Week 1 Flashcards
Three types of blood cells
Red blood cells
White blood cells
Platelets
Types of White blood cells
Monocytes Neutrophils Basophils Eosinophils Lymphocytes NK Cells
Production of blood cells are called
Hemopoiesis OR Hematopoiesis
Site of Hematopoiesis in Embryo
Yolk sac then liver
3rd-7th month - Spleen
Site of Hematopoiesis at birth
Mostly bone marrow, liver and spleen when needed
Site of Hematopoiesis in adult
Bone marrow of skull, ribs, sternum, pelvis, proximal ends of femur
How many cells are made per minute
100 million RBC/minute
60 million neutrophils/minute
150million platelets/minute
What is proliferation
Rapid increase in numbers
What is differentiation
Development of the features of the specialized end cell
Initial three tiers of the the Hemopoietic tree
Long term Hemopoietic Stem Cell –> Short Term Hemopoietic Stem Cell –> Multipotent progenitors
LT-HSC –> ST-HSC –>MPP
Multipotent Progenitors develop into what in the hemopoietic tree
Common Myeloid Progenitor
OR
Common Lymphoid progenitor
Common Myeloid Progenitor is precursor to
Erythrocytes – Megakaryocytes (Platelets) – Granylocytes – Monoblast (Macrophages) – Dendritic cells
Common Lymphoid progenitor is precursor to
T cells
B cells
NK cells
Dendrititc cells
Progression of Neutrophils from Myeloblast
Myeloblast –> Promyelocyte –> Myelocyte –> Metamyelocyte –> Band form –> Neutrophils
Progression to Erythrocyte from Common myeloid progenitor
CMP –> Pronormoblast –> Basophilic Erythroblast –> Polychromatophilic Erythroblast –> Orthochromatic erythroblast –> Erythroblast –> Reticulocyte –> Erythrocyte
How are platelets formed
Bud of Megakaryocyte
Names of the Granulocytes
Eosinophils
Basophils
Neutrophils
Structures of Neutrophils
Segmented nucleus
Neutral staining granules
Structure of Eosinophils
Bi-lobed
Bright orange/red granules
Function of Eosinophils
Fight parasitic infections
Involved in hypersensitivity
Often elevated in pt w/ allergic conditions
Structure of Basophils
Infrequent in circulation
Large deep purple granules obscuring nucleus.
Dark spots on top of nucleus on image
Basophils functions
Circulating version of tissue mast cells
Granules contain histamine
FcReceptors bind IgE, mediates hypersensitivity reactions
Structure of Monocytes
Large single nucleus
Faintly staining granules, some vacuoles
Function of Monocytes
Circulating version of Macrophages
Phagocyose invades, kill and present antigen to lymphocytes
Attract other cells
More long lived than neutrophils
Structure of Mature Lymphocytes
Small w/ condensed nucleus and rim of cytoplasm
Function of Neutrophils
Phagocytose invaders
Kill with granule contents and die in the process
Attract other cells
Short lived
Structure of Atypical (activated) Lymphocytes
Large w/ plentiful cytoplasm extending around nearby RBC.
Atypical lymphocyte during viral infection (EBV) has what
A relatively open chromatin pattern of nucleus
Where is a common site for bone marrow aspiration
Posterior illiac crests
How is a core biopsy taken of the bone marrow
With a Jamshidi needle
Properties of mature RBCs
Packed w/ hemoglobin
No nucleus or mitochondria
No DNA/RNA, no cell division
Life span 120 days
Where is RBC produced and broken down
Produced in Red bone marrow
Removed by spleen and liver
What component of RBC is broken down to bilirubin
Heme group (minus iron)
What protein regulate RBC production
Erythropoietin released by kidneys
When is the nucleus extruded during Erythropoesis
During erythroblast stage, right before Reticulocyte
Structure of Erythrocytes
Biconcave disc (8um in diameter, 2um thick at edge, 1um in middle) Maximized surface to volume ratio
What is Hematocrit
Volume of RBCs as % of total blood volume
Normal male 40-50%
Female 36-46%
If you spin a test tube with blood you get what layers
Top layer - Plasma ~55%
Buffy coat - Platelets and WBC
How does RBCs get energy
Anaerobic glycolysis
What is Methemoglobin
HbFe3+
HbFe2+ is normal
What is Glutathione and what is its role
Tripeptide (Glutamate, cysteine, glycine)
Reduced GSH combats oxidative stress
Maintains reduced state in a cell
What is needed for reduced Glutathione production
NADPH is needed
Glucose 6-phosphate dehydrogenase insufficiency leads to
NADPH deficiency
Reduced GSH insufficiency
Cell damage
What are the forms of CO2 transport
10% Physically dissolved in solution
30% Bound to Hb
60% As bicarbonate ion - HCO3-
What enzyme facilitate Bicarbonate production, formula
CO2+H2O –> H2CO3 –> H+ +HCO3-
Carbonic anhydrase facilitate first part of reaction
What part of the hemoglobin does oxygen bind to, Carbondioxide
O2 - Heme group
CO2 - Globin portion
How is HCO3- transported through the cell membrane
Chloride/bicarbonate exhange. Chloride ions facilitates the diffusion
Describe adult hemoglobin
4 protein subunits (globin) each containing a single heme group.
