Haematology Flashcards
(240 cards)
1
Q
A
2
Q
What is anaemia?
A
When there is a decrease in haemoglobin.
3
Q
What two things cause low haemoglobin levels?
A
Reduction in cell mass
Increased plasma volume
4
Q
What element is key for making Hb?
A
Iron
5
Q
What is the normal mean cell volume?
A
80-100 femtolitres
6
Q
What are the 3 main subtypes of anaemia?
A
Microcytic- low MCV indicating small sized RBC
Normocytic- normal MCV indicating normal sized RBC
Macrocytic- high MCV indicating large sized RBC
7
Q
What are the 5 causes of microcytic anaemia?
A
T- Thalassaemia
A- Anaemia of chronic disease
I- Iron deficiency
L- Lead poisoning
S- Sideroblastic anaemia
TAILS
8
Q
What are 5 causes of normocytic anaemia?
A
A- anaemia of chronic disease
A- Acute blood loss
A- Aplastic
H- haemolytic
H- Hypothyroidism
3 As and 2 Hs
9
Q
What are the two subtypes of macrocytic anaemia?
A
Megaloblastic
Normoblastic
10
Q
What is megaloblastic anaemia and what causes it?
A
Problem in DNA synthesis caused by vitamin deficiency
Folate
B12
11
Q
What causes normoblastic anaemia?
A
Alcohol
Hypothyroidism
Liver disease
Drugs such as azathioprine
12
Q
What are the generic signs of anaemia?
A
Pale skin
Conjunctivital pallor
Tachycardia
Raised respiratory rate
13
Q
How common is iron deficiency anaemia?
A
Most common cause in the world
14
Q
What can cause iron deficiency anaemia?
A
Vegetarian diet
H. pylori infection
Pregnancy and breastfeeding
IBS
Coeliac
PPI’s
Increased iron loss through bleeding (this is the principal cause if Fe deficiency)
15
Q
Why does iron loss cause microcytic anaemia?
A
Iron is needed for the formation of haemoglobin and when there is a lack of iron not enough haemoglobin is made to make normal sized RBC’s.
Therefore smaller RBC’s are produced by the bone marrow which can’t carry enough oxygen to meet the bodies demand hence hypoxia
16
Q
Where is Iron mainly absorbed in the body?
A
Duodenum and jejunum
17
Q
Why are women more prone than men to iron deficiency?
A
Women lose about 2mg daily when menstruating where as men will only on average lose 1mg a day
18
Q
How can pregnancy cause anaemia?
A
Pregnancy results in net loss of 580mg of iron, due to expansion of RBC mass and growth of the foetus and placenta. Most occurs in the third trimester
19
Q
Why does H.Pylori cause iron deficiency?
A
It traps Fe itself in the stomach preventing it from reaching the duodenum
20
Q
How do PPI’s cause iron deficiency?
A
Iron requires acid from the stomach to stay in it’s soluble form fe2+ where as without acid it becomes insoluble Fe3+. Therefore PPI’s as they reduce amount of stomach acid can lead to Fe deficiency
21
Q
Why can hair and nails be affected by Iron deficiency?
A
As iron is required for enzymes in the mitochondria, and as hair and nails are fast growing they are most affected by this deficit
22
Q
What are the signs of Iron deficiency?
A
- Conjunctivital pallor
- Koilonychia (spoon shaped nails)
- Angular stomatitis (redness around mouth)
- Glossitis
23
Q
What are the symptoms of iron deficiency?
A
- Fatigue
-Dyspnoea on exertion - Dizziness
- Headache
- Nausea
- bowel disturbance
- Hair loss
24
Q
What investigations would you perform for a patient with suspected iron deficiency?
A
FBC- would have low Hb, low MCV
- Iron studies would measure the: serum iron, serum ferritin and total iron binding capacity
If ferritin in the blood is low it is highly suggestive of iron deficiency. If ferritin is high then this is difficult to interpret and is likely to be related to inflammation rather than iron overload. A patient with a normal ferritin can still have iron deficiency anaemia, particularly if they have reasons to have a raised ferritin such as infection.
transferrin levels increase in iron deficiency and decrease in iron overload.
25
How would you treat iron deficiency?
- Treat underlying cause
- Oral iron supplements ferrous sulphate/fumarate
- Iron infusion e.g., cosmofer
- Blood transfusion in severe cases
26
What are the complications associated with iron deficiency?
- Cognitive impairment
- Impaired muscular performance
- Preterm delivery
- High output heart failure
27
What is Thalassaemia?
Thalassaemia is an autosomal recessive haemoglobinopathy which causes a microcytic anaemia.
28
What is alpha thalassemia (AT)?
A genetic disorder where there is a deficiency in the production if the alpha chains of Hb. Autosomal recessive
29
Where is AT most common?
Asia and Africa
30
What chromosome is the gene affected in AT found on?
2 on each 16
31
What are the 4 types of AT?
- Silent carrier- 1 gene deletion
- AT trait- 2 gene deletions. mildly anaemic
- Haemoglobin H disease (HBH)- 3 gene deletions moderate to severe disease
- Haemoglobin barts (HBB) - 4 gene deletions they will die in utero
32
How does HBH cause problems?
Unable to form alpha chains which means beta chains for tetramers which damages RBC
HBH causes haemolysis as well as having a higher affinity for oxygen so oxygen not released at tissues
33
How does HBB cause problems?
- Gamma chains form tetramers (**Hb Barts**), which cannot carry oxygen efficiently
- Severe hypoxia leads to high-output cardiac failure and massive hepatosplenomegaly, resulting in oedema all over the body, called hydrops fetalis.
A consequence of hypoxia is that it signals the bone marrow, as well as extramedullary tissues like the liver and spleen, to increase production of RBCs.
This may cause bones containing bone marrow, as well as the liver and spleen, to enlarge.
34
What are the key presentations of AT?
- Family history
- Risk factors
- Symptoms of anaemia
- Splenomegaly due to destruction of RBC
35
What are the symptoms of AT?
- Shortness of breath
- Palpitations
- fatigue
- Swollen abdomen
36
What investigations would you perform for AT?
