Phase 2 - Haematology Flashcards
1
Q
3 catagories of anaemia
A
Microcytic (MCV <80)
Normocytic (MCV 80-95)
Macrocytic (MCV >95)
2
Q
Causes of microcytic anaemia
A
TAILS
- Thalassaemias
- Anaemia of chronic disease
- IRON DEFICIENCY
(lead poisoning)
- Sideroblastic - unable to put iron into haemoglobin - linked to alcohol excess, heavy metal poisoning, VIt B deficiency (Als deficiency - iron trapped in mitochondria - autosomal recessive)
3
Q
Causes of normocytic anaemia
A
- BLOOD LOSS (acute - too rapid to adjust)
- HAEMOLYTIC (high cell turnover)
- SICKLE CELL
(- Malaria) - Hereditary spherocytosis - spherocytes are more fragile (a membranopathy)
- G6PDH (glucose 6 phosphate dehydrogensase) deficiency - haemolysis occurs when exposed to certain triggers
- Autoimmune Haemolytic anaemia
- SICKLE CELL
- Non-haemolytic (low reticulocytes)
- aplastic anaemia
- CKD - normal cells, just fewer present)
- Myelophthisic - bone marrow failure due tp malignant invasion
- HAEM MALIGNANCY
4
Q
Causes of macrocytic anaemia
A
- Megaloblastic causes (related to impaired DNA synthesis)
- B12 DEFICIENCY
- Folate deficiency
- Non-megaloblastic (nothing wrong with DNA synthesis)
- HYPOTHYROID
- ALCOHOL
- LIVER disease (increase membrane cholesterol of RBCs - increased surface area)
- esp NAFLD
- CKD
- Bone marrow failure (esp MDS - increased immature RBCs)
- drugs (Methotrexate, hydroxyurea)
(Haemolytic anaemia - more rbcs destroyed so more young, large reticulocytes present)
5
Q
Iron metabolism process
A
~15-20mg average daily intake but only ~1mg (or 10%) absorbed in DUODENUM
- actively transported into DUODENAL EPITHELIAL CELLS by intestinal HAEM TRANSPORTER (HCP1) - highly expressed in duodenum
Some stored intracellularly bound to FERRITIN (usually - more easy to mobilise) in:
- reticuloendothelial cells (e.g. monocyte derived - esp in liver)
- hepatocytes
- skeletal muscle
or in HAEMOSIDERIN:
- in macrophages (esp liver, spleen, bone marrow)
Circulating iron bound to TRANSFERRIN
- transports to bone marrow to make erythrocytes
6
Q
Iron deficiency anaemia - causes
A
most common cause of anaemia
Blood loss:
- menorrhaegia
- Hookworm (leading cause of deficiency worldwide)
- GI bleeding
Poor diet: - esp in children (uncommon in adults) - esp in poverty
- PROLONGED BREAST FEEDING in infants (poor Fe source)
Malabsorption - Coeliac disease, IBD
Increased demands (growth, pregnancy)
RARE in ELDERLY - RED FLAG SIGN for COLON CANCER BLEEDING (recomen urgent endoscopy for any >60y/o w/ Fe def)
7
Q
Risk factors for iron deficiency
A
- Less developed countries/poverty
- High veg diet (iron best absorbed from animal products)
- VEGAN
- premature infants
- Delayed introduction of mixed feeding (breastmilk contains less iron)
8
Q
Signs and symptoms of anaemia
A
Symptoms (non-specific):
- FATIGUE, headaches and faintness
- Dyspnoea
- Intermittent claudication (ischaemic pain in peripheries)
- COLD
- PALPITATIONS
- Angina (if there is pre-existing coronary disease)
- Anorexia
Signs (may be absent even in severe anaemia):
- Pallor (esp conjunctival)
- Brittle hair
- Leukonychia (white patches on nails)
- Tachycardia
- Systolic flow murmur
- Cardiac failure
9
Q
presentation of iron deficiency
A
- anaemic symptoms
- Brittle nails/hair
- spoon nails (koilonychia - dip in nails)
- tongue papillae atrophy (atrophic glossitis)
- ulceration of corners of mouth (angular cheilitis/stomatitis)
10
Q
Diagnosis of iron deficiency anaemia
A
- Blood film
- low blood count
- MICROCYTIC and HYPOCHROMATIC
- pokilocytosis (variation in shape); anisocytosis (variation in size)
- TARGET CELLS (bulls eye pattern - non specific)
- HOWELL JOLLY BODIES (nucleated RBCs - non-specific)
- LOW FERRITIN (diagnostic)
- tho it is an acute phase protein so will be normal/high in inflammation even if anaemic
- IRON STUDY:
- low serum iron (not very useful)
- LOW TRANSFERRIN SATURATION <19%
(more transferrin made to bind as much iron as possible so higher quantity of transferrin which is not saturated) - HIGH TOTAL IRON BINDING CAPACITY (lots of transferrin so highly bound)
(high serum soluble transferrin receptors)
- LOW RETICULOCYTE count
Further examinations if blood loss (e.g. GI tract exam)
11
Q
Management of iron deficiency
A
Treat underlying cause
ORAL IRON - FERROUS SULPHATE
- Side effects:
* nausea, abdo discomfort, diarrhoea/constipation, black stools (from increased free iron)
- Vit C improves absorption
- Alt: FERROUS GLUCONATE
If severe:
- IV/IM iron
* rare anaphylaxis; potential sub epidermal staining
Hb should increase by 20 every month - continue for 3 months after Hb/MCV normal to replenish stores
12
Q
Define thalassaemia
A
reduced production of a specific Hb chain type - IMBALANCE OF Hb SYNTHESIS
- causes INEFFECTIVE ERYTHROPOIESIS (death of precursors in bone marrow from precipitation of globin chain imbalance)
- precipitation in mature RBCs -> HAEMOLYSIS
Beta Thalassaemia - reduced B chain
Alpha thalassaemia - reduced A chain
13
Q
Beta thalassaemia - pathophysiology
A
low B chain synthesis = EXCESS A CHAINS
- combine with delta + gamma chains
- increased HbA2/HbF
Usually caused by point mutations (>200 varieties)
-> defects in transcription, RNA splicing/modification, translation -> UNSTABLE B-GLOBIN - can’t be utilised
If heterozygous - ASYMPTOMATIC microcytosis; maybe MILD anaemia
14
Q
3 variations in b-thalassaemia presentation
A
B-THALASSAEMIA MINOR (aka carrier/trait)
B-THALASSAEMIA INTERMEDIA (symptomatic but not requiring regular transfusions)
