Haematology Flashcards
1
Q
name the 3 types of blood cell?
A
RedWhitePlatelets
2
Q
give the term for the production of blood cells?what are all blood cells derived from?
A
-haematopoiesis-pluripotent stem cells
3
Q
Give the sites of haematopoiesis at the following stages:-Embryo-Birth-Birth to maturity-Adult
A
-yolk sac then liver, in 3rd to 7th month- spleen-mostly bone marrow, liver and spleen when needed-no. of active sites in bone marrow decreases but retain ability for haematopiesis-bone marrow of skull, ribs, sternum, pelvis, proximal ends of femur
4
Q
name the cell from which all blood cells derive?why must blood cell turn over be high?
A
-Haematopoietics stem cell-in order to maintain homeostasis
5
Q
what needs to happen to a stem cell to make blood?
A
Proliferation + Differentiation
6
Q
describe the quiescent state of stem cells?
A
basically means they are dormant
7
Q
-Describe the stages of Erythropoiesis in terms of cell names?at what stage does the RBC leave the bone marrow?-what’s the pattern of size change here?-what main features differentiate mature RBCs from immature RBCs?
A
PronormoblastBasophilic/early normoblastPolychromatophilic/intermediate normoblastOrthochromatic/late normoblast——————————leaves BMReticulocyteMature red cell (erythrocyte)-gets smaller with maturation-Have no nucleus RNA degrades after it leaves BM making it smaller and paler
8
Q
give a basic overview of what the following cells do:-RBCs-platelets-White cells
A
-carry O2, other roles e.g. buffer-stop bleeding-fight infectioncancer prevention
9
Q
give the 3 types of granulocytes?
A
Eosinophils BasophilsNeutrophils
10
Q
Neutrophils-Structure& stain? (2)-Functions?(5)
A
-segmented nucleus Neutral staining granules-short life in circulation (transit to tissues)Phagocytose invaderskill with granule content and die in the processAttract other cellsInc by body stress e.g. infection/trauma
11
Q
Eosinophils -structure & stain (2)-Function (2)-elevated in what?
A
-bi-lobedBright orange/red granules-fight parasitic infections -involved in hypersensitivity (allergic reactions)-often elevated in patients with allergies
12
Q
Basophils -structure? (2)-Function ?(5)
A
-infrequent in circulation large deep purple granules obscuring nucleus -Circulating version of tissue mast cell mediates hypersensitivity reactionsFcReceptors bind IgEGranules contain histamine
13
Q
Monocyte -structure & staining? (2)-Function (4)
A
-large single nucleusfaintly staining granules, often vacuolated-circulate for a week then enter tissues to become macrophagesPhagocytose invaders to kill them and then present antigens to lymphocytes attract other cellslive longer than neutrophils
14
Q
Lymphocytes-structure (two forms)? (2)-Function? (3)
A
-mature= small with condensed nucleus and rim of cytoplasmActivated (often called atypical)= large with plentiful blue cytoplasm extending round neighbouring red cells on film, nucleus more open -B, T and NK subtypescognate response to infection B cells-secrete antibodiesT cells- helper and Killer T cells, killer are cytotoxicNK cells- also cytotoxic
15
Q
How do you recognise more primitive precursor cells?
A
Immunophenotyping expression profile of proteins (antigens) on the surface of cellsBio-assays culture in vitro and show lineage of progeny in different growth conditions
16
Q
what are the main areas that should be covered when examining the haemopoietic system
A
look at: peripheral bloodbone marrowspecialised tests of bone marrowalso for splenomegaly, hepatomegaly, lymphadenopathy
17
Q
where is the most common site for bone marrow aspiration & biopsy-name of marrow biopsy?
A
-posterior iliac crests -trephine biopsy
18
Q
See written notes for this cause It makes no sense on cards :))
A
look at the notes, don’t you dare miss them out
19
Q
definition of Haemopoiesis?
A
formation of blood cells
20
Q
Give the 3 main types of blood cells and their subgroups and functions?
A
Red cellsErythrocytes- transport O2/Co2PlateletsPrimary Haemostasis White cellsGranulocytes-Neutrophils, phagocytosis + acute inflammation-Eosinophils, destroy parasites + modulate hypersensitivity reactions-Basophils, modulate hypersensitivity rections Monocytes –> Macrophages modulate immune reactionsPhagocytic clearance Lymphocytesregulatory functions Lymphocytes-B cells, produce antibodies -T cells, cell mediate immunity + regulatory functions-NK cells, anti viral/tumour
21
Q
describe what kind of nucleus granulocytes have
A
segmented
22
Q
state the lifespan of RBCs, Neutrophils & platelets?-why is this relevant?
A
RBCs- 120 daysneutrophils- 7-8 hrsPlatelets- 7-10 days -if bone marrow suddenly shuts down neutrophils will be the first to drop
23
Q
what are erythroblasts and myeloblasts?what are reticulocytes?
A
name the primitive nucleated precursor for erythroblasts and myeloblasts-immediate red cell precursor, polychromasia if in increased levels
24
Q
What are Megakaryocytes?What are Myelocytes?
A
-platelet precursor, polyploid-nucleated precursor between neutrophils and blasts
25
Name the cell that produces precursor blood cells
haemopoetic progenitor cell
26
Name the cell that produces progenitor cells?
haemopoitic stem cells
27
Give the sites of haemopoiesis at each stage of development:-Where are all haemopoitic stem cells derived from?-wk 5- wk 10-wk 6-week 12-wk 16-adulthood
-mesoderm-yolk sac-liver-spleen (small contribution)-bone marrow-axial skeleton- vertebra/sternum/ribs
28
where are bone marrow biopsies collected in: -children?-adults?
-shaft of the tibia-illiac crest or sternum OR can mobilise stem cells from the marrow into blood for collection and transplantation
29
give the 3 different compartments in the bone marrow?-where is the most haemopoetic activity?-what is the endosteum?
cellular (haemopoietic cells and non haemopoitic cells)Vascular elements connective tissue matrix -trabecular bone, found throughout the metaphysis such that many cells in this region are close to the bone surface -the interface between bone and bone marrow, covered by bone lining cells
30
-what are sinusoids?-what is their function?-describe the vascular relationship of the sinusoids?
specialised venues that form a reticular network of fenestrated vessels-to regulate the passage of cells in and out of the circulation-arteries feed into the sinusoids
31
what do reticular cells do in th bone marrow?
contains smooth muscle and can contract and regulate opening of holes between endothelial cells and the BM
32
-how do mature cells enter the circulation?-how do different cell types travel to the sinusoid?
-can pass through fenestrations in endothelial cells to enter circulation -neutrophils actively migrate towards the sinusoidMegakaryocytes extend long branches called pro platelets into the sinusoidal vesselsRBC release assoc with sinusoidal dilatation and inc blood flow
33
-what is the difference between red bone marrow and yellow bone marrow?-what happens within the bone marrow with age?
Red- haemopoietically active yellow- fatty, inactive marrowthere is a reduction in marrow cellularity with age
34
what is the myeloid:erythroid ratio?-how might it change in haemolysis?
the relationship of neutrophils and precursors to proportion of nucleated red cell precursors (from 1.5:1 to 3.3:1)-see an increase in erythroid activity and the ratio reverses
35
haemopoiesis regulation-how is haemopoiesis regulated?-what regulates neutrophil maturation?-what regulates the growth of megakaryocytic from their precursors-
interplay of random intrinsic properties of cells (stem cells) nd signals from immediate surroundings and the periphery + activation of lineage specific transcription factors -G-CSF-Thrombopoietin
36
why are cells located in different places within the bone marrow?what is are the 2 clinical indications fro this?
the haemopoitic niche exists for the haemopoitic stem cell-Niche can shift in states of marrow stress-drug can be used to mobilise HSC from niche for collection and transplantation
37
How do you asses haemopoiesis?
blood countcell indicesmorphologyless commonly: bone marrow examination
38
how might you asses precursor cells?-how does this work?
expression of antigens indicating lineage or take of development can be studied in /on cells = Immunophenotyping -identify patterns of antigen expression unique to cell lineage and use antibodies specific to different antigens
39
How are donated stem cells collected?-what is the issue with this method?-how is it resolved?
-collected due to specific gravity-the specific gravity and morphology is fairly similar in all WBCs -Use antibodies with fluorescent markers to distinguish between CD3/CD34 then use flow cytometry to determine the volume of stem cells gathered
40
describe briefly the origins of lymphoid cells
haematopoietic stem cellsprecursor lymphoid cells-to thymus for t cell maturationOR- to bone marrow for B cell maturation ---> secondary lymphoid organs
41
give the primary (2) and peripheral (5) components of the lymphoid system?
Centralbone marrowThymusPeripheralLymph nodesSpleen TonsilsEpithelia lymphoid tissueBone marrow
42
what are the main functions of the lymphatic system?
to return lymph to the circulation to maintain fluid homeostasis and prevent excess accumulation of fluid in the tissue To filter lymph before it returns to the circulation and has interactions with immune component cells
43
give 3 examples of conditions that occur when lymph fails to drain
LymphoedemaChylous Ascitiespulmonary oedema
44
lymph nodes-located where?-normal size?-function?-how does lymph move within the system?-where is lymph filtered in the node?
-along the course of lymphatic vessels -up to 2.5cm-blind ending vascular channels that collect fluid from tissues and return to blood stream-passive movement of fluid with valves ensuring unidirectional flow -within the node parenchyma , here interactions can occur between cells in the node and cells in the lymph
45
Describe the role of the lymphoid system in immunity?
houses cells go the innate immune system Traffic of APCs links innate and adaptive immune responses seat of the adaptive immune response (specificity, inducible, memory, Enhanced secondary reaction)
46
Name the different cell populations in a lymph node (7 types)-name where 2 of these cells are located within the node?
Lymphocytes:B cells- assoc with follicles & germinal centres, inter follicular, plasma cells in medullaT cells- T helper cells, T cytotoxic cellsNK cellsMacrophagesantigen presenting cellsDendritic cells+ endothelial cells
47
Enlarged lymph nodes -Why might lymph nodes be enlarged?-lymphadenopathy, give the 3 main causes and give examples for each)
-due to reactive processneoplastic disorders (mets or primary)-Local inflammation infectionvaccination/trauma/dermatopathicSystemic inflammationinfectionautoimmune/CT disordersMalignancy Haematological (lymphoma/leukaemia)Mets+sarcoidosis/castlemans disease
48
What is lymphangitis?
inflammation of the walls of lymphatic vessels, often seen with superficial lesion infection
49
Ddx in generalised lymphadenopathy?-investigations
suggests systemic inflammatory process or widespread malignancy e.g. lymphoma/leukaemia -Take FBC before doing biopsy- might be evident from blood what the Dx is
50
what might the following cell response indicate in a lymph node:-B cell predominant?-Phagocytic?-T cell predominant?
-auto immune or infection -draining a tumour site-Viral infections/drugs
51
what kind of organ is the spleen?-describe the weight and size of a normal spleen -name the two key aspects of the spleen-describe the vascular supply -what happens when a spleen ruptures?
-a secondary lymphoid organ-150-200g and is impalpable unless substantially enlarged -Diaphragmatic surfaceVisceral surface -Highly Vascular supplied by splenic artery and drained by splenic vein (forms portal vein with SMV)-considered a surgical emergency, a diseased spleen is more likely to rupture
52
-describe the structure of the spleen (types of pulp and their function)-what is the overall function of the spleen?