FBC- measure MCV would show microcytic anaemia
Blood film- **microcytic, hypochromic erythrocytes**, as well as target cells (look like bullseyes due to scrunching up of the cell membrane) and nucleated RBCs (**Howell-Jolly bodies**). With moderate alpha thalassaemia, there may be golf-ball like RBCs, due to precipitated HbH molecules.
37
What would the treatment for AT trait and silent carrier AT?
Iron supplement if required
38
What would the treatment for HBH AT be?
- Folic acid supplementation (first line)
- Iron chelation to prevent overload
- Splenectomy
- RBC transfusion
- Then a bone marrow transplant can be curative
39
What are the complications of AT?
- **Heart failure:** severe anaemia can lead to high output cardiac failure
- **Hypersplenism:** compensatory extramedullary hematopoiesis takes place in the spleen leading to splenomegaly and hypersplenism. This, in turn, can cause pancytopaenia
- **Aplastic crisis**: associated with parvovirus B19 infection and can result in pancytopaenia with reduced reticulocytes
- **Iron overload due to regular transfusions:** excess iron leads to secondary haemochromatosis which can affect the liver, heart, pancreas, skin, and joints
40
What is beta thalassaemia?
Beta thalassaemia is a genetic disorder where there’s a deficiency in the production of the β-globin chains of haemoglobin.
It is an autosomal recessive condition.
41
Where are the beta chains coded for (which chromosome)?
11
42
What are three types of BT?
BT trait- often asymptomatic
BT intermedia- variable presentation
BT major- will be severe
43
What is BT trait/minor?
Patients with beta thalassaemia minor are carriers of an abnormally functioning beta globin gene. They have one abnormal and one normal gene.
Thalassaemia minor causes a mild microcytic anaemia and usually patients only require monitoring and no active treatment.
44
What is BT intermedia?
Patients who have two abnormal copies of the beta-globin gene. Two defective genes or one defective and one deletion.
This will cause more significant anaemia
45
What is BT major?
Have tow deletions of the beta-globin gene. They have no functioning beta globin genes
Will cause severe anaemia
46
What happens to a patient with BT major?
- When there’s a β-globin chain deficiency, free α-chains accumulate within red blood cells, and they clump together which damage the red blood cell’s , causing haemolysis
- This causes an excess of unconjugated bilirubin leads to jaundice, and excess iron deposits leads to secondary hemochromatosis.
- The haemolysis can also lead to hypoxia.
- A consequence of hypoxia is that it signals the bone marrow, and extramedullary tissues like the liver and spleen, to increase red blood cell production, which may cause bone marrow containing bones, like those in the skull and face, as well as the liver and spleen, to enlarge.
47
What are the signs of BT major/intermedia?
- Onset after 2 years of age as no longer gamma chains
- Jaundice (excess bilirubin)
- Pallor
- Splenomegaly
- Chipmunk face enlarged forehead and cheekbones
- Failure to survive
48
What are the symptoms of BT major?
- SOB
- Palpitations
- Fatigue
- Swollen abdomen
- Growth retardation
49
What are the first line investigations for BT?
- 1st line
- **FBC**: microcytic anaemia with more RBC's as bone marrow compensates in Beta
- Lab work may also show high serum iron, high ferritin, and a high transferrin saturation level.
- **Blood** **film**: microcytic, hypochromic erythrocytes, as well as target cells (look like bullseyes due to scrunching up of cell membrane) and nucleated RBCs (Howell-Jolly bodies)
-
50
What other tests might you do for BT?
Skull x-ray- hair-on-end appearance due to marrow hyperplasia
- DNA testing
51
What are the complications of BT?
Same as AT. These include iron overload, high output heart failure, gallstones, aplastic crisis, hypersplenism
52
How would you manage BT?
Blood transfusions, folate supplementation, iron chelation, splenectomy, and bone marrow transplant
53
What is sideroblastic anaemia?
When there is ineffective Erythropoiesis leading to increased iron absorption and loading in the marrow. Will not respond to iron think this when anaemia doesn't respond to iron.
54
What is sickle cell anaemia?
Sickle cell anaemia is caused by an autosomal-recessive single gene defect in the beta chain of haemoglobin, which results in production of sickle cell haemoglobin (HbS).
55
Where is sickle cell most prevalent?
highest prevalence in sub-Saharan Africa s it is protective against malaria
56
What are the risk factors for sickle cell?
- **African**: 8% of black people carry the sickle cell gene
- **Family history**: autosomal recessive pattern
- **Triggers of sickling**: dehydration, acidosis, infection, and hypoxia
57
What causes sickle cell anaemia?
Sickle cell anaemia is an autosomal recessive condition where there is an abnormal gene for beta-globin on chromosome 11. One copy results in sickle cell trait and 2 result in sickle cell disease
58
Describe how sickling occurs?
- Unusual haemoglobin proteins HbS are formed these can carry oxygen perfectly well
- However HbS molecules change it's shape to allow it to aggregate with other proteins and form long polymers that are crescent in shape this process is called sickling
59
What can trigger sickling?
Dehydration
Acidosis
Infection
Hypoxia
60
What are the problems with sickle shaped RBC's?
- Repeated sickling of RBC's can damage their cell membranes leading to haemolysis which can cause anaemia can lead to splenomegaly
- To counteract haemolysis increased formation of RBC's lead to bone enlargement
- In sickled form RBC's can get stuck in capillaries and cause vaso-occulsion
61
What are the chronic symptoms of sickle cell anaemia?
- Pain
- Anaemia related symptoms
- Haemolysis leading to jaundice and gallstones
62
What is a sickle cell crisis and what different ones are there?
Sickle cell crisis is an umbrella term for a spectrum of acute crises related to the condition.
- Sequestration crisis
- Aplastic crisis
- Haemolytic crisis
- Vaso-occlusive crisis
- Acute chest syndrome
63
What is a sequestration crisis?
- RBCs sickle in the spleen causing pooling of blood this can lead to severe anaemia and circulatory collapse (hypovolemic shock)
- Support with blood transfusions and fluids for shock
- Abdominal pain and splenomegaly will also occur as symptoms
- Can lead to infarction of the spleen if repeated
64
What is an aplastic crisis?