B-THALASSAEMIA MAJOR (severe homozygous - requires lifelong transfusions)
15
Q
How do you differentiate between B-thalassaemia minor and iron deficiency
A
Both have hypochromic, microcytic RBCs
BUT serum ferritin/iron stores normal
Hb electrophoresis -> raised HbA2 and often raised HbF
16
Q
Presentation of B-thalassemia intermedia
A
- SPLENOMEGALY (from haemolysis)
- Bone deformaties
- Recurrent leg ulcers
- Gallstones
- Infection
17
Q
Presentation of B-thalassaemia major
A
Presents in children in 1ST YEAR OF LIFE
- failure to thrive - recurrent bacterial INFECTION
- severe ANAEMIA from 3-6 months (when switch to HbA)
- EXTRAMEDULLARY HAEMATOPOIESIS - ineffective RBC OUTSIDE MARROW
-> HEPATOSPLENOMEGALY (from haemolysis) - bone marrow expansion (distictive appearance)
Clinically:
- hair on end skull x-ray
- bone abnormalities
- Low MCV - MICROCYTIC
- Blood film: large and small irregular hypochromic RBCs
- NORMAL SERUM FERRITIN
18
Q
Diagnosis of homozygous b-thalassaemia
A
BLOOD COUNT and FILM
- HYPOCHROMIC, MICROCYTIC anaemia
- RAISED RETICULOCYTES
- NUCLEATED RBC in PERIPHERALS
Haemoglobin electrophoresis - increased HbF; absent/less HbA
19
Q
Treatment of beta-thalassaemia
A
In more severe:
- regular (2-4 weeks) LIFE-LONG transfusions to keep Hb above 90g/L AND SUPPRESS ineffective EXTRAMEDULLARY HAEMATOPOIESIS
-> to allow normal growth - Splenectomy if hypersplenism persists -> INCREASING TRANSFUSION DEMANDS
- do after childhood -> reduce infection risk
- Bone marrow transplant
- Long term FOLIC ACID
20
Q
Complications of blood transfusion
A
INCREASED IRON LOADING -> overload
- Mainly deposit in liver/spleen -> liver fibrosis/cirrhosis
- also in endocrine glands + HEART ->
- Diabetes
- Hypothyroidism
- Hypocalcaemia
- Premature death
21
Q
Treatments for the complications of blood transfusions
A
IRON-CHELATING agents - STOP iron OVERLOAD
- oral DEFERIPRONE
- sub-cutan DESFERRIOXAMINE
- side effects: cataracts, deafness
ASCORBIC ACID (large dose) -> increases urinary exc of iron
22
Q
Pathophysiology of Aplha-thalassaemia
A
- 2 copies of gene for a-goblin on both chromosomes 16 normally
- in a-thalassaemia: 1 (most common) or both of the genes are deleted on one or both chromosomes
23
Q
Clinical presentation of 4 alpha-globin gene deletion
A
INCOMPATIBLE WITH LIFE - stillborn/die shortly after birth
- HYDROPS FETALIS
* Pale
* Oedematous
* hepatosplenomegaly
(Only Hb Barts present - 4 gamma chains - can’t carry O2)
24
Q
Presentation of 3 gene alpha-globin deletion
A
HbH disease (common in parts of asia) - severe alpha reduction
HbH = 4 beta chains
Moderate ANAEMIA and SPLENOMEGALY
Usually not transfusion dependant
25
Presentation of 2 gene a-globin deletion
trait/ CARRIER
MICROCYTOSIS - potential MILD ANAEMIA
26
Presentation of 1 gene a-globin deletion
Usually normal blood picture
27
Treatments for a-thalassaemia
DAILY FOLIC ACID
Blood transfusions as needed (-> chelation therapy)
May need splenectomy or venesectomy
28
Pathophysiology of sickle cell anaemia
SINGLE BASE MUTATION: ADENINE -> THYMINE
- VALINE substituted for GLUTAMIC ACID (6th CODON) in BETA-GLOBIN chain
-> HbS -> INSOLUBLE + POLYMERISES when DEOXYGENATED -> sickling (RIGID)
Initially reversible but repeated sickling -> lose membrane flexibility -> IRREVERSIBLY SICKLED
- DEHYDRATED + DENSE
- shortened RBC survival -> HAEMOLYSIS
- impaired passage through microcirculation
-> OBSTRUCTION, INFARCTION, PAIN
Also get cytopenias of other cell types (esp NEUTROPENIAS) as bone marrow focusses on producing more ineffective RBCs
29
What precipitates sickling
- Infection
- Dehydration
- Cold
- Acidosis
- Hypoxia
30
Why do sickle cell patients often feel well despite being anaemic (when not in crises)
HbS release oxygen more readily (lower oxygen binding affinity)
31
Clinical presentation of sickle cell trait
Symptom free but can sickle under increased hypoxia/stress e.g. anaesthesia, upressurised aircarft
- vaso-occlusion may occur
PROTECTIVE against FALCIPARUM MALARIA
Slight increased risk of renal disease/cancer
32
Conditions caused by homozygous sickle cell anaemia
Vaso-occlusive crises
ACUTE CHEST SYNDROME
Pulmonary hypertension
Anaemia
- can complicate to BONE MARROW APLASIA (usually after PARVOVIRUS B19 infection)
33
S&S of vaso-occlusive crisis + complications
- ACUTE PAIN
- HANDS and FEET (dactylitis) in KIDS
- LONG BONES such as the femur, spine, ribs and pelvis - ADULTS
* vaso-occlusion of small vessels and AVASCULAR NECROSIS of BONE MARROW
- Possible CNS infarction in children
-> stroke, seizures and cognitive defects
- Attacks vary in frequency - can occur as much as every day to once a year depending on patient
34
What occurs in Acute chest syndrome + S&S + causes
PULMONARY VASO-OCCLUSIVE CRISIS
(occurs in 30%)
Caused by INFECTION (CHLMYDIA, MYCOPLASMA, STREP PNEUMONIAE)
-> FAT EMBOLISM from NECROTIC BONE MARROW
OR
-> PULMON INFARCT - SEQUESTRATION of sickle cells
SOB, CHEST PAIN, HYPOXIA (vicious cycle)
35
Define pulmonary hypertension
Mean pulmonary artery pressure greater than 25mmHg
(checked by right heart CATHETERISATION - inserted into right heart)
36
Pulmonary hypertension in sickle cell
Occurs in 10% of patients
- Most probably caused by damage from repeated chest crises and repeated thromboembolism and intravascular haemolysis
- Increases the risk of hypoxaemia and worsening sickle cell crises
Common cause of death in adults with SCD
37
Anaemia in SCD
Stable low haemoglobin in CHRONIC HAEMOLYSIS