-encapsulated organ, parenchyma includes red pulp and white pulpred pulp sinusoids and cordssinusoids- fenestrated, lined by endothelial cells, supported by hoops of reticulin cords- contain macrophages and some fibroblasts and cells in transit (RBC, WBC, PC and some CD8+ T cells)white pulpperi-arteriolar lymphoid sheath (PALS) with CD4 cellsAlso lymphoid follicles (can show reactive changes)Antigens reach white pulp via the blood -acts as a filter for the blooddetects, retains and eliminates unwanted foreign or damaged material facilitates immune response to blood bourne antigens carries out haemolysis of old RBCs and might undertake Haematopoiesis in marrow disease
53
see pic on circulation within spleen
look at it pls
54
splenic enlargement-presentation -give the triad of hypersplenism
-dragging sensation in LUQdiscomfort with eatingpain if infarction-Triad of: SplenomegalyFall in one or more cellular components of bloodcorrection of cytopenias by splenectomy
55
Give the 6 causes of splenomegaly and give examples of each
InfectionEBV, Malaria, TB, Typhoid, Brucellosis, Leishmaniasis, Trypanosomiasis Congestionportal (hepatic cirrhosis, portal/splenic vein thrombosis/ Cardiac failure)Haematological diseaseLymphoma/leukemia, haemolytic anaemia, ITP, Myeloproliferative disordersinflammatory conditionsRA, SLEstorage diseasesGaucher's, Neimann-Pick diseaseMiscellaneousAmyloid, Tumours, cysts
56
causes of hyposplenism
most commonly from splenectomy (need life long vaccination)also Coeliac diseaseSickle cell diseaseSarcoidosisIatrogenic- non-surgical
57
What are Howell Jolly Bodies?
They are RBCs with residual DNA that would normally be removed from circulation, they indicate hyposplenism
58
name the 5 stages of normal haemopoiesis
Self renewalProliferationDifferentiation or lineage commitment MaturationApoptosis
59
how do we identify progenitors/stem cells?
immunophenotyping using surface antigens
60
why happens in malignant haemopoisis? (4)
increased proliferationFailure of differentiationLack of maturationlack of apoptosistherefore get increased no.s of dysfunctional cells and may have loss of the normal haemopoietic reserve
61
Describe what bone marrow looks like in acute leukaemia?
overrun by mononuclear, monotonous cells, proliferating aggressively but not maturing
62
what causes haematological malignancy? -describe the difference between driver and passenger mutations?
genetic, epigenetic and environmental interactionsomatic mutations in regulatory genes (driver vs passenger)recurrent cytogenic abnormalities e.g. deletions, translocations etc but these are contributory rather than causative Driver mutations confer growth upon the cell, carrying them and have been positively selected during the evolution of the cancer Passanger mutations do nt confer growth advantage but happen to her present in an ancestor of the cancer cell when it acquired a driver mutation
63
what is the difference between normal haemopoiesis and malignant haemopoiesis?
normal- can be polyclonalMalignant- usually monoclonal
64
types of haematological malignancy-name the 3 ways in which they can be categorised?
-speed of presentation: Acute or chronic-Site:Medullary (marrow)/extramedullaryBlood (leukaemia)/lymph-node (lymphoma)Based on lineage:MyeloidLymphoid
65
describe the following malignancies:-Acute Myeloid leukaemia (AML)-Acute lymphoblastic Leukaemia (ALL)-Chronic Myeloid Leukaemia-Chronic Lymphocytic leukaemia-Myeloma
-a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells-overproduction and accumulation of cancerous, immature white blood cells, known as lymphoblasts.-increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood (philadelphia chromosome)-In CLL the abnormal cells develop from the lymphoid blood stem cells. The cancerous white blood cells are B cells, can involve blood, bone marrow and lymph nodesalso get high grade and low grade lymphoma i.e. malignancy in lymph nodes Plasma cell malignancy in marrow
66
Acute leukaemia-give the definition (3)-types?
-rapidly progressive clinical malignancy of the marrow/blood with maturation defects excess of blasts >20% in blood or BMdec/loss of normal haemopoietic reserve -ALL, AML
67
Acute lymphoblastic leukaemia -disease of what cell?-common in what age group?-presentation? (3)
-lymphocytes-childhood-marrow failure = anaemia, infections, bleeding leukaemia effects, high WCC and involvement of extra-medullary areas e.g. CNSlymph nodes might cause evens obstruction Bone pain (endostium expands)
68
Acute Myeloid Leukemia-common in what age group?-cause?-Presentation?-subtypes characteristically present with what?
-elderly-de novo mutation or secondary to chronic blood disorder-similar to ALL-DIC- disseminated intravascular coagulationGum infiltration
69
Investigation in acute Leukemia-what is seen on investigation?-in what disease are Auer Rods seen?-definitive Dx via what? Treatment of acute leukaemia -ALL?-AML?-SE of treatment (probs of marrow suppression (3) + general SE)-what form of treatment in potentially curative in some patients?
-blood count and filmCoagulation screen Bone marrow aspirate (Morphology, immunophenotyping, Cytogenetics, Trephine)-Blood film:reduction in normal + presence of abnormalabnormal blasts cells with high nuclear:cytoplasmic ratioBone marrow:morphology- mononuclear immunophenotyping used to check if lymphoid or myeloid -acute myeloid leukaemia -immunophenotyping-Multi agent chemocan last 2-3 yrs different phases of treatment of varying intensity (induction, consolidation, intensification maintenance)targeted treatments at certain subsets -Multi agent chemointensive2-4 cycles of chemoprolonged hospitalisation Hickman lines used in both cases-AnaemiaNeutropenia (severe, drawn out infection)Thrombocytopenia (purpura & petechiae)general:Nausea and vomitingHair lossLiver/renal dysfunctiontumour lysis syndromeinfection late effects (loss of fertility, cardiomyopathy)-Allogenic stem cell transplantation
70
What kind of infections should be considered in a neutropenic patient?-management of neutropenic fever?
-gram neg organisms, if prolonged and unresponsive to antibiotics then think fungalalso consider protozoal -empirical treatment with broad spec antibiotics covering gram negs
71
what subgroup of leukaemia is associated with a coagulopathy?
acute promyelocytic leukaemiatreated with vitamin and Arsenic
72
Lymphoma-presentation?-investigations?
-a lump i.e. lymphadenopathy night sweatsweight loss+ itch without rashalcohol induced pain fatigue -lymph node biopsy- whole node, not diagnosed on CT
73
Lymphadenopathy-what should be on the Ddx?-when are nodes regionally and generally enlarged?-see chart on slide 13 of lecture
-reactiveBacterial infectionViral infectionmetsLymphoma -regional- bacterial inf/ mets/lymphomaGeneral- viral
74
Lymph node biopsy -enables what?-Describe the following investigations used to look at biopsied nodes:HistologyImmunohistochemistryImmunophenotypingCytogenetic analysis Molecular analysis
-exclude other causes e.g. reactiveclassification of lymphoma to guide treatment -Histology Immunohistochemistry (confirms lymphoma and helps subclassify, looks at pattern of proteins on surface of lymphoma cells and uses antibodies against thesestain brown if +)Immunophenotyping (uses cells in liquid phase Cells tagged with antibodies attached to fluorochrome-emits a specific colour of light when laser shone on it so can determine pattern of CD numbers)Cytogenetic analysis (there are specific patterns of chromosome abnormality in certain lymphomas Aspirate node, grow cells in culture and look at spread of chromosomes)Molecular analysislooks at patterns of genes switched on and off, can further identify lymphoma and subtypes suitable for specific treatment
75
Describe the classification of lymphoma
Lymphoma can be:-Hodgkin's-T cell NHL-B cell NHL (high grade OR low grade)
76
What is:- Hodgkins Lymphoma -Burkitt’s Lymphoma-Mantle cell Lymphoma-Marginal Zone lymphoma
-Lymphoma within which a Reed-Sternberg cell is detected -NHL, starts in B cells-NHL, also starts in B cells-NHL,occurs outside lymph nodes between red and white pulp
77
definition of pancytopenia?-what is seen in bloods clinically?
deficiency of blood cells of ALL lineages (but generally exclude lymphocytes)Anaemia + Neutropenia +thrombocytopenia
78
What happens in a steady state in terms of haematopoiesis
cell loss balanced by cell production
79
name the two main reasons pancytopenia occurs?
Reduced productionIncreased destruction
80
Give the cause of reduced production of haematocytes & the 2 subtypes
Bone marrow failure inherited syndromesAcquired (primary/secondary)
81
give the triad found in inherited Marrow failure Syndromes?
Impaired haemopoiesisCancer pre-dispositionCongenital anomalies
82
Give the hallmarks of Fanconi's anaemia (9)-underlying defect?-clinical presentation? (bloods, age)
short statureskin pigment abnormalitiesRadial ray abnormalitiesHypogenitiliaEndocrinopathiesGI defectsCardiovascularRenalHaematological-unable to correct inter-strand cross-links-Macrocytosis then thrombocytopenia then neutropenia age 7 presentationBM failure 84% risk by 20 yrs
83
give the 3 main causes of Primary Acquired BM failure?
Aplastic anaemiaMyelodysplastic syndromes (MDS)Acute leukaemia
84
Aplastic anaemia-what is it?-describe the pathogenesis?-what is seen in the Bone marrow?
-Autoimmune attack against haemopoietic stem cell-Auto-reactive T cells, attack Cells at the LT-HSC, MPP and CMP levels, this causes the release of IFN-y and TNF-a. This means that there are reduced levels of erythrocytes, platelets and granulocytes -complete aplasia with all the haemopoitic cells replaced by fat
85
Myelodysplastic syndrome -definition?-Give the 3 features of MDS?-what is there a risk of this developing into?
-Are a group of cancers in which immature blood cells in the bone marrow do not mature and become healthy blood cells.-DysplasiaHypercellular marrowIncreased apoptosis of progenitor and mature cells (ineffective haemopoiesis) -AML- acute myeloid leukaemia
86
Why can acute myeloid leukaemia cause pancytopenia?
get proliferation of abnormal cells from leukaemic stem cells There is a failure to differentiate or mature into normal cellsPrevent normal haemopoietic stem/progenitor development by hijacking i.e. altering the haemopoietic niche and marrow microenvironment
87
Give the 4 causes of secondary BM failure
Drug induced e.g. chemo, chloramphenicol, alcohol B12/folate deficiency (nuclear maturation can affect all lineages)Infiltrative- non-haemopoieotic malignant infiltration, lymphoma viral/storage disease Remember HIV
88
give the 3 main causes for the increased destruction of Blood cells
Hypersplenism sepsisImmune
89
What is hypersplenism?-give the 3 main causes and examples?
increased destruction of blood cells that exceeds bona marrow capacity, usually assoc with splenomegalyincreased splenic pool i.e. more cells stay in the spleen-Splenic congestion Portal hypertension congestive cardiac failure systems diseaseRAHaematological diseaseSplenic lymphoma
90
Give the clinical features associated with Pancytopenia (5)
Anaemia causes:FatigueSOBCV compromise Neutropenia:Infections (more likely gram neg/ fungal)Thrombocytopenia:bleeding (purport and petechiae)
91
investigations in Pancytopenia?
Hx inc fam hxFBC, blood filmB12/ folate, LFTs, virology autoantibodiesBM examinationspecialised tests will be guided by above (cytogenetics)
92
describe the marrow cellularity in:-aplastic anaemia-MDS, B12/folate def, hypersplenism
-hypocellular-hypercellular
93
Treatment of pancytopenia -supportive?-specific (Primary BM disorder, secondary BM disorder, hypersplenism)
-SupportiveRed cell transfusions Platelet transfusions Antibiotic treatment and prophylactic use-Primary bone marrow disorderMalignancy- consider chemoCongenital- consider BM transplantidiopathic aplastic anaemia- immunosuppression -Secondary BM disorderdrug reaction- STOPViral- treat e.g. HiVReplace B12/folate-HypersplenismTreat cause if possible consider splenectomy
94
Treatment of neutropenic fever?
If patient has a temperature >37.5 or clinical evidence of significant sepsis and neutrophil count <0.5 x 10^9/L then initiate antibiotic therapy within 1 hour. 1. Standard risk patient - Neutropenia - Sepsis - SEWS <6 Commence piperacillin/tazobactam (penicillin allergy: teicoplanin + aztreonam)No routine gentamicin 2. High risk patient - Neutropenia - Severe sepsis/septic shock - SEWS >=6 or acute leukemia or allogenic transplant Commence piperacillin/tazobactam + gentamicin (penicillin allergy: teicoplanin + aztreonam + gentamicin) Monitor all patients hourly. Reassess antibiotic therapy after 48-72 hours.
95
what is the function of B cells:-derived from?-belong to what part of immune system?-roles?