- Infection caused by parvovirus B19 causes bone marrow suppression
- It leads to significant anaemia. Management is supportive with blood transfusions if necessary. It usually resolves spontaneously within a week.
65
What is a Vaso-occlusive Crisis (AKA painful crisis)
Vaso-occlusive crisis is caused by the sickle shaped blood cells clogging capillaries causing distal ischaemia.
It is associated with dehydration and raised haematocrit. Symptoms are typically pain, fever and those of the triggering infection. Also priapism in men
66
What is a Haemolytic crisis?
- When there is an increased rate of haemolysis
67
What are the investigations for anaemia?
- New born screening with heel prick happens at day 5
- **FBC:** normocytic anaemia with reticulocytotic
- **Blood film:** sickled RBCs, target cells, Howell-Jolly bodies (RBC nuclear remnants seen later in the disease due to hyposplenism)
- **Hb electrophoresis and solubility: diagnostic** investigation, demonstrating ****increased HbS (2 alpha chains and 2 abnormal beta chains) and reduced/absent HbA (α2 β2)
68
What is the treatment for sickle cell crises?
- Have a low threshold for admission to hospital
- Treat any infection
- Keep warm
- Keep well hydrated (IV fluids may be required)
- Simple analgesia such as paracetamol and ibuprofen
- Penile aspiration in priapism
69
What is the long term management for sickle cell anaemia?
- Avoid dehydration and other triggers
- Ensure up to date vaccines
- Antibiotic prophylaxis to protect against infection (phenoxymethylpenicillin)
- Hydroxycarbamide will stimulate the production of foetal haemoglobin which prevents sickle cell crisis
- Blood transfusion
- Bone marrow transplant
70
What is the prognosis for sickle cell anaemia?
Prognosis is variable. The median age at death is 40-50 for patients with sickle cell disease, with a third of patients dying during an acute crisis
71
What is aplastic anaemia?
A stem cell disorder. It is characterised by anaemia, leukopenia and thrombocytopenia
72
What causes aplastic anaemia?
- Idiopathic
- radiation and toxins
- Drugs
- Infections HIV
73
What causes aplastic anaemia?
- The most common cause of aplastic anaemia is autoimmune destruction of haematopoietic stem cells.
- Research shows that there are alterations in the immunologic appearance of haematopoietic stem cells because of genetic disorders, or after exposure to environmental agents, like radiation or toxins.
74
What are the signs of Aplastic anaemia?
Pallor
75
What are the symptoms of aplastic anaemia?
- **Fatigue**
- **Palpitations**
- **Dizziness**
- **Headaches**
- **Chest pain and shortness of breath:** as heart works harder to compensate for low RBC count
- **Increased bleeding and petechiae:** due to thrombocytopenia
- **Recurrent infections:** due to leukopenia
76
What investigations would you run for aplastic anaemia?
- FBC would should leukopenia, thrombocytopenia and low reticulocyte count
- increased erythropoietin
- Increased bleeding time
- Bone marrow biopsy
77
What is the treatment for aplastic anaemia?
- **Removal/ treatment of causes** e.g. drugs or infections
- **Transfusions**
- **Stem cell transplant**
- **Immunosuppressive treatment**
78
What is G6PD deficiency?
G6PD deficiency is a condition where there is a defect in the G6PD enzyme normally found in all cells in the body.
79
What is G6PD deficiency?
G6PD deficiency is a condition where there is a defect in the G6PD enzyme normally found in all cells in the body. Makes people more susceptible to haemolytic anaemia
80
What is the epidemiology of G6PD?
- It is inherited in an X linked recessive pattern, meaning it usually affects males.
- It is more common in Mediterranean, Middle Eastern and African patients.
- 6DPD deficiency can be protective against malaria
81
Explain the pathophysiology of G6PD?
- G6PD is an enzyme that helps to produce NADPH in the RBCs to protect them from damage by free radicals. The G6PD mutations cause defective G6PD enzymes to be produced that have a shorter half-life.
- Normal red cells can increase generation of NADPH in response to oxidative stress; this capacity is impaired in patients with G6PD deficiency. Failure to withstand oxidative stress damages haemoglobin and the red cell membrane and causes haemolysis.
82
What are the triggers for anaemia in someone with G6PD deficiency?
- Stress
- Infections
- Acidosis
- Fava beans and soy products
- Red wine
- Medications e.g., Chloroquine
83
What are the signs of G6PD?
- Jaundice
- Pallor
- Splenomegaly
- Dark tea coloured urine
Symptoms are anaemia, SOB, tiredness dizziness, headaches, palpitations
84
What are the investigations for G6PD?
- **FBC:** low levels of RBC, high reticulocytes
- **LDH:** elevated
- **Bilirubin:** elevated
- **Haptoglobin:** low
- **Coomb's test:** negative (used to detect immune mediated anaemias)
- Diagnosis can be made by doing a **G6PD enzyme assay**
85
What is B12 deficiency anaemia?
Anaemia caused by B12 deficiency it is a macrocytic megaloblastic anaemia
86
What causes B12 deficiency?
- Inadequate intake (vegans and vegetarians as it is found in animal products)
- Inadequate secretion of intrinsic factor
- Malabsorption (crohn's, patients who have had a gastric bypass)
- Inadequate release of B12 from food (alcohol abuse and gastritis)
- Can also be caused by pernicious anaemia which is where there is autoimmune destruction of the gastric epithelium
87
Why does B12 deficiency affect RBCs?
- It is a essential vitamin in DNA synthesis so it will affect rapidly dividing cells e.g., RBC's and tongue causing glossitis.
88
What are the signs of B12 deficiency?
- Pallor
- Signs of neurological defect
89
What are the symptoms of B12 deficiency?
- SOB
- Palpitations
- Headaches
- Fatigue
- Glossitis
- CNS involvement - **Personality change**
- **Depression**
- **Memory loss**
- **Visual disturbances**
- **Numbness, weakness and paraesthesia affecting the lower extremities**
- **Ataxia**
- **Loss of vibration sense or proprioception**
- **Autonomic dysfunction (e.g. bladder/bowel dysfunction)**
90
What would the first line investigations for B12 deficiency be?
