Where is bone marrow found in an adult?
Pelvis Sternum Skull Ribs Vertebrae
Where is bone marrow found in an infant?
Throughout the skeleton
How is bone marrow obtained?
Trephine biopsy (aspiration of bone marrow, rarely done now) GCSF mobilised stem cells in the peripheral blood, collected by leucopharesis Umbilical cord stem cells at time of normal delivery
Which hormone controls differentiation of HPSCs into common myeloid progenitors?
Interleukin-3
Which adult tissue/cell has the greatest power of self-renewal?
Haemopoietic stem cell
What can HSPC’s do?
Self-renewal
Differentiate into variety of specialised cells
Mobilise out of bone marrow into circulating blood
Apoptosis
What are the phagocytic cells?
Monocytes Macrophages Kupffer cells Tissue histiocytes Microglial cells in CNS
What is the reticuloendothelial system?
Part of the immune system, made up of a network of tissue and cells which contain phagocytic cells
Can identify and mount an appropriate immune response to foreign antigens
Main organs are spleen and liver
Extra cellular fluid travels via lymphatics to the lymph nodes
Eg. Since all blood passes through the spleen, the RES cells in the spleen can dispose of damaged or old red blood cells
What makes up the spleen?
Red pulp (sinuses lined by endothelial macrophages and cords) and white pulp (similar structure to lymphoid follicles)
How do different cells move through the spleen?
Blood enters through the splenic artery
White cells and plasma preferentially pass through the white pulp
Red cells preferentially pass through the red pulp
What are the functions of the spleen in adults?
Sequestration and phagocytosis (old/abnormal red cells removed by macrophages)
Blood pooling
What is the name of a condition where the spleen is abnormally large?
Splenomegaly
How do you palpate a patient to diagnose an enlarged spleen?
Start in Right Lower Quadrant, move towards costal margin after exhalation
It is never normal to palpate the spleen below the costal margin - splenomegaly
The spleen should move towards hand upon inspiration
Measure in cm from costal margin in mid-clavicular line
What are the possible causes of splenomegaly?
Back pressure (portal hypertension in liver disease)
Over working red pulp
Over working white pulp
Reverting to foetal function (extramedullary haemopoiesis)
Infiltration by cells that shouldn’t be there (blood cancer eg leukaemia, other cancer metastases)
Infiltration by other material (Gaucher’s disease, sarcoidosis)
What does Gaucher’s disease do to the spleen and liver?
Enlarges it
What could cause massive splenomegaly?
Chronic myeloid leukaemia, myelofibrosis, malaria, schistosomiasis
What could cause moderate splenomegaly?
Chronic myeloid leukaemia, myelofibrosis, malaria, schistosomiasis
Plus, lymphoma, leukaemia, myeloproliferative disorders, liver cirrhosis with portal hypertension, infections such as Glandular fever caused by EBV
What could cause mild splenomegaly?
Chronic myeloid leukaemia, myelofibrosis, malaria, schistosomiasis
Plus, lymphoma, leukaemia, myeloproliferative disorders, liver cirrhosis with portal hypertension, infections such as Glandular fever caused by EBV
Plus, infections such as infectious hepatitis, endocarditis, infiltrative disorders such as sarcoidosis, autoimmune diseases such as AIHA, ITP, SLE
What is hypersplenism?
Overactive spleen
Results in low blood counts due to pooling of blood in an enlarged spleen
What are the risks associated with having an enlarged spleen?
Hypersplenism
Risk of rupture if enlarged and no longer protected by rib cage
If ruptured, can lead to a haematoma in the capsule around the spleen, leading to hypovolaemia and even death
Infarction, as when spleen enlarges its tissues get squashed and so don’t get enough oxygen, leading to tissue death
What is hyposplenism?
Underactive spleen
Lack of functioning splenic tissue
What can cause hyposplenism?
Splenectomy
Sickle cell disease (typically not in young children)
Coeliac disease
What are Howell Jolly bodies?
DNA remnants in erythrocytes
How can a blood film show an underachieve spleen?
Hyposplenia can be seen if Howell Jolly bodies are present (DNA remnants in erythrocytes). They look like normal RBCs but have a little black dot inside.
Why is hyposplenism so dangerous?
It puts patients at very high risk of sepsis, especially from encapsulated organisms eg. Pneumococcus, Haemophilus influenzae, Meningococcus
If patients have an underactive they are put on prophylactic penicillin for the rest of their lives, eg. if they have sickle cell disease
What is the normal RBC count?
4.4 - 5.9 x10^12 /l
What is the normal Hb value?
13.5 - 16.7 g/dl
What is the normal Mean Corpuscular Volume (MCV) value and what does it mean?
80 - 100 fl
The size of the RBCs
What are the functions of RBCs?
Deliver oxygen to the tissues Carry haemoglobin Maintain haemoglobin in its reduced (ferrous) state Maintain osmotic equilibrium Generate energy
How is haemoglobin synthesised?
Globin chains (from chromosomes 11 and 16) are synthesised independently and combined to form different Hbs
When does the switch from foetal to adult Hb occur?
3-6 months of age
What is haemolytic anaemia?
Abnormal breaking down of RBCs, either intravascular or extravascular (usually the spleen)
Can be due to changes in components of cell membrane, changing cell shape, making it more easily broken down and less deformable, so spleen recognises cell as ‘abnormal’
Red cell survival reduces below 120 days, causing anaemia
How do the kidneys deal with anaemia?