-Derived from pluripotent haematopoietic stem cellsPart -adaptive immune system -antibody production and act as antigen presenting cells
96
What are immunoglobulins?-composed of what?-name the different immunoglobulins and describe their structure
-antibodies produced by B cells and T cells -proteins made up of 2 heavy and 2 light chains -Monomer IgD, IgE, IgGDimer, IgAPentamer, IgM
97
B cell development -where does initial development occur?-what influences the variable nature of the Ig variable element?-What antigens are expressed on B cell surface?-what do plasma cells do?
-in the BM-it is generated from V-D-J region recombination in early development -CD19+ and CD20+-they secrete antibody
98
Describe the path of B cells after they leave the BM?
travel to the follicle germinal centre of the lymph node identify the antigen and improve fit by somatic mutation or be deleted returns to marrow either as plasma cell OR memory cell in circulation
99
Plasma cell-function?-appearance on H&E
-secretes antibody-eccentric clock face nucleusopen chromatin due to synthesising mRNAplentiful blue cytoplasm pale perinuclear area
100
definition of : -Polyclonal antibodies-Monoclonal antibodies-what triggers a polyclonal increase in Ig? commonly what virus?-What triggers a monoclonal rise in Ig?-what is the name for a monoclonal Ig?-how are Ig's detected -How are paraproteins detected?-how are abnormal proteins classified?
-secreted by different B cell lineages within the body -come from clonal expansion of a single B cell lineage -reactive response to infection, autoimmune, malignancy, liver disease, commonly HIV-Marker of an underlying B cell disorder, not normally present-paraprotein -via serum electrophoresisseparated serum proteins appear as distinct bands Ig's are located in the gamma region -there will be a distinct band in the gamma region -via serum immunofixation
101
What are Bence-Jones proteins?-Why are they present?-how are they detected?-present in what disorder?
They are free immunoglobulin light chains -if there is polyclonal or monoclonal increase in the no. of plasma cells then the amount of free light chains in the plasma increases -detected via urine electrophoresis -Any clonal B cell disorder, most commonly MGUS
102
Myeloma-what is it?-what effects does it have on the body? (2 main driving factors)-how is myeloma classified?-characterisitc on Xray?
-malignancy of plasma cells-direct tumour effects bone lesions-lytic bone disease hypercalcaemia bone painreplace normal BM leading to BM failure & pancytopeniaParaprotein mediated effects renal failure immunosuppressionhyperviscoscityamyloid -according to type of antibody produced, IgG most common-Lytic bone disease giving pepper pot skull
103
Why does lytic bone disease occur in myeloma?
plasma cells take over the BM and shift the balance in bone turnover They release increased IL 6 which encourages proliferation of Myeloma cells but also down regulation of osteoblasts and up regulation of osteoclasts causing increased bone destructionthis also explains why Ca 2+ levels increase
104
Give the symptoms of hypercalcaemia? (7)
stonesbonesabdominal groanspsychiatric moansthirstdehydrationrenal impairment
105
Myeloma and the kidney-name the different mechanisms by which myeloma can cause kidney damage? (6)
-tubular cell damage by light chains, light chain deposition leads to cast nephropathy-sepsis can cause damage -hypercalcemia + dehydration-drugs e.g. NSAIDS-amyloid-hyperuricaemia
106
Explain how cast nephropathy occurs?-how is it managed?
-free light chains can be filtered through the glomerular pores and have a half life in the serum of 2-6 hrs.The proximal tubule reabsorbs the light chains. if the proximal tubule is overwhelmed the light chains pass into the loop of Henle.Here an insoluble Tamm-Horsfall protein is produced and this can combine with free light chains to produce insoluble casts.-may be reversible with prompt treatment, use steroids or chemo to switch off light chain production
107
Myeloma treatment -describe the treatment regime used?-how is response measured?-how are symptoms controlled? (pain, spinal cord compression, hypercalcaemia, bone pain, fractured bone)
-corticosteroids; dexamethasone or prednisolone alkylating agents (chemo) e.g. cyclophosphamide, melphalan, Novel agents e.g. thalidomideHigh dose chemo/autologous stem cell transplant in fit patients -opiate analgesia (avoid NSAIDs)local radiotherapy, compressionBisphosphonatesVertebroplasty
108
What is the definition of MGUS?
Monoclonal Gammopathy of uncertain significance-Paraprotein <30 g/lBM plasma cells <10%+ no evidence of myeloma end organ damage i.e. Normal Ca, Normal renal function, Normal Hb, No lytic lesions, no inc in infection
109
Describe the process of AL amyloidosis?-clinical effect of increased levels of amyloid on kidney, heart, liver, NS, GI?-how is AL amyloidosis Dx & staged? (6)-what is seen on biopsy under polarise light?
mutation in the light chains leads to altered structure so they precipitate in tissues as an insoluable beta pleated sheet Accumulation in the tissues causes organ damageits a slowly progressive multi system disease -nephrotic syndromecardiomyopathyorganomegaly and deranged LFTsautonomic & peripheral neuropathy Malabsorption-organ biopsyuse congo red stain rectal/fat biopsy if highly suspicious + SAP scan, echocardiogram and heavy proteinuria -apple green birefringence
110
What is Waldenstrom's Macroglobulinaemia?-what paraprotein is produced?-effects of tumour? (3)-effects of paraproteins? (2)-Clinical features (2)-treatment? (2)
lymphoplasmacytoid neoplasm clonal disorder of the cells between lymphocytes and plasma cells-characteristic IgM paraprotein production (pentameric)-lymphadenopathysplenomegaly Marrow failure-hypervsicosityNeuropathy -hyperviscosity syndrome (fatigue, visual disturbance, confusion, coma, bleeding, cardiac failure)night sweats, weight loss-Chemoplasmapheresis (remove plasma rich in IgM and replace with donor plasma)
111
what is the definition of remission in malignancy?
In complete remission, all signs and symptoms of cancer have disappeared, although cancer still may be in the body.
112
give the two classifications of cytotoxic drugs
Cell cycle specificnon-cell cycle specific
113
what are the general characteristics of cell cycle specific agents?-give the 2 categories?
tumour specificthe duration of exposure is more important than the dose-antimetabolites (impair nucleotide synthesis/incorporation)mitotic spindle inhibitors
114
Give the names and action of 3 antimetabolite drugs?
Methotrexateinhibits dihydrofolate reductase6-Mercaptopurine/cytosine arabinoside/Fludarabineincorporated into DNAHydroxyureaimpaired deoxynucleotide synthesis
115
Name 2 mitotic spindle inhibitors?
Vinca alkaloids e.g. VincristineTaxotere
116
give the general characteristics of non-cell cycle specific agents?
non-tumour specific, damage normal stem cellsCumulative dose more important than duration
117
Give the names and mode of action of 3 non-cell cycle specific agents?
Alkylating agents e.g. chlorambucil/melphalanthese bind covalently to bases of DNA and causes breaks in DNA strand due to free radical production Platinum derivativesCis-platinum/carboplatin cytotoxic antibioticsanthracyclines: daunorubicin/doxorubicin/idarubicinthey cause reversible DNA intercalation impairs RNA transcription and DNA stand breaks
118
What are the SE of cytotoxic drugs?Immediate effects-In general? (3)-vinca alkaloids?-Anthracyclines?-Cis-platinum ?Long term-alkylating agents? -Anthracyclines?
-BM suppression (infection)gut mucosal damageHair loss-neuropathy-cardiotoxicity-nephrotoxicity -infertility, secondary malignancy -cardiomyopathy
119
what 3 criteria must be met by the drugs used in combination chemo? (3)
non-cross resistant drug combinations non-overlapping toxicity spectraadditive/synergistic mechanisms of action
120
Why does chemotherapy fail? (4)
slow tumour doubling timestumour sanctuaries (CNS and testes)drug resistance P53 mutation- P53 is the guardian of the genome mediates apoptosis so if it is not functioning properly then the DNA damage caused by chemo drugs does not cause cell destruction
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Give 4 ways in which tumour cells can develop drug resistance?
decreases drug accumulation via MDR-1/PGPaltered drug metabolism Increased DNA repairAltered gene expression
122
what limits the intensification of chemotherapy?-how is this overcome? (3)
myelosuppression -use haematopoitic growth factors combine myelosuppressive/non-myelosppressive agents intensify doses of active drugs + stem cell rescue (i.e. store BM when patient in remission after killing malignancy cells with highly ablative chemo)
123
give the different sources of stem cells for transplantation
blood vs bone marrowAutologous (patient's own cells) vs Allogenic (donor)
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-indication for use of autologous stem cells?-indication for use of allogenic stem cells?
-induce blood count recovery after myeloablative doses of chemo-after myeloablative chemo looking for a graft vs malignancy effect
125
what does the philadelphia chromosome cause?
chronic Myeloid leukaemia
126
definition of Myeloproliferative disorder?
the name for a group of conditions that cause platelets, granulocytes, and red blood cells, to grow or multiply by rapidly producing new tissue, parts, cells or offspring they are clonal haemopoietic stem cell disorder with inc production of one or new types of haemopoitic cells
127
difference between MPD and AL?
maturation is preserved in MPD
128
subtypes of MPD-what gene is not found in other MPD but found in CML?-give the 3 subtypes of MPD which do not have the gene present in CML?
-BCR-ABL1 positive -Idiopathic myelofibrosis(fibrosis and scarring in BM)Polycthaemia Rubra Vera (overproduction of RBCs)Essential Thrombocythaemia (overproduction of platelets)CML
129
When should MPD be considered clinically? (6)
High granulocyte count +/-High RBC/Hb count +/-High platelet count +/-Eosinophilia/basophiliaSplenomegalyThrombosis in an unusual place ONLY IF NO REACTIVE EXPLANATION
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Chronic Myeloid Leukaemia -what is it?-describe the disease progression? (2)-clinical features?-changes seen on FBC?-treatment-what chromosome is seen, how does it occur? what gene is formed? what is the product of this gene and how can it be managed?
-proliferation of Myeloid cells(granulocytes and precursors and other lineages (platelets) -Chronic phase- with intact maturation for 3-5 years Blast crisis- reminiscent of acute leukaemia with maturation defect -AsymptomaticSplenomegaly Hyper metabolic symptomsGouthyperleukocytosis problems, Priapism (erect penis does not return to normal state)-Hb Normal/decLeucocytosis neutrophilia myeloid precursors (myelocytes) Eosinophilia Basophilia Thrombocytosis -fatal without a BM tranplant in chronic phase -Philadelphia chromosome reciprocal translocation from chromosome 9 to 22forms the BCR-ABL1 genegene product is tyrosine Kinase causing abnormal phosphorylation and changes seen in CMLuse tyrosine kinase inhibitors e.g. Imatinib to manage
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give the 5 features common to MPD?
