Block 4 W1 Flashcards
What is the composition of blood?
- Liquid composition - 55% plasma
2. Formed elements - 45% RBC + WBC + platelets
Outline the components of plasma.
92% water
7% plasma proteins - albumin, globulins
1% other substance - electrolytes, hormones, nutrients
Describe the function of plasma.
ECM of blood - keeps blood cells in suspension.
Serum is plasma devoid of clotting factors.
Where is the site of haematopoiesis prenatally?
Yolk sac -> liver and spleen
Where is site of haematopoiesis post-birth?
Bone marrow
How is haematopoiesis controlled?
By environment within bone marrow i.e. stromal cells and growth factors and cytokines:
- EPO, erythropoietin - RBC
- TPO, thrombopoietin - platelets
- Interleukin, G-CSF, GM-CSF and SCF - WBCs
Where is the site of erythropoiesis?
Bone marrow - 2.5x10^6 new RBC/sec
How is erythropoiesis initiated?
Hypoxia detected by kidney -> releases EPO into blood -> binds erythropoietin receptor on progenitor cells.
Describe the process of erythropoiesis.
Multipotent stem cell -> common myeloid progenitor -> proerythroblast -> phase 1 ribosome synthesis (basophilic erythroblast) -> phase 2 haemoglobin accumulation (polychromatic erythroblast) -> phase 3 nucleus rejection (orthochromatic erythroblast) > reticulocyte -> erythrocyte.
Describe haemoglobin.
4 global polypeptide chain - 2alpha and 2beta -> each associated with haem.
HB - binds O2 for transportation and CO2 for removal.
Describe haem.
Porphyrin ring + iron molecule as cofactor.
Describe structure and function of erythrocytes.
RBC
Bi-concave, no nucleus for optimal O2 function and flexibility.
Lifespan - 120 days
Damaged cells removed by macrophages in spleen.
Describe structure and function of thrombocytes.
Platelets
Small, no nucleus
Initiates blood clotting at site of injury.
Lifespan - 7-10 days
Describe thrombopoiesis.
10^11 made/day
1 megakaryocyte generates 5000 platelets -> fragment to make platelets.
30% stored in spleen.
Where is TPO made?
Liver and kidney
List innate immune cells.
Neutrophils Eosinophils Basophils Monocytes NK cells
Describe neutrophils.
Lifespan - 5 days
60-70% of WBC (most common)
Phagocytes - ingest and kill pathogens and damaged cells. Initiate inflammatory process.
Describe eosinophils.
Lifespan - 2-5 days
0.2%
Phagocytic against helminths
Describe basophils.
Lifespan - 1-2 days
0.2%
Allergic reactions
Describe monocytes.
Lifespan - 1-7 days
2-10%
Phagocytic and differentiate to become macrophages.
Describe natural killer cells.
Lifespan - 14 days
15%
Kill virally infected cells
Describe lymphocytes.
Adaptive immune cells
T and B cells
Lifespan - weeks to years
20-40%
Describe haematocrit test.
Separates blood into 3: plasma + WBC and platelets + RBC F = 37-47% M = 42-52% Reduced - anaemia Increased - polycythaemia
Define polycythaemia vera.
Primary form of myeloproliferative disorder.
Increased Hb, PCV and RBC.
95% due to mutations in JAK2 gene.
Define essential thrombocythaemia.
Secondary form of myeloproliferative disorder.
Normal Hb and WBC but increased platelets.
JAK2 mutations.
Define myelofibrosis/myelosclerosis.
Elevated WBC and platelet count.
JAK2 mutations.
How does JAK2 gene mutation cause myeloproliferative disorders?
Janus kinase 2 acts in signalling pathway downstream of EPO and TPO receptors.
Point mutation -> constitutively activates receptors in absence of EPO.
What are the treatments of polycythaemia?
- Venesection
- Chemotherapy - hydroxycarbamide
- Low dose aspirin
What is the ABO blood group?
