Haematology Flashcards
1
Q
WHAT IS MULTIPLE MYELOMA?
https: //www.youtube.com/watch?v=jdytgW5wKa4
https: //www.youtube.com/watch?v=ghvoKhpAc64&t=471s
A
Cancer of plasma cells
2
Q
What is the epidemology of myeloma?
A
Older age
Afro-Caribbeans more
3
Q
What is the pathophysiology of multiple myeloma?
What is there an abnormal proliferation of?
What is secreted?
A
Abnormal proliferation of a single clone of plasma cells
Secretion of immunoglobulin (Ig) or an Ig fragment
Dysfunction of many organs (esp kidney).
4
Q
What are the two proteins produced as a result of myeloma?
A
Paraprotein (just the light chain of Ig)
Bence Jones protein in the urine
5
Q
How do osteoblasts and osteoclasts work?
What else does an osteoblasts do?
A
Osteoblasts secrete osteoid
Osteoclasts break down bone by HCl
Osteoblasts regulate osteoclasts by RANKL
When RANKL binds to RANK on osteoclasts it makes them work
Osteoblasts also secrete OPG which inhibit this
6
Q
How do the amount of osteoclasts in multiple myeloma increase?
A
Bone marrow stromal cells which normally regulate haemotopoesis
Theese bone marrow stromal cells interact with multiple myeloma cells
Which activates cytokine mediated cell growth, durg resistance and migration
Secrete IL-3 stopping osteoblast production
DKK1 inhibit OPG
MIP1alpha and RANKL to increase osteoclast activity
7
Q
What parts of B cell production damages what?
A
Recurrent infection
Monoclonal Igs
Renal impairment
Free Light Chains
Bone lesions
(IL-6) & ↑ Ca
8
Q
What is the difference between MGUS, symptomatic and asymptomatic myeloma?
A
Monoclonal gammopathy of undetermined significance (MGUS)
Low amount of plasma cells in BM, no ROTI (related organ or tissue involvement), no evidence of amyloid or other LPD (lymphoproliferative disorder)
Asymptomatic myeloma (aMM)
>10% Moderate amount of plasma cells in BM, no ROTI
Symptomatic myeloma (sMM)
Paraprotein, >10% clonal plasma cells in BM or Bx proven plasmacytomata, ROTI nb CRAB
9
Q
What are the symptoms for myeloma?
A
Remember babs the CRAB! Calcium, Renal, Anaemia, Bones
Hypercalcaemia
Renal impairment
Anaemia, neutropenia, or thrombocytopenia
Infiltration
Osteolytic bone lesions
Causing backache, fractures and vertebral collapse.
Recurrent bacterial infections
Immunoparesis, and neutropenia due to the disease and from chemotherapy.
10
Q
What tests can you do for myeloma?
(Thick about the symptoms)
A
FBC (Full blood count)
Result in normocytic normochromic anaemia
ESR or PV (Erythrocyte sedimentary rate or plasma viscosity)
Both would be increased
U&E, Ca, albumin
All increased
Serum and urinary EP
Peak in IgG, M spike
XR of suspect areas
Lytic ‘punched-out’ lesions
Pepper-pot skull
11
Q
What are the diagnostic features of myeloma?
A
Monoclonal protein band
Plasma cells increase
Evidence of end-organ damage from myeloma
Bone lesions
12
Q
What Ig’s does myeloma normally produce?
A
IgG (2/3), IgA (1/3)
Rarely IgD, IgM or IgE
Monoclonal free light chains (Bence Jones proteins)
FLC only (15%)
13
Q
What are the complications of myeloma?
A
Hypercalcaemia
AKI
Hyperviscosity
Cord compression
Amyloid
14
Q
What is the treatment for myeloma?
A
C – Ca – hydration +/- bisphosphonates
R – Renal – hydration +/- dialysis
A – Anaemia– transfusion +/- EPO
Neutropenia - antibiotics
B – Bones – analgesia + bisphosphonates
Chemo +/- BMT
15
Q
WHAT IS LYMPHOMA?
https: //www.youtube.com/watch?v=_QVO75CihYQ
https: //www.youtube.com/watch?v=FfuP7j4A1cs
A
Basically a malignant growth of white blood cells
16
Q
Where does the growth of white blood cells in lymphoma normally happen?
A
Predominantly in lymph nodes
But also:
Blood, bone marrow
Liver, spleen
Anywhere.
17
Q
What is the primary lymphoid organ?
A
Bone marrow
18
Q
What is the secondary lymhpoid organ?
A
Lymph nodes
19
Q
What happens in the bone marrow and lymph nodes (B cells)?
A
Precursor B cells turn into naive B cells
Then travel through the blood to the lymph nodes
Go to the cortex inside the lymph nodes
B cells can then divide into plasma cells which are found in the medulla (centre of lymph node)
20
Q
What happens when a B cells antibody meets a particular antigen?
A
Can divide directly into plasma cells and secrete IgM
Go to centre of a primary follicle in the lymph node and differentiate into centroblasts and divide
This form a germinal centre, these have a rearrangement of their Ig genes and switch from forming IgM to IgG or IgA
The centrocyte in the middle of the centroblast can divide into plasma cells which go to the medulla or memory B cells which go to blood or MALT (mucosa assocaited lymphoid tissue)
21
Q
What happens after the bone marrow to the thymus (T cells)?
A
Precursor T cells travel to thymus where they go into either
CD4 (helper)
OR
CD8 (cytotoxic)
These then circulate in blood and live in paracortex or lymph nodes
22
Q
What are the two different types of lymphoma?
A
Hodgkin’s
NHL.
23
Q
WHAT IS HODGKINS LYMPHOMA?
