (tests bone marrow function)
Descriptions of anaemia Macrocytic
Large cells. Do B12/folate and bone marrow tests (bone marrow infiltration). Deficiency in B12 or folate results in macrocytic anaemia.
Serum Ferritin (Low)
Iron deficiency anaemia
Serum Ferritin (normal or increased)
Thalassaemia (without iron deficiency but looks like iron deficiency anaemia under the microscope due to microcytic hypochromic cells)
Sideroblastic anaemia
Iron Metabolism
Amount you absorb from the duodenum of the gut (bound to plasma protein transferrin) is secreted in urine, faeces, nails, hair and skin
Iron is recycled from bone marrow to haemoglobin to macrophages to plasma, in a cycle
Iron is stored
In ferritin in the liver
Ferroportin
Protein that allows Iron to be transferred from the duodenum to transferrin. Also need this to put into the hepatocytes and the bone marrow.
Hepcidin
Control ferroportins action, preventing it working, prevention of absorption of iron when it is not needed.
Synthesised in the hepatocytes in response to inflammation.
Commonest cause of Anaemia
Iron Deficient Anaemia
Common history of iron deficient anaemia
Dyspepsia - GI bleeding, carcinoma of the colon, gastritis
Menorrhagia
Diet
Increased requirement (pregnancy)
Malabsorption - gastrectomy, coeliac disease
Clinical Features of Iron Deficiency
Koilonychia
Atrophic tongue
Angular Chelitis
Investigations of Iron Deficinecy Anaemia
endoscopy
Barium Studies
Management of Iron Deficient Anaemia
Correct the cause with diet, ulcer therapy, surgery if bleeding
Iron (oral adequate)
Transfusion if severe.
Increased Reticulocyte Count
Blood Loss (acutely) Haemolysis
Normal Reticulocyte Count
Secondary Anaemia
Haemolytic Anaemia
This is accelerated red cell destruction, compensation by the bone marrow by producing reticulocytes.
Intravascular Haemolysis
Red cells are destroyed in the circulation due to toxins or drugs, valve related.
Congential Haemolytic Anaemia
Hereditary spherocytosis (HS) Enzyme deficiency (G6PD deficiency) Haemoglobinopathy (HbSS)
Acquired Haemolytic Anaemia
Autoimmune Haemolytic Anaemia (extravascular)
Mechanical (valve)
Severe infection
Drugs
Direct Antiglobulin Test
Detects antibody or complement on the red cell membrane.
Reagent contains either
anti-human IgG
anti-complement
Reagent binds to antibodies on red cell surface and causes agglutination in vitro. Implies immune basis for haemolysis.
Postive Direct Antiglobulin Test
Immune mediated haemolysis
Warm Autoantibody
Autoimmune
Drugs
CLL
Cold Autoantibody
CHAD
Infections (mycoplasma infections)
Lymphoma
Alloantibody
Transfusion reaction, antibodies made after transfusions
Immune Haemolysis Film
Spherocytes on the film
Agglutination in cold AIHA
Antibody in autoimmune haemolytic anaemia (extravascular)
IgM
Intravascular haemolysis blood film
Red cell fragments (schistocytes)
Results in free haemologin which is very toxic to the kidneys
Evidence that the patient is haemolysing
FBC, reticulocyte count, blood film
Serum bilirubin (direct/indirect), LDH (due to increased haemolysis results in increased unconjugated haemoglobin)
Serum haptoglobin
Deciding the mechanism of Haemolytic Anaemia
History and examination
Blood film
Direct Antiglobulin Test (Coombs’ test)
Urine for haemosiderin/urobilinogen
Management of Haemolytic Anaemia
Folic acid (supports bone marrow function)
Correct the cause
Immunosuppression if autoimmune
Remove the site of red cell destruction
Consider transfusion
Secondary Anaemia
Anaemia of chronic disease.
Mostly normochromic normocytic with increased ferrtin and hepcidin.
Treat underlying cause
Megaloblastic Anaemia (B12/Folate Deficinecy)
Anaemia and neurological symptoms (unexplained neuropathy)
Causes of B12 deficiency
Pernicious anaemia
Gastric/ileal disease
Folate deficiency causes
Dietary
Increased requirements (haemolysis)
GI pathology
Signs of megaloblastic anaemia
Lemon yellow tinge to the skin. Elevated Bilirubin and LDH.
Oval macrocytes of blood film
Vitamin B12 Absorption
Dietary B12 binds to intrinsic factor, secreted by gastric parietal cells B12-IF complex attaches to specific IF receptors in distal ileum Vitamin B12 bound by transcobalamin II in portal circulation for transport to marrow and other tissues
Pernicious Anaemia
Autoimmune disease against intrinsic factors, resulting in malabsorption of vitamin B12.
Treatment of Megaloblastic Anaemia
B12 deficiency by B12 IM loading dose then 3 monthly maintenance
Folate Deficiency oral folate replacement
Other causes of Macrocytosis
Alcohol Drugs Methotrexate, Antiretrovirals, hydroxycarbamide Disordered liver function Hypothyroidism Myelodysplasia