2 antigens on surface of RBCs determines a persons blood type.
What are A and B antigens?
Carbohydrate structures present on RC membrane glycoproteins and glycolipids.
What are the major carriers of A and B antigens?
N-glycosylated glycoproteins Anion exchanger Glucose transporter (GLUT 1)
What do the types A, B and O gene encode?
A - N-acetylgalactosaminyltransferase
B - galactosyltransferase
O - no transferase
Describe the inheritance of ABO.
Ch 9 -> 3 allelic variants
i, IA and IB
IA and IB co-dominant
4 blood groups, A, B, AB and O.
What are rhesus D antigens?
Expressed on RBC surface. 5 major Rh antigens: D, C, E, c and e. D = most immunogenic RhD- = no expression of antigen. 85% RhD+ 15% RhD-
Describe the gene of RhD.
Encoded by RHD and RHCE gene.
No anti-D antibodies present in blood.
How does haemolytic disease of the newborn (HDN) occur?
- Rh+ father
- Rh- mother carrying her first Rh+ foetus. Rh antigens from foetus enters mothers blood during pregnancy.
- Mother makes anti-Rh antibodies and becomes sensitised.
- If mother pregnant with another Rh+ foetus, anti-Rh antibodies crosses placenta and damages foetal RBCs.
What are the complications of HDN?
Range: mild anaemia -> intrauterine death at 18 weeks (hydrops fetalis).
Kernicterus - severe jaundice causes brain damage or deafness.
What is the prevention of HDN?
Routine antenatal serology + prophylaxis anti-D therapy.
Anti-D immunoglobulin binds and neutralises any RhD+ cells preventing formation of maternal antibodies.
What do incompatible blood transfusions cause?
Agglutination - IR facilitated by antibody-antigen interactions. Haemolysis Renal failure Shock Death
Define anaemia.
Reduced no. of RBC or decreased HB -> reduced levels of oxygen delivery.
What are the signs of anaemia?
Pallor Tachycardia Glossitis Koilonychia - spoon nails Dark urine
What are the symptoms of anaemia?
Lethargy Dizziness SOB Chronic fatigue Poor concentration
What are the severe symptoms of anaemia?
Jaundice, splenomegaly
Hepatomegaly, angina
Cardiac failure, fever
How does changes in bone marrow cause anaemia?
Pure red cell aplasia (PRCA) - conditions affecting specifically erythropoiesis in bone marrow.
Pancytopenia - affecting production of RBCs, WBCs and platelets.
Give an example of congenital PRCA.
Diamond Blackfan anaemia - reduced proliferation of erythroblasts.
What conditions causes acquired PRCA?
Infections: EBV, HIV, Hep B
Malignancy: solid tumours, haematological tumours.
Autoimmune disease: SLE, RA.
Other causes: drugs (methotrexate), pregnancy.
How does pancytopenia occur due to changes in bone marrow?
No self-renewal stage of haematopoietic stem cell -> exhaustion.
Define haemolytic anaemia.
Premature destruction of RBC by extrinsic/instrinsic mechanisms i.e. drugs, abnormal types of Hb.
Define allo-immune haemolysis.
Alloantibodies are made in response to immune recognition of foreign erythrocyte introduced via blood transfusion or pregnancy.
e.g. HDN
Define auto-immune haemolysis.
Patient’s IS produces antibodies that recognise own RBCs as foreign and destroys. 3 causes:
- idiopathic
- secondary - other illness e.g. lymphoproliferative disorders, SLE, Crohn’s.
- drug-induced - alpha-methyldopa and penicillin.
How is haemolytic anaemia diagnosed on blood films?
Schisocytes, polychromasia, nucleated erythrocytes and spherocytes.
Define haemoglobulinopathy.
Autosomal co-dominant genetic defects -> abnormal structure of globin chains in Hb.
e.g. sickle cell anaemia
Why are iron, vitamin B12 and 6 and folic acid need for erythrocyte function?