A
Malignancy of mature lymphocytes that arises in the lymphatic system
In Hodgkin’s lymphoma, characteristic cells with mirror-image nuclei are found, called Reed–Sternberg cells
24
Q
What is the epidemology of HL?
A
BIMODAL
Young adults and elderly.
25
What are the risk factors for Hodgkin's lymphoma?
EBV
SLE
Post-transplantation
Obesity
26
How does Hodgkins lymphoma present?
Enlarged lymph nodes
Hepatosplenomegaly
Sweats, weight loss
27
What can make lymph node pain worse?
Alcohol
28
How do you diagnose Hodgkins lymphoma?
**_Biopsy_**
Reed-Sternberg cells
29
What is the staging system called for lymphoma?
Ann Arbor system
30
How many stages does Hodgkin's lymphoma have?
Four.
**_A - asymptomatic_**
* *_B - symptomatic_**
* *_I_** Confined to single lymph node region.
* *_II_** Involvement of two or more nodal areas on the same side of the diaphragm.
* *_III_** Involvement of nodes on both sides of the diaphragm.
* *_IV_** Spread beyond the lymph nodes, eg liver or bone marrow.
31
What is the treatment for Hodgkin's lymphoma?
Chemo +/-RT
BMT for relapse
32
WHAT IS NHL?
This includes all lymphomas without Reed–Sternberg cells —a diverse group.
33
What are some examples of NHL?
Low grade e.g. Follicular Lymphoma
High grade e.g. Diffuse Large B Cell Lymphoma
Very high grade e.g. Burkitt’s Lymphoma
34
Which cell line are most NHL derived from?
Which is the most common?
B-cells
Diffuse large B-cell lymphoma (DLBCL) is commonest.
35
What are some causes of NHL?
**_H.Pylori_**
HIV
Toxins
36
What are the symptoms of NHL?
Same as Hodgkin’s
+ GI symptoms if small bowel lymphomas
Skin involvement in T-cell lymphomas
37
What are the tests for NHL?
**_Blood_**
FBC, U&E, LFT
**_Marrow and node biopsy_**
Classification.
**_Cytology_**
LP for CSF cytology if CNS signs.
38
What is an example indolent or low grade lymphoma? What are its characteristics?
Follicular Lymphoma
Slow growing
Usually advanced at presentation
Incurable
39
What is an example high grade or aggressive NHL? What are its characteristics?
Diffuse Large B Cell Lymphoma
Usually nodal presentation
1/3 cases have extranodal involvement
Patient usually unwell
Often short history.
40
What is the treatment for NHL?
**_Low grade (follicular)_**
W&W
**_High grade (diffuse large B cell)_**
Chemo
BMT for relapse
**_Monoclonal antibodies_**
Rituximab
**_Steroids_**
Prednisolone
41
What is an example of a monoclonal antibody for lymphoma treatment?
Rituximab.
42
What does Rituximab do?
Monoclonal antibody
Anti CD-20
Targets CD20 expressed on cell surface of B-cells
Chimeric mouse/human protein
Minimal side-effects.
43
What is an example of a T cell engaging therapy?
Blinatumomab
44
What does Blinatumomab do?
bi-specific Antibody
Targets CD19 on B cells
And CD3 on T cells
Directs own immune system.
45
WHAT IS LEUKAEMIA?
https: //www.youtube.com/watch?v=itkRVTqfPsE
https: //www.youtube.com/watch?v=itkRVTqfPsE
Malignant proliferation of haemopoietic cells.
46
What are some different types of leukaemia?
https://www.youtube.com/watch?v=itkRVTqfPsE
Acute Myeloid leukaemia (AML)
Chronic Myeloid Leukaemia (CML)
Acute Lymphoblastic Leukaemia (ALL)
Chronic Lymphocytic Leukaemia (CLL).
47
What is acute myeloid leukaemia a disease of?
Myeloblasts.
48
What is chronic myeloid leukaemia a disease of?
Basophils, Neutrophils and Eosinophils.
49
What is acute lymphoblastic leukaemia a disease of?
Lymphoblast.
50
What is chronic lymphocytic leukaemia a disease of?
B lymphocytes.
51
What is the stain called which allows you to distinguish between myeloblasts and lymphoblasts?
Sudan black stain
52
WHAT IS ACUTE MYELOID LEUKAEMIA?
https://www.youtube.com/watch?v=itkRVTqfPsE
Clonal expansion of myeloblasts in BM, blood and other tissues
53
Above what percentage of blasts cells does there have to be for AML?
More than 20% blasts cells in bone marrow
54
What is the epidemology of acute myeloid leukaemia?
The commonest acute leukaemia of adults
55
What is the aetiology of acute myeloid leukaemia?
(Who is at increased risk)
Aetiology usually not obvious but risk increased in:
Preceeding Haematological disorders
Prior chemotherapy
Exposure to ionising radiation
56
What are the symptoms of acute myeloid leukaemia?
**_Marrow failure_**
Symptoms of anaemia, infection or bleeding.
**_Infiltration_**
Hepatomegaly and splenomegaly
GUM HYPERTROPHY + BLEEDING
57
How can you diagnose acute myeloid leukaemia?
**_FBC_**
↓RBC
↓PLT
WCC variable
Usually w/ neutropenia
**_Bone marrow biopsy_**
Blast cells may be few in the peripheral blood
**_Clotting screen_**
DIC may occur
58
What is diagnositc of AML from ALL?
Auer rods are diagnostic of AML
Myeloperoxidase makes this
59
What is the treatment for acute myeloid leukaemia?
