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Haematology Flashcards

1
Q

What is multiple myeloma?

A

Cancer of bone marrow PLASMA CELLS (differentiated B lymphocytes)

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2
Q

What is the peak incidence for multiple myeloma?

A

60-70 years

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3
Q

What are the clinical features of multiple myeloma?

A 
CRAB
Calcium (raised)
Renal impairment 
Anaemia
Bone lesions/disease

Also: bone disease, infection, paraprotein production, amyloidosis, macroglossia, etc

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4
Q

What are the SYMPTOMS of myeloma that patients will present with?

A 
Osteolytic bone lesions
Backache
Pathological fractures
Sx hypercalcaemia
Sx anaemia
Frequent infections
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5
Q

What test should be done in all patients over 50 with back pain?

A

Serum protein electrophoresis + ESR

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6
Q

Give 6 Ix that should be done for multiple myeloma

A

FBC (anaemia)

Serum IgG/IgA

Urine Ig (Bence Jones proteins)

BM biopsy (^plasma cells)

Blood film (rouleax formation)

XR - lytic ‘punched out’ lesions (raindrop skull) or MRI, PET scans

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7
Q

What 2 conditions are Bence Jones proteins found in?

A

Multiple myeloma

Waldenstrom’s macroglobulinaemia

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8
Q

In what bodily fluid are Bence Jones proteins found?

A

Urine

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9
Q

What is seen on BM biopsy in multiple myeloma?

A

Increased plasma cells

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10
Q

What type of anaemia is seen in multiple myeloma?

A

Normocytic normochromic

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11
Q

What is the definition of hypercalcaemia?

A

Serum corrected Ca++ >2.6 mmol

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12
Q

What is the treatment for symptomatic or marked (>3.5 mmol) hypercalcaemia?

A

Aggressive IV hydration with 0.9% saline
IV bisphosphonates
Calcitonin

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13
Q

What is seen on blood film in multiple myeloma?

A

Rouleax formation

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14
Q

In serum electrophoresis of a patient with multiple myeloma, which is the most common paraprotein (Ig) found?

A

IgG > IgA > IgD

IgM is associated with Waldenstrom rather than MM

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15
Q

What are the 3 major criteria for diagnosis of multiple myeloma?

A

Plasmacytoma

30% plasma cells in BM sample

Elevated levels of M proteins (paraproteins) in blood or urine

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16
Q

Which cells produce paraproteins?

A

Plasma cells

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17
Q

Give 4 poor prognostic features of multiple myeloma

A

> 2 osteolytic lesions
Beta-2 macroglobulin >5.5mg/L
Hb <11g/L
Albumin <30g/L

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18
Q

What are the principle of management for myeloma?

A

Only treat SYMPTOMATIC patients

For asymptomatic MM and MGUS - regular monitoring

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19
Q

What is MGUS?

A

Monoclonal gammopathy of unknown significance

Paraproteins present, but plasma cells only occupy <10% bone marrow

May progress to MM

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20
Q

What are the features of MGUS?

A

Usually asymptomatic
No bone pain/increased infections
10-30% have demyelinating neuropathy

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21
Q

Give 3 plasma cell dyscrasias

A

MGUS
Multiple myeloma
Waldenstrom macroglobulinaemia

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22
Q

What type of amyloidosis may occur with plasma cell dyscrasias?

A

Amyloid light chain (AL) amyloidosis

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23
Q

How is symptomatic multiple myeloma managed?

A

Induction treatment

  • chemo
  • immune modulation
  • protease inhibitors
  • steroid

+ autologous stem cell transplant (if suitable)

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24
Q

How can MGUS be differentiated from myeloma?

