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Year 5 Pathology > Haematology > Flashcards

Flashcards in Haematology Deck (300):
1

Anticoagulant molecules expressed by the vessel wall

Thrombomodulin
Endothelial protein C receptor
Tissue factor pathway inhibitor
Heparans

2

Antiplatelet factors expressed by the vessel wall

Prostacyclin
Nitrous Oxide

3

Effects of inflammation which make vessel wall prothrombotic

Downregulation of anticoagulant molecules
Upregulation of adhesion moiecules
Expression of tissue factor
Reduced prostacyclin production

4

Effects of stasis (of blood flow) that create a prothrombotic environment

Accumulation of activated factors
Promotes platelet adhesion
Promotes leukocyte adhesion and transmigration
Hypoxia produces inflammatory effect on endothelium

5

Causes of stasis (of blood flow)

Immobility: surgery, paraparesis, travel
Compression: Tumour, pregnancy
Viscosity: Polycythaemia, paraprotein
Congenital: Vascular abnormalities

6

Clotting factor increased in pregnancy:

Factor VIII

7

Bence Jones proteins are Ig...

IgG

8

Multiple myeloma is a neoplasia of which cells?

Plasma cells (effector B cells)

9

B cell differentiation and maturation (in germinal centre). Name cells starting with antigen activated B cell to mature fully differentiated plasma cell

Antigen activated B cell
Centroblast
Plasmablast
Plasma cell

10

The premalignant state of multiple myeloma is...

Monoclonal gammopathy of undetermined significance (MGUS)

11

Monoclonal gammopathy of undetermined significance (MGUS) is...

The premalignant state of multiple myeloma. It carries most of the key genetic abnormalities of MM such as translocations but the cells do not do much harm. Sit in the bone marrow and secrete.

(The older we are the more likely we have it)

12

Chromosomal abnormalities common in multiple myeloma (2)

Translocations between chromosome 14 at locus 32 and an oncogene (seen in 50%)
Deletions of parts of chromosome 13 (seen in 50%)

13

Key clinical features of myeloma

Calcium elevated: thirst, bones, moans, stones, groans,
Renal failure (plus amyloidosis and nephrotic syndrome)
Anaemia (and pancytopenia): fatigue, infections
Bones: pain, osteoporosis, osteolytic lesions, wedge compression fractures (back pain), pepper pot skull (more correct: raindrop skull), hyperviscosity syndrome.

Infections

14

Key investigations (and results) for multiple myeloma

Serum electrophoresis: Dense narrow band
Blood film: Rouleaux
Urine: Bence-Jones protein
ESR: Very high
Bone marrow: >10% plasma cells in bone marrow
Monoclonal plasma cells

15

Staging system of multiple myeloma

Durie-salmon

16

Criteria for MGUS

Monoclonal serum protein 70y)

17

Multiple myeloma:
a) median age at diagnosis
b) Most common in which racial group?

65-70
Black people

18

Multiple myeloma immunophenotypes:
a) MM cells are typically positive for
b) MM cells are typically negative for

a) CD38, CD138, CD56/58, monotypic cytoplasmic Ig
b) CD19, CD20, surface Ig, light chain restriction

19

Features of "smouldering myeloma"

>10% plasma cells in BM but no CRAB/organ/tissue involvement.

CRAB= raised calcium, renal failure, anaemia, bone pathology

20

Features of myeloma bone disease:

Lytic lesions
Low bone density
Pathological fractures
Spinal cord compression (paralysis)
Hypercalcaemia (renal failure)
Bone pain

21

Explain relationship between multiple myeloma and bone disease

Plasma cells secrete cytokines that activate osteoclasts and cytokines that inhibit osteoblasts. Osteoclasts stimulate osteoclasts. So treating myeloma bone disease is very important.

Osteoclast activating: RANK-L, MIP1-alpha, TNFalpha. IL-6, IL-3

Osteoblast inhibiting: Dkk-1, sFRP3, HGF, TGF-beta1, sclerostin

22

Briefly describe pathogenesis of myeloma nephropathy

Light chains of paraproteins precipitate in the kidneys, they form a glue and block normal flow. Induces an inflammatory response that leads to kidney failure.

23

Treatment of multiple myeloma

Steroids
Classical cytostatic drugs e.g. melphalan
Proteosome inhbitors
IMIDs: e.g. thalidomide
Supportive treatment for CRAB

Autologous stem cell transplantation (makes use of high dose melphalan)

24

Mechanism of action of melphalan

Alkylating agent (nitrogen mustard type).
Adds alkyl group to DNA (guanine) forming crosslinks and therefore blocks DNA replication.

25

Mechanism of action of proteosome inhibitors

Proteosome in the cell degrades damaged/unnecessary proteins into amino acids ready to reenter protein production.

Misfolding of (large proteins happens when you have to fold a large amount of protein. The proteins are non-functional and precipitate easily and clog up the ER killing the cell. The proteins are exported and degraded by the ER. If the proteosome is inhibited you get a backlog of this protein, increasing the chance of it clogging the ER and killing the cell. Also causes a shortage of amino acids to create new protein.

26

Examples of proteosome inhbitors

Bortezomib, carfilzomib, and ixazomib

27

% of multiple myeloma patients with lytic lesions or low bone density

80-90%

28

Features of Waldenstrom's macroglobuinaemia
Histology, clinical,

AKA lymphoplasmacytoid lymphoma

Increased risk in elderly men
Lymphoplasmacytoid cells produce monoclonal iGM that infiltrates lymph nodes and bone marrow
Weight loss, fatigue, hyperviscosity (visual problems, confusion, CCF, muscle weakness)

29

Treatment of Waldenstrom's macroglobuinaemia

Plasmaphoresis for hyperviscosity
Chlorambucil, cyclophosphamide and other chemo

30

FBC changes in pregnancy

Mild anaemia (dulutional effect)
Macrocytosis (but beware folate deficiency)
Neutrophilia
Thrombocytopenia (increased platelet size as younger platelets are released)

31

Consequences of iron deficiency in pregnancy

Iron deficiency may cause IUGR, prematurity, postpartum haemorrhage

32

The recommended daily allowance of iron in pregnancy is

30mg

33

WHO recommendations for iron and folate supplementation in pregnancy

60mg iron
400mcg folic acid

34

Folic acid should be taken in pregnancy until at least... weeks

12

35

Causes of reduced platelet count in preganancy

Physiological: ‘gestational’/incidental thrombocytopenia (most likely if plt between 100-150)
Pre-eclampsia
Immune thrombocytopenia (ITP)
Microangiopathic syndromes
All other causes: bone marrow failure, leukaemia, hypersplenism, DIC etc.

