3 Anaemia and Leukemia Flashcards
Main sites of haemopoiesis throughout life
Foetus:
First few weeks = yolk sac
2 - 6/7 months = liver and spleen
6/7 months = bone marrow (& liver/ spleen -> 2wks PP)
Infant: all bone marrow
Adult: central bone marrow and proximal femur (as 70% marrow replaced by fat)
What are the 3 fates of haemapoietic stem cells?
Apoptosis
Self-renewal
Differentiation
What are the 6 types of stromal cells and what do they produce (6)?
Cells: >Macrophages >Epitheliod cells >Fibroblasts >Fat cells >Reticulum cells
Produce: >Fibronectin >Haemonectin >Collagen >Laminin >Proteoglycans
What is bone marrow environment composed of/ how does it support haemapoietic stem cells?
Stroma (produces proteins for growth/ differentiation and cell adhesion)
Extracellular matrix
Microvascular network
Difference between bone marrow aspirate and trephine
Aspirate = small biopsy of cells Trephine = core biopsy of 1-2cm and marrow structure is maintained
Define “clonal” proliferative disorder
Arise from a single ancestral cell
Define the Philadelphia chromosome, the condition in which it is present, and how it causes abnormality (3)
Present in CML - short chromosome 22
Due to reciprocal translocation between chromosomes 22 and 9
BCR-ABL gene (tyrosine kinase) constantly on > turns on downstream targets by phosphorylation > cell becomes malignant
What are the 3 main myeloproliferative disorders
Essential thrombocytosis (inc platelets)
Polycythemia rubra vera (inc Hb and RBC)
Myelofibrosis (inc fibrosis and scarring)
What is a myeloproliferative disorder
Abnormal clonal proliferation, leading to increased numbers of a mature myeloid blood cell type
What mutation are most myeloproliferative disorders associated with
JAK2- V617F
Calreticulin
Clinical features and classification of essential thrombocytosis
Thrombotic complications
Haemorrhagic complications
Splenomegaly (and hepatomegaly in myelofibrosis)
Progression to PRV/ myelofibrosis/ leukemia
Histological features of essential thrombocytosis (blood and marrow)
Blood - lots of clumps of platelets
Marrow - clumps of megakaryocytes
Treatment of essential thrombocytosis in low risk med risk high risk pregnancy elderly new options?
low risk - aspirin OR other antiplatelet (clopidogrel)
med risk - aspirin ± hydrocarbamide
high risk - aspirin + hydrocarbamide (1st) or anagrelide (2nd)
pregnancy - IFN-alpha
elderly - Busulphan/ radioactive phosphorous
new options - JAK2 inhibitors
What are myelodysplastic syndromes?
Dysplasia of one or more types of myeloid cells, leading to ineffective haemopoiesis
How do myelodysplastic syndromes present (3)?
20% Incidental on FBC
20% Bleeding and infection (WBC/plts)
Most anaemic/ tired (RBCs)
Main treatment options for myelodysplastic syndrome
Supportive care = blood/plasma transfusion, and consider iron chelation in younger patients
What is Fanconi anaemia?