A 
Normal immune function
Normal beta-2 macroglobulin levels
Lower level of paraproteinaemia than myeloma
Stable level of paraproteinaemia
No clinical features of myeloma
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25
What is lymphoma?
Malignant proliferation of lymphocytes These accumulate in lymph nodes and cause lymphadenopathy (but can also be found in peripheral blood/other organs)
26
What is the cause of most lymphomas?
Unknown
27
Give some infections which are RFs for lymphoma
EBV HTLV-1 Helicobacter pylori
28
Give 3 primary immunodeficiency causes of lymphoma
Ataxia telangiectasia Wiscott-Aldrich syndrome Common variable immunodeficiency
29
Give 2 secondary immune deficiency causes of lymphoma
HIV | Transplant patients
30
What is the clinical presentation of lymphoma?
Enlarged, painless, non-tender, 'rubbery' superficial lymph nodes Asymmetrical Nodes may fluctuate in size Constitutional 'B' symptoms Alcohol-induced lymph node pain
31
What is Pel-Ebstein fever?
One of the 'B' symptoms of lymphoma. Cyclical fever - temp rises abruptly, stays high for a week, then drops and stays low for a week
32
What are the 2 peaks of incidence for lymphoma?
20s and 60s
33
What might blood tests show in Hodgkin's lymphoma?
Normocytic anaemia Eosinophilia Raised LDH
34
What investigations should be done for lymphoma?
``` LN biopsy (tissue diagnosis) Bloods (FBC, film, ESR, LFT, LDH) Immunophenotyping, cytogenetics, molecular techniques Imaging +/- BMBx ```
35
What is the histological cell type associated with Hodgkin's lymphoma?
Reed-Sternberg cells | mirror-image nuclei appearance
36
What is the gold standard diagnosis for Hodgkin's lymphoma?
Excision of a complete LN - submitted for detailed histological evaluation
37
What staging system is used for lymphoma?
Ann Arbor
38
According to the Ann Arbor classification, what is 'Stage 1' lymphoma?
Confined to ONE lymph node region
39
According to the Ann Arbor classification, what is 'Stage 2' lymphoma?
Confined to 2 or more LN regions on the SAME SIDE of the diaphragm
40
According to the Ann Arbor classification, what is 'Stage 3' lymphoma?
Affecting LN regions on BOTH sides of the diaphragm
41
According to the Ann Arbor classification, what is 'Stage 4' lymphoma?
Spread beyond lymph nodes (e.g. liver, bone marrow)
42
Each Ann Arbor stage of lymphoma is further split into either A or B. What is meant by this?
A - no systemic symptoms other than pruritus B - symptoms such as weight loss, fever, night sweats present
43
What are the 4 subtypes of Hodgkin's lymphoma?
Nodular Sclerosing (NSHL) - most common Mixed-Cellularity (MCHL) Lymphocyte-Depleted (LDHL) - worst prognosis Lymphocyte-Rich classical (LRHL) - best prognosis
44
Which subtype of Hodgkin's lymphoma is most common?
Nodular Sclerosing Hodgkin's Lymphoma (NSHL)
45
Which subtype of Hodgkin's lymphoma carries the worst prognosis?
Lymphocyte-depleted Hodgkin's lymphoma (LDHL)
46
Which subtype of Hodgkin's lymphoma carries the best prognosis?
Lymphocyte-rich classical Hodgkin's lymphoma (LRHL)
47
Give 4 poor prognostic indicators of Hodgkin's lymphoma
Lymohocyte-depleted subtype Male Increasing age Stage 4 disease Raised ESR and low Hb also indicate worse prognosis
48
How is Hodgkin's lymphoma treated?
Stage 1-2A - short course combination chemo followed by radio Stage 2B-4 - combination chemo
49
What is the combination chemotherapy used in the treatment of Hodgkin's lymphoma?
``` ABVD Adriamycin (doxorubicin) Bleomycin Vinblastine Decarbazine ```
50
Give 5 side effects of the ABVD chemo regime used to treated Hodgkin's lymphoma
``` Infertility Lung damage (bleomycin) Peripheral neuropathy (vinblastine) Cardiomyopathy (doxorubicin) Second cancers Psychological issues ```
51
Which is more common, Non-Hodgkin Lymphoma (NHL) or Hodgkin Lymphoma (HL)?
NHL (90%)
52
What is the median age of presentation for NHL?
>50 years
53
What is the term for the cyclical fever seen in Hodgkin's lymphoma?
Pel-Ebstein fever
54
Which type of lymphoma is more likely to invade the bone marrow and cause cytopenias?
NHL
55
In the treatment of which type of lymphoma is tumour lysis syndrome most likely to occur?
NHL
56
What is tumour lysis syndrome?
1. Dangerous complication of chemotherapy 2. Destruction of cancer cells results in release of intracellular components into circulation 3. Results in hyperkalaemia, hyperuricaemia, hyperphosphataemia (which causes hypocalcaemia) 4. Can cause fatal arrhythmias, AKI, acute gout
57
What is given as prophylaxis for tumour lysis syndrome?
Allopurinol or Rasburicase (uric acid reducing drugs) | IV hydration
58
Give some features of Non-Hodgkin's lymphoma
``` Painless widespread lymphadenopathy Hepatosplenomegaly Raised LDH Paraproteinaemia Autoimmune haemolytic anaemia Extra-nodal disease ```
59
What are the 2 main subtypes of NHL?
1. Indolent (low-grade) NHL, e.g. Follicular | 2. Aggressive (high-grade) NHL, e.g. Diffuse large B-cell (DLBCL), Burkitt lymphoma
60
Which type of lymphoma is usually preceded by H pylori infection?
Gastric mucosa associated lymphoid tissue (MALT) lymphoma (a low-grade NHL)
61
What is Mycosis fungoides?
Localised, cutaneous manifestation of T-cell NHL
62
What are some extra-nodal features of NHL in the: 1) Skin 2) Oropharynx 3) Gut
1) Cutaneous T-cell lymphomas, e.g. Mycosis fungoides 2) Waldeyer's ring lymphoma (sore throat/obstructed breathing) 3) Gastric MALT, Non-MALT gastric lymphomas (usually DLBCL), Small bowel lymphomas (can be associated with coeliac disease)
63
What is the classic treatment regime seen for NHL?
``` R-CHOP (up to 6 rounds) Rituximab Cyclophosphamide Hydroxydaunorubicin (doxorubicin) Oncovin (vincristine) Prednisolone ```
64
How many different subtypes of NHL are there?
>60
65
What is the role of rituximab in treating NHL?
Monoclonal antibody Anti-CD20 - Targets CD20 proteins expressed on cell surface of B cells - Kills CD20+ cells by antibody-directed cytotoxicity +/- apoptosis - Sensitises cells to the CHOP part of R-CHOP
66
What are some poor prognostic indicators for NHL?
``` Age >60 Systemic symptoms Bulky disease (abdomen mass >10cm) Raised LDH Disseminated disease at presentation ``` 30% 5 year survival for high grade
67
Give 6 possible acute presentations of lymphoma?
``` Infection SVC obstruction Sensation of 'fullness in the head' Dyspnoea Blackouts Facial oedema ```
68
What is leukaemia?
Malignant proliferation of haematopoietic cells
69
What are the 4 types of leukaemia, and which cell line do they involve?
Acute myeloid leukaemia (AML) - myeloblasts Chronic myeloid leukaemia (CML) - granulocytes (basophils, neutrophils, eosinophils) Acute lymphoblastic leukaemia (ALL) - lymphoblasts (precursors to B and T cells) Chronic lymphocytic leukaemia (CLL) - cancer of B lymphocytes
70
Which is the most common adult acute leukaemia?
AML
71
What is acute promyelocytic leukaemia? What is a key risk?
A subtype of AML typically seen in younger patients Characterised by t(15:17) translocation Often shows features of DIC High risk of fatal haemorrhage during early stage of treatment Best prognosis after initial phase
72
What is AML?
Clonal expansion of myeloblasts May occur as primary disease Or following secondary transformation of a myeloproliferative disorder
73
Give 5 risk factors for AML?
``` Down's syndrome Age Previous chemo/radio Myelodysplasia Myeloproliferative disorders CML ```
74
What is the key gene mutation seen in myeloproliferative disorders?
JAK2
75
Give 3 examples of myeloproliferative disorders
Polycythaemia rubra vera Primary (essential) thrombocythaemia Primary myelofibrosis
76
What is myelofibrosis?
A myeloproliferative disorder 1. Hyperplasia of abnormal megakaryocytes 2. Release of PDGF (platelet derived growth factor) 3. Fibroblasts stimulated 4. Haematopoiesis develops in liver and spleen
77
What are some features of myelofibrosis?
Elderly person with anaemia, e.g. fatigue is most common presenting Sx Massive splenomegaly Hypermetabolic symptoms - weight loss, night sweats, etc.