Asymptomatic increased cellular turnover (gout, fatigue, weight loss, sweats)Symptoms/signs due to splenomegaly Marrow failure (fibrosis or leukaemia transformation: lower with PRV and ET)Thrombosis (TIA, MI, abdo vessel thrombosis, claudication, erythromelalgia)
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Polycythaemia rubra vera (PRV)-What is it?-what must it be distinguished from? (2)-clinical features? (3)-investigations? (4)-what mutation is commonly found in PRV-treatment? (3)
-high Hb/haematocrit accompanied by erythrocytosis i.e. true increased RBC masscan have excess production of other lineages -Secondary Polycythaemia(chronic hypoxia, smoking, EPO tumour)Pseudopolycythaemia(dehydration, diuretic therapy, obesity)-features of MPDHeadache, fatigueItch- aquagenic pruritus-HxExamination- splenomegaly FBC, FilmJAK2 mutation status rarely EPO levels and BM-JAK2, a kinase causes loss of auto-inhibition and activation of erythropoiesis in the absence of ligand -Vensect to haematocrit <0.45 (be aware of splenomegaly risk)Aspirin cytotoxic oral chemo e.g. hydroxycarbamide
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Essential thrombocythaemia (ET)-What is it?-clinical features?-diagnosis-what must be excluded?-investigations? (3)-treatment? (2)
-uncontrolled production of abnormal platelets-MPD features (esp vasoocclusive complications)abnormal platelet function characterised by thrombosis and bleeding due to acquired Von Willebrand disease -exclude reactive thromobocytosis (due to blood loss, inflammation, malignancy & iron deficiency), CML-JAK2 mutation and MPL mutation characteristic BM appearance- megakaryocyte hyperplasia -Anti platelet agents (Aspirin)Cytoreductive therapy to control proliferation (hydroxycarbamide, anagrelide, interferon alpha)
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Myelofibrosis-name the 2 types-name the 5 cardinal features of MF?-describe the clinical features (3)-investigations & Dx? (4)-treatment? (4)
-Idiopathic Post-polycythaemia or essential thrombocythaemia -Marrow failureBM fibrosis extra medullary haematopoiesis (liver & spleen)Leukoerythroblastic film appearance Teardrop shaped RBCs in peripheral blood -marrow failure (anaemia, bleeding, infection)Splenomegaly (LUG abdo pain, early satiety, portal hypertension)hypercatabolism -blood film- typical leucoerythroblastic appearance and tear shaped RBCs BM- dry aspirate needed due to fibrosis, fibrosis on trephine biopsy Genetic screen- JAK2 or CALR mutation in a proportion FBC- high platelet count + anaemia -supportive care (blood transfusion, platelets, antibiotics)Allogenic stem cell transplantation (if under 50 & fit)Splenectomy ??JAK2 inhibitors e.g. ruxolitinib(improve spleen size)
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causes of a leucoerythroblastic blood film? (3)
reactive in sepsisMarrow infiltration Myelofibrosis
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Give the reactive causes of raised counts of the following cells:-Granulocytes-Platelets-Red cells
-infection e.g. pyogenic bacteria causing nuetrophilia physiological e.g. post op/ steroids-infectionFe defMalignancyBlood loss-Dehydration (diuretics): pseudopolycythaemiaSecondary polycythaemia e.g. hypoxia induced
137
give the definition of Haemostasis?
the arrest of bleeding and the maintenance of vascular patency
138
name the 4 requirements of haemostasis?
permanent state of readinessPrompt responseLocalised responseProtection against unwanted thrombosis
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Name the steps and components of a normal Haemostatic system? (4)
Primary Haemostasis:Formation of platelet plugSecondary haemostasis:formation of fibrin clot FibrinolysisAnticoagulant defences
140
how are platelets formed?
in the BM by budding off from megakaryocytes
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describe the structure of platelets?-describe the function of platelets?-Name one protein released by endothelial damage?
-small nucleated discs with a mean life span of 7-10 days -platelets have receptors that detect protein produced as a result of endothelial damage and this causes platelet adhesion at the site of injuryThere is then secretion of various chemicals from the platelets leading to platelet aggregation -Von Willebrand Factor
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what is primary haemostasis?describe how this process occurs?
-the formation of a platelet plug -3 different stages stage 1- vasoconstriction smooth muscle in endothelium constricts stage 2- platelet adhesion blood vessel injury causes VWF to be released by the endothelial cells.The VWF binds to sub endothelial collagen and also to plateletsthe platelet is activated and changes shape, degranulation occurs releasing VWF and fibrin al well as serotonin, ADP and Ca.serotonin- constricts smADP- activates platelets and promotes aggregation Ca- needed for secondary haemostasis Stage 3-Platelet aggregation this is mediated by 2B/3A receptor on surface of platelets and cause the formation of a PLATELET PLUG
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give reasons for failure of the platelet plug? (4)
Vascular reduced no. platelets e.g. thrombocytopenia platelets unable to function Von Willebrand factor absent or inactive
144
what are the consequences of a failure of primary haemostasis? (4)
spontaneous bruising and purpuramucosal bleeding (epistaxis, GI, Conjunctival, Menorrhagia)inter cranial haemorrhage Retinal haemorrhage
145
screening test for primary haemostasis? (1)
Platelet countno simple tests for other components
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What is secondary haemostasis? -describe the process?
Fibrin clot formationplatelets are made up of phospholipids which are negatively charged Degranulation of the platelet causes the release of Calcium onto the + charged platelet surface clotting factors are - charged and so are attracted to the platelets.Tissue factor is released from the damaged endothelial cell and activates clotting factor VIIThis in turn activates factors V and X to produce Thrombin from prothrombin which produces Fibrin generated from fibrinogen Thrombin produces XII and IX which activates more V/X to initiate a rapid feedback loop and causes a prompt response at site of injury
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why might secondary haemostasis fail?
single clotting factor deficiency (usually hereditary e.g. haemophilia)multiple clotting factor deficiencies (usually acquired, e.g. DIC/liver failure)Increased fibrinolysis (usually part of a coagulopathy)
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Give the 3 types of haemophilia?-give an example of a clinal sign?
-Haemophilia A- missing factor VIIIHaemophilia B- missing factor IXHaemophilia C- missing factor XI-Haemarthrosis into major weight bearing joints
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-What is fibrinolysis?-What enzyme meditates the process?-What are the products?
the process whereby fibrin is degraded by plasmin.-Plasmin, activated from plasminogen by Tissue plasminogen activator-FDPs, the cross linked form of which is D-dimers
150
What are the consequences of secondary haemostasis failure?
no characteristic clinical syndrome may be combined primary/secondary haemostatic failure pattern of bleeding will depend on abnormalities and clotting factors involved
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Name the screening tests for fibrin clot formation?-if both of these are prolonged what does it indicate?-which factors do warfarin and Heparin effect?
prothrombin time (PT)tests clotting factor VIIactivated partial thromboplastin time (APTT)tests clotting factors VIII & IXa -global problems with haemostasis and multiple clotting factors or and intrinsic problem with clotting factors V/X-Warfarin: affects VIIHeparin: affects VII/IX
152
Important questions to ask in bleeding disorder hx?
any bleeding bruising?duration- life long?prev surgery/ dental extractions?Drug HxFamily Hx+ exam
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Name the naturally occurring anticoagulants?-what is the risk in deficiency of these?
-Serine protease inhibitors i.e. Thrombin binds to thrombomodulin to switch off thrombin and factors V & VIII and achieve haemostasis Protein C and protein Sthese inhibit factors V/X/VIII/IX-venous thrombosis
154
What is thrombophilia?
-deficiency of naturally occurring anticoagulants, may be hereditary-increased risk of PE/DVT
155
what is the definition of shock?
Acute tissue hypoperfusion due to circulatory failure
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briefly describe the basic physiology of shock -what 4 mechanisms effect the mean arterial pressure?
Mean arterial pressure drops (50-60 mmHg)slow blood flow to organs (possible thrombus)Inadequate perfusion of cellular metabolic requirements --> acidosis and lactate formation -HR & SV = COCO & systemic vascular resistance = Mean arterial pressure
157
Give 3 consequences of inadequate perfusion?
systemic acidosis(worsens enzyme function and cellular performance) Microcapillary thrombus with patchy tissue injury and even large vessel thrombus with organ infarction eventual cellular necrosis results in mortality
158
What are the signs of shock? (3)
MottlingGlasgow coma score <15- confusion/agitation Reduced urine output <0.5ml/kg/h
159
Hoe do you confirm Shock?
Lactate levels>2mmol/l of lactate highly suggestive of shock
160
Cardiogenic shock -physiological cause?-clinical sign?-treatment?
-Reduced force of cardiac contraction soReduced SV soReduced CO soReduced Mean arterial pressure-Cool clammy peripheries due to increased SVR-depends on cause Arrythmia- cardioversionPoisoning- DialysisMI-PCIcardiomyopathy- drugsValve failure- surgery
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Obstructive shock-cause?-clinical signs?-treatment?
-Obstruction to cardiac outflow e.g. cardiac tamponade, tension pneumothorax, PE -evidence of raised JVP and Distended Neck veins due to venous back pressure -again depends on cause cardiac tamponade- pericardiocentesis/thoractomyTension pneumothorax- thoracocentesis/thoractomy PE- anticoagulation/thrombolysis
162
Hypovolaemic shock-describe the physiology-clinical sign? (2)-what obs should be tested in suspected haemorrhage?-treatment?
-reduced blood volLower venous return to heart reduced force of cardiac contraction and CO-tachycardia cool, clammy peripheries -RRHRBPMental stateUrine output-haemorrhage(temporising measures, Find and stop bleeding, cross-match blood and blood product)Dehydration(fluids & electrolytes, specialist unit care steroids/insulin)
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Distributive shock -describe the physiology -clinical sign?-causes?-memorise the rapid assessment table on slide 36
-Reduced systemic vascular resistance due to vasodilation reduced mean arterial pressure compensatory increase in CO-Warm, red peripheries bounding, hyper dynamic circulation -most commonly sepsis
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What result from a fluid challenge suggests poor systolic function?
no increase in SV after volume challenge
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name the components of a normal Haemostasis?
-formation of platelet plug (primary)Formation of fibrin clot (secondary)Fibrinolysis+anticoagulant defences
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Why might a platelet plug fail to form?
vascular problemPlatelet problem VWF deficiency
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Give a cause for vascular abnormality-hereditary?-Acquired?-paeds?
- Marfans can mean less collagen in the vessel wall-Age- loss of collagenscurvy in alcoholics-Henoch-Schonlein Purpura
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Thrombocytopenia -definition?-causes? which causes more bleeding?
-reduced platelets-increased destruction reduced production (BM problem) BM problem = more bleeding
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Give the causes of peripheral platelet destruction? (3)
Coagulopathy (disseminated intravascular coagulation)Autoimmune (immune thrombocytopenic purpura (ITP))Hypersplenism larger spleen means more platelets poolmay be due to alcoholic liver disease, portal hypertension and back pressure
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Why might platelets have functional defects? (2)
Drug inducede.g. Aspirin, NSAIDsRenal failureuraemia interferes with platelet function
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vWF deficiency -acquired cause?-inheritance?-catagories?
-antibody to vWF produced in hypothyroidism, V rare -autosomal dominant-varied severity, tends to be women
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causes of failure of the fibrin clot?
Multiple clotting factor deficiencies (acquired e.g. DIC)Single clotting factor deficiency (hereditary, e.g. haemophilia)
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cause of multiple clotting factor deficiencies? (3)-findings in coagulation screen?
liver failure (hepatocytes synthesise clotting factors)Vit K deficiency/Warfarin therapy Complex coagulopathy e.g. DIC-prolonged PTprolonged APTT
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what clotting factors are carboxylated by Vit K?-give 2 sources of Vit K?-where is it absorbed & why?-give causes of Vit K def?
-II, VII, IX, X-Diet (broccoli) & intestinal synthesis -upper intestine as needs bile salts for absorption-poor dietary intakemalabsorptionobstructive jaundiceVit K antagonists Haemorrhage disease of the newborn
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Disseminated intravascular coagulation (DIC)-definition -give the 2 underlying physiological mechanisms and the clinical signs that result?-causes?-treatment?
-excessive and inappropriate activation of the haemostatic system -microvascular thrombus formation (end organ failure)Clotting factor consumption (bruising, purpura, generalised bleeding) -sepsisobstetric emergencymalignancyhyovolaemic shock -treat underlying cause + replacement therapy: transfuse platelets and plasma and fibrinogen replacement
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Haemophilia-what is it?-name the 3 types and the underlying mechanisms?-features (bleeding from which vessels)?-clinical features if severe (3)-Investigations? (4)-treatment?
-An x-linked hereditary disorder in which abnormally prolonged bleeding recurs episodically at one or a few sites on each occasion -Haemophilia A(factor VIII deficiency)Haemophilia B(factor IX deficiency)Haemophilia C(factor XI deficiency)-platelet levels normal, primary haemostasis functions normallyget bleeding from large & medium blood vessels -recurrent HaemarthrosisRecurrent soft tissue bleedsprolonged bleeding after dental extractions, surgery & invasive procedureseventual destructive arthropathy due to recurrent bleeding -PT- normalATPP- markedly prolonged plts- normal-IV injection of factor 8/9 every 2nd or third day
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Describe the characteristics of venous thrombosis?
low pressure system platelets not activated activated coagulation cascade so clots rich in fibrin
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How do you treat venous thrombosis? (3)
heparinWarfarinnew oral anticoagulants these interfere with secondary haemostasis
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clinical signs of:- DVT?-PE?