ACUTE FALL:
- SPLENIC SEQUESTRATION
-> splenomegaly + acute fall in Hb
-> Fibrotic, non-functioning spleen (potentially)
- BONE MARROW APLASIA
- PARVOVIRUS B19 (slapped cheek appearance) INVADES PROLIFERATING ERYTHROID PROGENITORS
-> NO RETICULOCYTES IN PERIPHERAL - FAILURE OF ERYTHROPOESIS in marrow
* Aplastic crisis
38
Long term complications of SCD
Growth + development delayed
Avascular necrosis of hips, shoulder; compression of vertebrae; shortening of peripheral small bones
- Osteomylelitis from S. aureus, S. pneumoniae, Salmonella
Cardiomegaly, arrhythmias (+ iron overload cardiomyopathy)
- MI
25% -> TIA, fits, cerebral infarcts, coma
Chronic hepatomegaly + dysfunction
Chronic tubulointersitial nephritis
Retinopathy/detachment, vitreous haemorrhage
Impaired placental flow in pregnancy -> spontaneous abortion
39
Diagnosis of SCD
Blood count:
- Hb 60-80 g/L
- RAISED RETICULOCYTES
Blood film - SICKLED ERYTHROCYTES
SICKLE SOLUBILITY TEST - positive
Hb ELECTROPHORESIS [- DIAGNOSTIC]
- 80-95% HbS (NO HbA)
Best to diagnose with CORD BLOOD at BIRTH -> PROMPT PNEUMOCOCCAL PROPHYLAXIS
40
General reatment of SCD
Avoid/rapidly treat precipitating factors e.g. prophylaxis vaccine
FOLIC ACID for all HAEMOLYTIC ppl
41
Treatment for acute painful attacks in SCD
IV fluids
ANALGESIA (morphine, codeine, paracetamol, NSAIDs)
O2 + antibiotics if needed
42
Treatment for SCD anaemia
BLOOD TRANSFUSION (iron overload risk)
- Acute chest syndrome
- Acute anaemia due to acute splenic sequestration
- Aplastic crisis
- Stroke
- Heart failure
ORAL HYDROXYCARBAMIDE/HYDROXYUREA
- Increases HbF conc
Stem cell transplant
43
How long can body store folate
Low stores for ~ 4 months
44
Where is folate absorbed
Duodenum/proximal jejunum
45
Folate deficiency pathophys
Folate - essential for DNA synthesis
In deficiency:
-> impaired DNA synthesis
-> DELAYED NUCLEAR MATURATION
-> large RBCs + decreased RBC production
Affects all cells in body but BONE MARROW most affected due to HIGH ACTIVITY
Also needed for fetal development so -> neural tube defects
46
Causes of folate deficiency
POOR INTAKE (main cause)
Increased demand (pregnancy, increased cell turnover - haemolysis, malignancy, inflam disease, renal dialysis)
MALABSORPTION (coeliac/crohn's)
ANTIFOLATE DRUGS (METJOTREXATE, TRIMETHOPRIM)
47
Risk factors for folate deficiency
- Elderly
- Poverty
- Alcoholic
- Pregnant
- Crohn's/coeliac
48
Presentation of Folate deficiency
May be asymp
Symptoms of anaemia
GLOSSITIS can occur (sore tongue)
NO NEUROPATHY (unlike B12)
49
Diagnosis of folate deficiency
Blood count/film:
- MEGALOBLASTIC
- MACROCYTIC RBCs
- OVAL MACROCYTES and HYPERSEGMENTED NEUTROPHILS (>=6 lobes) in peripheral film
SERUM + RBC folate - LOW
GI investigation to exclude
Serum bilirubin may be high - from ineffective erythropoiesis -> increased haemolysis
50
Treatment of folate deficiency
FOLIC ACID TABLETS daily for 4 months - BUT ONLY WITH NORMAL B12/B12 SUPPLEMENTS! (may worsen B12 def -> spinal cord degeneration)
Treat underlying cause
51
What food is folate found in
Green veg (spinach, broccoli)
Nuts
Yeast
Liver
52
What food is B12 found in
Meat
Fish
Dairy
(NOT PLANTS)
53
How long do B12 body stores last
4 years
54
How is B12 absorbed
Binds to INTRINSIC FACTOR from PARIETAL CELLS (in stomach)
Absorbed in TERMINAL ILEUM
55
Pathophys of B12 deficiency
ESSENTIAL for THYMIDINE -> DNA synthesis
IMPAIRED DNA synth -> DELAYED NUCLEAR MATURATION
-> Megaloblasts + reduced RBC production
Bone marrow most affected (high activity)
56
Causes of B12 deficiency
Dietary (vegans)
Malabsorption (lacking intrinsic factor, ileal resection)
PERNICIOUS ANAEMIA (most common)
57
Risk factors for Pernicious anaemia
Elderly (>60)
FEMALE
Fair-haired, blue-eyed
Blood group A
OTHER AUTOIMMUNE (Thyroid, Addison's)
58
Pathophys of pernicious anaemia
- Parietal cell antibodies (present in 90% - but NON-SPECIFIC)
- INTRINSIC FACTOR ANTIBODIES (only present in 50%)
-> Autoimmune gastritis of FUNDUS - plasma cell/lymphoid INFILTRATION
Parietal/CHIEF cells REPLACED BY MUCIN-SECRETING cells
-> ACHLORHYDRIA (reduced HCl)
-> ABSENT INTRINSIC FACTOR secretion
59
Presentation of B12/Pernicious anaemia
INSIDIOUS ONSET - increasing symp of anaemia
Potential LEMON-YELLOW skin - pallor + mild jaundice (from haemolysis)
GLOSSITIS + ANGULAR CHEILOSIS/STOMATITIS (potentially)
NEURO FEATURES if V. LOW B12:
- Symmetrical parasthesia - fingers + toes
- LOSS OF VIBRATION + PROPROCEPTION (1ST thing lost)
- Progressive weakness/ataxia
-> potential PARAPLEGIA
Dementia, psychiatric problems, hallucinations, delusions
and optic atrophy may occur
(from vitamin B12 deficiency)
60
Diff diagnosis for pernicious anaemia (megaloblastic + B12 def)
Folate def (also megaloblastic) - no neuropathy
Other causes of B12 deficiency
- Terminal ileum disease/bacterial overgrowth
Gastrectomy
61
Diagnosis of pernicious anaemia
Blood count/film:
- MEGALOBLASTIC
- MACROCYTIC
- Peripheral: OVAL MACROCYTES + HYPERSEGMENTED NEUTROPHILS
Potential raised biliirubin
LOW SERUM B12
LOW Hb + RETICULOCYTE COUNT
INTRINSIC FACTOR ANTIBODIES (DIAGNOSTIC)
(- low sensitivity, not present in all patients)
62
Treatment of B12 deficiency
If malabsorption - INJECTIONS
-> IM HYDROXOCOBALAMIN
Oral B12 if dietary
Treat other underlying causes
63
Prophylactic folate in pregnancy (dose)
400mg for first 12 weeks
64
Types of leukaemias
Acute Lymphoblastic leukaemia (lymphoblast)
Acute Myeloid lukaemia (myeloblast)
Chronic myeloid leukaemia (myeloid progenitor???)