Each heme group has a single Fe2+ ion that can bind one O2 molecule.
What is the structure of the heme group
Porphyrin ring with Fe2+ in the middle
HbF has what components
Alpha2-gamma2
HbA has what components
Alpha2-Beta2
What is the affinity of HbF vs HbA of O2 and 2,3BPG
O2 - HbF has higher affinity
2,3HBG - HbA has higher affinity
Spectrophotmetric method for measuring [Hb]
Lyse cells
Stabilize Hb molecules (cyan-metHb)
Measure optical density
OD is proportional to conc (Beer’s Law)
Bodies response to Anemia
Increased red cell production
Peripheral blood reticulocytosis
What are Reticulocytes
Immature RBCs
Larger than average RBCs
Still have RNA (purple/deep red stain)
Polychromatic on blood film
Two main causes of Anemia
Decreased production (low reticulocyte count) Increased loss or destruction of red cells (High reticulocyte count)
Likely underlying defect in microcytic vs macrocytic anemia
MCV low (microcytic) defect with hemoglobinisation MCV high (macrocytic) defect with maturation
Why is microcytic anemia linked to hemoglobin production
Hb is synthesized in cytoplasm. Problems with the production of heme such as shortage of components, results in a smaller cytoplasm and low Hb content. Also hypochromic
To make Hb you need
Globins
Heme (Porhyrin ring and Iron)
Hypochromic, microcytic anemia =
Defective hemoglobin synthesis: cytoplasmic defect
Commonest causes of hypochromic microcytic anemias
Heme deficiency - Lack of iron
Globin deficiency - Thalassemia
Problems with porphyrin synthesis is very very rare but can be due to
Lead posioning
Pyridoxine responsive anemias
Congential Sideroblastic anemia causes what
Heme deficiency so Hypochromic microcytic anemia
Where is most of the bodies iron
In red blood cells, 2500mg.
In comparison, we absorb only 1mg/day
Iron in RBCs are in hemoglobin, in which form is iron in Liver and macrophages stores
Bound to Ferritin
What is the form of circulating iron
Bound to transferrin
Measure of Transferring indicates what
% saturation of transferring measures iron supply
What is the best way to measure iron storage
Serum ferritin, tiny amount present but good representation
Iron deficiency can be confirmed by
Combination of microcytic hypochromic anemia and low serum ferritin
Causes of iron deficiency
Not eating sufficient
Loosing too much -blood loss
Not absorbing enough - malabsorption
Iron deficiency due to not enough intake can be divided into two groups
Relative deficiency - women of child bearing age and children
Absolute deficiency - vegetarian diets
Causes of chronic blood loss
Menorrhagia
GI (Tumors, ulcers, NSAIDs)
Hematuria
What is koilonychia
Spoon shaped nails
Sign of iron deficiency anemia
Skin changes seen in Iron deficient anemia
Angular Cheilitis
Pale skin
Smooth red tongue
What is macrocytic anemia
Anemia in which the red cells have a larger than normal value
What is normal cell volume
80-100femtoliters
What are the main categories of causes of true macrocytosis
Megaloblastic
Non-Megaloblastic
What is a megaloblast
An abnormally large nucleated red cell precursor with an immature nucleus
What causes megaloblastic anemias
Predominant defects in DNA synthesis and nuclear maturation with relative preservation of RNA and hemoglobin synthesis
Why does DNA synthesis defect cause macrocytic cells
Cytoplasm has developed and is ready to divide but nucleus is running behind. As the nucleus matures to division stage the cytoplasm continues to grow. Cell is not large due to increase in production, it is big because it fails to divide itself
Causes of megaloblastic anemia
B12 deficiency
Folate deficieny
Others - Drugs, rare inherited abnormalities
Why does B12 and folate cause megaloblastic anemia
They are essential co-factors for nuclear maturation. Part of the cycles that produce nucleosides for DNA synthesis
What two cycles are B12 and folate involved in
Methionine cycle and Folate cycle (both inter-linked)
How is Vitamin B12 ingested
Together with foods, found in meat, eggs normally.