Type of aplastic anaemia (pancytopenia) as a result of AR genetic bone marrow failure
Main features of Fanconi anaemia
>Somatic abnormalities: Short stature, digital abnormalities, GI/GU malformations > Chromosomal instability > CNS: metal retardation, hydrocephalus > Hearing problems > Micropthalmia > Cafe au lai spots (neurofibromas)
High malignancy risk
Main treatment/ management of Fanconi anaemia
Allogeneic stem cells transplant
Monitor for 2y tumours
Inc blood count - corticosteroids/androgens
Supportive care
2 types of stem cell transplant and their uses
Autologous: relapsed H lymphoma, NH lymphoma, Myeloma
Allogeneic: leukemias, relapsed lymphoma, aplastic anaemia and hereditary disorders
Types of allogeneic transplant donors (5)
Syngeneic = identical twin Allogeneic sibling - HLA identical Haplotype = 1/2 matched family member VUD/MUD = volunteer unmatched donor/ matched Umbilical cord transplant
5 steps of autologous transplantation by aphaeresis
1) move stem cells from marrow to blood with G-CSF
2) remove pt blood and take out stem cells and put blood back in = aphaeresis
3) stem cells preserved by freezing
4) patient receives high dose chemo and radio
5) thawed stem cells rein fused to patient
Describe myeloablative full intensity vs reduced intensity “mini” stem cell transplants
Myeloablative:
>High dose chemo and radio (completely destroying all patient stem cells), then rescue with donor cells so patient is 100% donor
Mini:
>Low dose chemo with radio/immunosuppression - not intended to eradicate all patient cells/malignancy
> donor introduced and patient becomes mixed chimera, then progresses to full donor (sometimes with help of DLI)
Pros and cons of umbilical cord blood stem cell transplants
Pros:
>More rapidly available
>Requires less tissue matching as immune system still naive
Cons:
> small amounts - adult often require double transplants
> if relapse, can’t treat with DLI
Describe DLI
Donor lymphocyte infusion:
>Given after initial STC (which has the anti-tumour effect), to prevent remission by GvL
>Given in incremental doses as has a high risk of GvHD (to reduce risk)
Describe graft vs host disease
Donor cells recognise host cells as foreign and attack
Chronic = over 100 days post transplant
Acute = within 100 days
Describe graft vs leukemia
Positive of GvHD - graft also recognises leukemias cells (and myeloma/lymphoma) as foreign and attacks them
What enzyme in RBCis responsible for the conversion of Co2 & H2O -> HCO3- & H+
And how does HCO3- leave the RBC
Carbonic anhydrase
Chloride shift - chloride comes in as bicarb leaves
How much iron is in the body and where is it stored/used (4)?
about 4g
Most in RBCs/ erythroblasts (3g)
Reticuloendothelial cells (macrophages) - 500mg
Enzymes - 100mg
Myoglobin - 200-300mg
What is the iron transport glycoprotein and where is it produced?
Transferrin
Liver
What happens to iron in erythroblasts?
Taken in via transferrin receptor (TfR) and either stored as ferritin or put in haem
What happens to iron (and RBCs in general) in the reticuloendothelial system (macrophages)?
Macrophages digest dead RBCs
Globin -> amino acids - released
Haem -> bilirubin - liver for conjugation
Iron -> stirred as ferritin or released to transferrin
How much iron do males/ females loose/need daily?
Females = 2mg Males = 1mg
What is the difference in how haem/ non-haem iron is absorbed in the GIT
Haem = readily absorbed (ferrous) Non-haem = needs to be connected to ferrous (from ferrate) before absorption
What regulates the amount iron released from RBC into plasma and how?
Hepcidin (made in liver) and ferroportin
Ferroportin increases release of iron from RES and increased absorption
Hepcidin binds and degrades ferroportin, reducing plasma iron
Define hereditary haemochromatosis
Hereditary disease where the body absorbs too much iron, possibly due to decreased amounts of hepcidin (defects in HFE gene)
Anaemias producing microcytic RBCs
Iron deficiency Anaemia of chronic disease Blood loss (longer term) Sideroblastic Thalassemia
Clinical signs of IDA (4)
Koilonychia
Angular stomatitis
Atrophic glossitis
Oesophageal webs (Plummer Vinson syndrome)
Describe 1st and 2nd stages of IDA
1st (latent iron def) - RBCs use up storage iron so Hb is normal but RES stores decrease
2nd - Hb and RES stores both decreased
Causes of IDA from GI bleed (4)
And most likely GI cause of silent IDA (no symptoms)
Diverticular disease/ diverticulitis
Rectal carcinoma - stricure
Bleeding peptic ulcer
Caecal tumour - asymptomatic
Until proven otherwise, most likely causes of IDA in:
> males/ post menopausal women
> young women
males/ post menopausal women = GI bleed
young women = menopausal bleeding
Treatment of IDA
Replace iron - ferrous sulphate/ gluconate (GI upset)/
IV (intollerant/ compliance/ renal IDA on dialysis with EPO)
Levels in IDA of:
RES iron stores
Ferritin
Transferrin
RES iron stores (dec)
Ferritin (dec)
Transferrin (inc)
Levels in anaemia of chronic disease of:
RES iron stores
Ferritin
Transferrin
RES iron stores (inc)
Ferritin (dec)
Transferrin (dec)
What other factor is raised in anaemia of chronic disease and what shape do RBCs form when this occurs
ESR - inflammation
Rouleaux
Causes of anaemia of chronic disease (3)
Bone marrow failure to produce RBCs
Bone marrow reduced response to EPO
RES blockage - trapped in macrophages (?herceptin)
How is B12 absorbed from GIT (5)
1) Ingested and released from food by enzymes
2) IF produced - parietal cells
3) IF binds B12
4) IF-B12 binds cubulin receptor- ileum
5) IF-B12 absorbed to blood - binds transcobalamin
What is the B12/ folate transport proteins?