-limb feels hot, swollen, tenderpitting oedema -Pulmonary infarction causing pleuritic chest painCV collapse and deathhypoxia R heart strain
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What are the risk factors for venous thromboembolism?-what is hypercoagulability associated with?
changes in: stasis, vessel wall, hypercoaguability AgeMarked obesityPregnancypuerperiumOestrogen therapyPrevious DVT/PETrauma/surgerymalignancy ParalysisInfectionThrombophilia-release of tissue factor, raised vWF and factor VIII
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Thrombophilia -what is it?-give the potential mechanisms by which this occurs?
-familial or acquired disorders of the haemostatic mechanism which are likely to predispose to thrombosis -inc coagulation activity: platelet plug formation and fibrin clot formation Dec fibrinolytic activity Dec anticoagulant activity (most common) e.g. deficiency in antithrombin protein C & protein S
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Hereditary thrombophilias-what are they?-name 5-when should screening be considered?-management
-group of genetic defects in which affected individuals have an inc tendency codevelop premature, unusual and recurrent thromboses-Factoe V LeidenProthrombin 20210 mutationantithrombin deficiency protein C deficiency Protein S deficiency *dont increase risk of venous thrombosis*-VT <45 recurrent VTunusual VTFam hx of venous thrombosisFam hx of thrombophilia -advice on avoiding riskshort term prophylaxis short term anticoagulation long term anticoagulation if recurrent events
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How do you asses the need for long term anticoagulation?-first episode?-second?-how do you asses risk of recurrent thrombosis?
Risk of recurrent thrombosis balanced with Risk of serious haemorrhage-anticoagulate for 6 months -lifelong anticoagulation-Hx prev thrombosisspontaneous= greater risk than acquiredfamily hxThrombophilia screen
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Acquired thrombophilia: antiphospholipid antibody syndrome -features?-describe the pathogenesis?-name the antibodies involved and their effect on the APTT?-associated with which conditions?-treatment?
-recurrent thromboses at young ageArterial & venousrecurrent foetal lossMild thrombocytopenia -antibodies lead to conformational change in Bets 2 glycoprotein 1 which leads to activation of both primary and secondary haemostasis and vessel wall abnormalities -autoantibodies with specificity for anionic phospholipids and which prolong phospholipid dependant coagulation tests in vitro- lupus anticoagulants -Autoimmune, Lymphoproliferative disorders, Viral infections, drugs, primary -Give treatment depending on thrombotic eventsAspirin- arterialwarfarin- venous
185
Give indications for anticoagulant drugs?
Venous thrombosisAtrial fibrillation Arterial thrombosisTIA
186
What do anticoagulants target in venous thrombosis?-which drug is given in AF? why?
-secondary haemostasis-Warfarin, stasis within L atrium predisposes to a fibrin clot, high risk of this breaking off into circulation and so need warfarin to prevent
187
Heparin-mode of action?-speed of effect?-route of administration?-forms?-monitering?-SE?-reversal?-why is it effective for use prior to surgery?
-Potentiates antithrombin, antithrombin works more effectively and this inactivates thrombin and factor 10 -immediate-parenteral (IV/SC)-unfractionated (more of n effect on thrombin)LMWH (more of an effect on Factor X, predictable and fewer SE)-unfractionated- APTTLMWH- not needed normally, Anti-Xa assay -Bleeding mainlyheparin induced thrombocytopenia (with thrombosis)HITT- check plts after 5-10 daysOsteoporosis long term (affects osteoclasts)-Stop heparin (short half life)if severe- protamine sulphate (complete reversal of unfractionated and partial reversal of LMWH) -short half life
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Coumarin anticoagulants-name 4 drugs in this category-what is their mechanism of action
Warfarin, Phenindione, acenocoumarin, phenprocoumon-Inhibition of Vit K
189
Vitamin K-type of vitamin?-where is it absorbed & how?-what is it's function?-Where is Vit K synthesised?
-fat soluble-upper intestine, needs bile salts for absorption -final carboxylation of glutamic acid residues in clotting factors II, VII, IX, X, protein S and C are also Vit K dependent-the liver
190
Warfarin -mechanism of action?-indications?-monitering?-maintenance?-SE & factors affecting severity?-reversal (depending on severity)?
-blocks the ability of Vit K to carboxylate Vit K dependent clotting factors in the liver so reducing coagulant activity -for slow initiation, e.g. AF in community-narrow therapeutic window, so need to have blood tests eery 6 wks after they have stabilised checked using the INR- should be 2-3 when on Warfarin -Take at the same time every day -haemorrhage, Mild (skin bruising, epistaxis, haematuria)Severe(GI, Intracerebral, Significant drop in Hb)factors that affect the risk of this are:intensity of anticoagulationConcomitant use of other medications Drug interactionsQuality of management -Omit dose (2-3 days)Administer oral Vit K 1-2mg (6 hrs)Administer clotting factors (FFP or Factor conc- immediate)
191
What is the INR?-describe the equation used to calculate INR
INR= international normalised ratio It is a mathematical “correction” (of the PT ratio) for differences in the sensitivity of thromboplastin reagents and allows for comparison of results between labs and standardises reporting of the prothrombin time-(Patients PT in seconds / Mean normal PT in seconds) x ISIISI- international sensitivity index
192
Give the 2 types of new anticoagulants?-advantages?-disadvantages?-indications?
Thrombin inhibitors e.g. dabigatran (oral)Xa inhibitors e.g. Rivaroxaban, Apixaban -oral no monitoring requiredLess drug interactions-Currently no specific antidote for reversal?kidney injury-prophylaxi prior to surgery stroke and AF [revention in some patients DVT/PE
193
Give the 2 cardinal features of arterial thrombosis?-general management?
atherosclerosis+ platelet rich thrombus -aspirin & other anti-platelet drugs +modify risk factors
194
What is atherosclerosis?
the formation of a cholesterol rich plaque on vessel walls, causing damage to the endothelium
195
describe a stable atherosclerotic plaque?-examples of pathology?
Hyalinised and calcified -e.g. in stable angina and intermittent claudication
196
Describe and unstable atherosclerotic plaque?-examples of pathology?
plaques rupture, platelets are recruited and cause acute thrombosis -Sudden onset of symptoms e.g. unstable angina /MIStroke
197
Describe how an arterial thrombosis occurs?
Plaque rupture is more likely in the high pressure environment of the arteries -The endothelium is exposed and vWF is released meaning platelets adhere-Platelets become activated and release granules that activate coagulation and recruit other platelets to develop platelet plug -platelet aggregation occurs via membrane glycoproteins
198
Risk factors for arterial thrombosis? (4)-give the 5 areas of preventing arterial thrombosis?
Hypertension (causes damage to the endothelium and platelet activation)Smoking(damage endothelium, platelets)High cholesterol (plaque accumulation)DM(endothelium, platelets, cholesterol) *ALL DAMAGE ENDOTHELIUM*-Stop smokingTreat hypertensionTreat diabetesLower cholesterolAnti-platelet drugs
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Platelets -where are platelets formed?-describe their structure?-how does platelet adhesion occur?-how does platelets aggregation occur?-what is platelet activation?-what process do antiplatelet drugs target?
Formed in the bone marrow by budding from megakaryocytes-small nucleated discs -endothelial damage exposes collagen and VWF and other proteins to which platelets have receptors- get platelet adhesion at the site of injury via binding with glycoprotein 1B and VWF-secretion of chemicals from the platelets (ADP, thromboxane 2) leads to aggregation, platelets attach to each other via glycoprotein 2B3A and fibrinogen -when platelets alter their shape to expose more phospholipid on the surface, providing greater SA for coagulation, activation and fibrin production to stabilise the clotfurther augmented by granules containing Thrombin, thromboxane A2 and ADP receptors to ADP on platelet surface -platelet aggregation
200
Aspirin-mode of action?-SE? (2)
inhibits cyclo-oxygenase necessary to produce thromboxane A2 -Bleedingblocks production of prostaglandins GI ulceration Bronchospasm
201
Clopidogrel, Prasugrel-mode of action?
ADP receptor antagonist so prevents platelet aggregation
202
Dipyridamole-mode of action?-adv?-disadv?
phosphodiesterase inhibitor- reduces production of cAMP which is a 'second messenger' in platelets activation-no prostaglandin inhibition-higher risk of bleeding
203
Abciximab -mode of action?
-GP 2B/3A inhibitors i.e. inhibit aggregation given IV
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bleeding on anti platelets-period of action?-reversal?
-need to stop anti platelet 7-10 days prior to surgery -serious bleeding- reverse with platelet transfusion
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Comparing arterial and venous thrombosis:-underlying cause?-type of clot?-preventative drugs?
-Arterialinflammatory disorder instigated by damage to endothelium Venouslow pressure system, mainly due to stasis-Arterial platelets central and recruited to ruptured plaquesVenous Platelets not largely involved and clots are fibrin rich -Arterial antiplatelet drugs Venous anticoagulant drugs
206
Why do lymphoma, CLL and acute ;leukaemia respond well to chemo and radiotherapy?
-lymphocytes are keen to undergo apoptosis in the normal lymph node-Lymphoma and CLL cells can be triggered to undergo apoptosis readily with chemo or RT-acute leukaemia is dividing quickly- more cells affected by chemotherapy
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SE of chemo and radiotherapy -why do these occur?-immediate effet?-long term effect?
-normal cells have DNA damage and undergo apoptosis -hair loss, nausea & vomiting, neutropenic infection Tiredness+++-heart damage, lung damage, other cancers
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Supportive therapy in chemostate the measures taken:-to prevent infection-to reduce fatigue
- prompt treatment of neutropenic infection/fever broad spec antibiotics Growth factors Prophylactic antibiotics & antifungals (ciprofloxacin)-Red cell and platelet transfusion
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Describe the course of action in a patient presenting with neutropenic fever?-antibiotic therapy in standard and high risk patients?
Asses patient within 15 mins Provide antibiotics within 1 hour full infection screen -standard risk patient (neutropenia + sepsis +SEWS < 6)Start Piperacillin/Tazobactam within 1 hr High risk patient (neutropenia + severe sepsis/septic shock or SEWS > 6)start piperacillin/tazobactam + gentamicin
210
what is given to prevent fungal infections?
itraconazole or posaconazole
211
What is behind the idea of risk adapted therapy?
can increase the doses in those who need to for cure and reduce or miss out chemo and radio in those who don't need it to avoid long term SEs
212
name the 3 different kinds of targeted therapy?
monoclonal antibodies biological agents Molecularly targeted treatments
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Monoclonal antibodies-how do they work?
-affect only cells which posses target protein however current;y used in combination with chemo rather than instead of but more effective than chemo alone
214
Rituximab-what is it?-describe the structure?-indicated in what?
-mouse/human chimeric MoAb-murine variable regions which bind specifically to CD20 on B cellshuman Kappa constant regions human IgG Fc domain works in synergy with human effector mechanismsnaked antibody so can attach on chemo drugs etc.-B cell non hodgekins lymphoma CLLmantle cell NHL
215
Anti-B cell antibodies -advantages over rituximab?
More direct kill of malignant B cells, use if patient not responding to rituximab
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Brentuximab Vedotin -used in what condition?-how does it work?
-Hodgkin's disease-CD30 protein present on hodgkin's cells and some T cell NHLchemo drug is conjugated on providing target chemotherapy
217
Biological treatments -general action?-exapmples?-indications?
not chemo so don't affect cells as they divide however there are a variety of modes of action Se as not targeted -proteosome inhibitors and IMIDs-Multiple myeloma and lymphoma
218
Proteosome inhibitors -purpose of proteosome?-mode of action?-indications?-SE?
-dustbin for old proteins inside cells breaks them done into amino acids-blocking allows accumulation of toxic proteins in cell causing apoptosis -mantle cell NHLlow grade NHL-nerve damage and thrombocytopenia
219
IMIDs -derived from what?-example?-mechanism of action?-indications?-SE?
-Derivative of thalidomide, -Revlamid -blocks IL 6, disimpairment of angiogenesis so myeloma cells starved of blood -low grade NHL and CLL Myeloma-risk to foetus effects blood count- fatigue other cancers neuropathy
220
Molecular/targeted treatment -must fit 3 criteria?-examples? (3)
-Target pathway specific to the cancer cellavoid SEmore effective than them -tyrosine kinase inhibitors in Chronic myeloid leukaemiaIbrutinib- CLL/NHLNivolumab helps prevent tumour evasion
221
Tyrosine Kinase inhibitors -what causes CML?-give an example?-SE?