-- **Full blood count (FBC):** raised MCV
- **Blood film:** megaloblastic anaemia +/- hypersegmented neutrophils
- **Haematinics:** look for iron, B12, folate deficiency
- **Lactate dehydrogenase (LDH):** may be elevated
- **Liver function tests (LFTs)**
91
What type of anaemia is folate (B9) deficiency?
Macrocytic megaloblastic
92
Where is folate deficiency most commonly seen?
- In areas with malnutrition
- High-risk groups include children, pregnant women and elderly
93
Why does folate cause anaemia?
- It is a essential vitamin in DNA synthesis and amino acid synthesis so it will affect rapidly dividing cells e.g., RBC's and tongue causing glossitis.
94
What else can a lack of folate cause?
- Neural tube defects in pregnancy e.g., Spina bifida
95
Where is folate absorbed?
Duodenum and jejunum
96
How long does folate deficiency take to occur compared to B12?
folate= a few months
B12= A few years
97
What can cause folate deficiency?
- Inadequate intake
- Malabsorption
- Increased requirement (malignancy and pregnancy)
- Increased loss (chronic liver disease)
- Alcohol abuse
98
What are the symptoms if folate deficiency?
- **Fatigue**
- **Dyspnoea**
- **Palpitations**
- **Headache**
- **Glossitis**
- **Features of pancytopenia** e.g. excessive bleeding and bruising due to thrombocytopenia, recurrent infections due to leukopenia
- **Symptoms of underlying cause** e.g.
- Coeliac disease: diarrhoea, bloating, dyspepsia and abdominal discomfort.
99
What investigations would you perform to look for folate deficiency?
- FBC would show a high MVC
- Blood film would show macrocytic megaloblastic cells
- Haematinics search for iron B12 and folate
100
How would you treat folate deficiency?
- **Treat underlying cause** e.g. stopping drugs or alcohol consumption
- **Folic acid supplements**: always give alongside B12, because replacement of folic acid in the presence of vitamin B12 deficiency may cause significant neurological disease.
101
What is Anaemia of chronic disease?
- A chronic disease due to chronic inflammation process from underlying infection, malignancy or systemic disease
- Normally normocytic but can be microcytic
102
How common is ACD?
ACD is the second most common cause of anaemia worldwide, and commonly seen among hospitalised patients.
103
What two processes are the main cause of ACD?
- Decreased lifespan as a result direct cellular destruction via toxins from cancers, viruses and bacteria
- Decreased production of RBC- inflammation inhibits iron metabolism and cytokines inhibit erythropoietin production in the kidney
104
What two cytokines inhibit erythropoietin release from the kidneys?
TNF-a
IFN-y
105
What are the symptoms of ACD?
- **Fatigue**
- **Pallor**
- **Shortness of breath**
- **Headache**
- **Dizziness**
- **May worsen palpitations, angina and intermittent claudication**
106
What are the investigations for ACD?
- Primary investigations
- **FBC:** normocytic normochromic anaemia (approx. 75%) OR microcytic anaemia
- **CRP**
- **Blood film**
- **Haematinics:** check for iron, B12 and folate deficiencies
- **Iron studies:**
- **Serum ferritin:** normal or raised
- **Serum iron:** tends to be low
- **Total iron binding capacity:** tends to be low
107
What is the treatment for ACD?
- Treatment of underlying cause
- EPO injections
- Parenteral iron
- Transfusions
108
How are the different types of leukaemia classed?
By the speed of onset (chronic or acute) and by which cell line they affect (myeloid or lymphocytic)
109
What do myeloid cells go on to form?
- Erythrocytes
- mast cells
- Megakaryocytes
- Myoblast (most WBC)
110
What do lymphoid cells go on to form?
- natural killer cells
- small lymphocytes (T and B cells)
111
Describe the general pathophysiology of leukaemia?
- Excessive production of a single type of cell type can lead to suppression of other cell types. This results in pancytopenia.
- Low RBC, Low WBC (Leukopenia) and platelets (thrombocytopenia)
112
What leukaemia's affect what ages?
ALL CeLLmates have CoMmon AMbitions
ALL- Acute lymphocytic leukaemia Under 5's and over 45s
CeLL- Chronic lymphocytic leukaemia Over 55s
CoMmon- Chronic myeloid leukaemia Over 65s
AMbitions- Acute myeloid leukaemia Over 75s
113
How can acute lymphocytic leukaemia be classified?
B-cell and T-cell ALL can be classified based on the origin (B cell or T cell) and maturity of the malignant cells:
114
What is the most common gene abnormality for children who develop ALL?
t (12;21)
115
What is the most common gene abnormality for adults who develop ALL?
t (9;22) Philadelphia chromosome
116
What are the risk factors for developing ALL?
- **Previous chemotherapy**
- **Radiation exposure**
- **Down syndrome:** 20-fold increased risk
- **Benzene exposure**: painters, petroleum, rubber manufacturers
- **Family history**: there is some evidence of genetic predisposition
117
What condition can increase the chances of getting ALL?
Down syndrome as there is an extra 21st chromosome
118
What happens when the cancer cells spill out of the bone marrow into the blood?
- Some cells especially lymphoblast's settle in organs and cause them to enlarge
119
What are the symptoms of ALL?
- **Fatigue**
- **Loss of appetite**
- **Weight loss**
- **Easy bruising, prolonged bleeding and mucosal bleeding:** due to thrombocytopaenia
- **Recurrent infections:** due to neutropaenia
- **Bone pain:** due to bone marrow infiltration
- **Fever**
- **Failure to thrive (**children)
- **Abdominal fullness:** due to hepatoslenomegaly
- **Localised pain in lymph nodes:** due to lymphadenopathy
120
What investigations would you perform to test for ALL?
- **FBC:** lymphocytosis, thrombocytopenia and normocytic anaemia with a low reticulocyte count
- **Blood film:** lymphoblasts - relatively small cells with coarse chromatin, which are clumped together and have small nucleoli. They have very little cytoplasm, which has glycogen granules.