Anaemia cause reduced pO2, detected in the interstitial peritubular cells in the kidney
Increased production of Erythropoietin by the kidney
Erythropoietin stimulates maturation and release of RBCs from marrow
Number of RBCs increased and so Hb rises
More oxygen can be delivered
Via feedback loop, erythropoietin production falls
How is haemoglobin catabolised?
Hb -> Bilirubin (-> liver -> bile duct -> small intestine -> large intestine ->…)
Eventually go to kidneys, then get excreted as urobilinogen
What can an excess of RBC destruction cause?
Haemolytic anaemia
Jaundice (due to excess bilirubin formation from broken down heme groups)
What is cytopenia?
Reduction in number of RBCs
What is the name for low RBC count?
Anaemia
What is the name for low WBC count?
Leucopenia
What is the name for low neutrophil count?
Neutropenia
What is the name for low platelet count?
Thrombocytopenia
What is the name for low RBC, WBC and platelet count?
Pancytopenia
What is the name for high RBC count?
Erythrocytosis
What is the name for high WBC count?
Leucocytosis
What is the name for high neutrophil count?
Neutrophilia
What is the name for high platelet count?
Thrombocytosis
What is the name for high lymphocyte count?
Lymphocytosis
What are neutrophils?
First-responder phagocytes, the commonest white cell,
essential part of innate immune system
How long can neutrophils live in the bloodstream once mature?
1 - 4 days
What is neutrophil maturation controlled by? What does it do?
G-CSF Increases production of neutrophils Decreases time taken to release mature cells from BM Enhances chemotaxis Enhances phagocytosis and killing of pathogens
How do you treat a patient with neutropenia and sepsis?
Recombinant G-CSF
(means manufactured)
Patients can self inject that to reduce neutropenic infections post-chemotherapy
What is the main cause of neutrophilia?
Infection
What can cause neutrophilia?
INFECTION Tissue damage Acute inflammation Cancer Cytokines eg. G-CSF Metabolic/endocrine disorders Smoking Myeloproliferative diseases Acute haemorrhage Drugs eg. steroids
What range of neutrophil count would diagnose neutropenia?
<1.5 x10^9 /L
Severe if <0.5 x10^9 /L
What can cause neutropenia?
Increased removal or use (from immune destruction, sepsis, splenic pooling)
Reduced production
Benign ethnic neutropenia
Cyclic neutropenia
What can cause reduced production of neutrophils?
B12/folate deficiency - building blocks
Infiltration of bone marrow by malignancy or fibrosis - no room
Aplastic anaemia - empty marrow, no precursors
Radiation - mature cells killed, precursors stunned
Drugs - chemotherapy, antibiotics, anti-epileptics, psychotropic drugs, DMARDs, Rituximab - poison the marrow
Viral infection - very common - temporarily sick
Congenital disorders - not working properly from birth
What can neutropenia cause?
Severe life threatening bacterial or fungal infection Mucosal ulceration (eg. mouth) Neutropenic sepsis (EMERGENCY - IV antibiotics given immediately)
What do monocytes do?
Respond to inflammation and antigenic stimuli
Migrate to tissues where they become macrophages
Contain lysosomes for digestion
Phagocytosis and pinocytosis
What do lysosomes contain?
Lysozyme, complement, interleukins, arachidonic acid, CSF
What causes monocytosis?
Chronic inflammatory condition (RA, SLE, Crohn’s, UC)
Chronic infection eg TB
Carcinoma
Myeloproliferative disorders/ leukaemias (CMML, aCML, JMML, AML)
How long do eosinophils circulate in the bloodstream? How long do they live?
3-8 hours
8-12 days
What do eosinophils do?
Responsible for dealing with some parasites
Mediator of allergic response
Migrate to epithelial surfaces
Contain granules
Phagocytosis of antigen - antibody complexes
Mediate hypersensitivity reactions
What do eosinophilic granules contain?
Arginine, Phospholipids, enzymes
What are some causes of eosinophilia?
Allergies Drug hypersensitivity Churg-Strauss Parasitic infection Skin diseases Hodgkin Lymphoma Acute lymphoblastic leukaemia Acute myeloid leukaemia Myeloproliferative conditions Eosinophilic leukaemia Idiopathic hypereosinophilic syndrome
Which WBC is the largest and least common?
Basophil
What do basophils do?
Active in allergic reactions and inflammatory conditions
Contain dense granules
What do the granules of basophils contain?
Histamine, heparin, hyaluronic acid, serotonin
Where do lymphocytes originate?
In the bone marrow
What are the three lymphocytes?
B cells
T cells
Natural Killer cells
What are some reactive causes of lymphocytosis?
Viral infections Bacterial infections (esp. whooping cough) Stress related (MI) Post splenectomy Smoking
What are some reactive causes of basophilia?
Immediate hypersensitivity reactions, ulcerative collitis, rheumatoid arthritis
What are some myeloproliferative causes of basophilia?
CML, MPN (ET/PRV/MF), systemic mastocytosis
What are some lymphoproliferative (malignant) causes of lymphocytosis?
Chronic Lymphocytic leukaemia (B cells)
T or NK cell leukaemia
Lymphoma (cells ‘spill’ out of infiltrated bone marrow)
What is pancytopenia?
Reduction in all cells; RBC’s, WBC’s, and platelets