**_Supportive_**
**_Treat Infection_**
**_Chemotherapy_**
(remission induction (regenerate) ➔ consolidation(intensification) ➔ maintenance: steroids
**_Bone Marrow Transplantation_**
During 1st remission
| (blood/platelets/fluids)
60
What drug can be used to prevent tumour lysis syndrome?
Where else is this used?
Allopurinol
Gout
61
What is acute premylocitic leukaemia?
Build up of premyelocytes from a problem with the retinoic acid receptor
62
What is the cause of premyelocitic leukaemia?
What chromsome translocation?
Translocation between chromosome 15 and 17
63
What happens with premyelocitic leukaemia?
What do you get with all the premyelocytes?
What does this cause?
Build up of premyelocytes
Lots of auer rods
Increase coagualation risk
Medical emergency
64
What is the treatment of premyelocitic leukaemia?
All trans retionic acid ATRA
65
WHAT IS CHRONIC MYELOID LEUKAEMIA?
https://www.youtube.com/watch?v=Wn3fylOqUZU&t=6s
CML is characterized by an uncontrolled clonal proliferation of myeloid cells
Only partialy differentiate
66
What happens with the cells in CML?
Where do they go to?
Divide too quickly
Spill out into blood and crowd it
67
Where do the myeloid cells go to through the blood?
Liver and spleen
Cause hepatosplenomegaly
68
What is the epidemology of chronic myeloid leukaemia?
Usually 40-60yrs age
Rare in childhood
Slight male dominance
69
What is the key diagnostic feature of chronic myeloid leukaemia?
Philadelphia Chromosome t(9;22)
80%
BCR/ABL on 22
Causes an activated tyrosine kinase
Worse prognosis if absent
70
What are the symptoms and signs of chronic myeloid leukaemia?
**_Symptoms_**
Weight loss
Tiredness
Fever
Sweats
Bleeding (platelet dysfunction)
Abdominal discomfort (splenic enlargement).
**_Signs_**
Splenomegaly (\>75%)—often massive.
Hepatomegaly, anaemia, bruising
71
What are the investigations for chronic myeloid leukaemia?
**_FBC_**
Raised WCC – all myeloid cells raised – neutrophils, macrophages, basophils, eosinophils).
Hb low or normal
Platlets variable
**_Cytogenetics (karyotype, FISH or PCR)_**
Philadelphia Chromosome
72
What is the treatment for chronic myeloid leukaemia?
**_Tyrosine kinase inhibitors_**
1st line Imatinib (Glivec)
2nd line Nilotinib, Dasatinib, Ponatinib.
Chemo
Stem cell transplant
73
WHAT IS ACUTE LYMPHOBLASTIC LEUKAEMIA?
https://www.youtube.com/watch?v=itkRVTqfPsE
Malignancy of B/T lymphocyte cell lines
74
What is the epidemology of acute lymphoblastic leukaemia?
Most common paediatric malignancy
Rarer in adults
75
What is thought to cause acute lymphoid leukaemia?
**_Genetic susceptibility_**
Translocations
**_+ an environmental trigger_**
76
What is the classification of acute lymphoid leukaemia?
**_Morphological_**
The FAB system divides ALL into 3 types (L1, L2, L3) by microscopic appearance.
**_Immunological_**
Surface markers are used to classify ALL into: • Precursor B-cell ALL • T-cell ALL • B-cell ALL.
**_Cytogenetic_**
Chromosomal analysis. Abnormalities are detected in up to 85%, which are often translocations.
77
What are the signs and symptoms for acute lymphoid leukaemia?
CNS involvement (cranial nerve palsies and meningism)
Lymphadenopathy
Orchidomegaly
+ Other leukaemia classics
78
What is the diagnosis for acute lymphoblastic leukaemia?
**_FBC_**
↓RBC, ↓PLT, WCC variable, usually w/ neutropenia
**_Blood film_**
Blasts cells unless confined to bone marrow (+ bone marrow aspiration)
**_Clotting screen_**
DIC may occur
**_Lumbar puncture_**
CNS involvement
**_Cytogenetics_**
79
How do you treat acute lymphoblastic leukaemia?
**_Supportive_**
**_Treat infection_**
**_Chemotherapy_**
(remission induction (regenerate) ➔ consolidation(intensification) ➔ maintenance: steroids
**_Bone Marrow Transplantation_**
(during 1st remission)
| (blood/platelets/fluids)
80
WHAT IS CHRONIC LYMPHOBLASTIC LEUKAEMIA?
https://www.youtube.com/watch?v=Wn3fylOqUZU&t=6s
Accumulation of mature B cells that have escaped programmed cell death
81
What happens to the cells in CLL?
Don't divide quickly enough
82
What is the epidemology of chronic lymphoblastic leukaemia?
Most common leukaemia
Generally elderly but 20% \<55yrs
83
What are the signs and symptoms for chronic lymphoid leukaemia?
**_Symptoms_**
Often none, surprise finding on a routine FBC.
May be anaemic or infection-prone.
If severe: weight loss, sweats, anorexia.
**_Signs_**
Enlarged, rubbery, non-tender nodes.
Splenomegaly, hepatomegaly.
84
What are the different stages of chronic lymphocytic leukaemia?
Rai Staging
1-5 based on examination and FBC
85
What are the tests for chronic lymphoid leukaemia?
Increased WBCs
**_Film_**
Smudge cells
B cell that have been broken
86
What are the complications for chronic lymphoid leuklaemia?
Autoimmune haemolysis.
Increased Infection due to hypogammaglobulinaemia
Marrow failure.
87
What is the treatment for chronic lymphocytic leukaemia?
Rituximab
Chemotherapy
Bone marrow transplant + Radio
88
WHAT ARE SOME EXAMPLES OF DIFFERENT HAEMOGLOBINOPATHIES?