78
What are 5 diagnostic findings of myelofibrosis?
Anaemia High WBC and platelet count in early disease 'Tear-drop' cells on blood film Unobtainable BMBx - 'dry tap' therefore trephine biopsy needed High urate and LDH (reflect increased cell turnover)
79
How does AML present?
Features of bone marrow failure: 1) Anaemia - pallor, lethargy, weakness 2) Neutropenia - frequent infections (even though WCC may be high) 3) Thrombocytopenia - bleeding 4) Infiltration - hepatosplenomegaly, gum hypertrophy 5) Bone pain 6) Fever 7) Skin involvement
80
Give 3 poor prognostic features of AMK?
>60 years >20% blasts after first course of chemo Cytogenetics - deletions of chromosomes 5 and 7
81
How was AML previously classified?
French-American-British (FAB) classification
82
Which gene translocation is acute pre-myelocytic leukaemia associated with?
t(15:17) | Fusion of the PML and RAR-alpha genes
83
What age group does acute pre-myelocytic leukaemia tend to present in?
Younger patients - average age 25
84
What is commonly seen at presentation of a patient with acute pre-myelocytic leukaemia? How is this complication treated?
DIC | ARTA (anti-trans-retinoic acid)
85
How is AML treated?
Supportive therapy - exercise can relieve fatigue - blood products - recognise and treat infections early Chemotherapy - curative vs palliative - intensive, long periods of suppression, 5 cycles/week - main drugs: daunorubicin, cytarabine Transplantation - allogenic bone marrow transplants (sibs, MUD) - cyclophosphamide + TBI to kill all leukaemia cells pre-transplant - cyclosporin +/- methotrexate to prevent GVHD post-transplant
86
What do the following stand for: 1) MUD 2) TBI 3) GVHD
1) matching unrelated donor 2) total body irradiation 3) graft vs host disease
87
What is the prognosis of AML?
Poor - rapid progression means death in 2 months without treatment, 20% 3yr survival with chemotherapy ``` Cure rates 60% in chikdren 50% in adults <50 <20% in older adults Decreased cure with age reflects ability of patient to tolerate the intensive treatment and disease itself ```
88
What is CML?
Chronic myeloid leukaemia | Uncontrolled clonal proliferation of myeloid cells
89
What percentage of leukaemias are CML?
15%
90
What age does CML tend to present?
60-70, slight male predominance
91
What causes CML?
Philadelphia chromosome (>95%) - t(9:22) created a fusion protein which has excess tyrosine kinase activity
92
What is the Philadelphia chromosome due to?
Translocation between long arm of chromosome 9 and 22 - t(9:22) Creates a fusion protein which has excess tyrosine kinase activity
93
How does CML present?
``` 30% detected by CHANCE Mostly chronic and insidious features -weight loss -tiredness -fever and sweats -may be GOUT due to purine breakdown -bleeding -abdo discomfort (due to splenomegaly) ``` Signs - splenomegaly in >75% - hepatomegaly, anaemia, bruising
94
What investigations should be done for CML?
Bloods (WCC high, Hb low, platelets variable, urate increased, B12 increased) Bone marrow biopsy (hypercellular) Cytogenetic analysis of blood/bone marrow - showing Ph Chr
95
How is CML treated?
Imatinib (Gilvec) = first line Hydroxycarbamide Interferon-alpha Allogenic bone marrow transplant
96
What type of drug is Imatinib (Glivec), and give 2 other examples of drugs in this class
Tyrosine kinase inhibitor Nilotinib, Bosutinib
97
What are the 3 phases of CML?
1) Chronic - lasting months or years, few if any symptoms 2) Accelerated phase - with increased symptoms, splenomegaly and difficulty controlling blood cell counts 3) Blast transformation - with features of acute leukaemia and death
98
What is the prognosis of CML?
Survival >90% at 5 years | Median survival 5-6 years
99
What is the most common malignancy affecting children?
Acute lymphoblastic leukaemia
100
What is the peak incidence of ALL?
2-5 years
101
What are some risk factors/associations with ALL?
Down's syndrome | Ionising radiation, e.g. X-rays during pregnancy
102
What are the 3 main types of ALL?
Common ALL (75%) - CD10 present, pre-B phenotype T-cell ALL (20%) B-cell ALL (5%)
103
What are the features of ALL?
Bone marrow failure features - Anaemia: lethargy, pallor - Neutropenia: frequent/severe infections - Thrombocytopenia: easy bruising, petechiae Other features - Bone pain (secondary to infiltration) - Splenomegaly/Hepatomegaly - Lymphadenopathy - Testicular swelling - Neurological (cranial nerve palsies, meningism)
104
What are some of the common and severe infections seen in children with ALL?
``` Chest - PCP Mouth - candidiasis Perianal Skin infections Bacterial septicaemia Zoster, measles, CMV ```
105
What tests are done for ALL?
``` Blood film (blasts) Bone marrow biopsy (blasts) WCC usually very high CXR/CT - look for mediastinal and abdo LN involvement LP to look for CNS involvement ```
106
How is ALL treated?
Supportive - Blood/platelet transfusion - IV fluids - Allopurinol (prevents tumour lysis syndrome) - Insert SC port system/Hickman line for IV access Infection management - Immediate IV Abx for infections - Start neutropenic regime (anti-fungals/virals/biotics) - Co-trimoxazole if PCP Chemotherapy - Induce remission - Consolidation - CNS prophylaxis - Maintenance Matched related allogenic marrow transplants
107
What is the prognosis for ALL? 1) in children 2) in adults
1) 70-90% cure rates for children | 2) 40% cure rates for adults
108
Give 6 poor prognostic factors for ALL
``` Age <2 or >10 WBC >20 at diagnosis T or B cell surface markers Non-caucasian Male sex Philadelphia chromosome present ```
109
Give 8 features in a person aged 0-24 should prompt a very urgent (within 48 hrs) FBC to investigate for leukaemia?
``` Pallor Persistent fatigue Unexplained fever Unexplained persistent infections Generalised lymphadenopathy Persistent or unexplained bone pain Unexplained bruising Unexplained bleeding ```
110
Give 2 features in someone aged 0-24 that would prompt urgent referral for ASSESSMENT for leukaemia?
Unexplained petechiae | Hepatosplenomegaly
111
Which is the most common leukaemia?
Chronic lymphocytic leukaemia
112
What is CLL?
Gradual accumulation of B lymphocytes in blood, bone marrow, spleen and lymph nodes
113
Is CLL more likely in men or women?
2x more likely in men
114
Give some features of CML
Often no Sx Constitutional - anorexia, weight loss Bleeding, infections Lymphadenopathy more marked than CML
115
What is the clinical course of CLL?
Variable Progressive lymphadenopahty/HSM BM failure Hypogammaglobulinaemia + infection Some remain stable for years, or even regress Death often due to infection - pneumococcus, haemophilus, meningococcus, candida, aspergillum or transformation to aggressive lymphoma (Richter;s syndrome)
116
What investigations are done to diagnose CLL?
Blood film - SMUDGE cells (aka smear cells | Immunophenotyping
117
Give 3 complications of CLL?
Hypogammaglobuinaemia leading to recurrent infections Warm autoimmune haemolytic anaemia in 10-15% patients Transformation to high-grade lymphoma (Richter's transformation)
118
What is Richter's transformation?
Occurs when leukaemia cells enter the lymph node and change into a high-grade, fast-growing, NH-lymphoma Patients often become unwell very suddenly
119
What are the symptoms of Richter's transformation?
``` LN swelling Fever w/o infection Weight loss Night sweats Nausea Abdo pain ```
120
How is CLL staged?
Binet staging A: lymphocytosis +/- < 3 nodal areas B: 3 or more nodal areas C: anaemia +/- thrombocytopenia
121
How is CLL treated?
Watch and wait Chemotherapy Monoclonal antibodies, e.g. anti-CD20 Rituximab Targeted therapy, e.g. brutal kinase inhibitors, ibrutinib BM transplant (autologous or allogenic) Supportive care - transfusions, IVIG if recurrent infections
122
What is the prognosis of CLL?
Rule of thirds: 1/3 never progress 1/3 progress slowly 1/3 progress actively
123
What is the difference between autologous and allogenic stem cell transplants?