36

Mangement of ITP in pregnancy

IVIG
Steroids
Anti-D (where Rh-D +ve)
Avoid ventouse delivery due to effect of ITP on baby (bleeding risk)

37

Features of microangiopathic haemolytic anaemia on blood film

Thrombocytopenia
Schistocytes(red cell fragment)
Anaemia

38

Brief pathophysiology of microangiopathic haemolytic anaemia

Formation of a fibrin/platelet mesh in small vessels. Damage to RBCs as they are forced through (form schistocytes)

39

Causes of microangiopathic haemolytic anaemia

Autoimune: Thrombotic thrombocytopaenic purpura
Haemolytic uraemic syndrome
DIC
Pre-eclampsia
Eclampsia

40

What is HELLP syndrome

A variant of pre-eclampsia. Abbreviation of 3 main characteristics
Hemolysis
Elevated Liver enzymes
Low Platelet count

Usually begins in 3rd trimester
High fetal/infant mortality

41

Causes of thrombocytopenia in pregnancy.
Which are definitively treated by delivery of the baby

TTP
HUS
HELLP
Pre-eclampsia

HELLP
Pre-eclampsia

42

Coagulation changes in pregnancy (changes in coagulation factors)

Factor VIII and vWF increase 3-5 fold
Fibrinogen increases 2 fold
Factor VII increases 0.5 fold
(Factor X)
RESULT IN HYPERCOAGULABLE STATE

Protein S falls to half basal
PAI-1 increase 5 fold
PAI-2 produced by placenta

RESULT IN HYPOFIBRINOLYTIC STATE

43

DVT in pregancy is more common on which side

Left
Because of reduced venous return

44

Risk factors for DVT in pregnancy

Hyperemesis/dehydration
Bed rest
Obesity
- BMI>29 3x risk of PE
Pre-eclampsia
Operative delivery
Previous thrombosis/thrombophilia
Age
Parity
Multiple pregnancy
Other medical problems:
-HbSS, nephrotic syndrome
IVF: ovarian hyperstimulation

45

Warfarin is most teratogenic in which trimester

1st

46

Complications in pregnancy associated with thrombophilia

Fetal growth restriction (IUGR)
Recurrent miscarriage
Late fetal loss
Placenetal abruption
Severe pre-eclampsia

Possibly due to impaired placental circulation

47

Heparin and aspirin can prevent complications in pregnancy associated with which thrombophilia?

Antiphospholipid syndrome
(in women with recurrent pregnancy loss)

48

Post partum haemorrhage is defined as...

>500ml blood loss

49

Haematological factors affecting risk of post-partum haemorrhage

Dilutional coagulopathy
DIC in abruption
Amniotic fluid embolism

50

DIC in pregnancy can be triggered by...

Amniotic fluid embolism
Placental abruption
Retained dead fetus
Preeclampsia (severe)
Sepsis

51

Signs associated with amniotic fluid embolism

Sudden onset shivers, vomiting, shock. DIC

52

Haemoglobinopathy associated with hydrops fetalis

Alpha 0 thalassaemia

53

Complications in pregnancy associated with sickle cell disease

Fetal growth restriction
Miscarriage
Preterm labour
Pre-eclampsia
Venous thrombosis

Increased frequency of vaso-occlusive crises

54

Managament of sickle cell disease in pregnancy

Red cell transfusion (top up or exchange)

Prophylactic transfusion:
reduces number of vaso-occlusive episodes
Not clear whether affects fetal or maternal outcome

Alloimmunisation -extended phenotype: Rh D c E, Kell

55

RBC count in:
a) iron deficiency anaemia
b) Thalassaemia trait

a) Low or normal
b) Increased

56

Causes of anaemia with low MCV

Iron deficiency
Thalassaemia trait
Anaemia of chronic disease

57

Presence of poikilocytes and anaemia suggests...

Iron deficiency

58

Anisopoikilocytosis and anaemia suggests...

iron deficiency

59

Basophilic stippling and anaemia suggests

Beta thalassaemia trait
Lead poisoning
Alcoholism
Sideroblastic anaemia

60

Neutrophils should contain a maximum of... segments

Five

61

Target cells are also known as

codocytes

62

Presence of target cells suggests

Iron deficiency
Thalassaemia
Hyposplenism
Liver disease

63

Howell-Jolly bodies are seen in

Hyposplenism

64

Causes of a poorly functioning spleen include...

Inflammatory bowel disease
Coeliac disease
Sickle cell disease
SLE

65

B12 is absorbed from the...

terminal ileum

66

Should be measured before starting a transfusion of blood products

Baseline temp, pulse, respiratory rate,BP

67

Most acute transfusion reactions will occur in within the first.... (duration) of a transfusion

15 minutes

68

Probable cause?
During or soon after transfusion (blood or platelets), rise in temperature of 1 degree, chills, rigors.

Febrile non-haemolytic transfusion reaction

69

Cause of febrile non-haemolytic transfusion reaction

White cells in blood products. The patient forms antibodies against them.

70

Treatment of febrile non-haemolytic transfusion reactions

Have to stop or slow transfusion
Treat with paracetamol
Can restart transfusion

71

Symptoms and signs of acute intravascular haemolysis

Restless, chest/ loin pain, fever, vomiting, flushing, collapse, haemoglobinuria (later)

72

The intravascular haemolysis due to ABO incompatible blood is mediated by....

complement

73

Antibodies involved in intravascular haemolysis

IgM

74

Cause of delayed haemolytic transfusion reaction.

Initially alloimmunisation occurs: the patient develops an immune antibody to the foreign antigen in the product.
Then if they are exposed to it again through another transfusion the antibodies will trigger extravascular haemolysis. The haemolysis is driven by phagocytes.

75

Clinical features of a delayed haemolytic transfusion reaction

Increased bilirubin
Increased reticulocytes
Decreased Hb
Haemoglobinuria
Can cause renal failure
May require additional transfusion

76

Treatment of delayed haemolytic transfusion reaction

Repeat cross match
Treat renal failure
May require another transfusion

77

3 causes of anaphylactic transfusion reaction

Previous exposure to an antigen, develop IgE antibody and react on next exposure (classically IgA deficiency)

IgE antibody passively transferred by transfusion

Antigen passively transferred by transfusion and patient has IgE antibody

78

Requirements for a diagnosis of transfusion associated circulatory overload

Any FOUR of the following that occur within SIX HOURS of transfusion:

Acute respiratory distress
Tachycardia
Increased blood pressure
Acute or worsening pulmonary oedema
Evidence of a positive fluid balance

79

What is TR-ALI

Transfusion associated acute lung injury:

Acute dyspnoea with hypoxia and bilateral pulmonary infiltrates during or within 6 hours of transfusion, not due to circulatory overload or other likely causes

80

Pathogenesis of Transfusion associated acute lung injury

Donor anti-leucocyte antibodies (HLA or anti-granulocyte Abs)
Interact with patient’s leucocyte antigens
Aggregates of white blood cells get stuck in the pulmonary small capillaries
Release neutrophil proteolytic enzymes and toxic oxygen metabolites causes lung damage

Mechanism not fully understood, antibodies do not always cause problems

81

How do we prevent transfusion associated acute lung injury?