**_Disorders of quality (abnormal molecule or variant haemoglobins)_**
Sickle cell disease
**_Disorders of quantity (reduced production)_**
a or b thalassaemia
89
What does normal haemoglobin contain and foetal?
Normal Hb 2xa, 2xb
Foetal Hb 2xa, 2xg
90
What does haemoglobin change from to during development?
Haemoglobin F to haemoglobin A.
91
WHAT IS SICKLE CELL ANAEMIA?
What type of anaemia is it?
https://www.youtube.com/watch?v=1ql-X60CUNQ&t=6s
Sickle-cell anaemia is an autosomal recessive disorder causing production of abnormal beta globin chains.
Microcytic anaemia
92
What is haemoglobin S?
Variant haemoglobin arising because of a point mutation in the b globin gene.
93
What happens with a carrier of sickle cell disease?
Carriers of HbS are symptom free
Carriage offers protection against falciparum malaria
Sickle cell diseases arise in the homozygous state (SS) or in combined heterozygotes (SC or Sb thalassaemia).
94
What gene changes occur in sickle cell anaemia?
Thiamine for adenine in 6th codon
Beta globin gene
Glutamic acid leaves
Valine comes in
95
What is the pathology of sickle cell disease?
What happens to the red blood cell?
HbS polymerizes when deoxygenated
RBCs deform, producing sickle cells
Which are fragile and haemolyse, and also block small vessels
Sickling cells appear at acidosis at at time when they deposit lots of oxygen
96
What are the symptoms of sickle cell disease?
Think about the crises'!
Fatigue and Anaemia
Pain Crises
Dactylitis and Arthritis
Bacterial Infections
Leg Ulcers
Aseptic Necrosis and Bone Infarcts
97
What are the different crises for sickle cell disease?
Haemolytic
Vaso-occlusive ‘painful’ crisis
Aplastic crisis (sudden reduction in marrow production)
Sequestration crisis (There is pooling of blood in the spleen ± liver)
98
What are the tests for sickle cell disease?
**_Screen neonate_**
blood/heel prick test
**_FBC_**
Low Hb, high reticulocyte count
**_Blood film_**
SICKLED erythrocytes
**_Hb ELECTROPHARESIS_**
For dx
HbSS present and absent HbA
99
What are some common complications of sickle cell disease?
**_Acute complications_**
Painful crisis
Sickle chest syndrome
Stroke
**_Chronic complications_**
Renal impairment
Pulmonary hypertension
Joint damage
100
What are the treatments for sickle cell anaemia?
**_Prophylactic ABX_**
Daily penicillin.
Pneumococcal & influenza vaccine
Folic acid
**_Pain relief for crisis_**
NSAIDs/paracetamol
**_Hydroxyurea_**
hydroxycarbamide
Increase conc. of HbF
101
WHAT IS THALASSAEMIA?
https://www.youtube.com/watch?v=uK\_uIBHnOWo&t=4s
The thalassaemias are genetic diseases of unbalanced Hb synthesis, with under-production (or no production) of one globin chain
102
What is the pathology of thalassaemia?
What happens to the red blood cells?
Unmatched globins precipitate
Damaging RBC membranes
Causing their haemolysis while still in the marrow.
103
What are the different types of Thalassaemia?
What different treatments do they require?
**_Thalassaemia Major_**
Transfusion dependent
**_Thalassaemia Intermedia_**
Less severe anaemia and can survive without regular blood transfusions
**_Thalassaemia Carrier/heterozygote_**
Asymptomatic.
104
What type of anaemia is thalassaemia?
Microcytic
105
WHAT IS BETA THALASSAEMIA?
What do you get less of?
What happens as a result?
In homozygous beta-thalassaemia, little/no normal beta chain production
EXCESS alpha chains.
Alpha chains combine w. whatever beta, delta or gamma chains available increased production of HbA2& HbF.
106
What is the cause of beta thalassemia?
Which chromosome is it defected in?
Point mutations in beta-globin genes
Chromosome 11
Decreased beta-chain production (beta+) or absence (beta0)
107
What is beta thalassemia major called?
Beta thalassaemia major (Cooley’s anaemia) denotes abnormalities in both beta-globin genes.
108
When does beta thalassaemia major present?
6 -12 months
109
What are the symptoms of beta thalassaemia major?
Failure to feed, listless, crying, pale.
**_Bones widen due to increased activity_**
Skull bossing
**_Anaemia_**
**_Hepatosplenomegaly_**
Lots of RBCs need to be destroyed
110
What is beta thalassaemia minor or trait?
This is a carrier state
111
What are the symptoms of beta thalassaemia minor?
Usually asymptomatic
Mild, well-tolerated anaemia (Hb \>90g/L)
112
What are the symptoms of beta thalassaemia intermedia?
Moderate anaemia but not requiring transfusions
There may be splenomegaly
113
What are the tests for Beta thalassaemia?
**_FBC & film_**
Hypochromic & microcytic anaemia
Irregular and pale RBCs.
Increased reticulocytes and nucleated RBCs
**_Dx by Hb electrophoresis_**
shows increased HbF & absent/low HbA.
114
What is the treatment for beta thalassaemia major?
**_BLOOD TRANSFUSIONS_**
**_Give iron chelation_**
Desferrioxamine
Decrease iron loading
**_Ascorbic acid_**
Increased urinary excretion of iron.
Long term folic acid supplements.
115
What happens when a child with Thalassaemia major has treatment by continuous blood transfusions?
Children require lifelong blood transfusions.
Consequence is an progressive increase in body iron load.
Can't eliminate the excessive iron
Patients inexorably develop a clinically worsening hemosiderosis
Liver and spleen, leading to liver fibrosis and cirrhosis.