What happens to protein-VitaminB12 complex when it comes to the stomach
Pepsin and Low pH breaks down the protein and renders VitB12 free.
Haptocorrin is released from salivary glands and parietal cells in stomach and binds VitB12
What happens to VitB12-Haptocorrin when it gets to the duodenum
Pancreatic proteases breaks down Haptocorrin and allows VitB12 to be bound to intrinsic factor produced by parietal cells.
What happens after duodenum to the VitB12-Intrinsic factor complex
In the mucosal cells of the distal ileum Cubulin receptors recognize the complex and absorbed VitB12
What happens to VitB12 when it is absorbed in distal ileum
Binds to transcobalamin and enters the blood
Causes of VitB12 deficiency
Vegans, atrophic gastritis, PPIs/H2 receptor antagonists, Gastrectomy/bypass. Jejunum (celiac, bacterial overgrowth) Duodenum (resection/Crohn’s disease) Cubulin receptor insufficiency
Where is Folate absorbed and in what form
Converted to monoglutamate and absorbed in Duodenum and Jejunum
How long is the bodies store of B12 and Folate
B12 - 2-4years
Folate - 4 months
Food source for B12 and Folate
B12 - Animal proteins
Folate - Leafy veg, yeast, destroyed by cooking
Causes of folate deficiency
Inadequate intake
Malabsorption
Excess utilisation (hemolysis, exfoliating dermatitis, pregnancy, Malignancy)
Drugs (Anticonvulsants)
Which antipsychotic drug causes agranulocytosis
Clozapine
Clinical features of both B12 and folate deficiency
Anemia
Weight loss, diarrhea, infertility
Sore tongue, jaundice
Developmental problems
Vitamin B12 deficiency only may cause __ before hematological findings occur
Neurological problems.
Dorsal column abnormalities, neuropathy, dementia or psychiatric manifestations
What is pernicious anemia
Autoimmune condition with resulting destruction of gastric parietal cells
What is pernicious anemia associated with apart from B12 deficiency related things
Atrophic gastritis
Blood film results in pernicious anemia
Macrovalocytes and hypersegmented neutrophils
FBC results in pernicious anemia
Macrocytic (megaloblastic) anemia
Pancytopenia in some pt
How does hypersegmented neutrophils look
Like someone cut up the nucleus into tons of small pieces
Auto-antibodies found in pernicious anemia
Anti Gastric-parietal cell (anti-GPC)
Anti-intrinsic factor (anti-IF)
Treatment for pernicious anemia
Vitamin B12 (Hydroxycobalamin) injections for life
Treatment of megaloblastic anemia
Treat cause where possible.
VitB12 and Folic acid replacement
Cause of non-megaloblastic macrocytosis
Alcohol – Liver disease – Hypothyroidism – Marrow failure
Types of Marrow failure that leads to non-megaloblastic macrocytosis
Myelodysplasia
Myeloma
Aplastic anemia
Is non-megaloblastic macrocytosis caused by alcohol, liver disease or hypothyroidism associated with anemia
May not. The change in blood cells is due to red cell membrane changes
What are some false causes of macrocytosis
Reticulocytosis
Cold agglutinins
Why are Reticulocytosis and Cold agglutini-disease considered false macrocytosis
Machine reads reticulocytes (which are bigger than mature RBC) as RBC and therefore increase the mean.
In cold-agglutinin disease cells clump together and machine count them as one giant cell.