Don’t give plasma from female donors:
Most FFP is male donor
If platelets are pooled from 4 donors, the plasma they are resuspended in is from a male donor
Virally inactivated FFP (pooled, solvent detergent treated) does not cause TRALI

Stop unnecessary use of FFP:
Use vitamin K or PCC/Octaplex for reversing warfarin

82

Which group of patients are most susceptible to transfusion related GvHD and how is it prevented?

Immunosupressed patients
or
If donor HLA matched or HLA-similar to the recipient

Prevention: Irradiate donor blood

83

What is Post Transfusion Purpura?

Purpura appears 7-10 days after transfusion of blood or platelets and usually resolves in 1 to 4 weeks but can cause life threatening bleeding

Affects HPA -1a negative patients
(HPA is human platelet antigen)

84

Treatment of post transfusion purpura

IVIG
and maybe HPA-1a negative platelets

85

Pathogenesis of haemolytic disease of the foetus and newborn

RhD negative mother pregnant with RhD positive foetus, foetal blood crosses placenta.

Mother develops antibodies against RhD 6 months later

Pregnant again with RhD positive foetus, the antibodies against RhD cross placenta into the foetus.

The antibodies coat the RhD positive foetal red cells and destroy them in the foetal spleen and liver.

Note: only IgG can cross placenta

86

Clinical features of haemolytic disease of the foetus and newborn

Fetal anaemia (haemolytic)

Haemolytic disease of newborn (anaemia plus high bilirubin - which builds up after birth as no longer removed by placenta)

87

Treatment of pregnancy when mother is alloimmunised to RBC antigens

All pregnant women Group and Antibody screen at around 11 weeks (booking) and again at 28 weeks to check for RBC antibodies
If RBC antibody present, quantify, check partner and monitor level of antibody (high or rising - more likely to affect fetus)
Monitor fetus for HDN – MCA Doppler ultrasound
Deliver baby early, as HDN gets a lot worse in last few weeks of pregnancy

If necessary, intra-uterine transfusion can be given to fetus

At delivery - monitor baby’s Hb and bilirubin for several days as HDN can get worse for few days

Can give exchange transfusion to baby if needed to bilirubin and Hb; plus phototherapy to bilirubin
Note: subsequent pregnancies usually worse

88

Mechanism of action of prophylactic anti-D Immunoglobulin

RhD positive (fetal) red cells get coated with anti-D Ig and then they get removed by the mother’s reticuloendothelial system (spleen) before they can sensitise the mother to produce anti-D antibodies

89

Times when fetomaternal bleed likely to occur

spontaneous miscarriages if surgical evacuation needed and therapeutic abortions
amniocentesis and chorionic villous sampling
abdominal trauma (falls and car accidents)
external cephalic version (turning the fetus)
stillbirth or intrauterine death

90

Doses of anti-D used after events likely to cause fetomaternal bleed

At least 250 iu - for events before 20 weeks of pregnancy
At least 500 iu - for events after 20 weeks of pregnancy
and at delivery

91

Doses (and timing) of anti-D given as prophylaxis during pregancy

At least 500 iu anti-D Ig at 28 and 34 weeks or 1500 iu anti-D Ig at 28-30 weeks

92

Antibodies that can cause severe haemolytic disease of the newborn

Anti-D
Anti-c
Anti-Kell

93

Effects of anti-Kell antibodies on a foetus

Haemolysis
Reticulocytopenia

94

Risk factors for lymphoma

Constant antigenic stimulation
Infection (viral infection of cells)
Immunosupression (HIV and immunosupressants)

95

Examples of conditions in which chronic antigenic stimulation leads to lymphoma

H. Pylori: Gastric MALT
Coeliac disease: Small bowel T cell lymphoma
Sjogren's syndrome: Parotid lymphoma
Hashimoto's thyroiditis: Thyroid marginal zone lymphoma

96

Viral infections that increase lymphoma risk

EBV infects B cells, carrier state regulated by T cells. T cells supressed by immunosupressants.
HIV: EBV infects B cells, HIV leads to loss of T cell regulation of infected B cells
HTLV1: Direct viral integration. Infects T cells by vertical transmission. May develop adult T cell leukaemia

97

Lymphoma associated translocations involve which locus

Ig promoter

98

Within a lymohoid follicle the mantle zone contains...

Naive unstimulated B cells

99

Most common type of non-hodgkin lymphoma

B cell

100

Types of Hodgkin lymphoma

Classical
Lymphocyte predominant

101

Types of Non-Hodgkin lymphoma

B cell
Precursor B cell neoplasms
Peripheral B cell neoplasms (high and low grade)

T cell
Precursor T cell neoplasms
Peripheral T cell neoplasms

102

Types of lymphoma that begin in the germinal centre

Follicular lymphoma
Burkitt's lymphoma
Diffuse large B cell lymphoma
Hodgekin lymphoma

(also multiple myeloma)

103

Types of lymphoma that begin in the mantle centre

Mantle cell lymphoma

104

Types of lymphoma that begin in the marginal zone

Diffuse large B cell lymphoma
Marginal zone lymphoma
Small lymphocytic lymphoma
Chronic lymphocytic lymphoma

105

Differentiating between B and T cells. B cells express CD... T cells express CD...