Endocrine glands and the heart, resulting in diabetes, heart failure and premature death.
Death ultimately occurs, mainly due to cardiac hemosiderosis.
116
What does degree of symptoms depends of in alpha Thalassaemia?
**_4 deletions_**
HbBarts, infants are STILLBORN(hydrops fetalis).
**_3 deletions_**
SEVERE anaemia.
**_2 deletions_**
Often ASYMP. carrier, may have mild anaemia.
**_1 deletion_**
Close to normal.
117
WHAT ARE MEMBRANOPATHIES?
Autosomal dominant conditions.
Deficiency of red cell membrane proteins caused by a variety of genetic lesions.
118
What are some examples of membranopathies?
Spherocytosis & elliptocytosis most common.
Neonatal jaundice.
119
WHAT IS HAEMOLYTIC ANAEMIA?
https://www.youtube.com/watch?v=9DoUcEEthv8
Anemia due to hemolysis
Either in the blood vessels (intravascular hemolysis) or
elsewhere in the human body (extravascular)
120
What are the causes of haemolytic anaemia?
**_Genetic_**
**_Red cell membrane abnormalities:_**
Hereditary spherocytosis, elliptocytosis
**_Haemoglobin abnormalities_**
Sickle cell anaemia, thalassaemia
**_Enzyme defects_**
G6PD deficiency, pyruvate kinase deficien
**_Acquired_**
Systemic lupus erythematosus (SLE)
Lymphoma
Chronic lymphatic leukaemia (CLL)
121
What is Elliptocytosis? What causes this?
Where the red blood cells are shaped elliptically.
Horizontal interactions.
122
What is Spherocytosis? What causes this?
Where the red blood cells are shaped spherically. Vertical interactions.
123
What is the pathology of haemolytic anaemia?
What does the RBC release?
RBC haemolyse because of different causes
Haemolgobin released.
Haptoglobin binds to haemoglobin to recycle it
124
What are some symptoms of haemolytic anaemia?
Pallor
Jaunidce
Splenomegaly
125
What are the tests for haemolytic anaemia?
↑Unconjugated bilirubin
↑LDH
Coombs test +ve
Reduced reticulocytes
126
What is the management for haemolytic anaemia?
Transfusion
Folic acid
Discontinue medications
Iron
Autoimmune haemolytic anaemia therapy
127
WHAT ARE ENZYMOPATHIES?
https://www.youtube.com/watch?v=DZS-diLCa1g
Inherited enzyme deficiencies leading to shortened red cell lifespan from oxidative damage.
128
What is the pathway for G6PD?
Pentose phosphate pathway
129
What do the enzymes do in the cell?
**_Provides the fuel for the red cell_**
NAD+ to NAPH
**_Generates redox capacity to protect red cell_**
Gluthathione
130
What does glucose 6 phosphate dehydrogenase deficiency have to do with haemolytic anaemia?
Common cause of haemolytic anaemia
131
How is Glucose 6 phosphate dehydrogenase deficiency caused?
Caused by a wide variety of mutations within G6PD gene
X linked but women may also be affected
132
What are the symptoms of Glucose 6 phosphate dehydrogenase deficiency?
Most asymptomatic
But may get oxidative crises due to decreased glutathione production, precipitated by drugs
In attacks, there is rapid anaemia and jaundice
133
How is Glucose 6 phosphate dehydrogenase deficiency diagnosed?
Diagnosed by screening test for NADPH
**_Film_**
Bite- and blister-cells
134
What is the treatment for glucose 6 phosphate dehydrogenase deficiency?
Avoid precipitants (eg, henna); transfuse if severe.
135
WHAT ARE PLATELETS AND HOW ARE THEY FORMED?
Anucleate cells formed by fragmentation of megakaryocyte (MK) cytoplasm in bone marrow.
136
What is important about platelets shape? What is their primary function?
Disc shape allows them to flow close to endothelium Important role in primary haemostasis
137
How are old platelets recycled and after how long?
Life span 7-10 days
Old platelets are phagocytosed by splenic macrophages in red pulp.
138
What does thrombopoietin do?
Stimulates production of platelets by megakaryocytes
Binds to platelet and MK receptors
↓plts = less bound TPO = ↑ free TPO able to bind to MK = ↑ Plt prodn.
139
Where is thrombopoietin produced?
Liver.
140
What happens after damage to the endothelium is done?
1) Platelets adhere to vascular endothelium via collagen & vWF (von Willebrand factor)
2) Binding of platelets to collagen stimulates shape change
3) Activation, leading to the release of platelet granule contents including ADP, fibrinogen, thrombin and calcium. Ends with production of fibrin
4) Aggregation of platelets then occurs, cross-linking by fibrin
5) Activated platelets also provide a negatively charged phospholipid surface, which allows coagulation factors to bind
141
What do platelet granules contain? What is the mechanism of the clotting cascade?
Contents that help the formation of fibrin, and provide a surface for clotting factors Va and Xa to function better.
142
What does Clopidogrel inhibit?
Platelets
P2Y12.
143
What does Tirofiban inhibit?
Platelets
Bp IIbIIIa.
144
What does Aspirin inhibit?
COX-1.
145
What is COX-1 needed to make?
Thromboxane A2 from prostaglandin H2.
146
What is needed to make Arachidonic acid?
P2Y12 and Gp IIbIIIa.
147
What is the platelet dysfunction: clinical features?
**_Mucosal bleeding_**
Epistaxis, gum bleeding, menorrhagia
**_Easy bruising_**
**_Petechiae_**
Red or purple spot on the skin, caused by a minor bleed from broken capillary blood vessels
**_Purpura_**
Red or purple discolored spots on the skin that do not blanch on applying pressure
**_Traumatic haematomas_**
(inc subdural).