Chronic Lymphocytic leukaemia (B lymphocyte)
65
Markers of high cell turnover in haemolytic anaemia
INCREASED LDH (lactate dehydrogenase - enzyme of cell turnover), and UNCONJ BILIRUBIN (from haemolysis)
LOW HAPTOGLOBIN (protein that binds to free haem - lots of free haem in haemolysis so haptoglobin being used up)
66
How do you differentiate between Normocytic anaemias
Non haemolytic (CKD, malig, Endocrine, mixed) have low reticulocytes
Can differentiate between Blood loss/haemolysis by presence of cell turnover markers in haemolysis
67
How to differentiate between microcytic anaemias
IRON PANEL:
- Ferritin low, TIBC high (iron def)
- Feritin normal, TIBC low, low serum iron (chronic disease)
- HIGH serum iron + low TIBC (Thal/Sideroblastic)
68
Risk factors for AML
- AGE > 65
- Down's, Patau's (trisomy 13) and Klinefelter's (XXY) syndrome
- Chemo (METHOTREXATE) - previous treatment
- Previous heamatological disorders e.g. MDS
- Irradiation
- Benzene exposure
- inherited genetic conditions (e.g. Fanconi's anaemia, ataxia telangiectasia, germilne TP53 mutation (tumour suppressor gene))
69
Pathophys of AML
Rapid proliferation of immature myeloid blasts in bone marrow, peripheral blood or extramedullary tissues (Granulocytes are not being made)
Rapid progression if not treated quickly (3y survival)
Defined by >= 20% blast cells in BM OR PERIPHERAL blood
**Acute promyelocytic leukaemia** subtype is particularly characterised by hypergranular promyelocytes + Auer rods and is linked to **t(15:17)**
70
Presentation of AML
BONE MARROW FAILURE:
- functional pancytopaenia
* Anaemia = pallor, fatigue, dizzy, palpitations
* Neutropenia = infections
* Thrombocytopaenia = bruising (ecchymosis or petechiae), bleeding (esp muscosal)
- bone pain
TISSUE INFILTRATION:
- swollen gums
- skin/testicular mass
- Hepatoplenomegaly
- lymphadenopathy
71
What is Plummer-Vinson syndrome
Web-like growth of membrane in throat from iron deficiency
Dysphagia, Upper oesophageal webs, IRON DEFICIENCY ANAEMIA
72
Diagnosis of AML
FBC/Blood film:
- **AUER RODS (dark rods in cytoplasm of neutrophils)**
- neutropenia (can have normal/high WCC)
- Anaemia
- Thrombocytopenia
- coag panel typically normal tho - abnormal suggests DIC
- serum LDH may be raised
*+ U+E, LFTs, RFTs, etc*
**Bone marrow BIOPSY (aspirate or trephine) or Peripheral BLOOD SMEAR >= 20% MYELOBLASTS (definitive, gold standard)**
- typicaly paler nuclei + lack of cell variety
History of pre-esisting malignancy (esp MYELODYSPLASTIC SYNDROME or Myeloproliferative neoplasm e.g. polycythaemia vera)
Acute promyelocytic leukaemia = t(15:17)
**Immunophenotyping = -ve for TdT (terminal deoxynucleotidyl transferase) + +ve for myeloperoxidase**
73
Differential diagnosis of AML
- Haematinic deficiency (B12/folate/iron)
- Infection (e.g. retroviral, herpervirus)
- Meds
- Autoimmune
- Liver disease
74
Management of AML in fit individual
CHEMO - ~4-6 weeks (~4 cycles)
(ATRA for acute promyelocytic leukemia - subtype)
- HICKMAN/PICC LINE or portacath
Supportive measures:
- transfusions
- treat infections
(- fertility cryopreservation)
Check basline cardiac, liver + renal function (blood tests, ECHO etc.) - damage can occur from chemo
75
Side effects of chemo
- Nausea/vomiting (antiemetics routinely given)
- Altered bowel habit (diarrhoea/ constipation)
- Loss of appetite
- Reduced fertility
- Fatigue
- Allergic reactions to chemo +/- other supportive medications
CYTOPENIAS (need transfusions + prophylactic antimicrobials)
Bystander organ damage
Hair loss
76
Less intensive (non curative) treatments for AML
Outpatient - for older/less fit
- Azacytidine +/- venetoclax
Low dose subcutaneous cytarabine
Trial drugs e.g. targeted therapy FLT3i, IDH2i (specifc genes)
Supportive measures
77
Pathophysiology of CML + Risk Factors
presence of BCR-ABL gene fusion in PHILADELPHIA CHROMOSOME (**t(9:22)**)
-> IRREVERSIBLY ACITIVATES TYROSINE KINASE
TYROSINE KINASE INCREASES CELL PROLIFERATION
- inhibits apoptotic pathway - JAK-STAT -> increased haematopoesis
-> myeloid hyperplasia of bone marrow
>=20% blasts on BM biopsy = Blast crisis -> AML
RFx:
- AGE 65-74
- Ionising radiation
- Male
78
Symptoms of CML
General leukaemia symptoms (BONE MARROW FAILURE + BONE PAIN)
- hyperviscosity (headaches, thrombosis)
MASSIVE HEPATOSPLENOMEGALY (if alongside malaria esp) -> abdo discomfort
B symptoms potentially (hypermetabolic) - weight loss, malaise, night sweats (from tissue infiltration) + fever
79
Diagnosis of CML
Genetic/Cytogenic tests for BCR-ABL/Philadelphia chromosome
- use either qRT-PCR or fluorescent in situ hybridisation (FISH)
- FBC - pancytopenia (but granulocytosis/leukocytosis) + raised WCC
- Metabolic panel (potential raised K+, LDH, uric acid)
- Peripheral blood smear: mature/maturing myeloid cells
- Basophil >= 20% = accelerated phase
Blast cell % shows severity - phases
(>10 chronic - best; accelerated phase - >=15, <30; >=20 BLAST CRISIS - can accelerate into AML)
BM biopsy - INCREASED GRANULOCYTES (diagnostic)
80
Treatment for CML
IMATINIB (400mg daily) - TK inhib
Chemo
- monitor FBC for haem normalisation
- reassess/monitor every 3 months
May need allogenic transplant
Very treatable - 40% chance of no recurrence after deep remission
81
Differentials for high WCC
Common - infection (c. difficle, tb, shigella)
Steroids or g-csf (granulocyte colony stimulating factor - growth factor)
Ethylene glycol (in polyester + antifreeze - poisoning I suppose)
MI
Mesenteric ischaemia
Gangrene
Paraneoplastic (non-haem malignancies - abnormal bone marrow response to neoplasm)
(haem malignancies uncommon)
82
Pathophys of acute lymphoblastic leukaemia
Genetic mutation + rapid uncontrolled proliferation of lymphoblasts/lymphoid progenitor cell -> replacing normal haematopoetic cells in BM + infiltrating organs
- **B cell lineage more commonly affected - linked to t(12:21)**
Good prognosis
83
Risk factors for ALL
**Particularly affects children <5 y/o**
Genetic:
- DOWN'S
- Neurofibromatosis (tumors that affect nervous system)
- FHx
Folate metabolism polymorphisms
- Hx of malignancy
- Radiation
- Chemo
84
Presentation of ALL
BONE MARROW FAILURE + BONE PAIN
- Anaemia (pallor, fatigue)
- Thrombocyotpenia (bruising, bleeding etc)
- Neutropenia -> infections + fever
Tissue infiltration:
- Hepatosplenomegaly
- Swollen testes, kidneys, **lymph nodes**, skin
