Haemopoiesis, Spleen And Bone Marrow Flashcards
What is haemopoiesis
The production of blood cells - occurs in the bone marrow
• RBC, Platelets and most WBC produced here
• Bone marrow extensive throughout the skeleton in infant
• More limited distribution in adulthood, predominantly:
Bone pain could indicate bone marrow problems
What is a bone marrow trephine biopsy?
Suck sample out of iliac crest, spread it, Examine it Core of tissue Decacified in lab Sliced thin
What is the name of the cell which all blood cells are derived from
Multipotential haematopoietic stem cell
Haemocytoblast
What do multipotential haematopoietic stem cells differentiate into?
Common lymphoid progenitor
(-> small lymphocyte -> T or B lymphocyte) - ILs/TNFs
Common myeloid progenitor
(->megakaryocyte -> thrombocytes) - TPO, GM-CSF
(-> erythrocyte) - EPO, GM-CSF
(-> myeloblast -> monocyte, basophil, neutrophil or eosinophil) - G-CSF, GM-CSF
What are properties of a HPSC?
• Has the greatest power of self-renewal compared to any other adult tissue
• It can renew itself, and .. ..can differentiate to a variety of specialised cells ..dependent on
different stimuli
• Can mobilize out of the bone marrow into circulating blood, and
• can undergo programmed cell death, apoptosis
• Research started in 1950s with experiments on mice - now HPSC transplantation is mainstream haematology activity (“bone marrow transplant”)
• Stem cells being used to encourage regeneration of a variety of tissues in the research setting
Where are HPSC collected from?
Sources of HPSC
• Aspiration of Bone Marrow - rarely done now (draining from ilium)
• Now GCSF mobilised stem cells in the peripheral blood (collected by leucopharesis; eg if donating stem cells to a sibling for a transplant or as a voluntary donor
- send blood circulating through machine, stem cells have cd34 receptor, machine recognises this, collects stem cells and returns the rets of the blood to patient)
• Umbilical Cord stem cells At time of normal delivery
What is the RES?
Reticuloendothelial system
- The RES is a network in blood and tissues which is part of the immune system (liver and spleen 2 main organs, network of blood and tissues) containing phagocytic cells:
monocytes macrophages kupffer cells tissue histiocytes microglial cells in CNS
- Cells of the RES can identify and mount an appropriate immune response to foreign antigens
- Main organs are spleen and liver
- All blood passes through the spleen, the RE cells in the spleen can dispose of blood cells (spot dead cells or cells with abnormal proteins), in particular damaged or old red cells
- Extracellular fluid travels via lymphatics to the lymph nodes
What are red pulp and white pulp?
The spleen consists of:
red pulp - sinuses lined by endothelial macrophages and cords white pulp similar structure to lymphoid follicles
What des the splenic vein drain into?
Portal vein
What enters via the splenic artery?
Blood enters via the splenic artery
White cells nad plasma preferentially pass through the white pulp
Red cells preferentially pass through the red pulp
What are functions of the spleen in adults
• Sequestration (holding onto) and phagocytosis - old/abnormal red cells removed by macrophages
• Blood pooling - platelets and red cells can be rapidly mobilised during bleeding (Proportion of circulating blood held in spleen - mobilise blood pool in spleen in injury)
• Extramedullary haemopoiesis - pluripotential stem cells proliferate during haematological stress or if marrow fails (eg myelofibrosis) (Blood production outside of bone marrow
Spleen can revert to making blood cells bc bone marrow cant)
• Immunological function 25% of T cells and 15% of B cells are present in the spleen
• More re infection
What is splenomegaly?
Enlargement of the spleen
How is splenomegaly detected?
- never normal to palpate the spleen below the costal margin
- Start to palpate in the RIF or will miss massive splenomegaly
- You feel the spleen edge move towards your hand on inspiration
- Feel for the splenic notch
- Measure in cm from costal margin in mid- clavicular line
Why would the spleen grow?