B cells: CD20
T cells: CD3 and CD5

106

High grade non-hodgkin lymphomas

Diffuse large B cell lymphoma

107

Low grade non-hodgkin lymphomas

Follicular lymphoma
Marginal zone lymphoma
Mantle zone lymphoma
Small lymphocytic lymphoma/chronic lymphocytic leukaemia

108

Key clinical features of follicular lymphoma

Middle age/ old age
Lymphadenopathy

109

Key histological features of follicular lymphoma

Follicular pattern
Germinal centre origin
CD10, bcl2

110

Translocation seen in follicular lymphoma

14;18 translocation involving bcl2 gene

111

Key clinical features of small lymphocytic lymphoma

Middle age/ elderly
Nodes or blood

112

Key histological features of small lymphocytic lymphoma

Small lymphocytes
Naive or post germinal centre memory B cell
Express CD5 and CD23

113

MALT lymphoma affects which cells

Post germinal centre memory B cells

114

Key clinical features of mantle cell lymphoma

Male predominance
Lymph nodes and GI tract
Disseminated disease at presentation

115

Key histological features of mantle cell lymphoma

Located in mantle zone
Pre-germinal centre naive B cells
Aberrant CD5 and cyclin D1 expression
Cyclin D1 overexpression

116

Clinical features of Burkitt's lymphoma

Seen in children and young adults
Endemic type (equatorial Africa, EBV associated)
Sporadic type (outside Africa, EBV associated),
Immune deficiency type (Non-EBV associated, HIV/post transplant)
Associated with EBV

117

Key histological features of Burkitt's lymphoma

Germinal centre cell origin
Starry sky appearance

118

Translocation seen in Burkitt's lymphoma

c-myc translocations
8:14
2:8
8:22

119

Key clinical features of diffuse large B cell lymphoma

Middle age/ elderly
lymphadenopathy

120

Key histological features of diffuse large B cell lymphoma

Germinal centre or post-germinal centre B cell
Sheets of large lymphoid cells

Germinal centre phenocyte= good prognosis
P53 positive, high proliferation fraction= poor prognosis

121

Enteropathy associated T cell lymphoma is associated with...

Coeliac disease

122

Features of peripheral T cell lymphomas

Middle age/ elderly
Lymphadenopathy and extranodal sites
Large T cells
Often associated with reactive cell population e.g. eosinophils
Aggressive

123

Most common form of cutaneous T cell lymphoma

Mycosis fungoides
(also known as Alibert-Bazin syndrome)

124

Key features of anaplastic large cell lymphoma

Clinical:
children and young adults
Lymphadenopathy

Histology
Large epithelioid lymphocytes
T cell or null phenotype

Molecular
t (2;5) translocation
Alk-1 protein expression (better prognosis if positive)

Aggressive

125

Key differences between Hodgkin and NH lymphoma

Spread:
Hodgkin spreads contigiously to adjacent lymph nodes
NHL spreads discontinuously

Locations:
HL: more often localised to a single nodal site
NHL: More often involves multiple lymph node sites

126

Key clinical features of classical Hodgkin lymphoma

Young and middle aged
Male predominance
Often involves single lymph node group
EBV associated
Moderately aggressive

127

Key histological features of classical Hodgkin lymphoma

Germinal centre/post germinal centre B cell origin
Sclerosis
Mixed cell population with scattered Reed-Sternberg and Hodgkin cells with eosinophils

128

Key clinical features of nodular lymphocyte predominant Hodgkin lymphoma

Isolated lymphadenopathy
NO association with EBV

129

Key histological features of nodular lymphocyte predominant Hodgkin lymphoma

Germinal centre B cell
B cell rich nodules with lymphocytic & histiocytic cells

130

Clinical features/presentation of Hodgkin lymphoma

Male predominance
Bimodal age incidence: 20-29 and >60
Painless lymphadenopathy (asymmetrical)
Constitutional symptoms: fever, weight loss, night sweats, pruritus, fatigue
Pel-Ebstein fever (cyclical 1-2 week)
Pain in affected nodes after alcohol

131

Staging of Hodgkin lymphoma

Stage 1: one lymph node region (can include spleen)
Stage 2: two or more LN regions on same side of diaphragm
Stage 3: two or more LN regions on opposite sides of the diaphragm
Stage 4: extranodal sites (liver, BM)

A: No constitutional symptoms (fever, unexplained weight loss, night sweats)
B: Constitutional symptoms

132

What is a Reed-sternberg cell

Bi-nucleate/multinucleate (owl eyed) cell on a background of lymphocytes and reactive cells.
Associated with Hodgkin Lymphoma

133

Imaging used in Hodgkin lymphoma

CT/PET

134

Chemotherapeutic combination used in Hodgkin lymphoma

Adriamycin (doxorubicin)
Bleomycin
Vincristine
Dacarbazine/DTIC

Every 4 weeks

135

Long term adverse affects of chemotherapy used to treat Hodgkin lymphoma

Pulomary fibrosis
Cardiomyopathy

(Preserves fertility)

136

Secondary malignancies seen after radiotherapy for Hodgkin lymphoma

Breast
Leukaemia
Lung
Skin

137

Hodgkin lymphoma:
Over...% of patients with stage 1 or 2 disease are cured
Around.... % of patients with stage 4 are cured

80%
50%

138

Clinical features/presentation of NH lymphoma

Painless lymphadenopathy often involving multiple sites
Constitutional symptoms (fever, weight loss, night sweats, etc)
NO pain after alcohol

139

Very aggressive Non-hodgkin lymphomas

Burkitt's

140

Treatment of diffuse large B cell lymphoma

Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisolone

141

Follicular Non-Hodgkin lymphoma prognosis

Incurable
Survival median 12-15 years (with chemo)

142

What is bcl2?

Anti-apoptosis protein

143

Laboratory findings in CLL

Lymphocytosis between 5 and 300 x 109/l
Smear cells
Normocytic normochromic anaemia
Thrombocytopenia

Bone marrow: Lymphocytic replacement of normal
marrow elements

Proliferation of mature B cells (CD19) co-expressing CD5

144

CD35 expressed by which type of B cell

Plasma cell

145

Name 2 systems used for staging CLL

Rai
Binet

146

Outline Rai staging system

Used to stage CLL
Stage 0 Lymphocytosis only

Stage 1 lymphocytosis plus lymphadenopathy

Stage 2 lymphocytosis plus hepatosplenomegaly +/- lymphadenopathy

Stage 3 lymphocytosis plus anaemia with or without lymphadenopathy, hepatomegaly, or splenomegaly

Stage 4 lymphocytosis + thrombocytopenia

147

Prophylaxis against infections in CLL patients

Aciclovir
PCP prophylaxis for those receiving fludarabine or alemtuzumab (Campath)
IVIG is recommended for those with hypogammaglobulinemia and recurrent bacterial infections
Immunisation against pneumococcus, and seasonal flu

148

50% of CLL deaths are due to

Infection

149

Treatment of autoimmune phenomena in CLL

1st line: steroids
2nd line: Rituximab

150

Indications for treating CLL (instead of watching and waiting)