- B symptoms - weight loss, malaise, night sweats (MORE COMMON than in AML/CML)
Can get CNS involvement -> neuro signs, raised ICP, meningism etc
85
Diagnosis of ALL
FBC - pancytopenia
Bloodfilm - INCREASED LYMPHOBLASTS
Blood film - 1x10^9 lymphoblasts per L
BM BIOPSY - >=20% LYMPHOBLASTS (DIAGNOSTIC)
+ hypercellular + lymphoblastic infiltration
Immunofluroscence/phenotyping - **TdT +ve lymphoblasts, but myeloperoxides -ve (opposite of AML)**
(TdT = terminal deoxynucleotidyl transferase - oligoclonal market characterising undifferentiated/poorly differentiated lymphoid blasts)
86
Treatment for ALL
Chemo:
- prednisolone/dexamethasone
- cyclophosphamide
- vincristine
- doxorubicin/daunorubicin
+ Methotrexate for CNS prophylaxis
consider allo transplant
Tyrosine kinase inhib if philadelphia chromosome +ve
87
Pathophys of Chronic lymphocytic leukaemia
INSIDIOUS/Indolent accumulation of incompetent mature lymphocytes, esp B cells (become continuously activated -> monoclonal b-cell lymphocytosis -> CLL) that occurs with increasing age
- failure of cell apoptosis
- lymphocytosis is sustained for at least 3 months
- >5 x 10^9/L
accumulation in BM (can crowd out functional cells?) -> BM failure
88
Presentation of CLL
Oft asymp
Lymphadenopathy (NON TENDER)
- BM FAILURE - pancytopenia
- Hepatosplenomegaly
Potentially B symps
89
Risk factors for CLL
Age > 60
Male
Genetics - FHx; White ethnicity
90
Diagnosis of CLL + Tx
FBC - WCC = lymphocytosis; cytopenia for rbcs, plts, other wc
Blood film - SMUDGE CELLS (old, broken)
May do BM biopsy (infiltration/overcrowding); CT scan (hepatosplenomegaly)
Tx:
- If asymp: observation
- Symp: immunochemotherapy e.g.
- High dose methylprednisolone + anti-CD20 (e.g. Rituximab)
91
Complication of CLL
Richter transformation
- massive B cell acumulation in lymph nodes
-> massive lymphadenopathy
-> transforms to aggressive lymphoma
92
Most common leukaemia in kids
ALL
93
Most common leukaemia in general/adults
CLL
94
Reactive vs cancer lymph nodes
Reactive - TENDER (+ has hilum?)
Cancer - rounded, rubbery, growing, NON-TENDER
95
Define lymphoma
Accumulation of cancerous lymphocytes forming tumour in lymph nodes
96
Risk factors for Lymphoma
EBV - glandular fever (in developing)
HIV (in developed)
SLE
Sjogrens (reduced fluid production e.g. tear/spit)
AGE (Hodgekin's esp in TEENS + ELDERLY)
97
Presentation of Hodgekin's lymphoma
- RFx
- B SYMPTOMS
**PAINLESS, RUBBERY LYMPHADENOPATHY**
- PAINFUL AFTER DRINKING ALCOHOL
98
Diagnosis of Hogekin's
LYMPH NODE BIOPSY (incisional or needle core biopsy, NOT fine needle biopsy)
- REED STERNBERG cell +ve (big, paler, looks multinucleated)
- subtype (nodular lymphocyte predominant Hodgekin's) -> POPCORN CELLS (popcorns are nodular)
Bloods:
- HIGH LDH (turnover - from metabolic panel)
- LOW Hb (anaemia of chronic disease)
- HIGH ESR (inflam)
CT/MRI for staging
99
Staging of lymphomas
ANN ARBOUR STAGING
1 - single lymph node
2 - 2 or more on one side of diaphragm
3 - 2 or more on both sides of diaphragm
4 - extra-nodal metastasis
A - no B symptoms
B - B symptoms present
100
Treatment for Hodgkin
ABVD chemo - 2 cycles:
Doxorubicin (Adriamycin)
Bleomycin
Vinblastine
Dacarbazine
+ interim PET/CT
101
Severe complication of chemo
FEBRILE NEUTROPENIA
- esp on high dose
Fever, tachycardia, sweats, rigors, tachypnoea
TREAT WITH BROAD SPECTRUM ANTIBIOTIC (amoxicillin, fluroquinolone)
102
Types of non-Hodgkin lymphomas
Low grade/indolent - slow growing, don't always require treatment, generally incurrable
High grade/aggressive - rapid but can be cured with timely treatment
103
Which cells can lymphomas affect
B, T (rare, poor prognosis) or natural killer cells
B lymphocytes most common (due to somatic hypermutation when trying to get right antibodies)
104
Types of indolent lymphomas
Marginal Zone lymphoma
Follicular Lymphoma
Mantle cell lymphoma
105
Types of high grade lymphomas
Diffuse Large B cell lymphoma
Burkitt Lymphoma
106
Complication of Low grade lymphoma
Richter's transformation -> aggressive, diffuse B cell lymphoma
Compression syndrome (could also get in high grade - fast growing)
107
Which drug is a risk factor for indolent lymphomas
Methotrexate (chemo + arthritis)
108
Symptoms of non-hodgkin lymphomas
PAINLESS RUBBERY LYMPADENOPATHY
- NOT AFFECTED BY ALCOHOL
B SYMPTOMS
indolent oft ASYMP or a LUMP - usually advanced at presentation
109
Diagnosis of Non-hodgkin lymphoma
FBC
LDH
ESR
CORE NEEDLE/EXCISION LYMPH NODE biopsy:
- NO RS/POPCORN
- BURKITT'S - CHARACTERISTIC STARRY SKY
Can also do BM biopsy
CT/PET/MRI - for staging
for differentials:
Organ functions
Viral screen
G6PD
Uric acid
B2 microglobulin
110
Why are fine needle biopsies unhelpful for lympadenopathy
They only extract fluid not tissue
111
Treatment of Low grade lymphoma
Asymp:
- watch + wait
- REGULAR follow-up (3-6 months)
Symp:
- Radiotherapy (could potentially cure)
Biologics:
BCL2 INHIBITOR - prevents anti-apoptosis
IMiDs (immunomodulatory imide drugs)
BiTE and CAR-T (risk of cytokine release syndrome)
112
Treatment of high grade lymphoma
Immunochemotherapy, with autograft
Radiotherapy
Check Point inhib (release host immune -> increased activity/ability)
Mononuclear antibodies
BITE/CAR-T
Allogenic transplant (uncommon)
113
Complication of allogenic transplant
Graft vs Host disease (tho a stronger immune reaction tends to fight off cancer better in long-run if graft is tolerated)
114
What is the standard Chemo used for non-Hodgkin lymphoma
R-CHOP:
Rituxumab (CD20 Ab),
Cyclophosphamide,
Hydroxydaunorubicin,
Vincristine,
Prednisolone (steroid)
115
Define multiple myeloma
Malignant monoclonal proliferation of plasma cells
- typically 1 specific Ab - esp IgG (55%) and IgA (20%)("monoclonal paraprotein")
>10% PLASMA CELLS IN BONE MARROW
116
Risk factors for multiple myeloma
AGE (>70)
Afrocarribean
HIV
117
Symptoms of MM
Old CRAB or CRABBI
Old (>70)
hyperCALCAEMIA
RENAL Failure
- hypercalcaemia -> calcium oxalate stones
- Ig light-chain deposition (nephrotoxic) - BENCE JONES PROTEIN
ANAEMIA (BM failure)
BONE LYTIC LESIONS
Bleeding
Infections
118
Pathophys of MM
Lack of apoptosis of differentiated b-lymphocytes. These plasma cells return to the bone marrow and overcrowd it reducing the production of other haem cells. This leads to bone marrow failure -> anaemia (tired all the time), thrombocytopaenia (bruising/bleeding), neutropenia (infections) except increased plasma cells.