Why would a patient with pernicious anemia present mildly jaundice
Ineffective erythropoiesis leads to death of red cells in marrow. Hemoglobin is broken down to bilirubin causing jaundince
Can pancytopenia occur due to B12/folate deficiency
Yes, needed for DNA reproduction
What are blood products
Purified constituents of the blood plasma. Ie. Human albumin, Iv Ig, Specific Ig, Anti-D Ig, Prothrombin complex conentrates
What is Fresh frozen plasma
Plasma that has been frozen within 8h of collection
To identify a blood component from a bag, what two things do you need
Component label (ie RBC) Donation number (long number with a letter at the end)
One donation gives how many units of platelets
1/4
Human blood products, one unit is derived from how many patients
Many, 100s
Quick description in how blood donations are taken and seperated
Taken into the primary bag
Spun to seperate layers
Attached bags’ valves are opened and Plasma goes up, RBC goes down and Buffy coat stays in primary bag.
What is RBC stored in and for how long
35days in 4C fridge
Nutrient solution with saline-Adenine-Glucose-Mannitol SAG-M
Must be transfused within 4h of leaving controlled storage.
May only leave controlled storage for less than 30 minutes if it is put back in controlled storage.
How ara platelets stored and for how long
22C w/ continual agitation
Shelf life of 5 days
Transfuse within 1h
How is fresh frozen plasma stored and for how long
-30C for up to 2years
Thawed prior to transfusion - transfuse within 4h
What are the types of blood groups that is tested for
ABO
Rh(D)
Others (currently 31 systems)
Most common types of ABO Group
O - 47%
A - 42%
If you are blood group B, which donor blood can you accept
From a B donor or a O donor
What antibodies does a paitent with blood group A
Anti-B antibodies
What types of antibodies are ABO-antibodies
Primarly IgM with a small proportion IgG
Where is ABO blood group genes located
Chromosome 9
What is the genetic of ABO blood group
A and B are dominant over O. A and B are co-dominant Genotype AB =Phenotype AB Gene AO or AA = Pheno A Gene OO = Pheno O Gene BB or BO = Pheno B
Where is RhD gene located
Chromosome 1
Describe genetic or RhD
2 alleles - D and d
d is silent = no protein
Gene dd = Phen RhD neg
Gene DD or D/d = Phen RhD pos
Most common type of RhD status
RhD positive = 83%
RhD negative = 17%
Name some Other blood groups
Kell group (K,k) Duffy group(Fy^a, Fy^b) Kidd group (Jk^a, Jk^b)
When are other blood groups taken into consideration
When the patient is known to have an antibody towards one or more of them
What type of anti bodies are irregular antibodies in the blood
IgG
How is irregular antibodies tested for
Donor O-blood with know irregular proteins on it is mixed with patient’s plasma. Left to intubate
Add Anti-Human IgG antibody who creates agglutination
What is the test for irregular antibodies called
Indirect Antiglobulin Test
How quick can blood components be transfused
As quick as patient tolerates them
2-3h per unit is average for non-urgent transfusion
How to give a blood transufsion
Check patient is correct Establish IV access Check bag and compatability label is correct Pre-transfusion obs (HR, BP, T) Check patient and bag correct
At what percent blood loss does a patient start to be symtpomatic and how
20%
Tachycardia, postural hypotension, weak thirst
How much blood loss is tolerated in a fit patient
30%
> 30% blood loss gives what symptoms
Confusion, restless, oliguria, air hunger, coma
> 50% blood loss indicate
Prompt resuscitation mandatory
Aim at acute blood loss and blood transfusion
Maintain normal pulse rate, BP consciousness, urine output >30ml/hr, Hb >100g/L
How long does an ABO and RH,D Ab screeen and cross-match take
1 hour
Where should platelets never be stored and why
Fridge
Cold activates the platelets
Commonest indication for fresh frozen plasma transfusion
Patients with liver disease who are bleeding
Indications for fresh frozen plasma transfusion other than bleeding pt w/ liver disease
Oral anticogulant overdose
Coagulopathy following massive transfusion
Disseminated intravascular coagulation (DIC)
What type of plasma can be given to anybody
AB donor plasma
No antibodies in the plasma
What happens if A blood is given to a O recipient, initially
Immediate hemolytic transfusion reaction
IgM binds the donor cells and the complement cascade is activated
Complement cascade is activated after a transfusion, what happens
Release of C3a and C5a - Powerful anaphylotoxins – increased vascular permeability (leaky) – dilated blood vessels – Serotonin and histamin release cause fever, chills, hypotension and shock
During Hemolytic Transfusion reaction, activated Factor XII activates the kinin system, what does that do
Formation of bradykinin - Arteriolar dilation and increased vascular permeability. Leads to hypotension which leads to release of catecholamines causing vasoconstriction within kidneys and other organs.
