Peter Browett Flashcards
Define haematopoesis.
The process by which mature blood cells are generated from stem cells in the bone marrow.
What are the haemotopoietic tissues?
The tissues producing cells other than lymphocytes. Bone marroe - mainly sternum ribs andsacrum.
Spleen (5%)
Where are haematopoietic tissues origionate from?
Generated from blood islands of the yolk sacs to produce transient primitive blood cells.
Then definitive cells from the endotheliem in the aorta-gonad-mesonephros region called haemangioblasts that can generate endothelial cells and haemotpoietic cells.
The haemangioblasts then seed at other sites, fetal liver and then the bone marrow.
What happens to the haematopoesis in myelofibrosis?
Extramedullar haematopoiesis. Spleen and liver generating blood cells.
Enlarged liver and spleen.
What cells are in the bone marrow?
Haematopoietic and stromal cells.
Stromal cells include fibroblasts, macrophages, fat cells and endothelial cells. They provide support and a microenvironment suitable for blood cell production.
What is the survival of RBC, platelets and neutrophils?
RBC - 120 days
Platelets - 5-6 days
Neutrophils - 5-6 hours
What happens as haematopoietic stem cells generate mature cells?
As cells mature they loose their capacity to proliferate.
This process is controlled by growth factors produced by the BM microenvironment. For example erythropoietin controls RBC production, thrombopoietin produces platelet productuin and G-CSF stimulates netrophil production.
Where can you isolate stem cells from?
Bone marrow, umbilical cord and peripheral blood.
For peripheral blood you need to give haematopoietic growth factors first.
What are the benefits of the shape of a RBC?
Allows deformity to fit through small capillaries and has a large surface area to volume to improve gas exchange.
Because the RBCs have no DNA or RNA they depend on enzymes that produce ATP and stop haemoglobin being oxidised.
G6PD enzyme deficiency - involved in oxidation stress. Can cause haemolytic anaemia.
What happens during RBC maturation and what cells can be found in the blood in some stress e.g blood loss?
Progressive increase in haemoglobin, chromatin clumping, excludes the nucleus. Loss of RNA.
Reticulocytes - still has RNA - If blood loss you expect to see reticulocytes. If there are none suggests that RBC production is defective e.g. aplastic anaemia
How is RBC production stimulated?
Erythropoierin is produced by the kidney in response to low oxygen tensions.
High altitude -> decreased FiO2 -> reduced O2 saturation -> kidney -> EPO
Narrowing of the artery to the kidey will also increase EPO
It binds to the EPO receptor:
- stimulation of BFU-E and CFU-E
- increases haemoglobin synthesis
- educes RBC maturation time
- Increases reticulocyte release.
EPO receptor - JAK STAT -> MAP kinase -> proliferation. Mutation -> polycythaemia
Who might receive recombinant erythropoietin?
Patients with kidney failure causing anaemia and myelodysplastic syndromes
What happens in RBC destruction?
They become less deformable with age, and are removed from the liver and the spleen.
RBC are broken down with release of Hb
Haemoglobin is broken down into globin chains and haem. Iron from the haem goes to the bone marrow for reuse and protoporphyrin is converted to bilirubin which goes to the liver and enters the bile which goes into the gut.
Extra haemolysis -> jaundice. The bilirubin is uncongugated in this situation because the conjugation system is overloaded.
What is the haematocrit?
The percentage of RBCs to total volume in a centrifuges blood sample. Correlates with haemoglobin.
What are the body’s response to anaemia?
Increased CO - SV and HR, a right shift in the haemoglobin dissociation curve
Fatigue, pale, SOB on exertion
What are the causes of impaired production of RBC?
Deficiency of things essential for production, folate, B12, iron.
Genetic defect, thalassaemia.
Failure of bone marrow, leukaemia, irradiation or drug damage
What are causes of reduced RBC survival?
Blood loss
Haemolysis, shortened survival of the RBCs
What are the most common causes of microcytic hypochromic anaemia?
Iron deficiency and thalassaemia.
Look at blood slide, check iron levels then do thalassaemia screen.
Think about cause of iron loss.
Thalassaemia heterozygotes have mild anaemia and homozygous have sever anaemia.
How do you diagnose iron deficiency?
Measure the serum ferritin. Also measure serum iron and iron binding capacity (transferrin). Iron saturation serum iron/transferrin (0.3).