Also causes bone lytic lesions -> hypercalcaemia as calcium from bone is releases. Some osteoporosis so pathological fractures can occur. Overall some profound bone deformity.
Hypercalcaemia increases risk of calcium oxalate renal stones. The increased deposition of the light kappa chains of immunoglobulins (ie Bence jones protein) in the kidneys is also NEPHROTOXIC -> kidney failure and Bence Jones protein in urine.
119
Diagnosis of MM
Bloods
- pancytopenia (NORMOCYTIC NORMOCHROMIC anaemia);
- HYPERCALCAEMIA
- Raised ESR
Blood film:
- Peripheral Rouleaux formation (RBCs stacking like coins in a line) - PATHOGNOMONIC
U+E - renal failure
- XR to check for stones
Urine dipstick - BENCE JONES protein
BONE profile
- HYPOcalcaemia + RAISED ALP
BM ASPRIATE - >10% PLASMA CELLS
SERUM ELECTROPHORESIS
- BAND for specific Ig paraprotein (hypergammaglobulinaemia - normally spread out)
XR SKULL - PEPPER POT SKULL
- osteolytic lesions
120
Differential diagnosis of MM
MGUS (mammyloid gammopathy undefined significance)
- precursor to myeloma (found in 10% at 80 y/o)
ASYMP
<10% BM plasma cells
no/little paraprotein spike
Amyloidosis (green on histology)
oft get end-stage renal failure
121
Treatment of MM
ONLY TREAT IF SYMPTOMATIC
CHEMO
MONOCLONAL ANTIBODIES - DARATUMUMAB
Bisphosphates (alendoronate)
Kyphoplasty - inject cement to support vertebrae
- blood transfusion
Consider BM stem cell transplant
122
Complication of MM
Richter transformation
123
Primary causes of Polycythaemia
POLYCYTHAEMIA VER (JAK2 V617 mutation)
EPO receptor mutation
(High O2 affinity Hb? seems more secondary)
124
Secondary causes of polycythaemia
HYPOXIA
HIGH EPO secretion
can also get RELATIVE POLYCYTHAEMIA from:
- ACUTE DEHYDRATION
- CHRONIC = apparent polycythaemia e.g in:
- EXCESS ALCOHOL,
- OBESITY,
- HTN
125
Pathophys of polycythaemia vera
Malignant proliferation of a pluripotent stem cell clone (clonal disordaer) caused by JAK2 mutation (a tyrosine kinase) which transduces signals (esp from things like erythropoietin)
The clones DON'T NEED EPO to AVOID APOPTOSIS
Excess proliferation of all haematopoietic cell lines = polycythaemia = raised haematocrit = HYPERVISCOSITY + THROMBOSIS
126
Presentation of polycythaemia vera
May be ASYMP - more common >60 y/o
Vague symp (common normally in old ppl anyways) from hyperviscosity:
- Headaches
- Tired
- Dizziness
- Visual disturbance
- Tinnitus
SEVERE ITCHING AFTER HOT BATH/when WARM
Erythromelalgia - burning sensation in fingers/toes
- HTN
- Angina
- Intermittent claudication
- Plethoric complexion - congested with blood in facial skin
HEPATOSPLENOMEGALY - distinguishes it as a malignancy
- may also get gout from high turnover
127
DIagnosis of PV
FBC:
- EVERYTHING raised (distinguishes from RBC only)
- RAISED Hb/HAEMATOCRIT
Genetic screen - JAK2 MUTATION
BM biopsy (prominent erythroid, granulocytic and
megakaryocytic proliferation)
LOW serum EPO
128
Treatment of PV
VENESECTION - LOWER HAEMATOCRIT + PLTS
- remove 400-500ml WEEKLY
(ft sole treatment)
Chemo:
- Hydroxycarbamide + Bulsulfan (esp if poorly controlled e.g. thrombocytocsis)
- Low dose ASPIRIN
Radioactive Phosphorus seeds (ONLY >70 y/o - increased risk of leukaemia)
129
Medication for gout
ALLOPURINOL - block uric acid production
130
In which diseases may Howell Jolly bodies be seen on microscopy
- MEGALOBLASTIC ANAEMIAS
- Sickle cell disease
-- Iron deficient anaemia
131
Presentation of essential thrombocytosis
- SPLENOMEGALY
- ARYTHOMELALGIA (red/blue discoloration + burning in peripheries)
- LIVEDO RETICULARIS (purply rash)
132
Types of Haemophilia
- Haemophilia A – Factor 8 deficiency
- Treatment – IV Factor 8
- Haemophilia B – Factor 9 deficiency
133
Epidemiology of Haemophilia
- X-linked recessive disorders – mainly affects men
- Haemophilia A is more common
134
Pathophysiology of Haemophilia A
X linked gene mutation causes FVIII deficiency. Leads to insufficient formation of tenase complex (IXa, VIIIa - ie the things that activate X), reduced thrombin generation, impaired fibrin deposition and poor clot formation.
The extrinsic pathway is also unable to compensate for the intrinsic deficit as it is down-regulated by TFPI (tissue factor pathway inhibitor) and the fibrinolytic pathway is up-regulated due to the low thrombin.
