Session 6: Haemopoeisis, Spleen and Bone Marrow Flashcards
What is haemopoesis?
- It is the process by which blood cells are formed.
- It involves specification of blood cell lineages and proliferation, to maintain an adequate number of cells in the circulation.
Compare haemopoiesis in adult vs children and infants
Infants and children: extensive throughout skeleton
Adult:
Limited in adult to 5 areas:
Pelvis, Sternum, Skull, Ribs and Vertebrae
How to sample bone marrow?
Trephine biopsy
5 major pathways for haemopoetic stem cells
Common lymphoid –>
lymphocyte (lymphopoesis)
Common myeloid progenitor –>
platelets (thrombopoesis)
Erythrocytes (erythropoesis)
Monocyte/macrophage (monocytopoesis)
Basophil, Neutrophil, Eosinophil (granulopoesis)
What is differentiation into different blood cell linages determined by?
Hormones
Transcription factors
Interactions with other non-haemopoetic cell types, like endothelial cells
Name the hormones involved in haemopoesis.
Where are they produced and what do they do?
Erythropoetin (from kidney, stimulates RBC production)
Thrombopoetin (from kidneys and liver, regulates platelet production)
Haemopoetic stem cells (3)
Capable of self renewal (more than any other adult tissue)
Can differentiate into variety of specialised cells, given appropriate stimuli
In Pathological conditions, (myelofibrosis/thalasaemia) they can mobilize into circulating blood to colonise other tissues. (like the spleen and liver). This is called extramedullary hamatopoeiesis
What is it called when blood cells are produced in other tissues?
Extramedullary haemopoesis
Sources of haemopoetic stem cells (for transplant)
Bone marrow aspiration (rare)
Umbillical cord blood stem cells (cord bank)
Granulocyte colony stimulating factor (GCSF) mobilises peripheral blood stem cells and they are collected via leucopharesis
What is the RES (reticuloendothelial system)
- Part of the Immune system made up of monocytes in blood and a network of tissues which contain phagocytic cells
- Main organs are liver and spleen
- Spleen RES cells dispose of RBC (if damaged/old)
Different macrophages and location
Kupffer cell (liver)
Tissue histiocyte (connective tissue)
Microglia (CNS)
Peritoneal macrophage (peritoneal cavity)
Red pulp macrophage (spleen)
Langherhans cell (skin and mucosa)
Spleen pulps
Red pulp: sinuses lined by endothelial macrophages
White pulp: similar structure to lymphoid follicles
Function of spleen
Sequestration and phagocytosis (old/abnormal RBC removed by macrophages)
Blood pooling (allows a rapid supply of red blood cells and platelets during bleeding)
Extramedullary haemopoesis (if marrow fails or under stress, e.g. in myelofibrosis)
Immunological function (25% of T cells and 15% of B cells are present in the spleen)
How does blood enter spleen?
Via splenic artery
- White cells and plasma pass through white pulp
- Red cells through red pulp
(preferentially)
Why does splenomegaly occur?
- Portal hypertension (liver disease)
(patients which have liver disease, its very difficult for blood to flow round liver. There is a connection in the portal system between liver and spleen, so the blood can’t come out of the spleen as easily, so spleen becomes engorged with blood as there is this back pressure due to portal hypertension)
- Over work (red/white pulp)
(e. g. patients with sickle cell disease) - Extramedullary haemopoesis causes spleen to be full of developing blood cells
- Infiltrated by cells (like cancer cells or other cancer metastases)
- Iinfiltrated by other material such as in sarcoidosis, granulomas are present in the spleen, which enlarges it
How to examine spleen?
- It is never normal for the spleen to be palpable below the costal margin
- Start to palpate in Right Iliac Fossa (RIF) and move up or may miss massive splenomegaly
- Put your hand in, ask the patient to brethe in and feel for spleen edge moving towards your hand
- Feel for the splenic notch
- Record how big it is by measuring in cm from costal margin in mid- clavicular line
Massive splenomegaly causes
Chronic myeloid leukaemia
Myelofibrosis
Malaria
Schistosomiasis
Moderate splenomegaly
- Lymphoma
- Leukaemias
- Myeloproliferative disorders
- Liver cirrhosis with portal hypertension
- Infections (eg Glandular fever)
Could also be due to all the causes of massive splenomegaly, but just in an earlier stage)
- Chronic myeloid leukaemia
- Myelofibrosis
- Malaria
- Schistosomiasis
Mild splenomegaly
- Infectious hepatitis
- Endocarditis
- Sarcoidosis/infiltrative disorders
- Autoimmune diseases
Could also be due to all the causes of massive and moderate splenomegaly, but just in an earlier stage)
- Chronic myeloid leukaemia
- Myelofibrosis
- Malaria
- Schistosomiasis
- Lymphoma
- Leukaemias
- Myeloproliferative disorders
- Liver cirrhosis with portal hypertension
- Infections (eg Glandular fever)
What can occur in blood counts for hypersplenism?