These essential micronutrients are needs for the metabolism of haem and formation of Hb.
What are the likely causes of lack of essential micronutrients?
Malabsorption
Malnutrition
How can iron deficiency anaemia be diagnosed on blood films?
Hypochromic (pale) and microcytic (small).
Define sideroblastic anaemia.
Failure to incorporate iron into haem in erythrocyte precursor cells -> iron-rich mitochondria
Where is haem synthesised in RBCs?
Cytoplasm and mitochondria.
What are the dietary sources of iron?
Dark-green leafy veggies, whole grains, beans, nuts, meat.
What makes iron absorption difficult?
Tea and coffee, PPI, Calcium, antacids, wholegrain cereals.
What are the main causes of deficiency of iron.
Poverty, helminths, pregnancy, occult bleeding, vegan/vegetarian.
Why is vitamin B12, 6 and folic acid required?
For maturation of RBCs and DNA synthesis in erythrocyte proliferation.
Patients have abnormally low reticulocytes.
What are the dietary sources of vitamin B12, 6 and folic acid?
Meat, salmon, milk, eggs, soy products.
What are the causes of deficiency of vitamin B12, 6 and folic acid?
Malnutrition and malabsorption, poverty, pregnancy, drugs, pernicious anaemia (deficiency of gastric intrinsic factor), gastrectomy, fish tapeworm, pancreatitis.
Define megaloblastic anaemia.
Due to inhibition of DNA synthesis in erythropoiesis due to deficiency in folate and B12, caused by malnutrition or malabsorption.
Characteristic - megaloblasts and hypersegmented neutrophils.
Define pernicious anaemia.
Caused by lack of intrinsic factor - required to absorb B12.
Due to autoimmune condition targeting gastric parietal cells.
Define thalassemia.
Occurs when body is unable to produce enough Hb.
Target cells, Heinz bodies.
Define aplastic anaemia.
Bone marrow and haematopoietic stem cells damaged so inability to make mature blood cells.
Where is vitamin B12 absorbed and stored?
B12 binds intrinsic factor in stomach and is absorbed in terminal ileum.
Stored in liver.
Where is folate absorbed and stored?
Absorbed in duodenum/proxmial jejunum.
Stored in liver.
Define primary lymphoid tissues.
Sites for development of lymphocytes and where lymphocytes differentiates to express antigen receptors.
Give examples of primary lymphoid tissues.
Thymus - T cells
Bone marrow - B cells
Define secondary lymphoid tissues.
Specialised sites for turning on the adaptive IR. T and B cells are educated to respond to specific antigens.
Give examples of secondary lymphoid tissues.
Lymph nodes
Spleen
Mucosal associated lymphoid tissue (MALT)
Draw simple diagrams of thymus, lymph node, spleen and Peyer’s patch.
PIC
What are the 3 components that all lymphoid tissues have?
Capsule
Vascular
Compartments
What is the role of lymph nodes?
Filter lymphatics
Anatomical meeting place for cells of IS and their exposure to antigen for IR.
Describe the events in a lymph node.
Afferent lymph comes from periphery. APCs sample antigens of incoming microbes. D cells pick up antigens from periphery and transport to LN -> LN concentrated in antigens so its easier for lymphocyte activation in same area. Lymphocytes and APCs leave via efferent lymph.
Describe the functions of the spleen.
Looks for infection in systemic circulation as directly connected to blood vessels.
- directs IR to antigens in blood (white pulp)
- destruction of RBC (red pulp)
What do the presence of Howell-Jolly bodies (erythrocyte with nuclear fragments) indicate?
Hyposplenism
Not fatal but pre-disposes to infections.
Where is spleen located?
Left hypochondria regions of abdominal cavity.
12x7x2.5
What are MALTs?
Aggregates of lymphocytes in reticular mesh.
Sites of IR to antigens that breach epithelia.
No incoming lymphatic vessels.