- **Bone marrow aspiration and trephine biopsy:** ≥ 20% lymphoblasts is **diagnostic**
121
How would you treat ALL?
- Blood and platelet transfusion
- Chemotherapy
- Steroids
- Allopurinol to prevent tumour lysis syndrome
- Control infections
- Bone marrow transplant
122
What is tumour lysis syndrome?
- The release of uric acid from cells that are being destroyed by chemotherapy
- Uric acid can form crystals and cause AKI
123
What is the prognosis of ALL?
Prognosis is dependent on age. 5-year survival in children is generally >90%.
124
What is chronic lymphocytic leukaemia?
Chronic lymphocytic leukaemia is where there is chronic proliferation of a single type of well differentiated lymphocyte, usually B-lymphocytes. They escape apoptosis.
125
How common us CLL?
Most common leukaemia more common in men and occurs at 70 most common
126
What are the symptoms of CLL?
Often asymptomatic
- Can show anaemia, weight loss, sweating and bleeding
- Can also have enlarged rubbery no-tender nodes
127
What are the complications of CLL?
- Autoimmune haemolysis
- Bone marrow failure
- Richter's transformation when it develops into a high grade lymphoma
128
What investigations would you run for CLL?
FBC- would show high WCC and high lymphocytes
Blood film- would show small mature lymphocytes smudge cells
129
What is the treatment for CLL?
- Watch and wait
- Chemotherapy if it develops
- rituximab antibodies
130
What is the prognosis of CLL?
5-year survival is 70-75% and early-stage disease is associated with a median survival of over 10 years.
However, Richter transformation occurs in 2-8% of cases and is associated with a poor prognosis.
131
What is acute myeloid leukaemia?
Involves the proliferation of myoblasts especially white blood cells
132
What is acute promyelocytic leukaemia?
- Involves the translocation (15;17)
- Presents in younger age groups average age 44
- Demonstrates Auer rods
- Good prognosis 80% cure rate
133
What is acute monocytic leukaemia?
- Monoblast accumulation and lack of Auer rods
- Results in gum infiltration
134
Describe the epidemiology of AML?
- Most common acute leukaemia
- AML is generally a disease of the older people and is uncommon before 45 most common in over 75s
135
What are the risk factors for developing AML?
- Age
- Myelodysplastic syndromes
- Down's syndrome
- Previous exposure to chemotherapy
- Benzene
136
What causes AML?
-A mutation in precursor blood cells in the bone marrow
- Mutation does two things affects proper maturation and also prevents other cells being made as they take up energy and space of bone marrow causes anaemia, thrombocytopenia and leukopenia
- Cells spill out and cause organmegaly
137
What are the signs of AML?
- Pallor
- Hepatosplenomegaly
138
What are the symptoms of AML
- Fatigue
- Loss of appetite
- Weight loss
- Fever
- **Bruising and mucosal bleeding:** due to thrombocytopaenia
- Recurrent infections: due to leukopaenia
- Pain and tenderness in the bones** can occur when there’s increased cell production which causes the bone marrow to expand.
- Abdominal fullness:** due to hepatosplenomegaly
- Localised pain in lymph nodes due to lymphadenopathy
- **Gingival swelling:** swollen gums seen in acute monocytic leukaemia
139
What are the symptoms of AML?
- Fatigue
- Loss of appetite
- Weight loss
- Fever
- **Bruising and mucosal bleeding:** due to thrombocytopaenia
- Recurrent infections: due to leukopenia
- Pain and tenderness in the bones can occur when there’s increased cell production which causes the bone marrow to expand.
- Abdominal fullness: due to hepatosplenomegaly
- Localised pain in lymph nodes: due to lymphadenopathy
- Gingival swelling: swollen gums seen in acute monocytic leukaemia
140
What would a AML blood film show?
A high proportion of blast cells. Myoblasts are seen as large cells with nucelli containing fine chromatin and Auer rods
141
What is the diagnostic test for AML and what would it show?
Bone marrow aspirate and biopsy: ≥20% myeloblasts is diagnostic
142
What is the diagnostic test for AT?
Hb electrophoresis: this is diagnostic. The pattern depends on the type of thalassaemia. HbH (beta chain tetramers) would be present in alpha thalassaemia
143
What is the diagnostic test for BT?
**Hb** **electrophoresis**: this is **diagnostic**. Reduced HbA and elevated HbA2 would be expected in beta thalassaemia
144
What would a blood film of G6PD show?
- **Blood film:** **Heinz bodies and bite cells**
145
What is the aim of treatment for AML?
To induce clinical and haematological remission <5% blast cells
146
What is the treatment for AML?
- Chemotherapy of cytarabine and anthracycline
- All-trans retinoic acid
- Allopurinol to prevent tumour lysis
147
What is the prognosis for AML?
5 year survival is 25%
148
What is chronic myeloid leukaemia?
Involves the **proliferation of partially mature myeloid cells**.
In particular **granulocytes** within the bone marrow
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What are the 3 phases of CML?
- Chronic phase- can last around 5 years and is often asymptomatic with a raised white cell count
- Accelerated phase- occurs when the abnormal blast cells take up a high proportion of the cells in the bone. (10-20%)
- Blast phase when the blast cells make up an ever greater proportion of the blood (>30%)
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What chromosome is seen in over 80% of cases of CML?
Philadelphia chromosome (9,22)
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How does CML progress to AML?
- As the CML cells divide quicker than they should, there’s a high chance that further genetic mutations can happen!
- If this occurs, CML might progress and accelerate into a more serious acute leukaemia which is called a **blast crisis.**
- A lot of cases of these blast crises include the formation of a trisomy on chromosome number 8, or the doubling of the Philadelphia chromosome.
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What are the signs and symptoms of CML?
- Loss of weight, fever, sweats and fatigue
- Gout (purine breakdown)
- Bleeding
- Abdominal pain
- Infection
- Bleeding
- Anaemia
- **massive hepatosplenomegaly**
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What would the blood film for CML show?
- An increase in all stages of maturing granulocytes
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What is the diagnostic test for CML and what would it show?