What is the net effect of Immediate hemolytic transfusion reaction
Systemic hypotension DIC Renal vasoconstriction Formation of renal intravascular thrombi Renal failure Shock OFTEN FATAL
Early symptoms of Immediate hemolytic transfusion reaction
Pyrexia/rigors/Pallor/Sweating Faintness/dizziness Tachycardia, tachypnea, hypotension Pain at infusion site Cyanosis/ Headaches Patient express that something is wrong
Actions in Immediate hemolytic transfusion reaction
Stop transfusion, DO NOT REMOVA CANULA
Start IV fluids to maintain BP and urine output
Obtain blood samples for another cross match
When does Delayed hemolytic transfusion reaction occur
5-10 days post transfusion
Features of Delayed hemolytic transfusion reaction
Similar to immediate but less acute
Unexplained fall in Hb
Jaundice, renal failure
Caused by irregular antibodies being produced
Positive Direct Antiglobulin test post transfusion
What causes Febrile Non-hemolytic transfusion reactions
Recipient have antibodies against contaminating white cells in transfusion OR
Release of cytokines and vasoactive substance from white cells during storage
Treatment to Febrile non-hemolytic transfusion reaction
Stop transfusion and make sure it’s not a more severe cause of symptoms.
Give anti-pyretic if it is FNHT
What is Urticarial reactions, symptoms
Mast cells have an IgE respone towards infused plasma proteins
Rash/weals within few minutes of starting transfusion
Treatement of Urticarial reactions
Slow the transfusion
Consider anti-histamines
Circulatory overload caused by transfusion leads to what, in who
Pulmonary edema
Elderly and those with Congestive Cardiac failure
Symptoms exactly as a mmediate hemolytic transfusion reaction but laboratory test come back saying it is not ABO incompatibility. Most likely cause
Bacterial infection
Start broad spectrum IV pending identification of the bacteria
Commonest bacterial infections carried in Red cells transfusion
Pseudomonas
Yersinia
Commonest bacterial infections carried in Platelet transfusion
Staph, Strep, Serratia, Salmonella
How common is Viral spread from blood transfusions of HIV, HBV, HCV
HIV - 1/7million
HBV - 1/1.2million
HCV - 1/29million
Parts of HbA, HbA2 and HbF
HbA - 2 alpha 2 beta chains
HbA2 - 2alpha 2delta chains
HbF - 2alpha 2gamma chains
On which chromosomes are Alpha and Beta protein genes
Alpha - chromosome 16 (2 genes/chromosome - 4 total)
Beta - Chromosome 11 (1 gene/chromosome - 2 total)
What are hemoblobinopathies
Hereditary conditions affecting globin chain synthesis
Two main groups of Hemoglobinopathies
Thalassemias (decreased rate of globin production)
Structural hemoglobin variants (normal production but abnormal globin chains)
Two types of Thalassemias
Alpha thalassemia (affect alpha chains) Beta thalassemia (beta chains affected)
Thalassemia leads to what features on blood film
Microcytic hypochromic anemia
Reduced and Absent synthesis is denoted how in relation to alpha thalassemia
Reduced a^+ (-a)
Absent a^0 (–)
Classifications of Alpha thalassemia
Unaffected -4 normal a genes (aa/aa) Silent a thal trait (-a/aa) a thal trait (--/aa OR -a/-a) HbH disease (--/-a) Hb Barts hydrops fetalis (--/--)
Features of Alpha thalassemia trait
Clinically asymptomatic, no Rx needed.
Microcytic, hypochromic red cells with mild anemia
How is Alpha thalassemia trait distinguished from iron deficiency since they have very similar blood films and anemia
Normal ferritin in Alpha thalassemia trait
What is HbH
Hemoglobin tetramer of four beta chains. Cannot carry oxygen.