148
What are some causes of platelet dysfunction? (TWO)
**_Reduced platelet number (thrombocytopenia)._**
Decrease in production.
Increase in destruction.
**_Normal numbers but reduced function._**
Congenital abnormality in platelet function
Medication e.g aspirin
Von Willebrand disease (reduced VWF activity)
Uraemia
149
What is thrombocytopenia?
Decreased platelet production.
150
What are the different types of thrombocytopenia?
**_Congenital thrombocytopenia_**
Absent / reduced / malfunctioning megakaryocytes in BM
**_Infiltration of bone marrow_**
Leukaemia, metastatic malignancy, lymphoma, myeloma, myelofibrosis.
151
What can cause a decreased production of platelets?
**_Reduced platelet production by bone marrow_**
Low B12 / folate
Reduced TPO (e.g. liver disease)
Medication: Methotrexate, chemotherapy
Toxins: e.g. Alcohol
Infections: e.g. viral (e.g. HIV) TB
Aplastic anaemia (auto immune)
**_Dysfunctional production of platelets in BM_**
Myelodysplasia.
152
What are some causes of increased destruction of platelets?
**_Autoimmune_**
Immune thrombocytopenia (ITP)
Primary, or secondary
**_Hypersplenism_**
Portal hypertension, splenomegaly
**_Drug related immune destruction_**
E.g. Heparin induced thrombocytopenia.
153
What are some diseases which increase destruction of platelets?
Disseminated intravascular coagulopathy (DIC)
Thrombotic thrombocytopenic purpura (TTP)
Haemolytic uraemic syndrome (HUS)
Haemolysis, elevated liver enzymes and low platelets (HELLP)
Major haemorrhage
154
WHAT IS IMMUNE THROMBOCYTOPENIA?
IgG antibodies form to platelet and megakaryocyte surface glycoproteins
Opsonized platelets are removed by reticuloendothelial system
155
What is primary ITP?
May follow viral infection / immunisation esp in children
156
What is secondary ITP?
Occurs in association with some
Malignancies, such as Chronic Lymphocytic Leukaemia(CLL)
Infections e.g. HIV / HepC
157
What is chronic ITP?
Chronic ITP runs a fluctuating course of bleeding, purpura, epistaxis and menorrhagia.
There is no splenomegaly.
158
What are the symptoms for ITP?
Easy bruising
Purpura
Epistaxis (nose bleed)
Menorrhagia (heavy bleed at period)
159
What are the tests for ITP?
Increased megakaryocytes in marrow
Antiplatelet autoantibodies often present
160
How do you treat immune thrombocytopenia?
Corticosteroids i.e. prednisolone
Splenectomy
161
WHAT IS DISSEMINATED INTRAVASCULAR CONGESTION?
https://www.youtube.com/watch?v=Gmh01S0msfY
Small blood clots develop throughout the bloodstream
Blocking small blood vessels maybe causing organ ischemia
Also depleting platelet supply leading to bleeding
162
What is the cause of DIC?
Sepsis
Malginancy
Obstetric complications
Intravascular haemolysis
163
What is DIC also known as and why?
Consumption coagulopathy, consumes platelets and clotting factors
164
What is the normal response to injury?
**_Primary haemostasis_**
Vasocontriction
Platelets then adhere to the damaged endothelial wall
These then activate other platelets and form a plug
**_Coagulation cascade_**
One coagulation factor gets proteolytically cleaved which cleaves other coagulation factors
This then cleaves fibrinogen into fibin which forms a mesh
165
What happens after a clot is formed?
Fibrinolysis
This stops the clot from becoming too big.
166
What normally favours clotting?
Sepsis, malignancy, trauma, obstetrics complications.
**_These favour procoagulants_**
Tissue factor
Lipopolysaccharide.
Enzymes that cleave clotting factors.
167
What is the pathology of DIC?
Underlying malignancy favours clotting
Widespread clot formation leading to
Ischaemia, necrosis and organ damage
Kidneys, Liver, Lungs and Brain.
Depletes clotting factors and platelets
Fibrin degradation products in circulation
Interferes with clot formation
168
What are the symptoms of DIC?
Bleeding
Internal bleeding
Bruising
Ischaemia
169
What are the investigations for DIC?
**_FBC_**
Thrombocytopenia
Low fibrinogen
Prolonged prothrombin time (PT)
Prolonged partial thrombopastin time (PTT)
High d-dimers - Fibrin degradation product
**_Chronic DIC_**
Could look normal due to compensation
170
What does a prolonged prothrombin and prolonged partial thromboplastin time represent?
LOW circulating coagulation factors
171
How do you treat DIC?
Platelets
FFP: contains clotting factors
Cryoprecipitate: contains fibrinogen and some clotting factors
Underlying cause
172
WHAT IS THROMBOTIC THROMBOCYTOPENIC PRUPURA?
In TTP, blood clots form in small blood vessels throughout the body
173
What is the pathophysiology of TTP (Thrombotic thrombocytopenic purpura)?
What is there a defect in?
There is a genetic or acquired deficiency of a protease (ADAMTS13) that normally cleaves multimers of von Willebrand factor (VWF).
Large VWF multimers form, causing platelet aggregation and fibrin deposition in small vessels, leading to microthrombi.
174
What are the causes of TTP?
Idiopathic (40%)
Autoimmunity (eg SLE), cancer, pregnancy, drug associated (eg quinine), bloody diarrhoea prodrome (as childhood HUS), haematopoietic stem cell transplant.
175
What are the tests for TTP?