- Back pressure ~ portal hypertension in liver disease
- Over working red pulp
- Over working white pulp
- Reverting to what it used to do ~ extramedullary haemopoiesis
- Expanding as infiltrated by cells which shouldn’t be there
- Cancer cells of blood origin eg leukaemia
- Other cancer metastases
- Expanding as infiltrated by other material
- Gauchers disease, sarcoidosis
- Cancer cells of blood origin eg Chronic Lymphocytic Leukaemia CLL Expanded white pulp
- Expanding as infiltrated by other material
- eg sarcoidosis
What could cause the spleen to grow to different sizes?
- Massive - chronic myeloid leukaemia, myelofibrosis, malaria, schistosomiasis
- Moderate - As above, PLUS lymphoma, leukaemias, myeloproliferative disorders, liver
- Mild - As above, also infections such as infectious hepatitis, endocarditis; infiltrative disorders cirrhosis with portal hypertension, infections such as Glandular Fever caused by Epstein Barr virus such as sarcoidosis; autoimmune diseases such as AIHA, ITP, SLE
- Low blood counts can occur due to pooling of blood in the enlarged spleen = hypersplenism
- Risk of rupture if enlarged and no longer protected by rib cage !!
Why should activities such as intense sport and gardening be avoided for someone with an enlarged spleen?
Could rupture
What is hyposplenism?
Hyposplenism
= Lack of functioning splenic tissue
• Causes
• splenectomy!
• sickle cell disease in older children and adults (due to multiple infarcts then fibrosis)
• coeliac disease
• Blood film reveals Howell Jolly bodies (DNA remnants - purple dots in RBCs)
• Patients at risk of overwhelming sepsis, particularly from encapsulated organisms eg Pneumococcus, Haemophilus influenzae, and Meningococcus = key clinical fact
- lifelong penicillin
What are functions of erythrocytes
- Deliver oxygen to the tissues
- Carry haemoglobin
- Maintain haemoglobin in its reduced (ferrous) state
- Maintain osmotic equilibrium
- Generate energy
Describe haemoglobin synthesis
• Globin gene clusters on chromosome 11 and 16
– Expressed at different stages of life
• Globin chains synthesised independently and combine to form different haemoglobins
• Switch from foetal to adult Haemoglobin occurs at 3-6 months of age
• Foetal and adult Hb and Hb variants have different properties
What do (congenital or acquired) changes in the components of cell membranes of red cells lead to
Change in the shape of RBCS
This can cause the red cells to be less deformable, more easily broken down and often recognised by the spleen as ‘abnormal’: red cell survival reduced (ie less than 120 days) and anaemia can develop = Haemolytic anaemia
What does excess RBC destruction lead to?
So an excess of red cell destruction causes an excess of bilirubin formation as removal processes in the liver cant keep up which in turn leads to hyperbullirubinaemia (JAUNDICE)
Describe the control o erythropoiesis
- Patient becomes anaemic … so Reduced pO2 - less oxygen delivered to tissues - detected in interstitial peritubular cells in kidney
- Increased production of Erythropoietin (hormone) by the kidney - also can e produced by liver
- Erythropoietin stimulates maturation and release of red cells from marrow
- Total red cells and so Haemoglobin rises
- More oxygen can be delivered
- Via feedback loop erythropoietin production falls
Name some forms of cytopenia
- Cytopenia is a reduction in the number of blood cells. It takes a number of forms:
- Low red cell count = anaemia
- Low white blood = leucopenia
- Low neutrophil count = neutropenia
- Low platelet count = thrombocytopenia
- Low red blood cells, white blood cells, and platelets = pancytopenia
What does -cytosis/-philia mean? Name some forms
= An increase in the number of blood cells. It takes a number of forms: • high red cell count = erythrocytosis • high white blood = leucocytosis • high neutrophil count = neutrophilia • high lymphocyte count = lymphocytosis • high platelet count = thrombocytosis
What is neutrophil maturation controlled by?
