1. Systemic Disease

Question 1

3 types of anaemia

Answer 1

• iron deficiency
• leukoerythoblasgtic
• haemolytic = immune, non-immune-mediated
• anaemia of inflammation (chronic disease)

Question 2

Fe deficiency anaemia: causes, biochemical/lab findings

Answer 2

bleeding until proven otherwise (menorrhagia pre-menopausal women, GI blood loss in men and post-menopausal women)

Occult blood loss:

• GI cancers = gastric, colorectal
• UT cancers = RCC, bladder cancer

Lab findings:

• low ferritin and TF saturation
• raised TIBC
• microcytic hypo chromic anaemia

Question 3

Leucoerythroblastic anaemia: what is it, blood film, causes

Answer 3

red and white cell precursor anaemia

blood film

• poikilocytosis (teardrop RBCs) and anisocytosis
• nucleated RBCs
• immature myeloid cells

Question 3

Leucoerythroblastic anaemia: what is it, blood film, causes

Answer 3

red and white cell precursor anaemia

usually first manifestation of a BM malignancy

blood film

• poikilocytosis (teardrop RBCs) and anisocytosis
• nucleated RBCs
• immature myeloid cells

Causes:

• malignancy = haematopoietic (leukaemia, lymphoma, myeloma), non-haematopoietic (breast, bronchus, prostate)
• severe infection = miliary TB, severe fungal infection
• myelofibrosis = massive splenomegaly, dry tap on BM aspirate

Question 4

Haemolytic anaemia: common lab features

Answer 4

shortened RBC survival

Question 5

2 types of haemolytic anaemias

Answer 5

Inherited → defects of red cell

• membrane = hereditary spherocytosis
• cytoplasm/enzyme = G6PD deficiency
• Hb = SCD (structural) or thalassaemia (quantitative)

Acquired → RBC healthy but due to defects in environment where RBC finds itself

• immune mediated = warm/cold AIHA, PCH
• non-immune mediated = PNH, MAHA, infection (malaria),

Question 6

Warm vs Cold AIHA

Answer 6

BOTH DAT+ve, spherocytes, agglutination

Warm AIHA (80-90%) IgG, extravascular haemolysis – lymphoma, CLL, drug allergy, SLE, idiopathic

Cold AIHA (10-15%) IgM (or IgG), intravascular haemolysis – M. pneumoniae, EBV, CMV

Question 7

DAT vs iDAT

Answer 7

Question 8

DAT vs iDAT

Answer 8

Question 9

Paroxysmal Cold Haemoglobinuria (PCH)

Answer 9

Hb in urine

viral infection = measles, syphilis, VZV

Donath-Landsteiner antibodies → stick to RBCs in cold → complement-mediated haemolysis on rewarming (self-limiting as IgG dissociate at higher tempo than IgM)

Question 10

Non-immune mediated anaemia features

Answer 10

DAT -ve

Schistocytes, thrombocytopenia, DAT-ve, hereditary spherocytosis

Question 11

Non-immune mediated anaemia: infection

Answer 11

MALARIA (commonest WW)

parasite enters RBC, causes it to die, shortening survival of RBC

Question 12

PNH = paroxysmal nocturnal haemoglobinuria

Answer 12

Acquired loss of protective surface GPI markers on RBCs (platelets + neutrophils) → complement-mediated lysis → chronic intravascular haemolysis especially at night.

Morning haemoglobinuria, thrombosis (+Budd- Chiari syndrome – hepatic v thromb).

Diagnosis: immunophenotype shows altered GPI or Ham’s test +ve (in vitro acid-induced-lysis).

Treatment: iron/folate supplements, prophylactic vaccines/antibiotics. Expensive monoclonal antibodies (eculizumab) that prevents complement from binding RBCs

Question 13

3 types of MAHA

Answer 13

Adenocarcinoma, HUS, TTP

Question 14

Adenocarcinoma

Answer 14

• Underlying adenocarcinoma releases granules into circulation
• These are pro-coagulant and activate the coagulation cascade
• Platelet activation, fibrin deposition, degradation
• Red cell fragmentation due to low-grade DIC
• Bleeding (low platelet and coagulation factor deficiency)

Question 15

HUS

Answer 15

E. coli toxin O157

triad: MAHA, thrombocytopenia, AKI

Question 16

TTP

Answer 16

Pentad = MAHA, thrombocytopenia, AKI, neurological impairment, fever

AI: ADAMTS13 mutation → deficiency in vWF cleaving protease

high vWF acts like cheese wire in blood vessels

tx = plasma exchange (NOT STEROIDS)

Question 17

Types of white blood cells in peripheral blood and bone marrow

Answer 17

Question 18

What do we ix when abnormal WBC

Answer 18

FBC = Hb, MCV, platelet count, WBC

Blood film = count, pancytopaenia?, which lineages abnormal?, morphology?