Bone marrow biopsy- would show myoblast infiltration
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What is the first-line treatment for CML?
- imatinib (tyrosine kinase inhibitor) may also be combined with INF-y
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What would be the second line treatment for CML?
High dose chemotherapy and stem cell transplantation
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What is the prognosis for CML?
CML has a good prognosis due to the introduction of targeted tyrosine kinase inhibitors, with a 75% 5-year survival rate.
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What are the two types of lymphoma?
Hodgkin's and non-Hodgkin's lymphoma
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What is the difference between HL and NHL?
- HL is a specific disease where as NHL refers to all other types of lymphomas
- Hodgkin lymphomas there is a presence of **Reed-Sternberg** cells
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What are the most common ages to get HL?
Bimodal peak at around 20 and 75
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What are the risk factors for developing HL?
HIV
Epstein-Barr virus
Autoimmune condition e.g., rheumatoid arthritis and sarcoidosis
Family history
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What will the enlarged lymph nodes in HL feel like?
They are characterised as non-tender and rubbery. Some patients will experience pain when drinking alcohol
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What are the systemic symptoms of HL?
Fever
Weight loss
Night sweats
Known as B symptoms
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What are some other symptoms of HL?
- Fatigue
- Itching
- Cough
- Shortness of breath due to mediastinal lymphadenopathy
- Abdominal pain
- Recurrent infections
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What is the key diagnostic test for HL?
Lymph node biopsy- will show Reed-Sternberg cells. They are abnormally large B cells that have multiple nuclei
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What other tests would you perform for HL?
Look for levels of lactase dehydrogenase elevated can indicate HL
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What is the management of HL?
- Chemotherapy- Adriamycin, Bleomycin, Vinblastine, Dacarbazine
- Radiotherapy
- Rituximab
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What is the prognosis for HL?
The prognosis is dependent on the stage and histological subtype. Early-stage disease has a 5-year survival of 90%. However, in advanced disease, this reduces to 75%.
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What is the Ann arbour staging?
Stage 1: confined to one group of lymph nodes
Stage 2: in more than one region but on the same side of the diaphragm
Stage 3: Affects lymph nodes above and below the diaphragm
Stage 4: Widespread involvement including non-lymphatic organs
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What are suffix A and suffix B?
Suffix A – No systemic symptoms other than puruitis (severe itching of skin)
Suffix B – Presence of B symptoms, such as fever, night sweats and weight loss
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What is the difference between lymphoma and leukaemia?
Lymphoma differs from leukaemia in that neoplastic cells predominantly involve the lymph nodes and extra nodal sites, unlike leukaemia which predominantly involves the bone marrow and blood.
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What is more common and HL or NHL and what is the most common type of lymphoma overall?
- NHL is far more common
- B-cell lymphoma are more common that T-cell lymphomas
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What are the risk factors for NHL?
HIV
Epstein-Barr virus
H.Pylori (MALT lymphoma)
Hepatitis B or C
Exposure to pesticides ( trichloroethylene)
Family history
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What are some different types of NHL?
- **Burkitt lymphoma** is associated with Epstein-Barr virus, malaria and HIV.
- **MALT lymphoma** affects the mucosa-associated lymphoid tissue, usually around the stomach. It is associated with H. pylori infection.
- **Diffuse large B cell lymphoma** often presents as a rapidly growing painless mass in patients over 65 years.
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Name some investigations for NHL
- **FBC:** may demonstrate leukocytosis but can also present with pancytopenia if the bone marrow is involved
- **Blood film:** certain lymphomas, such as hairy cell leukaemia, are associated with a characteristic blood film finding
- **LDH and uric acid**: often elevated and used as prognostic markers
- **Ultrasound of lymph nodes:** an initial ultrasound of the affected lymph nodes will indicate whether there are any concerning features of malignancy e.g. disruption of normal morphology
- **Excisional lymph node biopsy:** this is **diagnostic** and will show distorted lymph node architecture
- **Skin biopsy:** useful if a T-cell lymphoma is suspected
- **Bone marrow biopsy:** useful in staging disease
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What is the prognosis for NHL?
Overall 5-year survival is approximately 70%.
In general, high-grade lymphomas are curable, unlike low-grade lymphomas. However, high-grade lymphomas are more aggressive as cells divide quickly.
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What is myeloma?
- A cancer that affects plasma cells (these are the cells that produce antibodies)
- This results in large quantities of antibodies being secreted
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What is multiple myeloma?
When myeloma affects multiple areas of the body
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What is monoclonal gammopathy of undetermined significance (MGUS)?
When there is an excess of a single type of antibody
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What are the risk factors for developing MM?
- Family history
- Radiation exposure
- MGUS
- Black African ethnicity
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Describe the pathophysiology of MM?
- Plasma cells become activated to produce a certain type of antibody uncontrollably
- When you measure the antibodies in patients with multiple myeloma one of these antibodies will be particular abundant
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What are the most likely antibodies to be abundant in MM?
IgG (the most common occurs in 50% of patients) and IgA
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What is smouldering myeloma?
Smouldering myeloma is where there is progression of MGUS with higher levels of antibodies or antibody components. It is premalignant and more likely to progress to myeloma than MGUS.
Waldenstrom’s macroglobulinemia is a type of smouldering myeloma where there is excessive IgM specifically.
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What proteins can be found in urine of someone with MM?
**Bence Jones protein** found in light chains of antibodies
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What are the four main features of MM?
**C**- Calcium (elevated)
**R**- Renal failure
**A**- Anaemia
**B**- Bone lesions/pain
**CRAB**
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How does MM cause increased calcium levels and bone lesions?
There is more osteoclast than osteoblast activity.
This is caused by cytokines released from the plasma cells and the stromal cells (other bone cells) when they are in contact with the plasma cells.
This causes bone lesions in skull, spine, long bones and ribs. Also results in more calcium reabsorption
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How does MM cause renal disease?
Patients with myeloma often develop renal impairment. This is due to a number of factors:
- High levels of immunoglobulins (antibodies) can block the flow through the tubules
- Hypercalcaemia impairs renal function
- Dehydration
- Medications used to treat the conditions such as bisphosphonates can be harmful to the kidneys
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What tests would you order for MM?