Autologous - enables escalation of chemo with stem cell 'rescue' - relatively straightforward, mortality 2% Allogenic - much more toxic, mortality 15-30%. Stem cells attack residual tumour (Graft vs Leukaemia - GVL) - GOOD Stem cells also attack recipient (Graft vs Host Disease - GVHD) - BAD Used in acute and chronic leukaemias
124
What is the appearance of Burkitt lymphoma on lymph node biopsy?
'Starry sky' appearance Burkitt lymphoma is a rapidly proliferating B cell tumour
125
How does Burkitt lymphoma present?
Unusual ways due to its rapid proliferation | e.g. Nerve root compression due to the mass effect of the lesion
126
With which virus is Burkitt lymphoma associated?
EBV
127
Who is Waldenstrom's macroglobulinaemia seen in?
Older men
128
What is Waldenstrom's macroglobulinaemia?
Uncommon condition | Lymphoplasmacytoid malignancy characterised by secretion of monoclonal IgM paraprotein
129
How does Waldenstrom's macroglobulinaemia cause an increase in the risk of ischaemic stroke?
Paraproteins cause hyperviscosity of the blood, which increases the risk of ischaemic strokes
130
Which immunoglobulin is over-produced in Waldenstrom's macroglobulinaemia?
IgM
131
Give some clinical features of Waldenstrom's macroglobulinaemia
``` Systemic upset (weight loss, lethargy) Hyperviscosity syndrome (visual disturbance, stroke, headache, vertigo, retinopathy, seizures, spontaneous bleeding from mucus membranes) Hepatosplenomegaly Lymphadenopathy Cryoglobulinaemia (eg Raynauds) ```
132
What is anaemia?
Low Hb concentration | Either due to low red cell mass or increased plasma cell volume (e.g. in pregnancy)
133
Normal values for Hb in: 1) Men 2) Women
1) Men: 13.1 - 16.6 g/dL | 2) Women: 11.0 - 14.7 g/dL
134
Give 3 symptoms of anaemia
``` Fatigue Dyspnoea Faintness Palpitations Headache Tinnitus Anorexia Angina ```
135
Give 2 signs of anaemia
``` Pallor Sx hyperdynamic circulation (if severe) -tachycardia -flow murmur -cardiac enlargement -retinal haemorrhage (rare) -heart failure (late) ```
136
Give the 5 main causes of microcytic anaemia
``` TAILS Thalassaemia Anaemia of chronic disease Iron deficiency (most common) Lead poisoning (rare) Sideroblastic anaemia (rare) ```
137
Give 4 causes of iron deficiency anaemia
Blood loss (e.g. menorrhagia or GI bleed) Insufficient dietary intake Malabsorption (eg coeliac) Hookworm (in tropics)
138
Give 4 SIGNS of iron deficiency anaemia
Koilonychia (spoon shaped nails) Atrophic glossitis (big fat red tongue) Angular stomatitis (sores/ulceration in corner of mouth) Post-cricoid webs (Plummer-Vinson syndrome)
139
Give 2 things you would see on a blood film for iron deficiency anaemia?
1) Target cells | 2) Pencil poikilocytes
140
How is iron deficiency anaemia treated? | How long do you continue this treatment?
Treat cause Oral iron - ferrous sulphate Continue until Hb is normal + for at least 3 months to replenish stores (IDA with no obvious source of bleeding = careful GI workup)
141
Give 4 side effects of ferrous sulphate
Nausea Abdo pain Diarrhoea/constipation Black stools
142
What is the most common cause of anaemia in hospital patients?
Anaemia of chronic disease
143
What investigation results will be seen for anaemia of chronic disease?
Normocytic anaemia Ferritin normal/raised Check haematinics as causes of chronic anaemia are often multifactorial
144
How is anaemia of chronic disease treated?
Treat underlying disease vigorously EPO (effective at raising Hb and improves QoL in cancer pt) Iron (parenterally) Hepcidin inhibitors and inflammatory modulators
145
What is sideroblastic anaemia?
Red cells fail to completely form haem Leads to deposits of iron in the mitochondria that form a ring around the nucleus called a ring sideroblast
146
What are the causes of sideroblastic anaemia?
Congenital -Delta-aminolevulinate synthase 2 deficiency Acquired - Myelodysplasia - Alcohol - Lead - Anti-TB medications
147
How is sideroblastic anaemia diagnosed?
Hypochromic microcytic anaemia Bone marrow - sideroblasts and increased iron stores
148
How is sideroblastic anaemia managed?
Supportive Treat any underlying cause Pyridoxine (vitamin B6) may help Transfusion for severe anaemia
149
What will the blood results reflect for thalassaemia and sideroblastic anaemia?
Accumulation of iron, so: - Increased serum iron - Increased ferritin - Low total iron binding capacity (TIBC)
150
Causes of normocytic anaemia?
``` Anaemia of chronic disease Sickle cell disease Bone marrow failure Pregnancy Haemolytic anaemia Hypothyroidism ```
151
Causes of megaloblastic macrocytic anaemia?
B12 deficiency Folate deficiency Cytotoxics (hydroxycarbamide, phenytoin)
152
Causes of non-megaloblastic macrocytic anaemia?
Alcohol/Liver disease Hypothyroidism Pregnancy Reticulocytosis
153
What is the difference between macrocytes and megaloblasts?
Macrocytes = red cells with volume >100 fL Megaloblasts = abnormal, giant red cell precursors with disproportionately large, immature nuclei
154
What is the most common cause of megaloblastic anaemia?
B12/folate deficiency
155
What is the bioactive form of folate?
Tetrahydrofolate (THF)
156
What is the bioactive form of folate (THF) required for?
Purine and pyrimidine synthesis (thus RNA and DNA)
157
Why is it crucial to correct B12 deficiency before correcting folate deficiency?
To prevent neurological damage
158
Which B vitamin is folate? Where is it stored? Where is it absorbed?
B9 Liver Duodenum and jejunum
159
What are the 4 broad causes of folate deficiency?
1) Insufficient intake 2) Excessive loss 3) Abnormal THF activation 4) Increased folate demand
160
Why will a B12 deficiency always cause a functional folate deficiency?
Activation of folate into its active form (THF) is dependent on methionine synthase, a B12-dependent enzyme
161
How long do body stores of folate last?
4 months
162
Give 3 foods that provide a source of folate
Green veg Nuts Yeast
163
What can maternal folate deficiency cause to the foetus?
Neural tube defects
164
Give 2 drugs that can cause folate deficiency
Methotrexate | Trimethoprim
165
What is the role of folate in: 1) Heart disease 2) Cognition
1) lowers homocysteine levels = decreased risk of CVD | 2) benefits cognition
166
How is folate deficiency treated?
Assess for underlying cause (poor diet, malabsorption) | Treat with oral folic acid - 5mg/day
167
How is folate deficiency prophylaxis given in pregnancy?
0.4mg/day from conception until at least 12 weeks
168
Give 3 types of food B12 is found in
Meat Fish Dairy products
169
How long do body stores of vitamin B12 last for?
4 years
170
How is B12 absorbed?
Binds to intrinsic factor in the stomach, and is absorbed in the terminal ileum
171
Why does B12 deficiency cause a reduction in the rate of RBC production?
Synthesis of thymidine (hence DNA) is impaired
172
Causes of B12 deficiency?
Dietary (eg vegans) Malabsorption - Stomach, lack of IF (pernicious anaemia, post-gastrectomy, post-gastric-banding) - Terminal ileum (resection, Crohn's, bacterial growth, tapeworms, metformin use) - Congenital metabolic errors
173
Clinical features of B12 deficiency?
Normal features of anaemia (fatigue, etc) Neuropsychiatric (irritability, depression, psychosis, dementia) Neurological (paraesthesia, peripheral neuropathy, subacute degeneration of the spinal cord)
174
What is the triad of features seen in subacute degeneration of the spinal cord?
1) Extensor plantars (UMN) 2) Absent knee jerks (LMN) 3) Absent ankle jerks (LMN)
175
What is pernicious anaemia?
Autoimmune atrophic gastritis leading to achlorydia (absence of HCl in gastric secretions) and lack of intrinsic factor secretion
176
In what age does pernicious anaemia tend to develop?
Middle to old age
177
In which blood group type is pernicious anaemia more common?
Blood group A
178
What are some associations with pernicious anaemia?
``` Thyroid disease Type 1 diabetes Addison's disease Rheumatoid arthritis Vitiligo Hypoparathyroidism ``` Predisposes to gastric carcinoma
179