Controlled by a hormone G-CSF
- increased production of neutrophils
- less time to release of mature
cells from BM ڧ enhances chemotaxis ڧ enhances phagocytosis and killing of pathogens
- If a patient needs more neutrophils (eg w/ severe neutropenia and sepsis after chemotherapy)
- We administer Recombinant (manufactured) GCSF
- In fact many patients self-inject GCSF to reduce neutropenic infections post-chemotherapy
What are the causes of neutrophilia
Reactive: Infection - main cause but not always the cause Tissue damage Acute inflammation Cancer Acute haemorrhage Drugs eg steroids Cytokines - G-CSF Metabolic/endocrine disorders Smoking
Primary haematological problems:
Giver too much G-CSF
Myeloproliferative diseases
What is the neutrophil count that = neutropenia?
• Neutrophil count <1.5 x 109/L; severe if < 0.5
What causes neutropenia
- Reduced prodution
- Increased removal/use (immune destruction, sepsis, splenic pooling)
- Others (benign ethnic neutropenia, cyclic neutropenia ie count fluctuates through the month)
What does neutropenia cause
- B12/folate deficiency - the building blocks
- Infiltration of bone marrow by malignancy or fibrosis - no room
- Aplastic anaemia - empty marrow, no precursors
- Radiation (if includes high proportion of marrow) - mature cells killed, precursors stunned
- Drugs - chemotherapy, antibiotics, anti-epileptics, psychotropic drugs, DMARDs, Rituximab - poison the marrow
- Viral infection - v common- temporarily sick
- Congenital disorders - not working properly from birth
- All to be revisited in later lectures and group work
What are the consequences of neutropenia?
- Severe life threatening bacterial infection
- Severe life threatening fungal infection
- Mucosal ulceration eg painful mouth ulcers
Key clinical fact: Neutropenic sepsis is a medical emergency. Intravenous antibiotics must be given immediately
What are the roles of monocytes
Response to inflammation and antigenic stimuli
Migrate to tissues – macrophages
lysosomes contain lysozyme, complement, interleukins, arachidonc acid, CSF
phagocytosis, pinocytosis
What causes monocytosis
Reactive:
- Chronic inflammatory conditions such as RA, SLE, Chron’s, UC
- Chronic infection eg TB
- Carcinoma
Primary haematological problem:
- Myeloproliferative disorders/leukaemias: CMML, aCML, JMML, AML
What are the roles of Eosinophils
- 3-8 hours in circulation
- lifespan 8-12 days
- Responsible for dealing with some parasites
- Mediator of allergic response
- Migrate to epithelial surfaces
- Granules contain arginine, phospholipid, enzymes
- Phagocytosis of antigen - antibody complexes
- Mediate hypersensitivity reactions eg to drugs, in asthma, skin inflammation
What causes eosinophilia
Reactive:
•Allergic diseases: asthma, eczema, urticaria, hay fever, aspergillosis
•Drug hypersensitivity: penicillin
•Churg-Strauss
•Parasitic infection: Round worm, tapeworm, flukes
•Skin diseases: bullous pemphigoid
Primary haematological problem: •Hodgkin Lymphoma •Acute lymphoblastic leukaemia •Acute myeloid leukaemia •Myeloproliferative conditions •Eosinophilic leukaemia •Ideopathic hypereosinophilic syndrome
What are basophils?
- Least common but largest
- active in allergic reactions and inflammatory conditions
- Dense granules contain histamine, heparin, hyaluronic acid, serotonin
What causes basophilia?
Reactive
•Immediate hypersensitivity reactions
•UC
•RA
Myeloproliferative
•CML
•MPN: ET/PRV/MF
•Systemic mastocytosis
What are the roles of lymphocytes
B cells
- humoral immunity
- antibody production
T cells
- cell mediated immunity
- CD4+ and CD8+ helper cells
NK cells
- cell mediated cytotoxicity
What causes lymphocytosis
Reactive • Viral infections • Bacterial infections-esp whooping cough • Stress related: MI/cardiac arrest • Post splenectomy • Smoking
Lymphoproliferative ie malignant
• Chronic Lymphocytic Leukaemia (B cells)
• T- or NK- cell leukaemia
• Lymphoma (cells ‘spill’ out of infiltrated bone marrow)
What is pancytopenia
Reduction in all blood cells: white cells, red cells and platelets