- FBC low white blood cell count
- Calcium raised
- Plasma viscosity raised
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What to do after initial tests suspect MM?
B – Bence–Jones protein (request urine electrophoresis)
L – Serum‑free Light‑chain assay
I – Serum Immunoglobulins
P – Serum Protein electrophoresis
**Bone marrow biopsy is gold standard**
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How would you manage MM?
Chemotherapy
- Bortezomib
- Thalidomide
- Dexamethasone
A bone marrow transplant if possible
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How would you monitor MM?
- **Repeat blood tests, including serum and urine electrophoresis,** every 2-3 months
- **Bortezomib monotherapy** is recommended first-line following a first relapse
- Certain patients may be suitable for a **second autologous stem cell transplant,** if required
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What is the prognosis for MM?
Myeloma is an incurable disease and patients inevitably relapse a few years post-treatment.
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What is polycythaemia Vera?
Defined as an increase in haemoglobin, packed cell volume (PCV) and RBCs (opposite of anaemia)
194
What is the difference between primary and secondary polycythaemia?
- Primary is caused by a genetic mutation
- Secondary is caused by a disease that causes more circulating EPO
195
What mutation is the most common in PCv?
Janus kinase 2 (JK2) which means JK2 activates RBC without stimulation by EPO
196
Why is PCV dangerous?
- PCV is a primary polycythaemia that results in increased red blood cells (polycythaemia) as well as increased neutrophils (neutrophilia) and platelets (thrombocytosis). This causes hyperviscosity, increasing the risk of thrombosis.
- Platelets are often dysfunctional in PCV, which also increases the risk of bleeding, although major bleeding is rare.
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What are the symptoms of PCV
- Fatigue
- Dizziness
- Headache
- Blurred vision
- Facial flushing
- Pruritus (itchiness) - exacerbated after a hot bath
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What are the signs of PCV?
- **Splenomegaly:** because the excess red blood cells buildup in the spleen, which usually helps with removing excess cells.
- **Conjunctival plethora** (excessive redness to the conjunctiva in the eyes)
- **Plethoric appearance**
- **Palmar erythema**
- **Hypertension**
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What would the investigations be for PCV?
- **FBC:** elevated Hb, elevated haematocrit (males > 0.52; females > 0.48), whilst leukocytes and platelets may also be raised; haematocrit is more sensitive than Hb
- **U&Es and LFTs:** renal and hepatic disease may cause secondary polycythaemia
- **Ferritin:** iron deficiency anaemia can mask polycythaemia so ferritin should be checked
- **Erythropoietin (EPO):** to distinguish **primary** polycythaemia (EPO is **low**) from **secondary** polycythaemia (EPO is **raised**), which may be caused by hypoxia, COPD, high altitude and renal cell carcinoma
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What are the complications associated with PCV?
- Thrombosis (stroke, MI, DVT)
- Haemorrhage as platelets don't work as well
- Gout due to high turnover of RBC
- Progression to leukaemia 1-3%
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What is the prognosis for PCV?`
The most common cause of death in these patients is related to cardiovascular complications.
The overall survival rate varies in the literature but is approximately 19 years from diagnosis.
Up to 15% of patients progress to acute leukaemia, whilst thromboembolic disease is a significant cause of morbidity and mortality in patients (e.g. stroke).
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What is thrombocytopenia?
A low platelet count. The normal is between 150-450. There are lots of things that can cause it production (and sequestration) and destruction.
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What are the causes of production thrombocytopenia?
Sepsis
B12 or folic acid deficiency
Liver failure causing reduced thrombopoietin production in the liver
Leukaemia
Myelodysplastic syndrome
Splenic sequestration
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What are the causes of destruction thrombocytopenia?
- Medications (anti-histamines, PPI, methotrexate)
- Alcohol
- Immune thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura (TTP)
- Heparin induced
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What are some differentials for thrombocytopenia?
Haemophilia A and haemophilia B
Von Willebrand Disease
Disseminated intravascular coagulation
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What is Immune thrombocytopenic purpura (ITP)?
Where there are antibodies created against platelets.
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What is the difference between primary and secondary ITP?
- **Primary ITP:** when ITP occurs by itself
- **Secondary ITP:** triggered by another condition e.g. hepatitis C, HIV, or lupus
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Describe the destruction of platelets in ITP?
- Antibodies bind to platelet receptor Gp2B3A and target platelets for destruction in the spleen
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What are the symptoms of ITP?
- Petechiae
- Purpura
- Easy bruising
- Nose bleeds
- Menorrhagia (heavy menstruation)
- Gum bleeding
- **Major haemorrhage is rare**
- **Splenomegaly is rare**
210
What investigations would you perform for ITP?
- FBC would be nroaml except low platelet count
- Blood film would show megakaryocytes still releasing large platelets
- Platelets autoantibodies
- Abdominal ultrasound to rule out ITP triggered by infections
211
What would the management for ITP be?
- **prednisolone** first line
- IV immunoglobins
- Rituximab
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What is Thrombotic thrombocytopenic purpura (TTP)?
It is a condition where blood clots develop in small vessels of the body and this uses up platelets. It affects small vessels so is called **microangiopathy**
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What causes the development of blood clots in TTP?
- The is a problem with a protein called **ADAMRS13**
- This protein normally inactivates von Willebrand factor and reduces platelet activation
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How does TTP cause haemolytic anaemia?
The blood clots in the small vessels break up red blood cells, leading to haemolytic anaemia.
215
What causes a deficiency in ADAMTS13?
Genetic mutation or autoimmune disease
216
What are the the key presentations of TTP?
- Microangiopathic haemolytic anaemia
- Fatigue
- Fever
- Renal insufficiency
217
What are the investigations for TTP?
- **FBC:** thrombocytopenia and normocytic normochromic anaemia
- **Blood film:** schistocytes (fragmented red blood cells)
- **Unconjugated bilirubin:** raised
- **Lactate dehydrogenase:** raised
- **Haptoglobin levels:** decreased, because haptoglobin binds to free haemoglobin in the circulation
- **Creatinine levels:** may be elevated if there is kidney damage
- **Coombs test:** checks for immune mediated causes, negative
- **Prothrombin time:** normal
- **Partial thromboplastin time:** normal
- Management
218
What are the main treatments for TTP?