Progressive lymphocytosis:
>50% increase over 2 months
lymphocyte doubling time

151

Treatment of CLL with 17p deletion

BCR kinase inhibitor

152

Treatment of CLL (if not 17p deletion)

Rituximab+ Fludarabine+ Cyclophosphamide (FCR)

Add bendamustine and BCR inhibitor of relapse

153

Transformation of low grade to high grade lymphoma is known as

Richter transformation

154

Treatment of Richter's syndrome

Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisolone

155

Outline Binet staging system

Clinical staging system for CLL
A: Less than 3 lymphoid areas
B: More than 3 lymphoid areas
C: Anaemia / low platelets

156

Causes of a relative polycthaemia

Alcohol
Diuretics
Obesity

157

Causes of APPROPRIATE raised EPO

High altitude
Hypoxic lung disease
Cyanotic heart disease
High affinity haemoglobin

158

Causes of INAPPROPRIATE raised EPO

Renal disease (cysts, tumours inflammation)
uterine myoma
other tumours (liver, lung1)

159

Mutations associated with polycythaemia vera

JAK2 gene (acquired point mutations)
Calreticulin gene (acquired insertions and deletions, which activate STAT5 by unknown mechanism)

160

Average age of polycythaemia vera diagnosis

60
Also slightly more common in males

161

Presentation of polycythaemia vera

Incidental diagnosis on routine blood testing

Symptoms of increased hyper viscosity:
Headaches, light-headedness, stroke, Thrombosis, retinal vein engorgement
Visual disturbances
Fatigue, dyspnoea

Increased histamine release:
Aquagenic pruritus
Severe burning pain in the hands and feet with a reddish or bluish skin discolouration
Peptic ulceration

Plethora
Gout: due to red cell turnover and overproduction of uric acid
Splenomegaly

162

Treatment of polycythaemia

Reduce viscosity: venesection, hydroxycarbamide
Reduce risk of thrombosis: aspirin (keep platelets below 400)

163

Epidemiology (age and sex) of polycythaemia vera

Mean age two peaks 55 years and minor peak 30 years
Females :males equal first peak but females predominate second peak

164

Presentation of essential thrombocythaemia

Incidental finding in half the patients

Thrombosis: arterial or venous, so:
CVA, gangrene, TIA
DVT or PE

Bleeding: mucous membrane and cutaneous
Minor: headaches, dizziness visual disturbances
Splenomegaly usually modest

165

Treatment of essential thrombocythaemia

Aspirin: to prevent thrombosis
Anagrelide: specific inhibition of platelet formation from megakaryocytes, side effects include palpitations and flushing (Possible myelofibrosis risk?)
Hydroxycarbamide: antimetabolite. Suppression of other cells as well. Possible mildly leukaemogenic

166

Essential thrombocythaemia is associated with mutation of...

JAK2 gene

167

Long term complications of essential thrombocythaemia

Risk of myelofibrosis development
Leukaemic transformation in about 5% after >10 years

168

Chronic idiopathic myelofibrosis involves proliferation of which cells?

Mainly of megakaryocytes and granulocytic cells

169

Myelofibrosis can be secondary. A progression from

Essential thrombocythaemia or polycythaemia vera

170

Myelofibrosis (idiopathic) usually develops at what age

7th decade

171

Classical triad of Budd-Chiari syndrome

Abdominal pain
Ascites
Liver enlargement

172

Presentation of idopathic myelofibrosis

Incidental in 30%

Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massive
Budd-Chiari syndrome
Hepatomegaly

Hypermetabolic state:
Weight loss
Fatigue and dyspnoea
Night sweats
Hyperuricaemia

173

Budd-Chiari syndrome is caused by....

Occlusion of the hepatic vein

174

Investigations and diagnosis of myelofibrosis

Blood film: tear-drop poikilocytes (dacrocytes) and leukoerythroblasts.
Giant platelets
Circulating megakaryocytes

Bone Marrow: dry tap
Trephine biopsy:
Increased reticulin/collagen fibrosis. Megakaryocyte hyperplasia and clustering. New bone formation.

Liver and spleen:
Extramedullary haemopoiesis in spleen and liver

175

Treatment of myelofibrosis (and problems)

Blood products:
Platelet transfusions often ineffective
Splenomegaly makes RBC transfusions increasingly difficult
Splenectomy: often hazardous and can lead to worsening of the condition

Hydroxycarbamide: may lead to worsening of anaemia
Ruxolotinib: a JAK2 inhibitor
, thalidomide, steroids,
allogenic stem cell transplant: may be curative. Young patients only. Experimental.

176

Key features of pre-fibrotic and fibrotic stage of myelofibrosis

Pre-fibrotic: blood changes mild and may be confused with essential thrombocythaemia. Hypercellular marrow.

Fibrotic: Splenomegaly and blood changes. Dry BM tap. Prominent collagen fibrosis. Later Osteosclerosis

177

Ruxolotinib is...

JAK 2 inhibitor.
Used in myelofibrosis

178

Clinical features of CML

M:F 1.4:1

• 40-60 years

• Weight loss, lethargy, night sweats

• Splenomegaly

• Features of anaemia

• Bruising/bleeding

• Gout

179

Stages of maturation from blast cell to neutrophil

Myeloblast, promyelocyte, metamyelocyte, Band cell, neutrophil

180

Laboratory features of CML

•Leucocytosis between 50 – 500x109/l
Mature myeloid cells
Bi phasic peak Neutrophils and myelocytes
Basophils
No excess (

181

Genetic mutation found in large proportion of CML patients

translocation 9;22

Translocation of part of long arm of chromosome 22 to chromosome 9 and reciprocal translocation of part of chromosome 9 to chromosome 22.

The latter involves transfer of the ABL oncogene to a breakpoint cluster (BCR) region of chromosome 22. This creates the Philadelphia chromosome, and leads to creation of a fusion gene that leads to synthesis of abnormal ABL protein with tyrosine kinase activity higher than normal.

182

Phases of CML

Chronic phase
Accelerated phase
Blast phase

183

% of blood and BM made up of blast cells in CML:
Chronic phase
Accelerated phase
Blast phase

10%
>20%

184

Duration of CML chronic phase (natural history)

Months to 4-5 years

185

1st generation tyrosine kinase inhibitor

Imatinib

186

2nd generation tyrosine kinase inhibitor

Dasatanib, and Nilotinib

187

Treatment of CML chronic phase

Disease control: Imatinib 1st line
2nd line: dasatinib/nilotinib.

Potential cure with stem cell transplantation (usually young people)

Reduce symptoms with chemotherapy with: hydroxyurea, busulfan, omacetaxine, or interferon alpha with or without cytarabine. These used to be used for disease management, shorter chronic phase than with imatinib.