**_Blood and protein in urine_**
Haematuria/proteinuria
**_Blood film_**
Fragmented RBC
Decrease platelets
Decrease Hb
**_Clotting tests are normal_**
176
What is the treatment for TTP?
Plasma exchange
Steroids
177
WHAT ARE SOME CAUSES OF OVER-ANTICOAGULATION?
Warfarin and Heparin
178
What is HTP?
IgG antibody against platelet-heparin complex
IgG/plt/heparin complex causes pltactivation and THROMBOSIS
179
When does HTP occur?
After Cardiac bypass surgery
180
What are the symptoms of over-anticoagulation?
Bruising
Bleeding
Melena
Epistaxis
Hematemesis
Haemoptysis
181
What is the treatment for HTP and warfarin problems?
Stop drug straight away
182
WHAT IS ANAEMIA?
Reduced red cell mass +/- reduced haemoglobin concentration
183
What are the different types of anaemia?
What are the MCVs for each?
**_Microcytic_**
\<80
**_Normocytic_**
80-100
**_Macrocytic_**
\>100
184
What are the different microcytic anaemias?
Iron deficiency
Haemoglobinopathies e.g. Thalassaemia, sickle cell
Anaemia of chronic disease e.g. CKD and so lack of EPO
185
What are the causes of normocytic anaemia?
Acute blood loss
Combined haematinic deficiency
Anaemia of chronic disease e.g. CKD and so lack of EPO
186
What are the different causes of macrocytic anaemia?
B12/Folate deficiency
Alcohol excess/liver disease
Metabolic disease e.g. hypothyroidism
| (Megaloblastic)
187
What is the normal haemoglobin range?
Male Hb = 131 – 166 g/L
Female Hb = 110 – 147 g/L
188
What are the physiological consequences of anaemia?
Reduced O2 transport
Tissue hypoxia
Compensatory changes
- Increase tissue perfusion
- Increase O2 transfer to tissues
- Increase red cell production
189
What are some pathological consequences of anaemia?
Myocardial fatty change
Fatty change in liver
Aggravate angina/claudication
Skin and nail atrophic changes
CNS cell death (Cortex and basal ganglia)
190
Where are red blood cells removed?
Spleen. Liver. Bone marrow. Blood loss.
191
How long do red blood cells last?
120 days.
192
What are the different types of anaemias?
Microcytic.
Normocytic.
Macrocytic.
193
What are the causes of microcytic anaemia?
Iron deficiency.
Chronic disease.
Thalassaemia.
Rarely
Congenital sideroblastic anaemia.
Lead poising.
194
WHAT IS IRON-DEFICIENCY ANAEMIA?
Anaemia form a lack of iron
195
What type of anaemia is iron-deficiency anaemia?
Microcytic
196
What are the causes of iron-deficiency anaemia?
**_Blood loss_**
eg menorrhagia or GI bleeding
**_Poor diet_**
May cause IDA in babies or children (but rarely in adults), those on special diets, or wherever there is poverty.
**_Malabsorption_**
(eg coeliac disease) is a cause of refractory IDA.
**_Increased demand_**
Pregnant women and child/adolesence
197
What are the signs of iron-deficiency anaemia?
**_Koilonychia_**
Spoon shaped nails
**_Atrophic glossitis_**
Painful tongue
**_Angular stomatitis_**
Corners of mouth inflammed
**_Brittle hair and nails_**
**_RARELY_**
Post-cricoid webs (Plummer-Vinson syndrome).
198
How can you investigate iron deficiency?
**_FBC & film_**
MCV\<80
Variation in size (anisocytosis) & shape (poikilocytosis) of cells.
Low serum iron & ferritin
Low reticulocytes (due to reduced Hb production)
**_High TIBC_**
**_Ix of GI tract_**
**_Coeliac serology_**
199
What is the treatment of iron-deficiency anaemia?
Treat the cause.
Oral iron, eg ferrous sulfate
200
What does an elevated ferritin show?
Inflammation.
201
What is a megaloblast?
A megaloblast is a cell in which nuclear maturation is delayed compared with the cytoplasm.
This occurs with B12 and folate deficiency, as they are both required for DNA synthesis.
202
WHAT IS FOLATE-DEFICIENCY ANAEMIA?
Deficiency in folate
203
Where is folate found?
Green veg, liver, nuts and yeast.
204
What are the causes of folate deficiency?
Dietary
Malabsorption
Increased req (e.g. pregnancy); Folate antagonists
205
What are the tests for folate deficiency?
**_Low folate_**
**_Low Hb_**
**_Film_**
Hypersegmented polymorphs and Megaloblasts
206
What is the treatment of folate-deficiency anaemia?
Folic acid supplements
With B12
207
WHAT IS B12 DEFICIENCY?
Deficiency in B12
208
What food is B12 in? How long do our body stores of B12 last?
Found in meat, fish & dairy products. NOT in plants!!
Body stores last 4yrs! (in liver)
209
How is B12 abosrbed and what is produced in a deficiency?
Binds to intrinsic factor & absorbed in terminal ileum
Prod of DNA impaired w deficiency
Decreased RBC prod.
210
What are the causes of B12 deficiency?
**_Dietary_**
Vegans
**_Malabsorption_**
Crohn's
Coelaic
Gastritis
**_Congenital metabolic errors_**
211
How can you investigate B12 deficiency?
**_Blood film:_**
Megoblasts and hypersegmented polymorphs
**_Bone marrow biopsy:_**
IF antibodies
Schilling test (medical procedure used to determine whether you're absorbing vitamin B-12 properly)
212
What is the treatment of B12 deficiency?
Vitmain B12 injections or tablets
213
WHAT IS PERNICIOUS ANAEMIA?