B12 = cobalamin
Folate - none
What is the 2 main functions of B12 in cells?
1) Methylation of homocysteine > methionine
2) Methlymalonyl-CoA isomerisation
What are the main dietary sources of B12 and folate, and where are they absorbed?
B12 = meat (and dairy) Folate = raw green veg
How does B12/folate deficiency cause megaloblastic anaemia?
Affects downstream DNA synthesis = disparity in synthesis and upstream precursors
Makes abnormal large RBCs - prematurely destroyed in bone marrow before release
What type of anaemia is:
Iron deficiency
Anaemia of chronic disease
B12/folate deficiency
Iron deficiency = microcytic hypochromic
Anaemia of chronic disease = microcytic hypochromic
B12/folate deficiency = megaloblastic macrocytic
Other than anaemia, what other problems can be caused by B12/folate deficiency?
B12 - Dorsal column/spinal cord degeneration
Folate - Neural tube defects 1st 12 weeks of pregnancy
Both - thrombocytopenia, leucopenia, affect epithelial surfaces (GI/GU)
Clinical symptoms/ signs of B12/folate deficiency (4)
Anaemia - Pale, tried, SOB
Mild jaundice - haemolysis (bilirubin)
Bruises - thrombocytopenia
CNS defects
Causes of B12 deficiency (3)
Pernicious anaemia/ lack of IF
Gastrectomy - lack of IF/ acid
Terminal ileum problems - Chron’s, resection
Causes of folate deficiency (3)
> Diet deficiency
Increased cell turnover (pregnancy, haemolysis, severe skin conditions e.g. psoriasis) - low stores
Small bowel problems - severe Chron’s/ coeliac
Other causes of macrocytic cells (3)
> Reticulocytosis - increased reticulocyte production
Cell wall/ lipid abnormality - abnormal structure
Bone marrow failure syndromes - abnormal production
How many alpha and beta Hb genes do we receive from each parent?
And what chromosome are they on?
4 alpha - chr 16
2 beta - chr 11
What is the treatment for beta thalassemia major?
Transfusions from easy age > first few years
Consider iron chelation
What is the genetic abnormality causing sickle cell disease?
Codon 6 substitution on chromosome 11
Glutamine -> valine
SICKLED features of sickle cell anaemia
Splenomegaly
I Infarction (organs, osteonecrosis, stroke,)
C Crises - mesenteric, pulmonary,
K Kidneys
L Lungs/Liver (pul. hypertension, acute chest)
E Erection (maintained)/ Eyes (vascular retinopathy)
D Dactylitis
Treatment of sickle cell disease
Prevent crisis - fluid/analgesia, folic acid, prophylactic vaccination/abx for splenectomy (Pv)
Early intervention of crisis - fluid/o2/Abx/analgesia, transfusion/RBC exchange
Bone marrow transplant
Counts in haemolytic anaemia of:
Hb
Reticulocytes
Bilirubin
Hb - low
Reticulocytes - high
Bilirubin - high
3 main classes of congenital haemolytic anaemias, and examples
3 types of acquired haemolytic anaemias, and examples
Congenital:
1) RBC membrane abnormalities - hereditary spherocytosis
2) Hamoglobinopathies - thalassemias, sickle cell
3) Exzyme abnormalities - pyruvate kinase, Glucose-6-phosphate dehydrogenase
Acquired:
1) autoimmune - cold/ warm (drug induced)
2) isoimmune - HDN
3) non autoimmune - fragmentation haemolysis
3 main clinical signs of haemolytic anaemia
Jaundice
Fatigue/anaemia
Splenomegaly
Blood film appearance of hereditary spherocytosis and why
Polychromatic spherocytic
Treatment of hereditary spherocytosis and inheritance pattern
Autosomal dominant
None usually
If severe splenectomy with prophylactic penicillin V and vaccinations (pneumococcus, meningococcus, homophiles)
Pyruvate kinase deficiency haemolytic anaemia: >Mechanisms >Acute/ chronic >Intra/ extra vascular >Inheritance
> Mechanisms - prevents ATP production, so all cells die