What are the features of pernicious anaemia?
Lethargy Weakness Dyspnoea Paraesthesia Also: mild jaundice 'lemon yellow', diarrhoea, sore tongue Possible signs: retinal haemorrhages, mild splenomegaly, retrobulbar neuritis
180
Give 2 specific investigations for pernicious anaemia
1) Parietal cell antibodies | 2) Intrinsic factor antibodies
181
How is pernicious anaemia/B12 deficiency treated?
Treat underlying cause if possible B12 injections (hydroxycobalamin) -1mg IM every other day for 2 weeks/until CNS signs stop -Maintenance = 1mg every 3 months for life If cause is definitely dietary rather than malabsorption, oral B12 can be taken
182
What is aplastic anaemia?
Bone marrow failure leading to pancytopenia
183
What is the peak age at which aplastic anaemia is acquired?
30 years
184
What are the features of aplastic anaemia?
Normochromic, normocytic anaemia Leukopenia with lymphocytes relatively spared Thrombocytopenia May be the presenting feature of ALL or AML Minority of patients develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
185
What are the causes of aplastic anaemia?
``` Idiopathic Congenital - Fanconi anaemia, dyskeratosis congenita Drugs Toxins - benzene Infections - parvovirus, hepatitis Radiation ```
186
Give 4 medications that can cause aplastic anaemia
Phenytoin Cytotoxics Chloramphenicol Sulphonamides
187
Give 3 hereditary causes of haemolytic anaemia
Membrane - hereditary spherocytosis Metabolism - G6PD deficiency Haemoglobinopathies - sickle cell, thalassaemia
188
What are the acquired causes of haemolytic anaemia? 1) Immune (3) 2) Non-immune (4)
1) Immune Autoimmune (warm/cold Ab type) Allo-immune (tranfusion reaction, haemolytic disease of the newborn) Drugs (methyldopa, penicillin) ``` 2) Non-immune Microangiopathic haemolytic anaemia (MAHA) - TTP/HUS, DIC, malignancy, pre-eclampsia Prosthetic cardiac valves Paroxysmal nocturnal haemoglobinuria Infections - malaria Drugs - dapsone ```
189
What is G6PD deficiency?
Most common RBC enzyme defect More common in people from the Mediterranean and Africa X-linked recessive (affects males) Many drugs can precipitate a crisis as well as infections and broad (fava) beans
190
What is an important consideration when treating a patient with lymphoma who has G6PD deficiency?
They must not be given rasburicase as prophylaxis against tumour lysis syndrome (severe side effect of chemo treatment) They can be given allopurinol instead
191
Give 5 features of G6PD deficiency?
``` Neonatal jaundice Intravascular haemolysis Gallstones Splenomegaly Heinz bodies on blood films ```
192
Give 5 drugs that can precipitate haemolysis in G6PD deficiency
``` Anti-malarials (primaquine) Ciprofloxacin Sulphonamides Sulphasalazine Sulfonylureas ```
193
How is G6PD deficiency diagnosed?
G6PD enzyme assay
194
What is hereditary spherocytosis? | How is it inherited?
Most common hereditary anaemia in North Europeans AD-inheritance Normal biconcave disc shape of RBC replaced by a sphere-shaped one RBC survival reduced as destroyed by the spleen
195
Give 7 ways hereditary spherocytosis presents?
``` Failure to thrive Jaundice, gallstones Splenomegaly Aplastic crisis precipitated by parvovirus infection Degree of haemolysis variable MCHC elevaged Spherocytes on blood film ```
196
How is hereditary spherocytosis diagnosed?
Osmotic fragility test | Spherocytes on blood film - round, lack of central pallor
197
How is hereditary spherocytosis treated?
Folate replacement | Splenectomy
198
What level of Hb must be reached for someone to require a blood transfusion? 1) Patient without ACS 2) Patient with ACS
1) 70g/L | 2) 80g/L
199
Why is the transfusion threshold lower in ACS?
Anaemia can worsen the ischaemia in ACS because there is less Hb to carry oxygen, therefore heart has to work harder Important to provide immediate relief to anaemia of this level (<80) in someone with ACS
200
What are some complications of blood transfusions?
``` Acute haemolysis Non0haemolytic febrile reaction Allergy/anaphylaxis Infections TRALI (transfusion-related lung injury) Fluid overload Hyperkalaemia Iron overload Clotting ```
201
What causes an acute haemolytic transfusion reaction?
Mismatch of ABO blood group | Causes massive intravascular haemolysis
202
How long after a transfusion does an acute haemolytic transfusion reaction?
Symptoms begin minutes after transfusion starts (fever, abdominal and chest pain, agitation, hypotension)
203
What is the treatment for an acute haemolytic transfusion reaction?
Immediate transfusion termination Generous fluid resus with saline Inform lab
204
Give 2 possible complications of an acute haemolytic transfusion reaction
DIC | Renal failure
205
What causes a non-haemolytic febrile transfusion reaction?
White blood cell HLA antibodies Often the result of sensitisation by previous pregnancies or transfusions
206
What causes an allergic/anaphylactic blood transfusion reaction?
Hypersensitivity reaction to components within the transfusion
207
How long after a transfusion may an allergic/anaphylactic reaction occur?
Within minutes - can be varying severity
208
What symptoms/signs would a patient experiencing an allergic/anaphylactic reaction from transfusion present with?
``` Urticaria Hypotension Wheezing Dyspnoea Stridor Angioedema ```
209
Which type of infection is most likely to occur from a platelet transfusion? Why?
Bacterial infections Because platelets are stored at room temp, so provide a favourable environment for bacterial contamination
210
What is the universal donor blood group for: 1) Red cells 2) Fresh frozen plasma?
1) O Rh-ve | 2) AB Rh-ve
211
What is leucodepletion?
Process of removing white cells from a blood product to reduce risk of white-cell borne infection (including vCJD transmission and GVHD)
212
What does the ABO system refer to?
Various forms of the 'H' antigen on the surface of red cells
213
What is the ABO group if the H antigen is unmodified?
O
214
What are the five Rh antigens?
C, c, D, E, e
215
Presence of which allele confers Rh positive status?
D
216
Why does ABO incompatibility between mother and fetus not cause any problems, whilst Rh incompatibility does?
Antibodies against Rh D are IgG - small enough to cross placenta Antibodies against ABO are IgM - large, bulky, cannot pass placenta
217
What is a 'sensitising event'?
Event leading to development of anti-D IgG (antibodies) in Rh-ve females May result in haemolytic disease of the fetus/newborn
218
Give 5 examples of sensitising events
1) Normal pregnancy (small amounts of fatal blood enter maternal circulation) 2) Maternal trauma during pregnancy 3) Ectopic pregnancy 4) Abortion 5) Amniocentesis/chorionic villous sampling
219
How is Anti-D immunoglobulin delivered to Rh-ve females? | How does it work?
IM injection Coats fetal red cell D antigens that have entered maternal circulation, before maternal anti-D antibodies can be generated
220
What is haemolytic disease of the fetus (HDF)?
IgG anti-D antibodies cross placenta and lead to immune haemolysis and hydrops fetalis (prenatal heart failure in utero)
221
2+ units of blood can result in fluid overload. How can this be avoided?
Prescribe frusemide in between transfusions of each unit
222
In addition to red cell transfusions, what are some other transfusion products?
``` Platelets Granulocytes FFP Immunoglobulins Human albumin solution (HAS) Cryoprecipitate Clotting factor concentrates (single or combined) ```
223
What transfusion product is used to reverse warfarin in bleeding?
Prothrombin complex concentrate (a combined clotting factor concentrate)
224
What is Octaplex, and what is it used for? Why is it used in preference to FFP?
A PCC (prothrombin complex concentrate) Reduced risk of TACO (transfusion-associated circulatory overload)
225
What is Octoplas?
Detergent-treated FFP
226
Give 5 acute (within 24hr) life-threatening complications that may occur following transfusion
1) AHTR 2) Bacterial contamination 3) Anaphylaxis 4) TACO 5) TRALI
227