188

In context of CML what is a complete cytogenic response?

0% philadelphia chromosome positive cells on cytogenic analysis (20 metaphases)

189

Side effects imatinib

fluid retention
pleural effusions

190

What is Pelger-Huet anomaly?

dumbel shaped bilobed neutrophils. Associated with lamin B receptor

191

Myelokathexis is...

Congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The neutrophils are retained in the bone marrow.

The disorder is believed to be inherited in an autosomal dominant manner.

192

What is congenital dyserythropoietic anaemia?

Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood.

There are 4 types

193

What is sideroblastic aneamia

In sideroblastic anemia, the body has iron available but cannot incorporate it into hemoglobin, which red blood cells need to transport oxygen efficiently.

Ring sideroblasts are named so because iron-laden mitochondria form a ring around the nucleus. To count a cell as a ring sideroblast, the ring must encircle a third or more of the nucleus and contain five or more iron granules

194

What are Auer rods?

Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts

195

List subtypes of myelodysplastic syndrome (WHO classificiation)

Refractory anaemia without ringed sideroblasts
Refractory anaemia with ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
Refractory anaemia with excess of blasts 1
Refractory anaemia with excess of blasts 2
5q deletion syndrome/myelodysplastic syndrome with 5q deletion
Myelodysplastic syndrome unclassified: MDS with fibrosis, childhood MDS, others

196

Refractory anaemia without ringed sideroblasts
Blood features
Bone marrow features

Anaemia and no blasts

Erythroid dysplasia with

197

Refractory anaemia with ringed sideroblasts
Blood features
Bone marrow features

Anaemia and no blasts

Erythroid dysplasia with over 15% ringed sideroblasts
Less than 5% blasts

198

Refractory cytopenia with multinlineage dysplasia
Blood features
Bone marrow features

Cytopenia in 2 or more cell lines

Dysplasia in over 10% cells in over 2 cell lines
Less than 5% blasts

199

Mean age of onset of myelodysplastic syndromes

68 years

200

Refractory cytopenia with multinlineage dysplasia and ringed sideroblasts
Blood features
Bone marrow features

Cytopenia in 2 or more cell lines

Dysplasia in over 10% cells in over 2 cell lines
Over 15% ringed sideroblasts
Less than 5% blasts

201

Refractory aneamia with excess blasts 1
Blood features
Bone marrow features

Cytopenias, less than 5% blasts, no Aeur rods

Dysplasias and 5-9% blasts

202

Refractory anaemia with excess blasts 2
Blood features
Bone marrow features

Cytopenias or 5-19% blasts, or Aeur rods.

Dysplasias, 10-19% blasts or Aeur rods

203

Myelodysplastic syndrome with 5q deletions
Blood features
Bone marrow features

Anaemia, normal or increased platelets.

Megakaryocytes with hypolobulated nuclei and less than 5% blasts

204

Myelodysplastic syndrome unclassified

Complex- cytopenias, no Aeur rods, no blasts

Complex- myeloid or megakaryocytic dysplasia, less than 5% blasts

205

Causes of death among patients with myelodysplastic syndromes

1/3 die from infection
1/3 die from bleeding
1/3 die from acute leukaemia

206

Myelodysplastic syndromes develop into... in half of patients

AML

207

Treatment of myelodysplastic syndromes

Prolonging survival:
Stem cell transplant
Intensive chemotherapy

Supportive care:
Blood product support
Antimicrobial therapy
Growth factors (Epo, G-CSF)

Biological modifiers
Immunosuppressive therapy
Azacytidine
Lenalidomide

Oral chemotherapy:
Hydroxycarbamide

Low dose chemotherapy:
Subcutaneous low dose cytarabine

Intensive chemotherapy/ stem cell transplant
AML type regimens
Allo/VUD standard/ reduced intensity

208

All patients with myelodysplastic syndromes have less than....% blasts

20%
Over 20% is acute leukaemia

209

Clinical features of myelodysplastic syndromes

BM failure and cytopenias with expected effects (infection, bleeding, fatigue)
Hypercellular BM
Defective cells e.g.:
Ring sideroblasts (RBC)
Hypogranulation (in WBC)
Micromegakaryocytes

210

Which type of myelodysplastic syndrome affects platelets

MDS with 5q deletion

211

Which type of myelodysplastic syndrome affects WBCs

Refractory cytopenia with multilineage dysplasia

212

Basic classification of aplastic anaemia

Severe aplastic anaemia (SAA)
Non-severe aplastic anaemia (NSAA)

213

Camitta criteria for SEVERE aplastic anaemia

2 out of 3 peripheral blood features

An absolute neutrophil count (ANC) of less than 0.5×109/L

A platelet count (PLT) of less than 20×109/L,

A corrected reticulocyte count (CRC) of less than 1%.

214

Specific (non-supportive) treatment of idiopathic aplastic anaemia

Based on:
Severity of illness
Age of patient
Potential sibling donor

A. Immunosuppressive therapy – older patient
Anti-Lymphocyte Globulin (ALG)
Ciclosporin
B. Androgens – oxymethalone
C. Stem cell transplantation
Younger patient with donor (80% cure)
VUD/MUD for > 40 yrs (50% survival)

215

Late complications following immunosuppressive treatment for aplastic anaemia

1. Relapse of AA (35% over 15 yrs)

2. Clonal haematological disorders
Myelodysplasia
Leukaemia
~ 20% risk over 10 yrs
PNH (paroxysmal nocturnal haemoglobinuria)
May be a transient phenomenon

3. Solid tumours ~ 3% risk

216

Which patients with aplastic anaemia have immunosuppressive therapy

Older patients

217

Most common form of inherited aplastic anaemia

Fanconi anaemia

218

Mode of inheritance of Fanconi anaemia

X-linked or autosomal recessive

219

Genes responsible for Fanconi anaemia contribute to...

Genomic stability

220

Androgen used in aplastic anaemia

Oxymethalone

221

Age of onset of pancytopenia in Fanconi anaemia

5-10 years

222

10% of Fanconi anaemia cases terminate in...

Acute leukaemia

223

Features of Fanconi anaemia include pancytopenia and...

Short Stature
Hypopigmented spots and café-au-lait spots
Abnormality of thumbs
Microcephaly or hydrocephaly
Hyogonadism
Developmental delay

(Congenital malformations may occur in 60-70% of children with FA)

224

% of patients with Fanconi anaemia who develop aplastic anaemia

90%

225

% of patients with Fanconi anaemia who develop myelodysplasia

32% (30% approx)

226

Complications of Fanconi anaemia

Aplastic anaemia
Myelodysplasia
Leukaemia
Liver disease
Epithelial cancer

227

Skin pigmentation
Nail dystrophy
Leukoplakia
A classical triad seen in....