(2nd paragraph is extra info)
135
Symptoms/signs of Haemophilia
Depends on plasma levels of F8/9
- Levels **<1 IU/dL** (SEVERE) - associated with **frequent spontaneous bleeding into muscles and joints** -> crippling **arthropathy**
- 1-5 IU/dL - **severe bleeding following injury** + **occasional apparently spontaneous episodes**
- >5 IU/dL - mild disease: **bleeding only with trauma/surgery**
General s&s:
- Cerebral haemorrhage more common (than in general pop)
- Easy bruising
- Haematomas
- Prolonged bleeding after cut
- GI bleeding
- Haematuria
- Severe epistaxis
- Haemarthrosis
136
Investigations for Haemophilia
Bloods + PT + APTT
Factor 8/9 not extrinsic so:
- PT = normal
- VWF = normal
PROLONGED **ACTIVATED PARTIAL THROMBOPLASTIN TIME** (intrinsic)
Reduced plasma levels of factor 8/9
137
PT vs APTT
PT = Prothrombin time = part of the EXTRINSIC pathway (Warferin + vit K affects)
APTT = activated partial thromboplastin time = INTRINSIC pathway (Heparin affects)
138
Management of Haemophilia
- IV recombinant factor 8/9 concentrate – given as prophylaxis (before and after surgery) or to treat an acute bleeding episode
- Synthetic vasopressin – IV, s/c or intranasal administration, raises level of factor 8/9
- Hep A/B vaccinations
- Encouragement to join exercise regimes and avoid contact sport and aspirin
139
Complications of Haemophilia
Joint deformities and arthritis from recurrent bleeding into joints
140
VWF disease - pathophys
Autosomal DOMINANT mutation of VWF gene on chromasome 12
Reduced VWF (responsible for basis of platelet plugs) = more spontaneous bleeds/bruising
MOST COMMON inherited bleeding disorder
141
Diagnosis of VWF def
Affecting the intrinsic pathway so NORMAL PT but RAISED APTT
Bloods: normal Factors 8/9 (use an assay)
- reduced plasma VWF
142
Treatment of VWF def
No cure
DESMOPRESSIN - causes increased release of VWF from endothelial WEIBEL-PALADE BODIES (eleongated secretory organelles specifically in endothelial cells - contain VWF + other proteins for inflam, angiogenesis + tissue repair)
143
Pathophysiology of Disseminated Intravascular Coagulation
- Widespread generation of fibrin at points throughout the vascular system caused by the initiation of the coagulation pathway - typically the extrinsic pathway, starts with tissue factor
- Consumption of platelets/coag factors
- Secondary activation of fibrinolysis -> production of Fibrin + Fibrinogen Degredation Products (broken up fibrin) which inhibit fibrin poylmerisation and contribute to bleeding
- Activation of Tissue Plasminogen activator -> increased fibrinolysis/worse clotting
There is initial widespread thrombus formation throughout blood vessels (causing ischaemia) -> depletion of clotting factors -> increased tendency to bleed
144
Causes of DIC
Imbalance between formation of new clots and breaking down old clots
- Anything that causes mass activation of clotting cascade (ie severe inflam states)
- Malignancy – leukaemia t(15:17) translocation (acute promyelocytic leukaemia)
- Septicaemia
- Trauma
- Infections - meningitis
- Obstetrics causes
– amniotic fluid embolism
- abruptio placentae (detaches from inner wall before delivery)
- Haemolytic transfusion reactions
- Liver disease
145
Presentation of DIC
Range of presentation from no bleeding to complete haemostatic failure
- Bleeding - typically from venepuncture/IV sites + nose/mouth
- Bruising
- SOB (bleeding into lungs/ischaemia/necrosis)
- Haemoptysis
Can get ischaemia/necrosis -> organ damage
146
Investigations of DIC
Diagnosis suggested by history (severe sepsis, trauma, malignancy), clinical presentation and presence of severe thrombocytopenia
- Prolonged PTT, APTT and Thrombin Time (TT)
- Decreased fibrinogen and increased FDPs
- Blood film – shows schistocytes (fragmented red cells - cut up by excess fibrin strands)
147
Treatment of DIC
- Treat underlying cause – maintain blood volume and tissue perforation
- May need transfusions – platelets, RBCs and Fresh Frozen Plasma (FFP)
- Activated C protein (inhibts V and VII -> less clotting)
148
General causes (not specific) of thrombocytopenia
- Reduced platelet production in BM
- Excess peripheral destruction of platelets
- Problems of enlarged spleen
149
Types of Thrombocytopenias
- Immune thrombocytopenic purpura (ITP) - MORE COMMON
- Thrombotic thrombocytopenic purpura (TTP)
150
Epidemiology of ITP + types of ITP
- Type 1: in **children** 2-6 y/o (acute/primary)
- often **follows viral infection**,
- **rapid onset or purpura** which is *usually self-limiting*
- Type 2: in **adults, esp young women** (chronic/secondary)
- usually **less acute** than in children
- esp women with malig, HIV, other autoimmune
151
Pathopys of ITP
Autoimmune destruction of platelets (IgG antibodies to platelets and megakaryocytes)
- Often triggered by viral infection or malignancy
- The IgG antibodies coat the platelets which are then *removed* by binding to *Fc receptors on macrophages*
152
Presentation of ITP
- Easy bruising
- Purpura – red or purple spots on skin caused by bleeding underneath
- Epistaxis – nose bleed
- Menorrhagia
- Gum bleeding
Otherwise systemically well
153
Investigations for ITP
- FBC: Thrombocytopenia – low levels of platelets
- **Increased megakaryocytes** on BM examination
- May have detection of platelet autoantibodies
154
Treatment of ITP
- 1st LINE: **Corticosteroids** - PREDNISOLONE
- IV Immunoglobulin (e.g. IV IgG) - Decreases splenic platelet destruction
- 2nd line: Splenectomy
155
Pathophysiology of TTP
- deficiency in ADAMTS 13 - protease which is normally responsible for VWF degradation
- Causes extensive microvascular clots to form in small vessels -> low platelet count (due to platelet consumption) + organ damage
156
Epidemiology of TTP
- Adult FEMALES esp with:
- Malig
- HIV
- other Autoimmune
157
Presentation of TTP
- Easy bruising
- Purpura/PURPURIC RASH
- menorrhagia
- AKI
- (Microangiopathic) haemolytic anaemia (physical damage due to occlusion by fibrin deposition/platelet aggregation)
- neurological Sx
- Fever (SYSTEMICALLY UNWELL)
158
Diagnosis of TTP
- FBC:
- thrombocytopenia
- normal/increased megakaryocytes
- Reduced ADAMTS 13
- Coagulation screen: normal but LDH raised due to haemolysis
- Blood film: SCHISTOCYTES (fragmented parts of RBCs)
159
Treatment of TTP
- PLASMAPHERESIS/plasma exchange (remove blood through needle/catheter; circulate through machine; plasma is filtered out + altered/discarded -> removes ADAMTS 13 Ab)
- IV METHYLPREDNISOLONE
- IV RITUXIMAB
160
Define PT and INR. Normal PT and INR ranges
- PT = coag speed of EXTRINSIC PATHWAY (related to time taken for prothrombin -> thrombin)
- Normal ~ 10-13.5s
- INR (international normalised ratio) = patient PT/referance PT
- ~0.8-1.2
161
When may PT/INR be raised
- If on anticoag
- Liver disease
- Vit K deficiency
- DIC
162
INR if on Warferin
2-3
163
Define APTT + give normal range
- APTT (activated partial thromboplastin time) = coagulation speed of INTRINSIC PATHWAYS
- Normal ~ 35-45s
164
What is APTT raised in
- Haemophilia A + B
- VWF
(PT normal in both of above)
- can be prolonged if on Heparin (it inhibits intrinsic pathway at various points e.g. prothrombin)
165
APTT while on Heparin
~60-80s
166
Define G6PDH def
X-linked recessive enzymopathy -> halving of RBC life time + degradation
167
Epidemiology of G6PDH def
- X linked so more common in males
- typically in Mediterranean, African + Middle/Far Eastern ppl
- Protective against malaria falciparum
168
Pathophys of G6PDH def
- G6PDH catalyses first step in pentosephosphate pathway (makes NADPH).