Give 2 acute (within 24hr) mild complications that may occur following tranfusion
1) Febrile non-haemolytic transfusion reaction (FNHTR) | 2) Urticaria
228
Give 3 delayed (after 24hr) complications that may occur following transfusion
1) DHTR 2) Post-transfusion purpura (PTP) 3) taGVHD (transfusion-associated GVHD)
229
Give 2 chronic/late complications that may occur following transfusion
1) post-transfusion viral infection | 2) iron overload
230
Management of anaphylaxis from transfusion?
``` Stop transfusion Detach giving set Flush cannula with saline IM adrenaline (0.5mg) Lie flat and elevate legs IV crystalloids ``` *CALL ANAESTHETIST - airway* IV hydrocortisone + chlorphenamine
231
What are the features of post-thrombotic syndrome? How may these symptoms be managed?
``` Painful, heavy calves Pruritus Swelling Varicose veins Venous ulceration ``` Manage with: - Compression stockings - Leg elevation
232
What is the most common: 1) Clotting disorder (thrombophilia) 2) Bleeding disorder ?
1) Factor V Leiden (aka activated protein C deficiency) | 2) Von Willebrand disease
233
What is the usual lifespan of platelets?
7-10 days
234
How are platelets made (thrombopoiesis)?
TPO (made by liver) stimulates synthesis from megakaryocytes in bone marrow
235
ITP in children usually follows a viral infection and resolves spontaneously. In adults, it usually needs treatment. How is it managed?
1) Immunosuppression (steroids, ciclosporin, or rituximab) 2) IVIg/anti-D Ig given to saturate splenic macrophages 3) TPO mimetics to increase platelet count
236
Give 2 examples of TPO mimetics
Romiplostim | Eltromboplag
237
What is the classic pentad seen in TTP?
1) Fever 2) Transient focal neurological deficits 3) AKI 4) MAHA (microangiopathic haemolytic anaemia) 5) Thrombocytopenia
238
What is the name of the protease enzyme that cleaves large multimers of vWF?
ADAMTS-13
239
What is the usual underlying mechanism for TTP?
Acquired deficiency of ADAMTS-13 enzyme, resulting in persistence of large vWF multimers This leads to inappropriate haemostasis
240
TTP is a medical emergency and can be fatal if untreated. How is it managed?
``` Urgent plasmapheresis (removes anti-ADAMTS-13 antibodies and replaces deficient ADAMTS-13) ```
241
What is the most common cause of AKI in children?
Haemolytic uraemic syndrome (HUS)
242
What is the diagnostic triad of HUS?
AKI Low platelets Microangiopathic haemolytic anaemia (MAHA)
243
What usually causes HUS?
Infection with shiga-toxin producing E. coli (O157:H7 strain) Shiga-toxin inhibits ADAMTS-13 enzyme Microthrombi form in glomeruli of kidney
244
How does hypocalcaemia affect the coagulation cascade?
Calcium is required for activation of vitamin-K dependant factors (2, 7, 9, 10)
245
How does citrate in blood test tubes prevent clotting? How does this differ from EDTA?
It de-ionises calcium - this can be reversed by adding calcium (unlike EDTA, which irreversibly chelates the calcium ions)
246
What are the vitamin K dependent clotting factors?
2, 7, 9, 10
247
How does warfarin work?
Inhibits the enzyme vitamin K epoxide reductase - prevents regeneration of active form of vitamin K
248
Give some important questions to ask about in a bleeding history
1) Any mucocutaneous bleeding? (from gums, nose, rectum, easy bruising, etc) 2) Bleeding into joints? 3) Previous surgical complications? Excessive bleeding after eg dental extraction?
249
What are the 3 components of a clotting screen?
Prothrombin time Activated partial thromboplastin time Fibrinogen
250
Which part of the clotting screen represents the: 1) intrinsic pathway 2) extrinsic pathway How long are they?
1) APTT (usually 30-40s) | 2) PT (usually 10-14s)
251
Which blood test is most affected by warfarin overdose?
PT (prolonged) - also INR
252
What are proteins C and S? | Which vitamin are they dependent on?
Protein C = serine protease - destroys activated Va and VIIIa Protein S = cofactor for protein C Both are vitamin K-dependent
253
Give 4 intrinsic methods for anti-coagulation Which does heparin potentiate?
1) Tissue-factor pathway inhibitor (TFPI) - prevents extrinsic pathway of coagulation 2) Proteins C and S 3) Thrombomodulin (binds thrombin) 4) Antithrombin (inhibits some clotting factors) - potentiated by heparin
254
What is the name for the process that enables clot breakdown?
Fibrinolysis
255
What is plasmin? What is it activated by?
Serine protease that breaks down fibrin networks, degrading clots Activated by tPA (tissue plasminogen activator) or urokinase
256
What are D-dimers?
Small fibrin fragments
257
Which factor does rivaroxaban inhibit? How will PT and APTT be affected?
Xa Both prolonged
258
Which factor does dabigatran inhibit? How will PT and APTT be affected?
Thrombin (IIa) Both prolonged
259
Give 4 examples where fibrinogen may be high?
Pregnancy Acute/chronic inflammation Trauma Certain cancers, eg Hodgkin lymphoma
260
What is the difference between a thrombus and a thromboembolism?
Clot remaining at site of formation = thrombus If dislodged, thrombus = thromboembolism (pathologic)
261
What is Virchow's triad?
Haemodynamic disruption Endothelial injury/dysfunction Hypercoagulability
262
How long should someone be on Warfarin following a DVT?
Provoked (ie recent surgery) = 3 months Unprovoked = 6 months
263
What is the MOA for for: 1) Rivaroxaban 2) Apixaban 3) Dabigatran 4) Heparin 5) Warfarin
1) and 2) - direct factor Xa inhibitor 3) Direct thrombin (IIa) inhibitor 4) Activates antithrombin III 5) Inhibits factors 10, 9, 7, 2
264
Give 3 ways advanced liver disease increase bleeding risk?
1) All clotting factors (except vWF) synthesised by liver 2) Cirrhosis -> Portal HTN -> Splenomegaly -> increased platelet sequestration 3) Reduced TPO synthesis by liver reduced platelet production
265
Which antibiotic is recommended in an episode of neutropenic sepsis?
Piperacillin with tazobactam (Tazocin)
266
What are the 2 main classifications of polycythaemia (too many RBCs)?
1) Primary/proliferative - a true polycythaemia, e.g. a myeloproliferative disorder, polycythaemia rubra vera 2) Secondary (more common) - physiological response to tissue hypoxia
267
Give 6 causes of secondary polycythaemia
``` Altitude COPD/lung disease Smoking Cyanotic heart disease Obstructive sleep apnoea EPO/androgen excess ```
268
Give 4 causes of EPO/androgen excess which may cause secondary polycythaemia
Cerebellar haemangioma Hypernephroma Hepatoma Doping
269
What is polycythaemia rubra vera?
Myeloproliferative disorder - 'overactive bone marrow' Caused by clonal proliferation of marrow stem cells leading to an increase in red cell volume, often accompanied by over-production of neutrophils and platelets
270
What mutation is seen in 95% polycythaemia rubra vera?
JAK2 mutation
271
At what age is the peak incidence of polycythaemia rubra vera?
50s
272
Give 9 features of polycythaemia rubra vera
``` Hyperviscosity Thrombosis Pruritus, typically after hot bath Splenomegaly Haemorrhage (secondary to abnormal platelet function) Plethoric appearance HTN in 1/3 Gouty arthritis in 1/5 Abnormal FBC ```
273
How is polycythaemia rubra vera investigated?
FBC (raised haematocrit) JAK2 mutation screening Serum ferritin Renal and liver function tests
274
How is polycythaemia rubra vera treated?
Aspirin Venesection Bone marrow suppression (hydroxycarbamide)
275
What is sickle cell anaemia?
Autosomal recessive disorder causing production of abnormal beta globin chains HbS rather than HbA produced
276
In which group of people is sickle cell anaemia most common?
African origin (due to protection against plasmodium falciparum in heterozygous carriers)
277
What is the amino acid substitution seen in sickle cell?
Valine for glutamic acid
278
What happens to the HbS at low pO2? | What happens on reoxygenation?
Polymerises into long intracellular fibres - deforms RBC and causes capillary occlusion Initially reforms on reoxygenation, but will eventually become irreversibly sickled
279