This is caused by an autoimmune atrophic gastritis, leading to achlorhydria and lack of gastric intrinsic factor secretion.
214
What is pernicious anaemia associated with?
Other autoimmune diseases: thyroid disease, vitiligo, Addison’s disease, hypoparathyroidism.
215
What are the tests for pernicious anaemia?
Intrinsic factor (IF) antibodies
MCV increase
Serum B12 lower
Reticulocytes lower or normal as production impaired,
Hypersegmented polymorphs
Megaloblasts in the marrow
216
What is the treatment of pernicious anaemia?
Treat the cause if possible.
If a low B12 is due to malabsorption, injections are required.
Replenish stores with hydroxocobalamin (B12)
If the cause is dietary, then oral B12 can be given after the initial acute course.
217
WHAT DOES BONE MARROW DO?
The marrow is responsible for haemopoiesis. In adults, this normally takes place in the central skeleton (vertebrae, sternum, ribs, skull) and proximal long bones. In some anaemias (eg thalassaemia), increased demand induces haematopoiesis beyond the marrow (extramedullary haematopoiesis), in liver and spleen, causing organomegaly.
218
What is pancytopenia?
Pancytopenia is reduction in all the major cell lines:
Red cells
White cells
Platelets
219
WHAT IS APLASTIC ANAEMIA?
PANCYTOPENIA w. HYPOCELLULARITY (aplasia) of the bone marrow.
220
What is the pathology of aplastic anaemia?
Decreased number of pluripotent stem cells.
BM replaced by fat.
221
What are the causes of aplastic anaemia?
Mostly AI
Triggered by drugs
Irradiation
Fanconi anaemia (=inherited form)
Infections.
222
What is the test for aplastic anaemia?
**_BM exam for dx_**
HYPOCELLULAR
**_FBC_**
Pancytopenia
**_Film_**
223
What is the treatment for aplastic anaemia?
Withdrawal of offending agent, supportive care & some definitive tx:
Blood & platelet transfusions
Prophylactic ABX/prompttx of infections
**_\<40yo (curative)_**
Bone marrow transplant
**_\>40yo_**
immunosuppression w. anti-thymocyteglobulin & ciclosporin.
224
WHAT ARE THE MYELOPROLIFERATIVE DISORDERS?
These are caused by proliferation of a clone of haematopoietic myeloid stem cells in the marrow.
While the cells proliferate, they also retain the ability to differentiate into RBCS, WBCS or platelets.
225
What are the different myeloproliferative disorders?
RBC
Polycythaemia rubra vera (PRV)
WBC
Chronic myeloid leukaemia (CML, p352)
Platelets
Essential thrombocythaemia
Fibroblasts
Myelofibrosis
226
What is the haematicrit?
Cells that sink to the bottom of a tube when centrifuged.
227
WHAT IS POLYCYTHAEMIA RUBRA VERA?
https://www.youtube.com/watch?v=vOPuAPCioE4
Deficiency of the bone marrow, produces too many red blood cells.
Genetic disorder.
228
What is the cause of PRV?
What is the gene in primary?
**_Primary_**
Polycythaemia Rubra Vera (PRV)
JAK2 gene - increased sensitivty to EPO
**_Reactive/secondary_**
EPO excess, altitude, lung disease
229
How does PRV present like?
May present with no symptoms
May have
Easy bleeding/bruising
Fatigue
Dizziness
Headaches
230
What are the investigations for PRV?
FBC
Bone marrow biopsy
Genetic testing for JAK2 gene
231
How can you treat PRV?
**_Polycythaemia vera_**
Blood letting
Aspirin
**_Secondary_**
Treat the cause!
232
WHAT IS MALARIA?
Biology Spread: fig 2. Plasmodium protozoa injected by
Anopheles mosquitoes multiply in RBCS causing haemolysis, RBC sequestration and cytokine release.
233
What is fever paroxysms?
Fever paroxysms reflect synchronous release of flocks mero-
zoites from mature schizonts (fig 2).
3 phases:
1 Shivering (1h): “I feel so cold.”
2 Hot stage (2–6h): T≈41°C, flushed, dry skin; nausea/vomiting; headache.
3 Sweats (~3h) as T° falls.95
234
What are the signs of malaria?
Anaemia, jaundice, and hepatosplenomegaly. No rash or lymphadenopathy.
Anaemia is common, eg from haemolysis of parasitized RBCS (often serious in children). Thrombocytopenia.
235
What is the diagnosis of malaria?
Serial thin & thick blood films (needs much skill, don’t always believe –ve reports, or reports based on thin film examination alone); if P. falciparum, you must know the level of parasitaemia. Rapid stick tests are available if microscopy cannot be performed or previously treated seriously ill patient: see p383 for ParaSight F®. Serology is not useful. Other tests: FBC (anaemia, thrombocytopenia), clotting (DIC, p346), glucose (hypoglycaemia), ABG/lactate (lactic acidosis), U&E (renal failure), urin- alysis (haemoglobinuria, proteinuria, casts), blood culture to rule out septicaemia.
236
What is the treatment for malaria?
If the patient has taken prophylaxis, don’t use the same drug for treat- ment. If species unknown or mixed infection, treat as P. falciparum. Nearly all P. falciparum is resistant to chloroquine and in many areas also to Fansidar® (py- rimethamine + sulfadoxine). If in doubt, consider as resistant. Chloroquine103 is 1st choice for benign malarias in most parts of the world, but chloroquine-resistant P. vivax occurs in Papua New Guinea, Indonesia, parts of Brazil, Colombia and Guy- ana.104Neverrelyonchloroquineifusedaloneasprophylaxis.
