6.1 - Haematology 1 Flashcards
what is haemopoiesis
the production of blood cells from stem cells
- ie RBCs, platelets, and the majority of WBCs
- aka haematopoiesis
- occurs in bone marrow
- begins from haematopoietic stem cells
- in infants, takes place throughout the skeleton
- in adults, there is a limited distribution (mainly axial skeleton including pelvis, sternum, skull, ribs and vertebrae)
- begins from a single cell type: multipotent haematopoietic stem cell (HPSC)
- production of certain cell types is regulated by various hormones
what are different blood cell production stimulated by
Differentiation is determined by: Hormones, transcription factors, interactions with non-haemopoietic cell types
- RBC production stimulated by erythropoietin (EPO)
- platelet production stimulated by thrombopoietin
- Granulocytes ★ production stimulated by G-CSF
- Lymphocyte production stimulated by interleukins and TNF-α
the HPSCs differentiate into either… common myeloid progenitor cells or common lymphoid progenitor cells… and from them all the other blood cells develop
5 major lineage pathways arise from the haemopoietic stem cells in bone marrow (more detail on other cards)
granulocytes = eosinophils, basophils, neutrophils
what are the 5 main lineage pathways arising from the haemopoietic stem cells in bone marrow
details about each one on seperate cards
- thrombopoiesis (platelet formation)
- monocytopoiesis (macrophage formation)
- lymphopoiesis (T and B-lymphocyte formation)
- granulopoeisis (basophil, neutrophil, eosinophil formation)
- erythropoeisis (RBC formation)
thrombopoeisis
multipotent haemapoietic stem cell (HPSC) → common myeloid progenitor + common lymphoid progenitor → megakarocyte + erythroblast + mast cells + myeloplast → platelets
platelets aka thrombocytes
erythropoeisis
HPSC → common myeloid progenitor + common lymphoid progenitor → erythroblast + megakaryocyte + mast cells + myeloblast → reticulocyte → erythrocyte/RBCs
granulopoeisis
HPSC → common myeloid progenitor + common lymphoid progenitor → myeloblast + mast cell + erythroblast + megakaryocyte → basophil + neutrophil + eosinophils + monocytes
monocytopoeisis
HPSC → common myeloid progenitor + common lymphoid progenitor → myeloblast + mast cell + erythroblast + megakaryocyte → basophil + neutrophil + eosinophils + monocytes → macrophages
lymphoidpoeisis
HPSC → common lymphoid progenitor + common myeloid progenitor → natural killer cell + T-lymphocyte + B-lymphocyte
B-Lymphocytes can differentiate further into plasma cells
haemopoietic stem cells features + sources
features
- capable of self renewal (more than any other adult tissue)
- given appropriate stimulo it can differentiate into a variety of specialised cells
- in pathological conditions eg myelofibrosis or thalassaemia can mobilize into circulating blood to colonise other tissues (extramedullary hematopoiesis)
- HPSC transplantation now mainstream haematological procedure
- if bone marrow is damaged in adult, HPSCs can move to spleen and RBCs can be produced
sources
- bone marrow aspiration
- leucopharesis (more on another card)
- umbilical cord stem cells
what is leucopharesis
technically not on learning objectives
- a way of collecting haemopoeitic stem cells (HPSCs)
- give patients GCSF to move stem cells out of bone marrow
- can therefore be collected by blood
- getting stem cells out of bone marrow via aspiration/biopsy is painful and expensive
reticuloendothelium system (RES)
spleen detail on another card
- part of immune system
- main organs are liver + spleen
- filter blood to identify pathogens and cells that are old/damaged → starts immune response
- made up of monocytes in the blood and a network of tissues that contain phagocytic cells
- spleen detail on another card
spleen
- part of reticuloendothelial system
- has red pulp (sinuses lined by endothelial macrophages + cords) and white pulp (similar structure to lymphoid follicles)
- blood enters through the splenic artery
- white cells and plasma preferentially pass through the white pulp
- red cells preferentially pass through the red pulp
FUNCTIONS
- sequestration and phagocytosis where old/abnormal cells removed by macrophages
- blood pooling where platelets and red blood cells can be rapidly mobilised during bleeding
- extramedullary haemopoiesis ie haemopoiesis going on in tissue outside the bone marrow. Pluripotent stem cells proliferate during haemotological stress or if marrow fails
- immunological function a significant number of B and T cells are present in the spleen
splenomegaly causes
why would it grow
- portal hypertension (eg in liver disease) where there is back pressure in portein vein and therefore in splenic vein, blood pools in spleen, enlarged
- over work
- expanding as infiltrated by cells eg cancer cells (eg leukaemia or metastases)
- expanding as infiltrated by other material (eg granulomas)
underlying causes
- MASSIVE: myeloid leukaemia, myelofibrosis, malaria, schistosomiasis
- MODERATE: lymphoma, leukaemias, myeloproliferative disorders, liver cirrhosis, infections eg glandular fever
- MILD: infectious hepatitis, endocarditis, infiltrative disorders such as sarcoidosis and autoimmune diseases
note: risk of rupture if spleen is enlarged an no longer protected by the rib cage - avoid contact sports and vigourous activity