Formed due to excess beta chains
Features of HbH disease
HbH is present (1-40%)
Anemia with very low MCV and MCH.
Severe form of thalassemia
Clinical features of HbH disease
Wide variation: nearly asymptomatic to transfusion dependent)
Splenomegaly due to extramedullary hematopoiesis
Jaundice due to hemolysis and ineffective erythropoiesis
Growth retardation, gall stones and iron overload may occur
Where is HbH disease seen
South east asia
Middle east
Mediterranean
Management of HbH disease
Mild - transfusion only needed at times of intercurrent illness
Severe - transfusion dependent
Folic acid supplementation
Splenectomy may reduce need of transfusions
Hemoglobin seen in Hb Bart’s hydrops fetalis syndrome
Hb Barts - tetramer of gamma
HbH - tetramer of beta
Clinical features of Hb Bart’s hydrops fetalis syndrome
Pallor, edema – cardiac failure – growth retardation – Severe hapatosplenomegaly – Skeleteal and cardiovascular abnormalities
Most die in utero
Few survive to birth but die shortly after
How is Alpha thalassemia diagnosed on blood film
Target cells
Anisopoikilocytosis
What is Beta Thalassemia
Disorder of beta chain synthesis
Reduced (b^+) or absent (b^0) chain produciton
Usually caused by point mutation
Classifications of Beta thalassemia
B thal trait - B+/B OR B0/B
B thal intermedia - B+/B+ OR B0/B+
B thal major - B0/B0
Symptoms of Beta thalassemia trait
Asymptomatic
Low MCV/MCH
Raised HbA2 is diagnostic
Laboratory features of Beta thalassemia major
Moderate to severe anemia Very low MCV/MCH Reticulocytosis Target cells and Anisopoikilocytosis Mainly HbF present, HbA2 is elevated
Clinical features of Beta thalassemia major
Present aged 6-24 months
Failure to thrive
Pallor
Extramedullary hematopoiesis (causing hepatosplenomegaly, skeletal changes, organ damage)
Management of Beta thalassemia major
Regular transfusions
Iron restricted diet
Bone marrow transplant may be an option
What is a Codocyte
also called target cells.
Disproportional increase of surface to volume ratio
Drug therapy against Iron overload
Iron Chelating drugs - Desferrioxamine
Ocular/ototoxicity in high doses
Genetics of Sickle cell anemia
Autosomal recessive disorder
Point mutation in the Beta globin gene
(Codon 6 - Glutamine –>Valine)
Pathophysiology of Sickle cell anemia
Genetic mutation causes altered structure to beta chain. Resulting Hb is HbS. HbS polymerize if exposed to low oxygen for prolonged period. Distorts the red cell and damage the membrane,
What is Sicle Cell vaso-occlusion
Deformed RBCs cause occlusions, leading to tissue ischemia and severe pain
What is Sickle Cell trait
One abnormal beta gene
Assymptomatic carrier state
May sickle in severe hypoxia, high altitude or under anaesthesia.
Features of Sickle cell anemia
Tissue infarction due to vascular occlusion.
Digits (dactylitis) Bone marrow, spleen, CNS, lung, renal. Leg ulcers. Pain may be extremely severe.