Acute/ chronic - chronic
Intra/ extra vascular - extra
Inheritance - autosomal recessive
Glucose-6-phosphate dehydrogenase deficiency haemolytic anaemia: >Mechanisms >Acute/ chronic >Intra/ extra vascular >Inheritance
> Mechanisms - prevents NADP>NADPH, which normally protects from oxidative damage from drugs (triggers = drugs/ favism)
Acute/ chronic - acute, explosive episodes
Intra/ extra vascular - intra
Inheritance - X lined recessive
Causes of fragmentation haemolysis (3)
VAD
Mechanical heart valve
E. Coli 0157 - haemolytic uremic syndrome
Cold type AIHA antibody and causes/ associations
IgM + complement
Idiopathic
Lymphoproliferative disorders (lymphoma/CLL)
Mycoplasma pneumonia infection
Warm type AIHA antibody and causes/ associations
IgG ± complement
Idiopathic
Lymphoproliferative disorders (lymphoma/CLL)
Other autoimmune - thyroid, SLE
Drug induced
3 types/ methods of drug-induced AIHA
Hapten - drug binds RBC and attracts Abs
Immune complex - RBC is a bystander
Direct autoimmune - Drug causes Ab to attack RBC
Describe direct coombs test and what it is for
HDN/ AIHA
Mix pt blood with Abs and if they glutamate, they have AI Abs in their blood (+ve)
Describe indirect coombs test and what it is for
Transfusion
Mix pt plasma + transfusion RBCs +Abs, if they glutamate, the patient has Abs against the transfusion blood
Treatment of warm and cold autoimmune haemolytic anaemia
Cold - keep patient warm (mycoplasma self limiting)
Warm - steroids/ immunosuppression/ splenectomy
Describe how haemolytic disease of the newborn occurs
Mother Rhs -ve and foetus +ve (from father)
Fetal blood leaks into maternal blood and mother produces Abs against fatal blood
Abs cross placenta and attack RBCs
Which leukemias are more common in children and adults?
ALL - children, under 20
AML - adults, over 60
Clinical signs/ symptoms of acute leukemias
Rapid onset Anaemia - fatigue, pale Thrombocytopenia - bleeding/ bruising Leukopenia - infection Bone pain Gum swelling Skin rash Lymphadenopathy
What is M3 AML and its main pathopneumonic histological feature on blood film?
Translocation on cr 17/15
Medical emergency, assoc. with DIC
Granules in large blast cells with auer rods
What method is used to identify the cell types in acute leukemia?
What method is used to identify the genetic abnormalities in acute leukemia?
Cell types - flow cytometry
Genetic - cytogenetics, arrested in metaphase
What chromosome translocations are present in M3 AML and M2 AML
M3 = 15/17
M2 = 8/21
Drugs used in AML chemotherapy (2)
Cytarabine and anthracycline
Side effects of AML chemotherapy
Hair loss
Bleeding/ infection
Infertility
Mucositis
Presenting features of CLL (5)
1/3 asymptomatic
Weight loss/ night sweats/ fatigue
Abdo pain
Splenomegaly**
Diagnostic methods for CLL (4) and describe what is being looked for
1- surface antigens - CD 5/19/23
2- flow cytometry
3- Binet staging - A (<3), B (>3/spleen/liver), C (thrombocytopenia/anaemia)
4- cytogenetics (interphase FISH) - 17pdel, 11qdel
What are the main complications of CLL (2)?
Autoimmune - thrombocytopenia/ haemolytic anaemia
Infection - pulmonary
CLL presenting features
Asymptomatic
Weight loss/ night sweats/ fatigue
Anaemia
Lymphadenopathy
Splenomegaly
Diagnostic methods for CML (3)
1 - blood film/ test and history - clumping of cells
2- molecular testing for BCR-ABL
3- cytogenetics karyotype (translocation)
Treatment of CML and CLL
CML = imatinib CLL= nothing unless symptomatic
What are the main complications of CLM (2)?
Imatinib resistance/ intolerance
Accelerated phase/ blast crisis