splenomegaly causes
why would it grow
- portal hypertension (eg in liver disease) where there is back pressure in portein vein and therefore in splenic vein, blood pools in spleen, enlarged
- over work
- expanding as infiltrated by cells eg cancer cells (eg leukaemia or metastases)
- expanding as infiltrated by other material (eg granulomas)
underlying causes
- MASSIVE: myeloid leukaemia, myelofibrosis, malaria, schistosomiasis
- MODERATE: lymphoma, leukaemias, myeloproliferative disorders, liver cirrhosis, infections eg glandular fever
- MILD: infectious hepatitis, endocarditis, infiltrative disorders such as sarcoidosis and autoimmune diseases
note: risk of rupture if spleen is enlarged an no longer protected by the rib cage - avoid contact sports and vigourous activity
what is hypersplenism
- overactive spleen
- can cause splenomegaly
- low blood counts can occur due to pooling of blood in spleen
- when the spleen removes the blood cells to early and too quickly
- removes too many blood cells from the bloodstream
hyposplenism
features
- lack of functioning splenic tissue
- blood film reveals howell jolly bodies ★ which would normally be removed
causes
- splenectomy (have spleen removed), due to trauma or cancer
- sickle cell disease (affects membrane of RBC)
- gastrointestinal disease eg chron’s, colitis or coeliac
- autoimmune disorders eg lupus, rheumatoid arthritis or hashimoto’s (immune system also affects spleen, so cells leave spleen, and then spleen doesn’t function as it doesn’t have enough cells)
considerations
patients with this are at greater risk of sepsis from encapsulated bacteria (eg meningitis, Hib etc). As they are encapsulated, difficult for immune system to carry out response. Patients need to be given life long antibiotics.
★ DNA remnants which appear as tiny black dots in cells. Would normally be removed by fully functioning spleen
erythrocytes
red blood cells
- no nucleus and no mitochondria
- lifespan of 120 days
- bioconcave disk
- vital stats RBC (red blood cell count, how many?), Hb (haemoglobin, how effective?) and MCV (mean corpuscular volume, how large?)
functions
- deliver oxygen to tissues
- carry haemoglobin
- maintain haemoglobin in reduced (ferrous) state so it can bind to oxygen
- maintain osmotic equilibrium (maintains shape)
- generate energy (to keep cell membrane working)
haemoglobin
- tetramer of 2 pairs of globin chains
- each globin chain has its own haem group (includes iron)
- different globin chains will bind to make different forms of haemoglobin (has different properties, eg affinity)
- switch from fetal to adult Hb at 3-6 months of age
- exists as oxyhaemoglobin (relaxed binding structure) and deoxyhaemoglobin (tight binding structure)
red cell membrane structure and features
- bioconcave disk shape to maintain large surface area
- flexible so that it can squeeze through tiny capillaries
- changes in the components of the cell membrane (congenital or aquired) result in changes in RBC shape
- can cause cellls to become less deformable and more fragile
- spleen recognises cells as abnormal and removes them from circulation
- haemolytic anaemia can result
what is spherocytosis
technically not in LOs
come back to this
normal RBC is bioconcave, whereas these are sphere shaped
PROTEINS INVOLVED
- spectrin actin crosslinking and molecular scaffold protein that links the plasma membrane to actin cytoskeleton
- ankyrin links integral membrane proteins to the underlying spectrin-actin cytoskeleton
- band 3 facilitates chloride and bicarbonate exchange across membrane and also involved in physical linkage of membrane to cytoskeleton (binds with ankyrin and protein 4.2)
- protein 4.2 ATP-binding protein which may regulate the association of band 3 with ankyrin
degradation of haem
- when cells get old, senescent, they need to be removed
- senscent RBCs engulfed by macrophages in RES
- haem is released, and Fe2+ recycled
- unconjugated bilirubin released, and transported in blood bound to albumin (excess bilirubin causes jaundice)
- unconjugated bilirubin → bilirubin which is taken up by liver and conjugated with glucaronic acid (GA) → secreted in bile into duodenum
- in the duodenum, the GA is removed by bacteria, and bilirubin converted to urobilinogen which is subsequently oxidised to stercobilin
- some urobilinogen is absorbed into blood and transported to kidney
- urobilinogen is oxidised to urobilin and excreted in urine
note can distinguish between problems with liver/degradation of haem by looking at whether bilirubin is conjugated or unconjugated
this is because unconjugated bilirubin is named this before enters liver. Once it enters liver, called bilirubin
name: increase / reduction in the number of blood cells
reduction = cytopenia or pancytopenia
increase = panmyelosis
name: increase/reduction in the number of white blood cells
increase = leucocytosis
decrease = leucopenia
name: increase/reduction in the number of red blood cells
increase = polycythaemia or erythrocytosis
decrease = anaemia
name: increase/reduction in the number of lymphocytes
increase = lymphocytosis
decrease = lymphocytopenia
name: increase/reduction in the number of monocytes
inc = monocytosis
dec = monocytopenia
name: increase/reduction in the number of neutrophils