Question 19

Causes of neutrophilia

infections that don’t produce a neutrophilia

Answer 19

Pyogenic infection (most likely)

• corticosteroids
• underlying neoplasia
• tissue inflammation → colitis or pancreatitis
• myeloproliferative or leukaemic disorders

Infections that don’t cause neutrophilia:

• brucella, typhoid, viral infections

Question 20

Reactive/infection vs malignant (e.g. CML and ALL) neutrophilia

Answer 20

Reactive/infection:

• neutrophilia, toxic granulation, no immature cells
• only neutrophils, heavy granulation, vacuoles in neutrophils

Malignant → MASSIVELY RAISED

• neutrophilia/basophilia + immature cells (myelocytes) + splenomegaly = CML
• neutropenia + myeloblasts = AML

Question 21

Reactive vs chronic eosinophilic leukaemia

Answer 21

Reactive

• parasitic infection
• allergic diseases → asthma, rheumatoid, polyarteritis, pulmonary eosinophilia
• underlying neoplasms → Hodgkin’s, T-cell NHL
• Drugs → reaction erythema multiform

Chronic eosinophilic leukaemia

• eosinophils part of clone
• FIP1L1-PDGFRa fusion gene

Question 22

Monocytosis: chronic infections and primary haematological disorders

Answer 22

• TB, brucella, typhoid
• vira, CMV, varcella zoster
• sarcoidosis
• CMML, myelodysplastic syndrome

Question 23

Summary of increased phagocyte count

Answer 23

Question 24

Summary of increased phagocyte count

Answer 24

Question 25

Lymphocytosis and lymphpaenia causes

Answer 25

**Lymphocytosis [HIGH WCC]** * EBV, CMV, Toxoplasma * Infectious hepatitis, rubella, herpes infections * Autoimmune disorder * Sarcoidosis **Lymphopenia [LOW WCC]** * HIV * Auto immune disorders * Inherited immune deficiency syndromes * Drugs (chemotherapy)

Question 26

Evaluating lymphocytosis morphology

Answer 26

**Mature lymphocytes (PB)** * Reactive/atypical lymphocytes (IM) * Small lymphocytes and smear cells (CLL/NHL) **Immature lymphoid cells (PB)** * Lymphoblasts (ALL)

Answer 27

**Mature lymphocytes (PB)** * Reactive/atypical lymphocytes (IM) * Small lymphocytes and smear cells (CLL/NHL) **Immature lymphoid cells (PB)** * Lymphoblasts (ALL)

Question 28

Clonality in B-cell lymphocytosis (light chain restriction)

Answer 28

* Polyclonal = kappa and lambda (reactive) * Monoclonal (kappa ONLY or lambda ONLY (malignant)

Question 29

leukaemia vs lymphoma

Answer 29

The simplest way to think about it is that lymphomas are **solid tumors made up of blood cells.** This kind of cancer usually causes enlarged lymph nodes or solid masses. Leukemia, on the other hand, is seen in the **bloodstream –** it's a liquid kind of cancer and it flows and is pumped around with the blood

Question 30

Myeloid differentiation

Answer 30

Question 31

Myeloid differentiation

Answer 31

Question 32

What are the 3 acquired somatic mutations that cause leukaemia and lymphoma?

Answer 32

**Cellular proliferation (type 1)** * mutations in **TK** genes → excess proliferation * BCR-ABL = CML * JAK2 = MPD **Impair/block cellular differentiation (type 2)** * mutations in TF block differentiation * PMBL RARA in APL (a type of AML) **Prolong cell survival** * mutations in apoptosis genes in leukaemia * BCL2 = follicular lymphoma

Question 33

What parts of tissue biopsy do we look at to establish a diagnosis (4)

Answer 33

Gives LINEAGE and NORMAL COUNTERPART CELL **Morphology** * Malignant cells; large or small, mature or immature? * Lymph node diffuse invasion or forming follicles? **Immunophenotype** (flow cytometry or Immunohistology) * Myeloid or lymphoid? T or B lineage? * Stage of maturation precursor or mature? **Cytogenetics** (translocations or FISH studies) * Confirm morphology e.g. **Philadelphia Chromosome** \> _CML_ * Prognostic information e.g. **17p del** in _CLL_ * **t(8;14**) activates **c-myc oncogene** in _Burkitt Lymphoma_ **Molecular genetics** (PCR, pyro sequencing) * JAK2 mutation in suspected polycythaemia vera * BCR ABL cDNA detection and quantification

Question 34

examples of morphology and immunophenotype in diagnosis Precise classification is then used to… * **Predict the likely course** (i.e. polycythaemia vera is an indolent disorder) * Choose the **appropriate treatment** (i.e. ABL tyrosine kinase inhibitor for CML)

Answer 34

B-cell acute lymphoblastic lymphoma [**TOP**] * **TdT +ve** (indicates **_immature**_ cells; used in _**VDJ rearrangement_**) * **CD19 +ve** (indicates B-cell lineage) * **Surface Ig -ve** (abnormal) Multiple myeloma [**BOTTOM**] * **TdT -ve** (normal) * **Surface Ig +ve** (normal) * **CD138 +ve** (abnormal)

Question 35

Clinical problems with systemic disease

Answer 35

**Lympho-haemopoietic failure (a dispersed organ)** * _Bone marrow:_ anaemia, infection (neutrophils) bleeding (platelets) * _Immune system:_ recurrent infection **Excess of malignant cells** * Erythrocytes (polycythaemia): _impair blood flow_ to lead to stroke or TIA * Enlarged lymph nodes (lymphoma) _compress_ structures, bowel, vena cava, ureters, bronchus **Impair organ function** * CNS lymphoma * Skin lymphoma **Other problems**

Question 36

Summary

Answer 36

Question 37

Which is it? IDA, ACD, BM mets from breast Ca, MAHA, AIHA

Question 38

What is the likely diagnosis? ## Footnote B cell ALL Mature B cell lymphoproliferative disorder (e.g. CLL) Infectious mononucleosis (e.g. EBV) T cell acute leukaemia lymphoma

Answer 38

B cell ALL **Mature B cell lymphoproliferative disorder (e.g. CLL)** * no abnormal cells in the blood (all mature cells) Infectious mononucleosis (e.g. EBV) * IgG serology is historical (past infection), IgM is current T cell acute leukaemia lymphoma