What is the term for an acute episode of sickle cell disease?
Sickle cell crisis
280
Give 9 main complications of sickle cell disease
1) Chronic haemolytic anaemia 2) Haemolytic crises 3) Painful infarction crises 4) Aplastic crises 5) Splenic complications 6) Infection susceptibility 7) Acute chest syndrome 8) Cerebrovascular ischaemia 9) Priapism, Skin ulceration, Proliferative retinopathy
281
Give 2 possible triggers of aplastic crises in sickle cell disease How can it be differentiated from acute haemolytic crises?
1) Parvovirus B19 infection 2) Folate deficiency No reticulocytes present
282
Why does sickle cell disease cause chronic haemolytic anaemia?
Deformed RBCs are removed from the circulation more rapidly, reducing the lifespan from 120d to 10-20d
283
How can sickle cell disease cause splenic complications?
1) Repeated micro-infarctions result in hyposplenism/asplenism 2) Acute splenic sequestration may occur (trapped blood in spleen -> abdomen pain, splenomegaly, drop in Hb)
284
What are the 4 key diagnostic features of acute chest syndrome in sickle cell disease?
Dyspnoea Drop in arterial pO2 Chest pain Pulmonary oedema on xray
285
What type of infections are people with sickle cell disease at particularly increased risk of?
Encapsulated organisms
286
How may sickle cell disease cause TIA/strokes?
Micro-infarctions
287
What is the most common reason for hospital admission in patients with sickle cell anaemia?
Painful infarction crises
288
How is chronic sickle cell disease managed?
Input from haematology Hydroxycarbamide to suppress bone marrow if frequent crises Antibiotics and immunisation as prophylaxis for splenic infarct Febrile sickle cell children high risk for sepsis - give ceftriaxone
289
What is thalassaemia?
Genetic disease of unbalanced Hb synthesis, with deficiency/complete lack of one globin chain Unmatched globin chains precipitate, damaging RBC membranes, causing haemolysis whilst still in bone marrow
290
In which areas is thalassaemia common?
Mediterranean to Far East
291
What is beta thalasaemia?
Decreased (beta thalassaemia minor) or absent (beta thalassaemia major) production of beta chains
292
What is the most common cause of beta thalassaemia?
Point mutations in the beta globin genes on chromosome 11
293
What investigations are done for beta thalassaemia?
``` FBC + MCV (microcytic anaemia) Blood film Iron HbA2 and HbF raised Hb electrophoresis ```
294
How is beta thalassaemia managed?
Promote fitness and healthy diet Folate supplements Transfusions (every 2-4 wk) - keep Hb >90 Iron chelators to prevent iron overload (oral deferiprone, SC desferroxamine) Ascorbic acid (increase urinary iron excretion) Splenectomy if hypersplenism persists Hormonal replacement/treatment for endocrine complications Histocompatible marrow transplant can offer cure Genetic counselling/antenatal diagnosis can prevent
295
What is alpha thalassaemia?
2 separate alpha globin genes on each chromosome 16 4 genes termed aa/aa Alpha thalassaemias mainly caused by gene deletions If all 4 deleted (--/--) = in utero death (hydrops fetalis) If 3 genes deleted (--/-a) = moderate anaemia and features of haemolysis (splenomegaly, leg ulcers, jaundice) If 2 genes deleted (--/aa) or (-a/-a) = asymptomatic carrier state with decreased MCV With just one deleted, clinical state is normal
296
What are the clinical classifications of thalassaemia?
Thalassaemia major = transfusion dependent Thalassaemia intermedia = less severe anaemia, can survive without regular blood transfusions Thalassaemia carrier/heterozygote = asymptomatic
297
What is beta thalassaemia trait?
Autosomal recessive Mild hypochromic, microcytic anaemia – microcytosis is characteristically disproportionate to the anaemia HbA2 raised (>3.5%) Usually asymptomatic
298
What are the 3 types of autoimmune haemolytic anaemia (AIHA)?
1) Warm AIHA (haemolysis occurs at body temp) 2) Cold AIHA (haemolysis occurs below core body temp) 3) Paroxysmal cold haemoglobinuria
299
What test is used to detect AIHA?
Coomb's test (direct antigen test)
300
What are the four types of globin chains may make up a haemoglobin molecule?
Alpha Beta Delta Gamma
301
What are the following composed of: 1) HbF (foetal) 2) HbA (main adult) 3) HbA2
1) alpha2, gamma2 2) alpha2, beta2 3) alpha2, delta2
302
At what age do symptoms of beta-thalassaemia develop?
3-6 months old (when HbA takes over from HbF)
303
How can hydroxyurea help some patients with sickle cell crisis?
Stimulated production of fetal haemoglobin
304
What is haemophilia?
X-linked recessive disorder of coagulation
305
What are the 2 types of haemophilia?
A (factor 8 deficiency) | B (factor 9 deficiency) - Christmas disease
306
How does haemophilia present?
Haemarthroses (bleeding in joints) Haematomas (esp in muscle) Prolonged bleeding after surgery or trauma
307
What would appear on blood tests in someone with haemophilia?
Prolonged APTT Normal bleeding time, thrombin time and prothrombin time
308
How is haemophilia treated?
A: factor 8 replacement B: factor 9 replacement Up to 1-15% of patients with haemophilia A develop antibodies to factor VIII treatment
309
How are platelets produced? | What is their lifespan?
Anucleate cell fragments from megakaryocytes Thrombopoietin (TPO) - stimulates production of platelets by megakaryocytes, produced mainly by liver Lifespan 7-10 days
310
What are some causes of thrombocytosis?
Reactive (platelets are an acute phase reactant, so can increase in response to stress such as severe infection or surgery) Malignancy Essential thrombocytosis Hyposplenism (spleen breaks down old platelets so if its function is reduced, more platelets can circulate)
311
What is essential thrombocytosis?
A myeloproliferative disorder Overlaps with CML, PRV, myelofibrosis Megakaryocytic proliferation results in overproduction of platelets
312
What are some features of essential thrombocytosis?
Platelet count >600 Thrombosis (venous or arterial) Haemorrhage Characteristic symptom = burning sensation in hands
313
What mutation is seen in 50% essential thrombocytosis?
JAK2 mutation
314
How is essential thrombocytosis managed?
Hydroxyurea (hydroxycarbamide) - widely used to reduce platelet count Interferon alpha Low-dose aspirin to reduce thrombotic risk
315
What are some causes of severe thrombocytopenia?
ITP DIC TTP Haematological malignancy (bone marrow failure)
316
What are some causes of moderate thrombocytopenia?
``` Heparin-induced thrombocytopenia (HIT) Drug-induced (quinine, diuretics, sulphonamides, aspirin, thiazides) Alcohol/Liver disease Hypersplenism Viral infection (EBV, HIV, hepatitis) Pregnancy SLE/antiphospholipid syndrome Vitamin B12 deficiency ```
317
What is ITP?
Immune thrombocytopenic purpura Immune-mediated reduction in platelet count - antibodies are directed against glycoprotein 2b/3a or Ib-V-IX complex
318
What are the symptoms/signs of ITP?
Low platelet counts on bloods Isolated thrombocytopenia - rest of blood count is normal Non-blanching purpuric rash Easy bruising Evidence of mucosal bleeding - menorrhagia, nose bleeds, gum bleeding when brushing teeth
319
What are the features of acute ITP?
More common in children May follow infection or vaccination - antibody-viral antigen complexes bind to platelets, resulting in removal of platelets by reticuloendothelial system Usually self-resolves within 1-2 weeks
320
What are the features of chronic ITP?
More common in young/middle aged women Tends to run a relapsing-remitting course Often Hx autoimmune disease
321
How is ITP managed?
General: - Stop NSAID/aspirin - Observe platelet count Immunosuppression: - Steroid (Prednisolone) - Rituximab (second line) Reduce platelet destruction: -IVIG (saturates splenic macrophages) Increase platelet production -TPO mimetics, e.g. romiplostim, eltrombopag
322
What is Evan's syndrome?
ITP in association with autoimmune haemolytic anaemia
323
What is thrombotic thrombocytopenic purpura?
Medical emergency! | Rare form of thrombotic microangiopathy