Dyskeratosis congenita

Also get BM failure!!

228

Features of dyskeratosis congenita

Classical triad:
Nail dystrophy
Leukoplakia
Skin pigmentation

BM failure (85%)

229

What it dyskeratosis congenita

Inherited disorder characterised by:
Marrow failure
Cancer predisposition
Somatic abnormalities

Classical triad of:
Hairy leukoplakia
Skin pigmentation
Nail dystrophy

85% get BM failure

230

Somatic abnormalities/complications of dyskeratosis congenita

Epiphora
Learning difficulties/development/mental retardation Pulmonary disease
Short stature
Extensive dental caries/loss
Oesophageal stricture

Malignancy
Intrauterine growth retardation
Liver disease/peptic ulceration/enteropathy
Ataxia Hypogonadism/undescended testes
Microcephaly
Urethral stricture/phimosis
Osteoporosis/aseptic necrosis/scoliosis

231

Mode of inheritance of dyskeratosis congenita

X-linked
Autosomal dominant
Autosomal recessive

232

The genes involved in dyskeratosis congenita

DKC1 gene which results in defective telomerase function
TERC gene, which encodes the RNA component of telomerase
Additional recessive unidentified gene

233

Dyskeratosis congenita has 3 patterns of inheritance. All affect...

Telomeric structure and function

234

Management of severe aplastic anaemia: 1st line if:
a) acquired/idiopathic
b) Inherited/constitutional

a) Sibling stem cell transplant if under 40
Immunosuppressive therapy if over 40

b) Oxymethalone

235

Drugs used for immunosuppressive therapy in aplastic anaemia

Anti-Lymphocyte Globulin (ALG)
Ciclosporin

236

Philadelphia chromosome positive myeloproliferative disorder

CML

237

Bone marrow maximum tolerated irradiation dose

12Gy

238

Autologous bone marrow transplant can be used to treat

Acute leukaemia
Lymphoma
Solid tumours

239

BMT: After infusion of stem cells engraftment takes and immune recovery takes...

14-28 days
6-12 months

240

Organs affected by acute GvHD

skin, gastrointestinal tract and liver

241

Organs affected by chronic GvHD

skin, mucosal membranes, lungs, liver, eyes, joints

242

Risk factors for GvHD

Degree of HLA disparity
Recipient (and donor) age (older=higher risk)
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase (late is worse)
Viral infections

243

Treatments for GvHD

Corticosteroids
Cyclosporin A
FK506
Mycophenylate mofetil
Monoclonal antibodies
Photopheresis
Total lymphoid irradiation

244

Donor lymphocyte infusions induce remission via process called...

Graft vs tumour effect

245

Donor lymphocyte infusions are used when?

Patient has relapsed after a bone marrow transplant.

246

A non-myeloablative haematopietic stem cell transplant involves...

Preparative regiment followed by
Stem cell transplant followed by
Donor lymphocyte infusion

247

HLA genes are found on which chromosome

6 (short arm)

248

Disadvantages of using unrelated donor for stem cell transplant (compared to sibling)

Rejection+++
GvHD+++
More toxicity+++
Delayed immunoreconstitution +++
All worse than with sibling transplant

249

What are killer-cell immunoglobulin-like receptors (KIRs)?

Transmembrane receptors expressed on the surface of NK cells and a minority of T cells. They interact with MHC class 1 molecules and can differentiate between allelic variants. This allows them to recognise virally infected or transformed cells. They regulate the activity of their cells.

Most are inhibitory. Recognition of a healthy self cell leads to inhibition of of the NK cell cytolytic function.

250

Advantage of BMT from donor with alloreactive NK cells

Alloreactive NK cells won't be recognised by host KIRs (and therefore won't be inhibited). Advantages:

Alloreactive NK cells kill patient’s DC thus preventing priming of allogeneic T cells and, thus, GvHD

Alloreactive NK cells kill patient’s T lymphocytes. This facilitates engraftment

Alloreactive NK cells kill leukaemic cells. This may reduce leukaemic relapse.

251

Role of host dendritic cells in GvHD

Prime donor T cells (after initial tissue damage)

252

Leukaemia
Features of bone marrow failure

Anaemia: fatigue, pallor, breathlessness
Neutropenia: infections
Thrombocytopenia: bleeding

253

AML epidemiology (key points)

Increases with age
Prognosis worse with increasing age
40% of adults cured

254

Chromosomal inversion inv(16)/t(16;16) is found in which condition

AML

(Good prognosis)

255

Risk factors for AML

Familial or constitutional predisposition
Irradiation
Anticancer drugs
Cigarette smoking

256

The 2 types of genetic abnormality seen in acute leukaemia

Type 1 abnormalities
promote proliferation & survival

Type 2 abnormalities
block differentiation (which would normally be followed by apoptosis)

257

Examples of genetic abnormalities that lead to core binding factor leukaemias

Special feature of these leukaemias

Translocation 8;21
Inv(16)

There is some maturation. Not all cells produced are blasts

258

Core binding factor is...

dimeric transcription factor
master controller of haematopoiesis

259

Genetic abnormality found in 12% of adult AML

Inv(16) , t(16;16)

260

Key features of acute promyelocytic leukaemia
Including genetic abnormality
Key presenting feature
Key features of affected cells
Treatment

* The retinoic acid receptor alpha gene (RARA) on chromosome 15 is translocated (reciprocally) with the promyelocytic leukaemia (PML) gene on chromosome 17. The translocation is denoted as t(15; 17)(q22;q21).

* The fusion gene produced binds with strong affinity to DNA blocking transcription and differentiation of granulocytes (stops maturation at later stage than other acute leukaemias).

* There is an excess of promyelocytes, which contain large granules that can be released into peripheral blood.

* Often patients present with DIC

* Myeloblasts seen in peripheral blood:

* Large cells with large nucleus and relatively little cytoplasm

* Nucleoli present

* Sets of granules forming elongated needles (Auer rods) that are only seen in myeloblasts

* The initial translocation initiates the process but additional mutations are needed for leukaemia to develop.

* Can treat with retinoic acid

261

Treatment pf acute promyelocytic leukaemia

Retinoic acid

262

Genetic abnormality seen in 90% of patients with promyeloctyic leukaemia

t(15; 17)(q22;q21).