Sequestrian of Sickled RBCs in liver and spleen
Precipitants of Sickle Crisis
Hypoxia Dehydration Infection Cold exposure Stress/fatigue
Treatment of Painful Sickle Crisis
Opiate analgesia – Hydration – Rest – Oxygen – Antibiotics to treat underlying infection
Severe cases Exchange transfusion (Venesect – Transfuse – Venesect – Transfuse)
Longterm effect of Sickle cell anemia
Poor growth – Infections (hyposlenism due to repeated infarcts)
Organ damage (pulmonary hypertension, renal disease, avascular necrosis, CVA, Imptence etc)
Psychosocial problems
Long term treatment of Sickle cell anemia
Avoid precipitants
Reduce risk of infection (prophylactic penicillin, vaccinations)
Folic acid supplementation
Hydroxycarbamide (induces HbF production)
Other sickling disorders are caused by
Heterozygosity for HbS and another beta chain mutation
Heme to Bilirubin breakdown
Heme –> Biliverdin –> Bilirubin
Definition of Hemolysis
Premature red cell destruction
Bone marrow response to hemolysis
Reticulocytosis
Erythroid hyperplasia
Special stain of Reticulocytes are called and stains what
New methylene blue
Stains ribosomal RNA
Classifications of Hemolysis
Extravascular
Intravascular
Features of Extravascular hemolysis
Commoner
Hyperplasia at site of destruction (Splenomegaly +/- hepatomeglay
Release of protoporhyrin
Unconjugated birubinemia (jaundice, gall stones)
Urobilinogenuria
Intravascular hemolysis abnormal products
Hemoglobinemia
Methemalbuminemia
Hemoglobinuria
Hemosiduria
Signs of Hemogblobinuria
Pink urine that turns black on standing
Causes of Intravascular hemolysis
ABO incompatible transfusion
G6PD deficiency
Severe falciparum malaria (Blackwater fever)
Paroxyxmal Cold/Nocturnal hemoglobinuria PCH/PNH (very rare)
What is haptoglobin
Protein in the blood that binds and removes free hemoglobin
What are Heinz bodies on blood film a sign of
RBC oxidative damage
Dark lumps in RBC due to precipitated Hb
Autoimmune hemolysis can be caused by two types of antiboides
Warm (IgG)
Cold (IgM)
Causes of Warm autoantibody mediated hemolysis
Idiopathic (commonest) Autoimmune disorder (SLE) Lymphoproliferaticve disorder (CLL) Drugs Infections
Causes of Cold Autoantibody mediated hemolysis
Idiopathic
Infections (EBV, Mycoplasma)
Lymphoproliferative disorders
What test is done for Autoimmune hemolysis
Direct Coomb’s test
Causes of mechanical red cell destruction
Disseminated intravascular coagulation Hemolytic uraemic syndrome (E. Coli O157) Thrombotic thrombocytopenic purpura Leaking heart valve Infections (malaria)
Which anemia is related to mechanical valves
Microangiopathic hemolytic anemia (MAHA)
What is seen on blood films of Burns related hemolysis
Microspherocytes
What is Zieve’s syndrome
Hemolysis, Alcoholic liver disease, hyperlipidemia.
Presents w/ anemia, polychromatic macrocytes, irregular contracted cells.
Common in chronic alochol withdrawal
Causes of membrane defect hemolysis
Zieve’s syndrome
Vit E deficiency
Paroxsmal Nocturnal Hemoglobinuria
Genetic cause of red cell membrane abnormalities causing hemolysis
Hereditary Spherocytosis
Splenomegaly, jaundice and anemia
G6PD causes what
Failure to cope with oxidant stress. RBC mostly affected. Cells are damaged and go through hemolysis
What signs are seen in Beta thalassemia. General and on x-ray
Bone deformities - face widening
X-ray - hair on end appearance, rib within a rib
22y female, splenomegaly, intermittent mild jauncice. Gallstones, father had splenectomy in young adulthood for gallstones. Diagnosis…
Hereditary spherocytosis
Familial connection, older than congenital cause
Blood film with several red blood cells have ring stages inside them. possible diagnosis
Falciparum malaria.
Ring stages are the parasites
Differene between Ferric and Ferrous
Ferric - Fe3+
Ferrous - Fe2+
There’s an o in 2(two)
When and where would you take a Tissue biopsy to assess iron status
Bone marrow for Fe deficiency
Liver for Iron overload
What does % saturation of transferring measure
Iron supply
What is Hepcidin
Negative regulator of iron uptake
Produced by liver in response to iron overload
Down-regulates ferroportin (iron transporter in GI tract)
Where is Iron absorption in the GI tract, which transporters
Duodenum
DMT-1 (into duodenal cell)
Ferroportin (out of duodenal cell)
Hypochromic, microcytic anemia is caused by
Deficient hemoglobin synthesis. Cytoplasmic defect
How is iron deficiency confirmed
Combination of anemia and reduced storage iron (low serum ferritin)
How can you loose iron without noticing it?