inc = neutrophilia
dec = neutropenia
name: increase/reduction in the number of eosinophils
inc = eosinophilia
dec = eosinopenia
name: increase/reduction in the number of basophils
inc = basophilia
dec = basopenia
name: increase/reduction in the number of platelets
inc = thrombocytosis / thrombocythaemia
dec = thrombocytopenia
neutrophils
- derived in bone marrow
- first responder for immune system (phagocytosis)
- essential part of innate immune system
- circulate in bloodstream
- invade tissues
- live for 1-4 days
maturation controlled by G-CSF, a glycoprotein growth factor and cytokine which… - increases production of neutrophils
- speeds up release of mature cells from bone marrow
- enhances chemotaxis
- enhances phagocytosis + killing of pathogens (makes them more effective killers)
to note:
recombinant G-CSF is routinely administered in cases when more neutrophils are needed: eg a patient with sever neutropenia and sepsis after chemotherapy - protects immune system while undergoing chemotherapy
neutrophilia
technically not in LOs
an increase in the absolute number of circulating neutrophils
- mainly reactive to something, rarely due to mutation
- only those cells in circulating pool are actually measured in a blood count
- haemorrhage brings more cells out from marginated pool
causes of neutrophilia
- infection
- tissue damage
- smoking
- drugs/steroids
- myeloproliferative diseases
- acute inflammation
- cancer
- cytokines (G-CSF)
- metabolic disorders
- endocrine disorders
- acute haemorrhage
neutropenia
lack of neutrophils in blood
consequences of neutropenia
- severe life threatening bacterial or fungal infection
- mucosal ulceration (painful mouth ulcers)
- note: neutropenia + fever is an emergency… give strong antibiotics
causes of neutropenia
reduced production + increased removal/use
→ REDUCED PRODUCTION
- B12/folate deficiency (insufficent DNA synthesis)
- aplastic anaemia (empty marrow, no precursors)
- viral infection
- congenital (defective production from birth)
- infiltration (malignancy or fibrosis… no room for blood cell production)
- radiation (mature cells killed + precursors stunned)
- drugs (eg ★) poision marrow and inhibit blood cell production
→ INCREASED REMOVAL OR USE
- immune destruction (autoantibodies destroy neutrophils)
- sepsis (rapid migration into tissues, marrow unable to synthesise neutrophils fast enough to maintain circulatory numbers)
- splenic pooling (sequestration of neutrophils in the spleen means that less are available for general circulation)
★ chemotherapy, antibiotics, anti-epileptics, psychotropic drugs, DMARDS, Rituximab
monocytes
- important immune system first responder
- form of granulocyte
- normally the largest cell in blood
- circulate for 1-3 days before migrating into tissues where they differentiate into macrophages or dendritic cells
- carry out phagocytosis of micro-organism and break down + remove cellular debris
- antigen presenting role to lymphocytes
- important in defence against chronic bacterial infections (eg tuberculosis and chronic fungal infections)
causes of monocytosis
- bacterial infection eg tuberculosis
- inflammatory conditions eg rheumatoid arthritis, chron’s and colitis
- carcinoma
- myeloproliferative disorders + leukaemia
eosinophils
- granulocyte
- guard against parasitic infection
- in circulation for 3-8 hours before migrating into tissues
- lifespan is 8-12 days
- responsible for immune response against multicellular parasites (eg Helminths)
- mediator of allergic responses
- granules contain array of cytotoxic protein (eg elastase and eosinophil cationic protein)
- phagocytosis of antigen-antibody complexes
- inappropriate activation responsible for tissue damage and inflammation eg in asthma
causes of eosinophilia
common
- allergic diseases (eg asthma, eczema, urticaria, hay fever, aspergillosis)
- parasitic infection (eg round worms, tape worms, helminths)
- drug hypersensitivity (eg penicillin)
- churg-strauss (very rare autoimmune condition resulting in inflammation of small blood vessels)
- skin diseases (eg bullous pemphigold)
rare
- hodgkin lymphoma
- acute lymphoblastic leukaemia
- acute myeloid leukaemia
- myeloproliferative conditions
- eosinophilic leukaemia
- idiopathic hypereosinophilic syndrome
basophils
- least common cell in blood
- large cell
- active in allergic reactions and inflammatory conditions + hypersensitivity reactions
- large, dense granules containing histamine, heparin, hyaluronic acid + serotonin
- granules stain deep blue-purple and often so numerus that they mask the nucleus
basophilia
when body produces too many basophils
can be…
reactive
- immediate hypersensitivity reactions
- ulcerative colitis
- rheumatoid arthritis
myeloproliferative
- CML
- systemic mastocytosis
lymphocytes
- most live in spleed
- originate in bone marrow and include…
B-cells for humoral immunity. Anitbody (immunoglobulin) forming cells . Attack invaders outside cells.
T-cells for cellular immunity… includes CD4+ helper cells and CD8+ cells. Attack infected cells.
natural killer cells for cell mediated cytotoxicity
lymphocytosis
- most common in kids
- increase in number of lymphocytes
- can be…
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 (where cells ‘spill’ out of inflitrated bone marrow)