-a chromosomal translocation to produce the philidelphia chromosome- BCR-ABL gene, activity of this gene stimulates rapid proliferation via tyrosine kinase action -Imatinib-diarrhoea, plural effusion, neutropenia
222
Drugs affecting B cell signalling pathways -premise of action?-give examples?-indications?-SE's?
-CLL and lymphoma cells have abnormally active signalling mechanisms inside cells blockage of these signalling proteins can cause apoptosis if P53 is abnormal -Ibrutinib and Idelalisib -low grade NHL and B cell CLLnot responding to retuximab and chemo -Ibrutinib(fever, low platelets, anaemia, SOB)Idelalisib (Diarrhoea, rash, fatigue, liver abnormality, fever)
223
Checkpoint inhibitors -example of these drugs and mode of action?-explain how immune evasion occurs?-SEs?
- Nivolumab used in malignant melanoma sticks to PD-1 receptor chemicals and stops it binding to effector cells- immune system stays switched on and attacks cancer cell -the cancer cells produce chemicals that bind to receptors on surface of cells of the immune system called PD-1when the receptor cell is stimulated the immune system cell is switched off and ignores the tumour -long list, rash, dec platelet count, fatigue
224
Immune therapy -describe what this is?-detrimental effects?management?
-allogenic BM transplant from a matched donorT cells from the donor cause immune attack on cancer Graft Vs Leukaemia/Lymphoma effect- immune attack of normal cells in Graft VS host disease can give steroids but risk of malignancy returning
225
Adaptive immunotherapy -what is this?-an example of this?
when you make the patients own immune cells recognise the cancer as foreign and attack it -Chimeric Antigen Receptor (CAR) T cells These are the patients own T cells removed by leukophoresis that have been genetically modified to target a specific type of cancer give Chemo first to prevent rejection
226
what is the definition of anaemia?
reduced total red cell mass use Hb as a substitute to measure this male Hb <130g/lFemale Hb <120g/l
227
where does red cell production occur?
in BM
228
How is Hb measured?
Lyse Red cells to create a Hb solution stabilise the Hb molecules and then measure the optical density, the optical density is proportional to the concentrationHb concentration then calculated against standard solution
229
What is the haematocrit?
Ratio of the whole blood that is red cells if sample left to settle
230
When might Hb and haematocrit levels be a poor marker for anaemia?
if there is a rapid bleed and loss of blood volume and then plasma re-expansion i.e. haemodilaution
231
how does the body respond to anaemia?
increased production of reticulocytes
232
what are reticulocytes?-size?-content? -appearance on stain?
red cells that have just left the BM-larger than average RBC-still have RNA-stain purple and on blood film appear polychromatic
233
name the RBC components of a full blood count?-other investigations (2)
Hb concNo. of cellsMean cell volume i.e. sizeHaematocrit Mean cell haemoglobin (MCH)Mean cell haemoglobin Conc (MCC)-blood film reticulocyte count
234
Classification of anaemia -name the 2 ways in which we classify anaemia?
By pathophysiology by morphological characteristics
235
Pathophysiological classification of anaemia -state the 2 reasons for this kind of anaemia and the change to relic count seen?-give 2 reasons why these might occur
-decreased production (low relic count)increases loss or destruction of red cells(high relic count)-Dec productionHypo proliferative (reduced erythropoiesis)maturation abnormality (erythropoiesis present but ineffective due to cytoplasmic or nuclear defects)In destruction/lossbleedingHaemolysis
236
In abnormal maturation of RBCs, state what change to MCV is seen:-nuclear defects-cytoplasmic defects
-high, big cells i.e. macrocytic -low, small cells i.e. microcytic
237
Microcytic anaemia-where is Hb synthesised?-what components of Hb are needed for its synthesis?-shortage of these components means what?
-Hb synthesised in the cytoplasm -Hb needs Globins, haem, porphyrn ring and Iron -shortage of these results in small RBCs with a low Hb content = microcytic & hypochromic
238
Causes of hypochromic microcytic anaemias-Haem deficiency, give causes (3)-Globin deficiency, give cause (1)
-lack of Iron for erythropoiesis (iron def, anaemia of chronic disease)Problems with porforin synthesis (lead poisoning/ peroxiding responsive anaemias) Congenital sideroblastic anaemia -Thalassaemia (trait, intermedia, major)
239
Iron -can exist in what 2 states?-required for what in the body? (2)-generates what toxic components?
-Fe2+ or Fe3+ -O2 transport (for Hb, myoglobin)Electron transport (mitochondrial production of ATP)-free radicals so needs to be handled safely by body
240
Adult haemoglobin -describe the structure?-how many O2 molecules can 1 haem group bind?
-4 global subunits with single haem molecule haem group contains single Fe2+ ion each haem group can bind one O2 molecule
241
Iron metabolism-describe the system for Iron use in the body?-how much is excreted daily and where is Iron stored?-circulating iron binds to what?-how does iron get incorporated into RBCs -another storage method for iron?
-closed system -only absorb and excrete small amounts tiny amount in circulation most in storage in BM-circulation iron bound to transferrin -it is transferred to bone marrow macrophages that feed it to red cell precursors -ferritin, stored in the liver
242
whats used to asses iron status?-functional iron?-Transported Iron?-Storage Iron?
-Haemoglobin-serum irontransferrin transferrin saturation -Serum ferritin
243
Transferrin -what is it?-function?-reduced in?-increased in?
-protein with 2 binding sites for iron atoms-transports iron from donor tissues to tissue expressing transferrin receptor (erythroid marrow) -Iron defanaemia of chronic disease -genetic haemachromatosis
244
Ferritin -what is it?-function?-measures what?-reduced in?
-Large intercellular protein-spherical and stores up to 4000 ferric ions, tiny amounts present in serum - reflects intracellular ferritin synthesis in response to iron status of the host so indirect measure of storage iron -iron def
245
Causes of iron deficiency give the 3 main reasons
-dietary deficiency relative (to needs) and absolute (veggie)blood losse.g. GImalabsorption coeliac disease achlorhydria
246
Chronic blood loss-causes? (3)
-Menorrhagia (can lose 30-40ml/month which is 15-20mg/month)GI (tumours, ulcers, NSAIDs)Haematuria
247
what are the sequential consequences of negative iron balance physiologically?
1. Iron stores exhausted2. iron deficient erythropoiesis3. Microcytic anaemia 4. epithelial changes (skin, koilonychia)
248
Iron deficiency is NOT A DIAGNOSIS, SEARCH FOR UNDERLYING PROBLEM!!
FIND THE BLEED OR THE CANCER OR WHATEVER!!
249
Definition of macrocytosis?
Red cells present in large numbers in a size that's bigger than normal volume >100fl (femtolitres)
250
How is RBC size measured?
MCV
251
Size of a normal RBC?-appearance of normal RBC on blood film?
-80-100fl
252
Causes of macrocytosis-Genuine (2)-spurious (1)
-Megaloblastic Non-megaloblastic -high reticulocyte count resulting in false readings Cold agglutinins (measured as 1 giant cell)
253
what is a megaloblastic cell?
an abnormally large nucleated red cell precursor with an immature nucleus
254
describe briefly the changes an developing red cell undergoes to become a reticulocyte?
Erythroblasts are marrow based they accumulate Hb and reduce in size they then stop dividing and lose their nucleus
255
What characterises megaloblastic anaemias (3 defects, 2 preserved)?-describe the consequences of this to the cell?
defects in DNA synthesis and nuclear maturation preservation of RNA and Hb synthesis -cytoplasm develops and becomes mature and big enough to divide (i.e. enough Hb) but the nucleus is still immature and lags behind = bigger than normal red cell precursor
256
name the causes of megaloblastic anaemia?
B12 defFolate defOther: drugs & rare inherited abnormalities
257
Why does B12 and folate deficiency cause megaloblastic anaemia?
they are essential co factors for nuclear maturation they enable chemical reactions that provide enough nucleosides for DNA synthesisi.e. nucleus cannot mature
258
Describe the biochemical interactions between B12 and folate -what cycles are they involved in?-what are the products of these cycles?
involved in the methoinian cycle and folate cycle -methonian cycleproduces s-adenosyl methionine, a methyl donor to DNA, RNA, proteins, lipids, folate intermediates Folate cycle important for nucleoside synthesis (thymine)
259
Describe the absorption of vitamin B12?-what happens to B12 after it has been absorbed?-give reasons for Vit B12 deficiency? (5)
Dietary B12 is liberated from food and binds with haptocorrin B 12 then combines with intrinsic factor (secreted by gastric parietal cells) in the duodenum the IF-B12 complex then attaches to Cubulin receptors and is absorbed in the distal bowel passive absorption occurs through buccal, gastric and duodenal mucosae-absorbed B12 attaches to transcobalamin (TC) II which carries B12 in plasma to the liver, bone marrow, brain and other tissues. Most B12 in plasma is, however, attached to second B12 binding protein TC I and is functional inactive -insufficient intake- veganism stomach probs(PA, Atrophic gastritis, PPIs, Gastrectomy/bypass)Pancreatic probs(chronic pancreatitis)small bowel probs(Jejunum: bacterial overgrowth, coeliac diseaseDuodenum: resection, Crohn's disease)Inherited deficiency of cubulin receptors
260
How is folate absorbed:-what is it converted to?-where absorbed?-look over table on slide 29-causes of folate deficiency (4)
-dietary folate converted to monoglutamate -in jejunum -Inadequate intake (less stores than B12)Malabsorption (coeliac disease, Crohn's) Excess utilisation (Haemolysis, exfoliating dermatitis, pregnancy, malignancy)Drugs
261
Clinical features of B12/folate deficiency?-Common to both? (5)-B12 only? (1)
-signs of anaemia weight loss, diarrhoea, infertility Sore tongue- glossitis Jaundice Developmental probs -Neurological probsPost/dorsal column abnormalities neuropathydementia psychiatric manifestations
262
Pernicious anaemia -what is it?-associated with what?-describe the pathogenesis-presentation?
-autoimmune condition with resulting destruction of gastric parietal cells these cells normally produce intrinsic factor so get B12 def -autoimmune atrophic gastritis and personal/fam hx of autoimmune disorders-autoimmune attack directed by dendritic cells in the stomach that normally clear apoptotic parietal cells as part of normal turnover dendritic cells include paragastric lymph nodes, they activate CD4 cells that recognise H+/k+ ATPase expressed in gastric parietal cells -symptoms and signs of anaemia and B12 deficiency - neuropathy etc.Might be jaundiced due to intramedullary haemolysis (due to ineffective haemolysis)
263
How are megaloblastic anaemias diagnosed:-red cells in lab?-Blood film?-what else should be checked?
-Macrocytic anaemia & low red cells possible pancytopenia -macroovalocytes and hypersegmented neutrophils (3-5 segments normally)-Assay B12 and folate in serum Check autoantibodies for anti gastric parietal cells and anti-intrinsic factor
264
Treatment of megaloblastic anaemias?
basically treat cause where possible Pernicious anaemia: lifelong injections of B12folic acid tablets (5mg per day)
265
Causes of non megaloblastic macrocytosis? (4)
Alcohol liver diseaseHypothyroidism Marrow failure (Myelodysplasia, myeloma, Aplastic anaemia)
266
name the 3 labels on a unit of red cells?
Donation No. and barcode 14 character no. finishes with a letter component labeltells dr what is in the bag ABO labeltall and thin down the RHSgives blood group of donor and expiry date
267
How does the anticoagulant used on donor blood work?-what does this mean in terms of donation?
Citrate based, Citrate chelates Ca, needed at various point for coagulation -the anticoagulant needs to be present in the correct ratios and so 465ml should be taken
268
What tests must be done on blood from donors to ensure it is safe for recipients in terms of:-infective risk-Risk of disease transmission -what specific tests are done?