- This pathway maintains GLUTATHIONE in **reduced state**.
- Glutathione protects RBCs from OXIDATIVE STRESS (i.e ROS like H2O2 which -> haemolysis)
-in deficiency -> **increased haemolysis** -> NORMOCYTIC Anaemia
169
Presentation of G6PDH def
- Asymp until exposed to triggering factors that cause oxidative stress
-> Haemolytic anaemia - Presents with JAUNDICE
Diff types:
- Neonatal presentation (jaundice)
- CHRONIC HAEMOLYTIC ANAEMIA
- Acute haemolysis
- RAPID ANAEMIA (fatigue, pallor etc)
- JAUNDICE
Also:
- BACK PAIN
- DARK URINE (haemoglobinuria)
170
Triggers of G6PDH def attack
- FAVA BEANS (common in kids)
- contain GLUCOSIDES which are metabolised to ROS
- Drugs:
- quinine, quinalones (antimalarials),
- sulphonamides (sulphametoxazole, sulphasalazine),
- NITROFURANTOIN
- Aspirin
- Infections
171
Investigations for G6PDH def
- FBC – anaemia and raised reticulocytes (normal if inbetween attacks)
- Blood film – BITE CELLS (look like bite taken out) and blister cells, Heinz bodies (precipitated denatured haemoglobin in RBCs) (normal inbetween attacks)
- Enzyme assay (low G6PDH)
172
Management of G6PDH def
- Avoid precipitants (e.g. fava beans, henna)
- Blood transfusion if/when severe
173
Pathophys of Hereditary Spherocytosis
AUTO DOMINANT membranopathy
- Mutation causes deficiency in STRUCTURAL MEMBRANE PROTEIN - SPECTRIN
- **increases permeability to sodium** -> requires increased rate of active transport out of cells
- makes RBCs more SPHERICAL + RIGID (reduced SA:V ratio)
- Increased splenic recycling (extravascular haemolysis)
-> splenomegaly due to rigid cells getting stuck in splenic microcirculation + destroyed
-> risk of autosplenomegaly (spontaneous infarction -> hyposplenism)
-> NORMOCYTIC ANAEMIA
**Specifically, RBCs lose part of their cell membrane as they PASS THROUGH THE SPLEEN** - as lipid bilayer not adequatly structurally supported
174
Epidemiology of hereditary spherocytosis
Most common inherited haemolytic anaemia in N Europe + America
175
Presentation of hereditary spherocytosis
- Anaemia symps
- NEONATAL JAUNDICE
- SPLENOMEGALY
- *exacerbated during infection*
- GALL STONES (50% - due to excess bilirubin)
- can get leg ulcers
176
DIagnosis of spherocytosis
FBC + blood film:
- NORMOCYTIC NORMOCHROMIC anaemia
- Increased RETICULOCYTES
- SPHEROCYTES
(-Osmotic fragility test will show fragility in hypotonic solutions)
**DIRECT COOMBS TEST = -VE** (to rule out AHA)
177
Treatments for her spherocytosis
- **SPLENECTOMY**(as the main damage + destruction to RBCs occurs as they are going through the spleen)
- wait till at least 6y/o due to sepsis risk (spleen fights off encapsulated bacteria)
- Requires lifelong **penicillin prophylaxis** post-op
- folate supps
- transfusions
For neonatal jaundice:
- PHOTOTHERAPY (conjugates bilirubin)
- risk of KERNICTERUS if untreated (bilirubin accumulation in basal ganglia)
178
Pathophys of Autoimmune haemolytic anaemias
Can either be warm or cold subtype depending on what it is precipitated by.
Auto Ab bind RBCs -> intra/extravasc haemolysis
179
Presentation of AHA
- anaemia
- potential jaundice
- splenomegaly
180
Diagnosis of AHA
FBC + Blood film:
- NORMOCYTIC NORMOCHROMIC anamia
- increased reticulocytes
- oft see SPHEROCYTES
**DIRECT COOMBES +VE** (agglutination of RBCs w/ Coomb reagent)
- diff from spherocytosis which is coombs -ve
181
Tumour lysis syndrome
Oncologic emergency caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation
Can cause renal AKI/failure as uric acid, calcium phosphate or hypoxanthine can precipitate in tubules -> Acute tubular necrosis
-> electrolyte disturbances -> arrhythmias, siezures etc
182
Define sideroblastic anaemia
Oft X LINKED inherited ALA synthetase deficiency -> FUNCTIONAL Fe DEFICIENCY due to DEFECTIVE Hb synthesis in the MITOCHONDRIA
Can also be due to B6 deficiency
- Fe is raised but is not used in Hb synth so becomes trapped in mitochondria
183
Diagnosis of Sideroblastic anaemia + treatment
FBC + Blood film:
- MICROCYTIC
- RINGED SIDEROBLASTS
- BASOPHILIC STIPPLING (increased granules)
Fe studies:
- raised serum iron
- raised serum ferritin
- raised transferrin saturation
- Decrease Total Iron Binding Capacity
Tx:
- Pyridoxine (vit B6), thiamine/folate supps
- Blood transfusion
- Desferroxamine chelation for overload
184
RFx of Hodgkin's lymphoma
- Age 20-34 years AND >55 years
- esp young adults from higher socio-economic class
- EBV INFECTION
- FHx
- certain HLA types (tho no HLA class 2 expression has been associated with adverse prognosis)
- Jewish ancestry
185
Felty syndrome
Rare, potentially serious
Define by presence of triad:
- RA
- splenomegaly
- neutropenia -> repeated infections