324
What are some RFs for TTP?
Pregnancy/post-partum (up to 25% cases) HIV Autoimmune disease Cancer
325
What is the pathogenesis of TTP?
Abnormally large and sticking multimers of vWF (due to ADAMTS-13 deficiency) cause platelets to clump within vessels Overlaps with HUS
326
Features of TTP?
``` Classic pentad: Fever Cerebral dysfunction (confusion, headache, paresis, dysarthria, visual problems) Haemolytic anaemia Thrombocytopenia AKI ```
327
What are the two features of TTP required to make a diagnosis?
AIHA | Thrombocytopenia
328
How is TTP managed?
Urgent plasmapheresis Steroids Immune suppressants Vincristine
329
What are the 3 indications for a platelet transfusion?
Platelet count <30 with clinically significant bleeding (WHO bleeding grade 2 - haematemesis, melaena, prolonged epistaxis) Higher transfusion thresholds up to <100 (for patients with WHO bleeding grades 3/4 or bleeding at critical sites - e.g. CNS) Pre-invasive procedure (prophylactic)
330
Give 4 contraindications for platelet transfusion?
Chronic bone marrow failure Autoimmune thrombocytopenia Heparin-induced thrombocytopenia Thrombotic thrombocytopenic purpura
331
What is disseminated intravascular coagulation?
Dangerous condition due to widespread activation of coagulation cascades. Triggered by sepsis, trauma, burns, malignancy, massive blood loss etc
332
What is the underlying pathophysiology of DIC?
1) Systemic activation of clotting cascade -> 2) Microvascular thrombosis AND 1) Consumption of platelets and clotting factors -> 2) Bleeding Microvascular thrombosis can lead to organ failure
333
Which malignancy in particular can be a RF for DIC?
Leukaemias
334
Give some causes/RFs for DIC
``` Sepsis Malignancy - especially leukaemias Major trauma – crush syndrome, burns Complications of pregnancy – abruption, HELLP, pre-eclampsia Incompatible blood transfusion Transplant rejection Severe liver disease Pancreatitis Recreational drugs Snake bites Connective tissue disorders – incl. antiphospholipid syndrome ```
335
How is DIC investigated?
Look for underlying cause Clotting profile D-dimer (raised) +/- evidence organ failure
336
What would be seen on the blood tests for someone with DIC?
Low platelets Prolonged PT Prolonged APTT Prolonged bleeding time
337
How is DIC managed?
``` Treat underlying cause Supportive: -Platelets -FFP -Cryoprecipitate ```
338
What is the most common inherited bleeding disorder?
von Willebrand disease
339
How is von Willebrand disease usually inherited?
Autosomal dominant
340
How many von Willebrand disease present?
``` Mucosal bleeding (epistaxis, menorrhagia) Unlikely to have large haemarthroses/haematomas ```
341
What would blood investigation results show in vWD?
Prolonged bleeding time APTT may be prolonged Factor 8 levels may be reduced Defective platelet aggregation with ristocetin (substance that aims to force platelet aggregation)
342
How is vWD managed?
1) Tranexamic acid for mild bleeding 2) DDAVP (Desmopressin) - raises levels of vWF 3) Factor VIII concentrate
343
Where is vWF produced?
Endothelial cells
344
What is the most common type of VWD?
Type 1 (partial deficiency - if mild, may not show on clotting screen)
345
What are the 3 types of VWD?
``` Type 1 - partial deficiency Type 2 (A, B, M, N) - functional issue with protein Type 3 (absolute deficiency - may look like a haemophilia) ```
346
Why may factor VIII levels be low in someone with VWD?
Factor VIII has a short half-life | VWF binds to it and lengthens its half life
347
What is heparin-induced thrombocytopenia?
Development of IgG antibody against platelet-heparin complexes IgG-PF4-Heparin complexes bind to and activate platelets - > Platelet consumption increased - > Thrombosis (arterial or venous) - > Skin necrosis
348
Who is most at risk of heparin-induced thrombocytopenia?
Patients following cardiac bypass surgery with large amounts of unfractionated heparin treatment
349
How does heparin-induced thrombocytopenia present?
Sharp fall in platelets 5-10 days after starting heparin
350
How is heparin-induced thrombocytopenia managed?
Life-threatening: STOP HEPARIN IMMEDIATELY Use alternative anticoagulation (even if platelets low) Never re-expose patient to heparin
351
What are the 4 main haematological emergencies?
1) Neutropenic sepsis 2) Hyperviscosity syndrome 3) Tumour lysis syndrome 4) Acute sickle chest syndrome
352
Haematological malignancies are a common cause of tumour lysis syndrome. What causes this and how can it be prevented?
Chemotherapy (often) - due to rapid death of cells IV rasburicase or IV allopurinol can be given before chemo to reduce risk
353
What are the diagnostic criteria for tumour lysis syndrome?
Abnormality in 2+ of the following within 3 days before and 7 days after chemo: 1) Uric acid 2) K+ 3) Phosphate 4) Calcium Lab TLS + 1) ^serum creatinine 2) cardiac arrhythmia/sudden death 3) seizure
354
Give 5 complications of tumour lysis syndrome
``` Hyperkalaemia Hyperphosphataemia Hypocalcaemia Hyperuricaemia Acute renal failure ```
355
How is tumour lysis syndrome treated?
``` Aggressive IV fluid resus Allopurinol, rasburicase Control of electrolytes -BM monitoring in at-risk patients -Treat hyperkalaemia Early referral for dialysis if needed ```
356
What is the definition of neutropenic sepsis?
Neut <0.5 In a patient having anti-cancer treatment AND T >38 or other Sx consistent with clinically significant sepsis
357
Give the 5 types of recognised crises in sickle cell disease
``` Thrombotic, vaso-occlusive 'painful crises' Sequestration Acute chest syndrome Aplastic Haemolytic ```
358
Why might a patient being treated for leukaemia develop hip pain?
Steroids can cause avascular necrosis, in this case of the femoral head
359
What are the three main triggers of thrombotic/painful crises?
Infection Dehydration Hypoxia
360
What are the features of a thrombotic/painful crisis?
Microvascular occlusion causes severe pain Infarcts occur in various organs: - Bones (eg avascular necrosis of hip - Perthe's) - Hand-foot syndrome (children) - Lungs - Spleen - Brain
361
What are the features of a sequestration crisis? Who is most affected? How is it managed?
Sickling within organs (eg spleen, liver) Pooling of blood + worsening anaemia Mainly affects children as spleen has not yet undergone atrophy Splenomegaly, hepatomegaly Severe anaemia and shock Requires urgent transfusion
362
What are the key clinical features of acute chest syndrome?
Dyspnoea Chest pain Pulmonary infiltrations Low pO2
363
What are the features of aplastic crisis?
Triggered by parvovirus B19 (slapped cheek) Sudden reduction in marrow production, esp RBCs Sudden drop in Hb Usually self-limiting (2 weeks) but may need transfusion
364
How is an acute sickle cell crisis managed?
ABCDE Analgesia (eg IV opioids) X-match blood, FBC, retics, cultures, CXR if febrile/chest Sx Rehydrate with IVI and keep warm HiFlow O2 Ceftriaxone if T >38 Transfusion if Hb falls sharply (aim HbS <30%)
365
What is hyperviscosity syndrome?
Increase in blood viscosity due to raised Ig produced by malignant clones of plasma cells (eg myeloma) OR (rare): heavy white cell loads in leukaemia
366
What are the causes of hyperviscosity syndrome?
Increased antibodies 1) Myeloma 2) Waldenstrom's macroglobulinaemia Increased WBCs 1) CML 2) AML 3) ALL Increased RBCs 1) Polycythaemia
367
Clinical presentation of hyperviscosity syndrome?
``` Lethargy Headaches Confusion Cranial nerve defects Ataxia Retinal haemorrhages Dyspnoea and cough (pulmonary leukostasis - infiltrates on CXR) Mottling of skin ```
368
How is hyperviscosity diagnosed?
``` Clinical diagnosis Plasma viscosity level CT head to exclude other causes of neurological signs Globulin level FBC + Ig levels ```
369
How is hyperviscosity managed?
1) Plasmapheresis (if raised Ig level) 2) Leucophoresis (if raised WBCs) Avoid blood transfusions Urgently start appropriate chemo

Medicine - Finals (13 decks)

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