263

Clinical features of AML

Bone marrow failure:
Anaemia
Neutropenia
Thrombocytopenia

Local infiltration:
Splenomegaly
Hepatomegaly
Gum infiltration (if monocytic)
Lymphadenopathy (only occasionally)
Skin, CNS or other sites

Hyperviscosity if WCC is high:
retinal haemorrhages and exudates

264

AML:
CNS disease is more common with...

Monocytic differentiation

265

AML:

Cytogenic studies, molecular studies and FISH. Which applies to all patients?

Cytogenic studies

266

Treatment of AML

Supportive care
Red cells
Platelets
Fresh frozen plasma/ cryoprecipitate if DIC
Antibiotics
Long line
Allopurinol, fluid and electrolyte balance

Chemotherapy

267

Basis of selective toxicity in AML chemotherapy

Normal stem cells:
often quiescent
checkpoints allow repair of DNA damage

Leukaemia cells:
continuously dividing
lack of cell cycle checkpoint control

268

Why have results of treatment of AML improved?

Better supportive care
Identification of bad prognosis groups for more intensive treatment (more intensive chemotherapy or transplantation)
Specific treatment for acute promyelocytic leukaemia

269

ALL epidemiology

Peak incidence in childhood
Most common childhood malignancy
85% of children cured
Prognosis worse with increasing age

270

Clinical features of ALL

Bone marrow failure:
Anaemia
Neutropenia
Thrombocytopenia

Local infiltration:
Lymphadenopathy (± thymic enlargement)
Splenomegaly
Hepatomegaly
Testes, CNS, kidneys or other sites
Bone (causing pain)

Lymohadenopathy, CNS infiltration and testicular infiltration more common than in AML

271

ALL features in peripheral blood

Peripheral blood
Anaemia
Neutropenia
Thrombocytopenia
Usually lymphoblasts

272

ALL features in bone marrow

Lymphoblast infiltration
Lymphoblasts may be B-lineage or T-lineage

273

Impact of translocation t(9;22) on ALL treatment

t(9;22) — improved prognosis with tyrosine kinase inhibitors e.g. imatinib

274

Example of tyrosine kinase inhibitor

Imatinib

275

Imatinib is a...

Tyrosine kinase inhibitor

276

Treatment of ALL (general principles)

Specific therapy:
systemic chemotherapy
CNS-directed therapy

Supportive care:
blood products
antibiotics
general medical care

277

Supportive treatment used in ALL

Central venous catheter

Red blood cell and platelet transfusions

Broad spectrum antibiotics for fever

Prophylaxis for Pneumocystis jirovecii infection

Hyperuricaemia: hydration, urine alkalinization and allopurinol or rasburicase

Hyperphosphataemia; aluminum hydroxide, calcium

Hyperkalemia: fluids, diuretics

Extreme leukocytosis (WBC > 200 × 109/l): leukapheresis

Sometimes haemodialysis

278

3 (unique) Causes of polycythaemia in neonates

Twin-to-twin transfusion
Intrauterine hypoxia
Placental insufficiency

279

Unique causes of anaemia in the neonate

Twin-to-twin transfusion
Fetal-to-maternal transfusion
Parvovirus infection (virus not cleared by immature immune system)
Haemorrhage from the cord or placenta

280

Congenital leukaemia is particularly common in

Down syndrome

Note: This specific type of neonatal leukaemia (also sometimes called transient abnormal myelopoiesis or TAM) differs greatly from leukaemia in older infants or children

281

Key features of neonatal leukaemia

The leukaemia is myeloid with major involvement of the megakaryocyte lineage

It usually remits spontaneously and relapse one to two years later occurs in only about a quarter of infants

282

FBC:
Newborn babies, in contrast to adults, have...

Higher Hb

283

Globin chains that form:

HbA
HbA2
HbF

α2β2

α2δ2

α2γ2

284

HbSS
Red cells become sickle shaped in what sitatuon

Hypoxic conditions

285

Which type of marrow is more susceptible to infarction in sickle cell disease?

Red marrow

286

Sickle cell anaemia:
Why does splenic sequestration not occur commonly i older children and adults

Recurrent infarction has left the spleen small and fibrotic

287

Cause of hyposplenism in sickle cell anaemia

Recurrent infarction has left the spleen small and fibrotic reducing its ability to filter out bacteria and parasites.

288

Why does folic acid matter more in a child with sickle cell disease than in a normal child or an adult?

Hyperplastic erythropoiesis requires folic acid
Growth spurts require folic acid
Red cell life span is shorter so anaemia can rapidly worsen

289

When does beta thalassaemia manifest (age)?

First 3‒6 months of life

290

Clinical effects of poorly treated thalassaemia major

Anaemia leadfing to heart failure, growth retardation

Erythropoietic drive leading to bone marrow expansion, hepatomegaly, and splenomegaly

Iron overload leading to heart failure, gonadal failure

291

Most inherited haemolytic anaemias are due to defects in...

Red cell membrane
Haemoglobin molecule
Red cell enzymes—glycolytic pathway
Red cell enzymes—pentose shunt

292

Haemolytic anaemias in children:

Red cell membrane defects
Hereditary spherocytosis
Hereditary elliptocytosis

Haemoglobin defects
Sickle cell anaemia

Glycolytic pathway defects
Pyruvate kinase deficiency

Pentose shunt defects
G6PD deficiency

293

Features of G6PD deficiency in the blood film

Heinz bodies, which are denatured haemoglobin

Bite cells (cells with Heinz bodies that pass through the spleen have part of the membrane removed).

294

Causes of crises in G6PD deficiency

Illness (especially infections)
Certain drugs
Certain foods, most notably broad beans
Certain chemicals

295

Mode of inheritance of g6pd deficiency

X-linked recessive

296

G6PD deficiency affects which pathway

Pentose phosphate pathway

297

Importance of the pentose phosphate pathway

Production of NADPH

One of the uses of NADPH in the cell is to prevent oxidative stress. It reduces glutathione via glutathione reductase, which converts reactive H2O2 into H2O by glutathione peroxidase.

If absent, the H2O2 would be converted to hydroxyl free radicals by Fenton chemistry, which can attack the cell.

Erythrocytes, for example, generate a large amount of NADPH through the pentose phosphate pathway to use in the reduction of glutathione.

298

Autoimmune haemolytic anaemia is characterised by (lab results)

Spherocytosis
Positive direct antiglobulin test (Coombs’ test)

299

Which is more common?
Haemophilia A
Haemophulia B

Haemophilia A (5 times more common)

300

Presentation of autoimmune thrombocytopenic purpura

Petechiae
Bruises
Blood blisters in mouth