Low blood counts due to pooling of blood in enlarged spleen
Risk with splenomegaly
Risk of rupture (no longer protected by rib cage)
Avoid contact sports and rigourous activity
What is hyposplenism?
Lack of functioning splenic tissue
Causes of hyposplenism
Splenectomy (may be required due to splenic rupture from trauma or beasue of cancer)
Sickle cell disease (in older children and adults due to multiple infarcts/fibrosis)
GI disease (coeliac, crohns, ulcerative collitis)
Autoimmune disorders (systemic lupus, Rheumatoid Arthritis , Hashimoto’s disease)
Blood sign of hyposplenism
Howell Jolly bodies (contain DNA remnants, would usually be removed by functioning spleen)
What are patients with hyposplenism at risk of?
At risk of sepsis from encapsulated bacteria:
- Streptococcus pneumoniae
- Meningococcus
- Haemophilus influenzae
Prevention for encapsulated bacteria infection (for patients with hyposplenism)
Patients must be:
- Immunised
- Given life-long antibiotics prophylaxis
What does MCV show?
Mean size of RBC
RBC structure
No nucleus
No mitochondria
120 day lifespan
Biconcave, flexible disc
Function RBC
- Deliver O2 to tissues
- Carry haemoglobin
- Maintain haemoglobin in reduced (ferrous) state
- Maintain Osmotic equilibrium
- Generate energy
What happens at 3-6 months of age?
Switch from fetal to adult Hb at 3-6 months old
Haemoglobin structure
Two alpha sub units and two beta sub units
Each globin molecule has a haem, which contains an iron
What can occur if changes occur in RBC plasma membrane?
Haemolytic anaemia:
- Cells become less deformable and more fragile
- Spleen recognises them as abnormal and removes them from circulation
- Resulting in haemolytic anaemia
Disease relating to changes in RBC membrane
Hereditary spherocytosis
RBC membrane proteins
Spectrin (molecular scaffold that links plasma membrane to actin cytoskeleton)
Ankyrin (links integral proteins to spectrin-actin cytoskeleton)
Band 3 (chloride and bicarbonate exchange)
Protein 4.2 (ATP binding protein)
How is haem degraded?
1) Red cells are identified as abnormal by macrophages
2) The macrophages in the RES system engulf the RBC’s and break them down
3) The Fe2+ is released and recirculated (recycled)
4) The haem portion is metabolised to bilirubin (unconjugated)
What happens to (unconjugated) billirubin?
- It is transported to the liver (bound to albumin in the blood)
- The liver conjugates the bilirubin with glucuronic acid to form bilrubin diglucoronide
What happens to bilirubin diglucoronide?
Secreted in bile into duodenum
Converted to urobillogen
Urobillogen can be oxidised to: stercobilin (in faeces = brown) or urobilin (in urine = yellow)
What means increase in cells
Cytosis / philia
What means decrease in cells
penia
Fill in this table:
Describe the role of neutrophils
- First responder phagocyte
- Essential part of Innate immune system
- Circulate blood stream and phagocytose invading microbes and destroy them by by releasing reactive oxygen species.
What do Neutrophils look like on a blood film
3-5 segments of nucleus
What is maturation of neutrophils controlled by?
G-CSF (which is a glycoprotein, growth factor and cytokine)
What does G-CSF do?
- Increases production of neutrophils
- Speeds up release of mature cells from BM
- Enhances chemotaxis
- Enhances phagocytosis and killing of pathogens
G-CSF clinical relevance
Recombinant G-CSF is routinely administered when more neutrophils are needed
eg patient with sever neutropenia and sepsis after chemotherapy
What is Neutrophilia?
Increase in the absolute number of CIRCULATING neutrophils (some are marginated against vessel wall)
Causes of neutrophilia
- Infection or inflammation (most common cause) e.g.