-bacterial, viral, protozoal-malignancy, neurological conditions of uncertain aetiology -HIV 1+2 antibody/PCRHCV antibody/PCRHBV antibody/PCRSyphilis antibodyHTLV I+II antibodyHEV antibody
269
How are the following components stored:-Red cells-Platelets -Fresh Frozen plasma
-stored at 4+/- 2 deg shelf life 35 days cannot be removed from storage for longer than 30 mins must be transfused within 4 hours of leaving controlled storage -stored at 22 deg with continua agitation shelf life of 7 days transfuse within i hr once removed -stored at -30 deg for up to 3 years thawed prior to transfusion, transfuse within 4 hours
270
give the main blood groups (2)-name the antigens involved and the possible blood groups
-ABORh (D)-A antigen, B antigen Group A- membranes have antigen AGroup B- membranes have antigen BGroup AB- membranes have both A and B antigens Group O- membranes do not carry A or B antigens
271
ABO inheritance of blood groups -chromosome involved?-dominance?
-chromosome 9 -A and B are co dominant over O so genotype AO= phenotype A
272
Rh(D) inheritance -chromosome involved?-give the 2 alleles involved in this grouping, the possible genotypes and phenotypes
-chromosome 1 -D and dDD- Rh(D) posDd- Rh(D) pos dd- Rh(D) neg D codes for the Rh(D) protein, d does not code for anything
273
Describe the process of obtaining a sample for cross matching?
1. Obtain blood sample from patient (check name and DOB and confirm with wristband, write details on tube beside bed)- accurate ID is critical2. Complete request form: patient ID, location, indication for transfusion time required, number of units required, previous transfusion history, your name (legible) and contact number3. Send sample and form to the transfusion lab (if outwith normal hours, contact the MLSO)4. Prepare patient for transfusion
274
why might a patient have irregular red cell antibodies?
develop after previous exposure to red cells e.g. due to prev transfusion or pregnancy commonest e.g. Anti- D
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What is an indirect Coombs test?
A test that detects the presence of irregular antibody against RBCs in the patient's plasma
276
Describe the role of the doctor in the transfusion process?-role of nurses?
1. Prescribe red cells, no. units and special requirements, rate of transfusion, accompanying medication 2.ensure patient has established IV access3. record the indications for transfusion in the case notes *blood should be completely transfused within 4 hours after leaving the fridge*-They check the bag itself, to make sure there is no damage or leakage, and the contents of the bag, to ensure there are no bubbles (possible bacterial contamination), clots (insufficient anticoagulant or possible bacterial contamination) and that there does not appear to be any red cell haemolysis, also check date -check the name and DOB of the patient against the compatibility label on the bag record a patients pre-transfusion obs observe for the first 5 minutes to ensure no immediate adverse reactions
277
what are the 2 main indications for red cell transfusion?
Anaemia & Acute blood loss Anaemia low Hb +reduced exercise capacity coincidental medical/surgical probs heart or lung disease anaemic symptoms Acute blood lossif more than 50% of blood volume degree of tachycardia vasoconstriction Protection of brain, heart, adrenal cortexpulmonary hyperventilation fluid shift ECF to IV spacerenal conservation of Na+ and H2O
278
Acute blood loss-describe the approach the acute blood loss
1. Arrest Bleeding2. Gain IV access3. samples for cross matching and other tests 4. Restore and maintain blood vol (N saline, albumin gelofusine)5. ABO and Rh(D), Ab screen and cross match 6. aim to maintain normal pulse rate, BP, consciousness, urine output
279
Indications for a platelet transfusion (overall)?
Low platelet count Patient age Symptoms of bleeding direction of change of platelet count Platelet kinetics Underlying infection/feverconcomitant anaemia concomitant drugs recovery from surgery congenital platelet functional defects acquired platelet functional defectslow platelets count itself not enough, need to consider the clinical circumstances
280
Fresh frozen plasma -indications?
-bleeding /surgery in liver disease with impaired coagulation coagulopathy following massive transfusion (evidenced by abnormal lab results)DIC- coagulation factors to try and maintain haemostasis
281
(Acute) immediate haemolytic transfusion reaction -occurs due to what?-immunoglobulin involved?-pathophysiology?-explain the involvement of complement- what effect do these have on the body?-role of membrane attack complex?-presentation?-describe how the coagulation mechanism is triggered?-what activates the Kinin system?-What is the product of the kinin system and it's effects on the body?-NET effects of the complement activation, coagulation cascade and Kinin system? (8)-presentation? (9)-management? (6)
-ABO incompatible transfusion -IgM anti-A -binding of IgM anti-A or anti-B to its corresponding antigen on red cells immediately activates the complement cascade, coagulation and Kinin systems -release of C3a & C5a these are powerful anaphylotoxins:increase vascular permeabilitydilate blood vessels cause release of serotonin and histamine-formation of MAC leads to red cell rupture -thromboplastic material from haemolysed red cells causes indiscriminate activation of the coagulation cascade and DIC-Activated factor XII activates the kinin system -bradykinin arteriolar dilatation Inc vascular permeabilitythis leads to hypertension which in turn leads to release of Catecholamines causing vasoconstriction within kidneys and other organs -systemic hypotension, DIC, renal vasoconstriction, Formation of renal intravascular thrombi, shock, renal failureOFTEN FATAL-may begin after only 1ml transfusedpyrexia/rigorsFaintness/dizzinessTachycardia/tachypnoea/hypotensionpallor/sweatingheadaches/chest or lumbar painlocal pain at infusion site cyanosis sense of foreboding -stop transfusionStart IV fluids to maintain BP and urine output obtain blood samples (FBC< blood film, coagulation screen, biochem, blood future, serum heptaglobin)send remains of unit back to labinform senior staff immediately investigate blood transfusion
282
Delayed haemolytic transfusion reactions-what is it?-features? (4)-test carried out?-what are the lab features?
-haemolysis 5-10 days after transfusion -symptoms and signs similar to, but less acute than IHTRunexplained fall in Hb as transfused red cells destroyedjaundice, renal failure, biochemical features assoc with IHTRsdetection of positive to irregular antibodies in post-transfusion blood samples -direct antiglobulin test will be positive-anaemia, spherocytic cells on blood film elevated bilirubin and LDH positive DAGT and/or appearance of red cell aloo-antibody+/- a degree of renal failure
283
Febrile non-haemolytic transfusion reactions -signs?-due to what?-investigations?-Prevention?
-rapid temp rise of 1-2 degrees with chills and rigors -antibodies to contaminating white cells release of cytokines or vasoactive substances during storage hard to differentiate these symptoms from very early acute HTR-HLA antibodies may be detectable No evidence of red cell incompatibility -anti-pyreticsleucodepleted blood components
284
Urticarial reactions-due to what?-sign?-action?
-Mast cells and IgE response to infused plasma cells -rash/weals within few minuted of starting transfusion -slow transfusion and consider antihistamines
285
Circulatory overload -signs?-management?
-pulmonary oedema -reduce transfusion rate + diuretics
286
Bacterial infection -signs? (4)-organisms from RBCs (2) and platelets (4)
-fever, chills, vomiting, hypotension -RBCs: Pseudomonas, Yersinia Platelets: Staph, Strep, Serrate, salmonella
287
Describe the structure of Hb?
Tetramer, made up of 2 alpha globin like chains and 2 beta globin like chains ONE hame group attached to EACH globin chain
288
Name the major forms haemoglobin and their structure?-which form is present in adults greatest quantities?
-HbA (2 alpha chains and 2 beta chains)HbA2 (2 alpha chains and 2 delta chains)HbF (foetal) (2 alpha chains and 2 gamma chains)-HbA
289
What chromosomes are involved in alpha and beta globulin chain production?
Alpha like genes on chromosome 162 alpha genes per chromosome (4 per cell)Beta like genes are on chromosome 111 beta gene per chromsome (2 per cell)
290
What are haemoglobinopathies?-inheritance?-what are the 2 main groups?
hereditary conditions affecting globin chain synthesis -usually autosomal recessive -Thalassaemias and structural Hb variants
291
-What are structural Hb variants?
-normal production of structurally abnormal globin chain = variants Hb e.g. HbS
292
Thalassaemias -definition?-what type of anaemia does this cause?-what happens to the resulting RBCs?-where are thalassaemias most prevalent
-hereditary disorders of globin chain synthesis resulting in impaired Hb production -inadequate Hb production = Microcytic, hypochromic anaemia -there is ineffective erythropoiesis and so haemolysis occurs -malaria endemic areas
293
Alpha thalassaemia -mutation affects what?-underlying mutation?-Hb affected?-classification? (3)
-alpha globin chain synthesis i.e. giving reduced/absent alpha chain synthesis -deletion of 1 or both alpha genes from chromosome 16 -HbA, HbA2, HbF all affected -Alpha thalassaemia trait(one or two genes missing)HbH disease (only one alpha been leftHb Barts Hydrops fetalis(no functional genes)
294
Alpha thalassaemia trait -presentation?-lab results?-mistaken for what?
-asymptomatic, no treatment needed -Microcytic, hypo chromic red cells with MILD anaemia -iron def
295
HbH disease-how many genes per cell?-lab results?-what is HbH?-what can be seen on blood film?-clinical features & why? (5)
-one-anaemia + very low MCV and MCH-excess Beta chains form tetramers called HbH which cannot carry oxygen -HbH bodies -Anaemia Splenomegaly (extra medullary haematopoiesis) Jaundice (haemolysis and ineffective erythropoiesis) commonest in S.E. Asian/middle east/ Med patients
296
Hb Bart's hydrops fetalis syndrome -no. genes in cell?-consequence?-clinical features? (6)
-none-minimal or no alpha chain production i.e. HbA not madeHb Barts and HbH are then the majority of Hb at birth -severe anaemia cardiac failure, oedemagrowth retardation severe hepatosplenomegaly skeletal and CV abnormalities Most die in utero
297
Beta thalassaemia-what is it?-what Hb is affected?-caused by what form of mutation? -classification & features? (3)
-disorder of beta chain synthesis -only HbA-point mutations -B thalassaemia trait(asymptomatic, low MCV/MCH)Beta thalassaeia intermedia (moderate severity requiring occasional transfusion)Beta thalassaemia major (no Beta chains produced, severe)
298
Beta thalassaemia major-what is seen on lab tests?-blood film?-type of Hb mostly present?-clinical features? (6)-management?-main complication of ^?-other complications? (4)
-severe anaemia reticulocytosis, very low MCV/MCH-microcytosis, hypochromia, anisopoikilocytosis and target cells -HbF-present ages 6-24 moths failure to thrive pallorhaepatosplenomegalyskeletal changesorgan damage -regular transfusion programme to maintain Hua t 95-105g/lthis will suppress ineffective erythropoiesis and inhibit over absorption of ironBM transplant before complications develop-Iron overload -viral infection- HIV, Hep B and Calloantibodies- hard to cross matchtransfusion reactions increased risk of bacterial sepsis
299
What are the consequences of iron overload?-endocrine (3)?-cardiac (2)?-liver (2)?-management?
-impaired growth and pubertal development -cardiomyopathyarrhythmias -cirrhosis hepatocellular cancer -can't of venesection as already anaemic use Iron chelating drugs e.g. Desferrioxamine (these for an Fe/chelator complex and excess iron excreted in stool)
300
Diagnosis of thalassameia -exclude?-what is seen on blood film generally?-investigation?
-iron def-hypochromia, target cells, anisopoikilocytosis-high performance liquid chromatography this quantifies presence of HbA, HbA2 and HbFidentifies abnormal Hb
301
Describe the pathophysiology of sickling disorders:-type of mutation and location?-consequences of mutation?
-point mutation in codon 6 of the Beta globin gene that substitutes Glutamine to valine -alters structure of Hb to form HbS HbS polymerises if exposed to low O2 levels ad this distorts the red cell damaging the membrane
302
Sickle trait -how many abnormal genes?-presentation?-blood film?-main Hb present?