Iron deficiency - low ferritin, low serum iron, high transferrin.
Anaemia of chronic inflammation- serum iron low but transferrin also slightly low. Ferritin normal. (adapted transferrin).
Iron overload - high ferritin, high serum iron, all transferrin saturated (100% iron saturation).
What are some causes of iron deficiency?
Diet
Malabsorption - jejunim
Increased demands - pegnancy and breast feeding
Chronic blood loss - GU or GI
What is anaemia of chronic inflammation (AKA iron block)?
Inflammation causes the iron to be retained within macrophages as a defense against the pathogen that needs free iron. - normal ferritin but low serum iron and low transferrin. Saturation is normal.
Hepcidin does this by preventing iron absorption and release from macrophages. Hepcidin is induced by inflammatory cytokines.
Symptoms of homozygous thalassaemia?
Anaemia, fatigue, pale, SOB on exertion.
Hepatosplenomegaly and increase in bone marrow space to increase production of RBC.
What are the causes of macrocytic anaemia?
B12 or folate deficiency (causes impaired DNA synthesis; causes hyper-segmented neutriphil), liver disease, increased alcohol intake, primary bone marrow disorders, hypothyridism.
Why might the folate or B12 levels low?
Diet - vegens
Malabsorption - gastrectomy, pernicious anaemia, terminal ileum disease.
Low folate - lack of vegtables, malabsorbtion, increased demands (pregnancy, haemolytic anaemia).
How can you replace the levels of iron, B12 andfolate?
Iron: intravenous or oral
B12: IM injection
Folate: oral
What are the causes of haemolytic anaemia?
Shortened survival, inherited defect (G6PD), autoimmune destruction
What are the symptoms of haemolytic anaemia?
Anaemia, mild jaundice, increased spleen size.
Raised reticulocyte count
What is the growth factor for neutrophil development?
G-CSF and GM-CSF. IL-3
What are the functions of neutrophils?
Chemotaxis
Phagocytosis - C3
Killing of bacteria in lysosomal degredation
What is leukocytosis?
Increased WBC.
Can see increased neutrophils. If neutrophil leucocytosis then there can be some more immature neutrophils in the blood
What are the functions of mnocytes/macrophages?
Chemotaxis Opsinisation receptors C3 and Fc Killing of ingested bacteria Produce inflammatory molecules - Cytokines, complement, prostaglands Antigen presentation
What is monocytosis and what is the cause?
Increase in monocytosis
Reactive - chronic infections e.g TB
Malignant - acute myeloid leukaemia.
What is eosinophilia and the causes?
Increased eosinophils.
Parasitic infections, allergies, hypersensitivity reactions
What do basophils do?
Have IgE binding sites. Involved in type 1 hypersensitivity. Granules contain histamine. Similar to mast cells.
What are the causes of lymphopenia nad lymphocytosis?
Lymphopenia: HIV infection
Congenital immune defect, steroid therapy, bone marrow failure.
Lymphocytosis:
Viral infection, chronic
lymphocytic leukaemia
What are the blood and marrow cancers?
Leukaemias
Myeloproliferative neoplasms - polycythaemia vera
lymphomas
Myeloma - plasma cells
What are the causes of leukaemia?
Chemical/DNA damaging drugs
Radiation
Viral infections
Congenital/inherited risk factors (down syndrome)
What is an acquired cause of leukemia?
An acquired abnormality is seen in all chronic myeloid leukemias and some acute myeloid leukemias: Philadelphia chromosome t(9, 22) - makes a gene that codes for a tyrosine kinase (BCR-ABL) - causes proliferation through phosphorylation. Target with imatinib
What does someone with acute leukemia present with?
Failure of the bone marrow. Fatigue, anemia, dyspnoea, chest pain, SOB on exertion. Infection due to neutropenia.
Low platelet count (thrombocytopenia) - petechial haemorrhage (non-blanching).
Bone pain, enlarged liver and spleen
How do you diagnose leukaemia?
Bone marrow biopsy. Trephine and aspirate. >20% blasts. Immunophenotype to identify myeloid or lymphoid.
Chromosome studies and molecular studies
- for prognosis
How do you treat someone with leukemia?
Give RBCs and platelets
Manage infections
Patient and family support
Chemotherapy - induction to induce remission, consolidation to get residual cells, and then maitenance therapy for ALL
Stem cell transplantation - allogenic or autologous