- Tissue damage
- Drugs (ie steroids)
- Smoking
- Acute inflammation
- Cancer
- Myleoproliferative diseases (rare)
- Cytokines (eg G-CSF)
- Acute Haemorrhage (brings marginated pool cells out)
- Metabolic disorders
- Endocrine disorders
Causes of neutropenia types
Reduced production or increased removal or use
Reduced production neutropenia causes
B12/folate deficiency
Infiltration (maligancy/fibrosis)
Aplastic anaemia (empty marrow)
Viral infection
Congenital
Radiation (mature cells killed, precursors stunned)
Drugs (chemo)
Be Careful Doing Any IV Radiation Arthur(nmeumonic)
Increased removal/use causes of neutropenia
Immune destruction (autoantibodies) Sepsis (they rush to tissues and marrow cannot compensate) Splenic pooling (sequestration)
sis (NMEUMONIC)
Consequences of neutropenia
Severe life threatening bacterial infection
Severe life threatening fungal infection
Mucosal ulceration e.g. painful mouth ulcers
Neutropenia emergency
Neutropenic sepsis = medical emergency
Intravenous antibiotics immediately
Describe the role of Monocytes (4)
- Largest cells in blood
- Monocytes circulate in the blood for 1-3 days before moving into tissues where they differentiate into macrophages or dendritic cells.
- Phagocytose microorganisms and breakdown/remove cellular debris
- Antigen presenting role to lymphocytes
- Important in defence against chronic bacterial infections (e.g. tuberculosis and chronic fungal infections)
What do macrophages protect against?
Bacterial infections (TB and chronic fungal infections)
Causes of monocytosis
- Bacterial infection (e.g. TB)
- Inflammatory conditions (Rheumatoid arthiritis, Crohns, ulcerative colitis)
- Carcinoma
- Myeloproliferative disorders and Leukaemias
My car is blue (nmeuonic)
Monocyte appearance
purple with large nucleus
Eosinophils purpose (6)
- Responsible for immune response against multicellular parasites such as helminths - think of EO candy won (helminths are basically like worms in your blood)
- Mediator of allergic responses
- Phagocytosis of antigen-antibody complexes
- Granules release cytotoxic proteins
- Lifespan 8-12 days
- Circulate for 3-8 hours before moving into tissues
What do eosinophils release?
Their granules contain an array of cytotoxic proteins e.g. eosinophil cationic protein and elastase
Eosinophil appearance
Tomato with sunglasses (very pink, 2 lobed nucleus)
Inappropriate activation of eosinophils can result in…
Tissue damage and inflammation - e.g. in asthma
Common causes of eosinophilia
Drug hypersensetivity (penicillin)
Allergic diseases (asthma, eczema, hay fever)
Parasitic infections (tapeworm, helminths, round worm)
Skin disease (bullous pemphigoid)
Churg-Strauss (very rare autoimmune condition resulting in inflammation of small blood vessels)
Don’t all people sea colour - sunglasses blood cell - cant see colours
Rare causes of eosinophilia
Hodgkin Lymphoma
Acute Lymphoblastic leukaemia
Acute myeloid leukaemia
Myeloproliferative
Idiopathic hypereosinophilic syndrome
Has Anyone Ever Melted An Icecream
Basophils appearance
Blackberry - purple blobs (granules mask nucleus because stain deep blue)
What do basophil granules contain?
Histamine
Heparin
Hyaluronic acid
Serotonin
Basophil function
Activated in allergic reactions and inflammatory conditions - Do not eat the poisonous berries in fishermen as you can have an allergic reaction
Contain histamine, heparin, serotonin, which they release as part of the immune response
Basophils are the least common wbc
What are the reactive disorders that cause basophilia?
Hypersensitivity reactions
Ulcerative collitis
Rheumatoid Arthiritis
What are the Myeloproliferative disorders that cause basophilia?
Chronic myeloid leukaemia
Systemic mastocytosis
Lymphocytes appearance
deeply stained nucleus (purple) and small amount of cytoplasm) - D in the photo
Types of lymphocytes and their roles
B cells:
- humoral immunity - Bekah is funny
- Antibody production
- Presenting antigens to T cells to activate the T cells
T cells:
- cellular immunity
- direct killing of infected host cells
- Activate and stimulate other immune cells to partake in the immune response
- Include CD8+ helper cells and CD4+ cells
Natural killer cells:
- (cell mediated cytotoxicity) - direct action in killing abnormal cells or pathogens within the blood
Reactive disorders that cause lymphocytosis
Viral infections
Bacterial infections - especially whooping cough
Stress related: MI /cardiac arrest
Post splenectomy
Smoking
Lymphoproliferative (malignant) disorders that cause lymphocytosis
Chronic lymphocytic leukaemia
T or NK cell leukaemia
Lymphoma (cells spill out of infiltrated bone marrow)
What happens in people with haemolytic anaemias?
They can appear jaundiced:
- Because there is too much breakdown of erythrocytes, so excess unconjugated bilirubin in the blood
- Liver might not be able to deal with the bilirubin quickly enough so can cause jaundice (ie yellow sclera)
Name cell A-E
A - Neutrophil (3-5 segments of nucleus)
B - Monocyte
C - Basophil (looks like a blackberry and dark stained granules)
D - Lymphocyte (deeply stained nucleus and small amount of cytoplasm)
E - Eosinophil