-one abnormal gene-asymptomatic carrier (may sickle in extreme hypoxia)-normal-Mainly HbA, HbS < 50%
303
Sickle cell anaemia (HbSS)-no. of abnormal genes?-main Hb present?-presentation? (3)-precipitants of a crisis? (6)-treatment of painful crisis?-long term effects? (3)-long term treatment? (3)
-2 abnormal genes -HbS > 80%, no HbA-Sickle crisis (episodes of tissue infarction due to vascular occlusion can occur anywhere, pain may be severe) Chronic haemolysis (shortened RBC life span Hyposplenism(repeated splenic infarcts)-hypoxia, dehydration, infection, cold, stress/fatigue-opiate analgesiahydrationrestOxygen antibiotics if infection severe= red cell exchange transfusion (venesection + transfusion)-impaired growthrisk of sepsisrisk of organ damage (pulmonary hypertension, renal disease, avascular necrosis, leg ulcers, stroke)-hyposplenism requires prophylactic penicillin, vaccination against pneumococcus, meningococcus, haemophilus folic acid supplementshydroxycarbamide to induce HbF production
304
name another type of sickling disease?
compound heterozygosity for HbS and another Beta chain mutation e.g. HbS/Beta thalHbSC
305
screening for Haemoglobinopathies -how is this done?
Antenatal screening to identify carrier parents now standardfamily origin questionnaire and FBCfurther testing of from high risk area or abnormal RBS indices
306
definition of haemolysis?
Premature red cell destruction i.e. shortened red cell survival
307
Why are red cells susceptible to damage?
need to have biconcave shape to transit in the circulation successfully Have limited metabolic reserve and rely on glucose metabolism for energy Can't generate new proteins once in circulation
308
Compensated haemolysis definition?
increased red cell destruction compensated by increased red cell production i.e. Hb maintained
309
What is haemolytic anaemia?
decompensated haemolysis inc rate of red cell destruction exceeding bone marrow capacity for red cell production i.e Hb falls
310
what are the consequences of haemolysis?-to red cell production?-products?
-erythroid hyperplasia (increased production of red cells by the BM)Excess red cell breakdown products e.g. bilirubin
311
How does the bone marrow respond to haemolysis? (2)
reticulocytosis & erythroid hyperplasia
312
Reticulocytosis -what is it?-Blood film findings?-stain used?
-increase in number of immature (non-nucleated) RBCs-polychromasia (ribosomal RNA)-Supravital stain
313
Erythroid hyperplasia -what is it?
excessive growth of immature RBCs
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give the 2 classifications of heamolysis?-and the definition of each?-give causes for each intra (4) and extra (1)
Extravascular Vs intravascular -Extravasculartaken up by reticuloendothelial system intravascular red cells destroyed within the circulation -intra ABO incompatibilityG6PD deficiencysevere falciparum malaria Rarer still PNH, PCHExtraeverything else :/
315
Extravascular haemolysis -instance?-location & effect?-breakdown products? cause what?
-commoner-hyperplasia in organs at site of destruction e.g. liver and spleen-release of protoporphyrin causes unconjugated bilirubinaemia and jaundice/gall stones/Urobilinogenuria
316
Intravascular haemolysis -pathophysiological events and consequences? i.e. products of breakdown and clinical impact
haemoglobinaemia (free Hb in circulation)Methaemalbuminaemia(Methaemalbumin in blood)Haemoglobinuria: (urine pink, turns black on standing)Haemosiderinuria(brown urine)
317
investigations in heamolysis -to confirm the haemolytic state? (5)-to identify cause? (2)what should be looked for on blood film? (4)
-FBC (+Blood film)reticulocyte count serum unconjugated bilirubin serum haptoglobinsurinary urobilinogen-Hx & examination (genetic vs acquired)specialist inv e.g. Coombs test -spherocytes, red cell fragments, heinz bodies, sickle cells
318
Haemolysis can also be classified according to site of red cell defect, state the 4 site?s (4)
premature destruction of normal red cells (immune/mechanical)abnormal cell membrane abnormal red cell metabolismabnormal Hb
319
Give the two causes Of acquired, immune mediated haemolysis?
Autoimmune haemolysis Alloimmune haemolysis
320
Autoimmune haemolysis -warm (what Ig involved and associated with what (5)?)-cold (what Ig involved and associated with what (3)?)-test used to diagnose?
-IgGidiopathic autoimmune disorders e.g. SLELymphoproliferative disorder (CLL)Drugs e.e. penicillininfection -IgM idiopathicinfections Lymphoproliferative disorders -Direct Coombs' testthis identifies antibody and complete bound to own red cells patients RBCs + anti-human IgG = agglutination then +
321
Alloimmune haemolysis -immune response (seen in what? what Ig involved (2)?)-Passive transfer(seen in what? what Ig involved?)
-haemolytic transfusion reaction immediate- IgM (intravascular)delayed- IgG (extravascular)-antibody passively transferred across in haemolytic disease of the newborn RhD/ABO incompatibility
322
give causes of mechanical Red cell destruction? (5)
Disseminated intravascular coagulation Haemolytic Uraemia syndrome TTPleaking heart valve infection
323
What is seen on blood film in severe burns?
microspherocytes, the red cells are sheared as they pass through damaged capillaries
324
name 3 acquired membrane defects that result in haemolysis?Name 4 genetic membrane defects that result in haemolysis?
Liver disease- Zieve's syndrome(Haemolysis, Alcoholic liver disease, hyperlilidaemia)Vitamin E deficiency Paroxysmal Nocturnal haemoglobinuria all very rare -reduced membrane deformabilityincreased transit time though spleen Oxidant environment in spleen causes extravascular red cell destructionHereditary spherocytosis
325
name congenital causes off abnormal red cell metabolism? (2)acquired causes? (1)
G6PD deficiency (failure to cope with oxidative stress)failure to generate ATPsome drugs that initiate oxidative stress e.g. Dapsone
326
give congenital causes for abnormal Hb?
sickle cell disease
327
what is iron used for in the body? (2)-what is iron present in?
Oxygen transport(reversible O2 binding by Hb)Electron transport (in both ferrous and ferric forms)-Hb, myoglobin, Enzymes
328
Why can iron be dangerous? (2)
chemical reactivity- causes oxidative stressNo mechanism for excretion
329
Where is iron in Hb?
in the globin chain, the Fe ion sits in the porphyrin ring
330
Explain iron exchange within the body-see diagram on slide 7
More than 1/2 the iron in the body is stored in Hb Iron is recycled within the body Iron is absorbed (1mg/day) and then circulates briefly in the plasma bound to transferrin. It is then transported to BM and is then incorporated int o RBCs.When these are broken down the Iron is stored in Macrophages (+body tissues) until it is needed.
331
How do you asses iron status:-name the 3 compartments of iron within the body & how these are measured?
-functional iron (Hb conc)Transport iron(% saturation of transferrin with iron)Storage iron (serum ferritin & tissue biopsy BM or Liver)
332
Transferrin -what is it?-function?-what does transferrin saturation measure?-how is ^ calculated? -what is a normal level?-what will be seen in iron overload and iron deficiency?
-protein with 2 binding sites for iron atoms-transports iron FROM donor tissues (macrophages, intestinal cells and hepatocytes) TO tissues expressing transferrin receptors especially erythroid marrow -iron supply-serum iron/total iron binding capacity X 100%-about 20-50%-overload= transferrin saturation elevated deficiency= transferrin saturation decreased
333
Ferritin-what is it?-function & capacity?-what does serum ferritin measure?-what effects serum ferritin levels?
-Large intracellular protein-spherical and stores up to 4000 ferric ions in Fe3+ form -tiny amounts of serum ferritin reflects intracellular ferritin synthesis in response to iron- indirect measure of storage iron -acute phase protein so inc in infection/malignancy
334
How is iron absorption regulated:-intraluminal factors (3)-Mucosal factors (2)-Systemic factors (3)
-solubility of inorganic ions haem iron easier to absorb Reduction of ferric (Fe3+) to ferrous (Fe2+)-expression of iron transporters DMT-1 at mucosal surface Ferroportin at serial tissue -Hepcidinmajor negative regulator of iron uptake produced in liver in response to iron overload & inflammation Down regulates ferroportin)
335
explain iron absorption in the duodenum?
DMT-1 transports iron into the duodenal enterocyte Ferroportinfacilitates iron export from the enterocyte then passed on to transferrin Hepcidin Down regulates ferroportin so iron stored in enterocytes
336
Name the 3 categories of iron metabolism disorders?
iron deficiency Iron malutilisationIron overload
337
Give the consequences of a negative iron balance:-to erythrocytes?-causes what kind of anaemia?-epithelial changes? (3)
-iron def erythrocytes and falling red cell MCV-microcytic anaemia -Epithelial changes skin, koilonychia, angular stomatitis
338
give causes of hypochromic, microcytic anaemias? (2-2,1)
Haem deficiencyLack of Iron (iron def, anaemia of chronic disease)Congenital sideroblastic anaemia Globin defe.g. thalassaemias
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Causes of iron deficiency? (3)INVESTIGATE THE CAUSE
insufficient dietary intake to meet physiological requirements Loss of iron though bleeding(Menorrhagia, GI, tumours, ulcers, NSAIDs, parasitic infection)Haematuriamalabsorption
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Iron malutilisation -occurs in what?-briefly describe the pathophysiology (3)
-anaemia of chronic disease -increased transcription of ferritin RNA stimulated by inflammatory cytokines, ferritin synthesis increasesIncreased plasma Hepcidin blocks ferroportin-mediated release of iron results in impaired iron supply to marrow erythroblasts and eventually hypo chromic red cells
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Primary iron overload -describe the mechanism by who this occurs?
Long term excess iron absorption with parenchymal rather than ,macrophage iron loading = eventual organ damage
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Hereditary Haemochromatosis -what is it?-clinical features? (7)-investigation for diagnosis? -what gene is involved- name the mutation? inheritance? effect on body? penetrance? -treatment?-patients at greater risk from that conditions?-screening?
-herediatary disease characterised by excessive intestinal absorption of iron-weakness/fatiguejoint painsimpotenceArthritisCirrhosisDiabetesCardiomyopathy-Transferrin saturation, will be >50%liver biopsy if unsure -mutation of the HFE gene C282Y or H63D mutations Recessive so need to be homozygous for one or heterozygous for both Reduced hepcidin synthesis Incomplete penetrance -weekly phlebotomy 450-500mlinitial aim to exhaust iron stores then keep ferritin below 50ug/l-DM, infections, Cardiac failure, hepatic bleeding/variceshepatoma -of first degree relatives
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Secondary iron overload -causes? (6)-course of disease?-treatment?
-repeated RBC transfusion excessive iron absorption relating to over-active erythropoiesis(+thalassaemia syndromesSideroblastic anaemiasRed cell aplasiaMyelodysplasia)-occurs a lot more quickly than haemochromatosis, in thalassaemia can get transfusions every 2 wks -venesection not an optioniron chelating agents:DesferrioxamineDeferiproneDeferasirox
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causes of hypochromic microcytic anaemia? (6)
Iron deficiencyThalassamiaanaemia of chronic diseaselead poisoning Pyridine responsive sideroblastic anaemia
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Causes of macrocytic anaemia? (7)causes of macrocytosis without anaemia? (3)
Megaloblastic:B2 deficiencyFolate deficiency +Myelodysplasia MyelomaAplastic anaemia reticulocytosiscold agglutinins -alcohol, Liver disease, hypothyroidism
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Causes of normochromic, normocytic anaemia?
acute blood lossHypoproliferative:chronic diseaseanaemia of renal failure hypometabolic state marrow failure
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Describe the pathogenesis of renal anaemia in CKD?
kidneys can no longer produce Epo to stimulate erythropoiesis
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Anaemia of chronic disease-describe the pathogenesis?
inflammation central to the process T cells are activated e.g. by malignancy cells and produce cytokines.This stimulates hepatocytes to produce Hepcidin, inhibiting duodenal absorption of iron DMT-1 expression increases on macrophages and increases uptake of ferrous irontransferrin receptor expression is increased and uptake of iron into monocytes increasesferroportin is down regulated inhibiting iron export from macrophages ferritin expression is stimulated and and iron is retained in macrophages there is decreased iron in circulation and less is available for RBC production
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Describe the effects of an inflammatory stimulus on RBC production?-driven buy what?
increases hepatic synthesis of hepcidin (inhibits iron release from RES)Inhibits erythropoietin release (dec erythropoietic stimulation)Inhibits erythroid proliferation Augments Hemophagocytosis (causes release of recycled iron via ferroportin & reduced transferrin which limits iron availability) -IFN, TNF, IL-1B, IL-6