Define lymphatics.
Drainage system involved in regulating fluid balance, returning the fluid to blood i.e. excess interstitial fluid and plasma proteins.
Describe lymph capillaries.
Originates as closed tubes except in CNS, epidermis and cartilage.
Wall - overlapping endothelial cells that respond to fluid pressure.
Lymph capillaries anastomose to form lymphatics.
Where do superficial lymphatics drain into?
Superficial lymphatics follow superficial veins - flow into lymph nodes in axillary + cervical + inguinal -> drains into deep lymphatics.
Where do deep lymphatics drain into?
Deep lymphatics follow main vessels.
Lymph from 3/4 of body drains into left brachiocephalic veins via thoracic duct.
Lymph from upper right quadrant enters rights brachiocephalic vein.
Outline the dual circulatory route.
This allows immunological surveillance throughout the body:
- pathogens from site of infection reach LN via lymphatics.
- naive lymphocytes arrive at LN in arterial blood.
- lymphocytes and lymph return to blood via lymphatics
- venous blood returns to heart.
Define innate immunity.
Non-specific first line defence.
Prevents pathogen establishment and limits multiplication.
Early protection while adaptive reacts.
No memory and low specificity.
Define adaptive immunity.
Specific, delayed immune response.
Contains immunological memory.
Uses lymphocytes.
What are the components of innate immunity?
Physical barriers - mucous, epithelia, cilia
Complement system
IS cells - neutrophils, monocytes, basophils, eosinophils, NK cells, D cells, mast cells.
Describe the complement system.
Multi-catalytic system which enables amplification of IIR by enzymatic cascade. 3 pathways:
- Alternative -> activation by pathogen surfaces
- Lectin -> activation by lectin binding mannose on pathogen.
- Classical -> activation by antibody-antigen complexes.
C3a + C5a -> inflammatory and phagocytic function.
C3b -> opsonisation
C5b - C9 membrane lysis.
Describe the acute inflammatory process in the complement system.
Bacteria activates alternative pathway, recognised by C3 -> generates C3 fragment products.
C3b sticks to surface of bacteria.
C5a + C3a recruit inflammatory cells via mast cells -> degranulates and allows histamine to make endothelial walls more permeable to inflammatory cells.
Describe membrane lysis in the complement system.
C5b binds C6 and C7 -> complex C5b67 binds membrane via C7 -> C8 binds to complex and inserts into membrane -> C9 binds complex and polymerises -> pore -> lysis.
Describe opsonisation in the complement system.
C3b coats membrane of target cell - promotes binding of microbes to phagocytes -> microbe rapidly ingested.
How do macrophages recognise bacteria?
Distinguishes different classes of microbes due to PAMPs and PRRs e.g. LPS and glucan receptors.
Describe phagocytosis.
- Attachment via PRR
- Pseudopodia forming a phagosome
- Granule fusion and phagolysosome - allows for antigen presentation to lymphocyte
- Release of microbial products.
Define cytokines and chemokine.
- Hormones of IS
- Allows communication between variety of immune and non-immune cells.
- Chemokine - further family of chemotactic cytokines.
- Designed to work over short distances but can have systemic effects.
- Opposing effects of cytokines on macrophage function.
What are the roles of macrophages?
- phagocytosis
- recruitment - releases cytokines to induce inflammation
- presentation - APC
- extravasation
Outline the events in systemic acute phase response.
Trauma, stress, inflammation -> local réponse to make proinflammatory cytokines -> causes hepatocyte to modulate protein synthesis -> acute phase response (leukocytosis, complement activation, clotting and opsonisation -> resolution.
Describe the acute inflammatory response.
Damage:
- release of cytokines and chemokine which attracts leukocytes (leukocyte chemotaxis)
- mast cell degranulation of histamine -> causes vasodilation and increased permeability of capillaries.
- releases inflammatory mediators i.e. bradykinin and prostaglandins -> increases pain sensitivity.