Occult blood loss of 8-10ml per day can occur w/o signs or symptoms. That is 4-5mg iron lost which is the maximum dietary intake. Negative net iron occur
What is primary iron overload
Long-term excess iron absorption with parenchymal rather than macrophage iron loading, and eventual organ damage. Due to low levels of Hepcidin due to mutation
Clinical features of hereditary hemochromatosis
Weakness/fatigue – Joint pains – impotence – Arthritis – Cirrhosis – Diabetes – Cardiomyopathy
Most common type of mutation in Hereditary Hemochromatosis
HFE gene mutation (C282Y mutation or H63D mutation)
Caused reduced hepcidin synthesis
Diagnosis of Risk of iron loading and Iron load
Risk of iron loading - Transferrin saturation >50%
Iron load - Serum ferritin >300ug/L in men or >200ug/L
Treatment of Hereditary hemochromatosis
Weekly venesection
Reduces the iron.
Aim at Feritin
What is the cause of death in Hereditary hemochromatosis
Increased risk of Hepatocellular carcinoma
When does hereditary hemochromatosis present
Middle age or later.
May be asymptomatic until irreversible end organ damage has occured
Genetic inheritance pattern of Hereditary hemochromatosis
Autosomal recessive
What is the cause of Iron-loading anemias
Repeated RBC transfusions
Excessive iron absorption related to over-active erythropoiesis
What disorders cause Iron-loading anemias
Thalassemia disorders
Sideroblastic anemias
Red cell aplasia
Myelodysplasia
What is considered Iron overload
Total >5g
OR
Liver >15mg/g dry weight
How is secondary iron overload treated in an anemic person receiving regular blood transfusions
Iron chelating agents -Desferrioxamine (SC or IV) -Deferiprone (Oral) -Defereasirox (oral) Oral drugs not used as much
Two definitions of anemia
Reduction of Hb below optimum for that indiviudal
Reduction of Hb below 95%range for the population
What is the content of a reticulocyte
No nucleus
rRNA still present
Larger than a mature red cell
Signs and symptoms of Hemolytic anemia
Increased unconjugated serum bilirubin
Increased urinary urobilinogen
Anemia+Jauncide +/-splenomegaly
Describe breakdown of Heme
Heme –>porphyrin –>Bilirubin (All in macrophage)
Bilirubin enters plasma as unconjugated. Taken up by hepatocytes and becomes conjugated. Enters gut in bile.
Taken up as Urobilinogen and secreted through kidneys.
Stercobilinogen stays in gut an excreted through feces.
What does Mean Corpuscular Hemoglobin (MCH) measure
Hb/red cell count
What does Mean Corpuscular Hemoglobin Concentration measure
Hb/Hct
Iron deficiency causes what types of red cells
Microcytic and Hypochromic
VitB12 (Cobalamin) or Folate deficiency causes what type of red cells
Macrocytic - Megaloblastic anemia
Aplastic anemia, myeloma, myelodysplasia causes microcytic or macrocytic anemia
Macrocytic anemia
Causes of Normochromic normocytic anemia
Hypoproliferative stage Chronic inflammatory, infective or malignant disorder Renal failure Hypometabolic states (Hypothyroidsim) Marrow failure
How does Inflammation cause anemia
Inhibits Erythropoietin release throught IL-1beta and TNF-alpha
Inhibits erythroid proliferation
Augments hemophagocytosis
Increase hepatic release of Hepicidin through IL-6
What releases IL-6 and what does it do
Machrophages in response to inflammation. Acts on Hepatocyte to increase Hepcidin release
Anemia of chronic disease findings: Serum Iron – Transferrin – %transferrin saturation – Ferritin – MCV
Serum iron - Reduced Tranferrin - normal or reduced % transfer - reduced Ferritin - Normal or increased MCV - Normal (can be reduced)
Why does renal failure cause anemia
Because kidneys release Erythropoeitin. In renal failure the release is decreased in most cases
-penia means
Low
Ie. Neutropenia, thrombocytopenia
-cytosis menas
High
Monocytosis
-philia menas
High
Neutrophilia
What shifts the Oxygen dissociation curve to the left
Decreased acidity
Decreased DPG
Decreased Temp
(Note: Decreased acidity=Increase pH)
What shifts the Oxygen dissociation curve to the right
Increased acidity
Increased DPG
Increased Temp
(Note: Increased acidity=decreased pH)
What keeps Fe2+ in it’s reduced form in the RBC
NADH generated by Ebden-Myerhoff pathway
What does the Rapapoport-Lubering Shunt do
Generates 2,3 DPG which shifts the oxygen disassociation curve to the right
Lecture week 1 done
Yes