**Plasma exchange**
Steroids
Rituximab
219
What is HIT?
Where heparin causes antibodies to be produced against platelets (they target platelet factor 4)
220
What do the HIT antibodies cause?
- They bind to platelets and activate clotting mechanisms. This causes a hypercoagulable state (leading to thrombosis)
- They also bind to platelets and break them down leading to thrombocytopenia
221
What is haemophilia?
Haemophilia A and haemophilia B are inherited severe bleeding disorders. Haemophilia A is caused by a deficiency in **factor VIII**.
Haemophilia B (also known as Christmas disease) is caused by a deficiency in **factor IX**
222
What are the main causes of haemophilia?
- Inherited (X-linked condition so all male)
- Acquired, Liver failure, vitamin K deficiency, autoimmunity against clotting factor, Disseminated intravascular coagulation
223
What are the mutated genes in haemophilia A called?
F8 lack of factor 8
224
What are the mutated genes in haemophilia B called?
F9 lack of clotting factor 9
225
What are the symptoms of haemophilia?
- Abnormal bleeding
- Excessive bleeding
- Easy bruising
- - **Spontaneous haemorrhage**
- **Haematomas:** collections of blood outside the blood vessels
- **Hemarthrosis:** bleeding into joint
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Where would be common places for bleeding to occur in haemophilia?
- Gums
- Gastrointestinal tract
- Urinary tract causing haematuria
- Retroperitoneal space
- Intracranial
227
What would the main investigations be for haemophilia?
- activated partial thromboplastin time (aPTT) would be increased
- Plasma VIII and IX assay
Diagnosis is based on bleeding scores, coagulation factor assays and genetic testing.
228
What is the management for haemophilia?
- Infusions of deficient factor
- Desmopressin to stimulate the release of vWF factor
- Antifibrinolytics e.g., tranexamic acid
229
What is a complication of the treatment for haemophilia?
Antibodies are created against the clotting factors being infused
230
What is priapism?
Trapping of blood in the penis causing a painful and persistent erection. This is a urological emergency and is treated with aspiration of blood from the penis.
231
What would you use to treat tumour lysis syndrome?-
Allopurinol
232
What is hydroxycarbamide used for?
Will stimulate the production of foetal haemoglobin which prevents sickle cell crisis and can also be used for beta thalassemia
233
What two features are associated with a Vaso-occlusive crisis ?
Dehydration and raised haematocrit.
234
What is Disseminated intravascular Coagulation?
A serious disorder occurring in response to an illness or disease process which results in dysregulated blood clotting.1
In health, there is usually a balance between the clotting and fibrinolytic systems. However, in DIC inappropriate activation of one or both systems leads to a paradoxical tendency to both bleeding and thrombosis simultaneously, set off by **various triggers**
235
What some things may trigger Disseminated intravascular coagulation?
Shock
Sepsis/severe infection: these lead to the massive release of pro-inflammatory cytokines in a systemic inflammatory response. These cytokines can activate the coagulation system.
Major trauma or burns
Malignancies: including both solid organ and haematological malignancies. Acute promyelocytic leukaemia (APML) is strongly associated with DIC.
Obstetric emergencies
236
What are some typical symptoms of DIC?
Bleeding from unusual sites: ears, nose, gastrointestinal tract, genitourinary tract, respiratory tract or sites of venepuncture or cannulation. Bleeding from three unrelated sites is highly suggestive of DIC.
Widespread or unexpected bruising without a history of trauma
New confusion or disorientation: a sign of microvascular thrombosis affecting cerebral perfusion
Signs of haemorrhage: bleeding from cannula sites/venepuncture sites, melaena, haematemesis, rectal bleeding, epistaxis, haemoptysis, haematuria
Petechiae or purpura (Figure 3)
Livedo reticularis: a mottled lace-like patterning of the skin (Figure 4)
Purpura fulminans: widespread skin necrosis
Localised infarction and gangrene for instance of the digits
237
What are some investigations for DIC, and what would you see in them?
Full blood count: there is typically thrombocytopenia in DIC due to excessive consumption.
Coagulation screen: including PT and APTT. PT is a measure of the extrinsic and common pathways of coagulation (Figure 1) and is prolonged in 50-70% of patients with DIC. APTT measures the intrinsic and common pathways of coagulation (Figure 1) and is prolonged in 50-60% of DIC patients.
Clauss fibrinogen: typically decreased as fibrinogen is converted to fibrin in intravascular thrombosis. Clauss fibrinogen should be requested rather than the derived fibrinogen sometimes included as part of the standard coagulation screen, since this may overestimate the actual levels.
D-dimer/fibrin degradation products: are typically raised providing evidence of degradation of fibrin clots around the body.
238
What is some management options you would see in DIC?
Platelet transfusions should be considered if the patient is bleeding. The platelet count should be maintained >50 x 109/L in the presence of bleeding.
In bleeding patients with a prolonged PT and/or APTT, fresh frozen plasma can be considered.
Concentrated solutions of clotting factors may also be considered such as prothrombin complex concentrate, or specific factor infusions.
If there is severely low fibrinogen then transfusions of cryoprecipitate or fibrinogen concentrate should be considered.
If thrombosis is a prominent feature, then therapeutic doses of heparin should be considered.
239
What would you see in a biopsy in a patient with MM?
More than 10% of the bone marrow is occupied by plasma cells
240
Treatment PCV?
- **Venesection**: first-line, offered to all patients to maintain haematocrit below 0.45
- **Hydroxycarbamide (hydroxyurea):** the first-line cytoreductive agent to reduce thrombosis risk and is only used in patients with a high risk of thrombosis, e.g. > 60 years old or background of thrombosis
- **Aspirin:** 75 mg daily dose of aspirin for all patients
- **Ruxolitinib (JAK2 inhibitor)**: used as a second-line cytoreductive agent. Can also help with itching symptoms
