Haem - Haematological Changes in systemic disease

Question 1

What is the difference in cause of blood cancers and soluble factor disorders

Answer 1

Blood cancers: acquired somatic mutations

Soluble factors: germline mutations (cells that produce the factors do not have as rapid a turnover rate e.g.hepatocytes, endothelial cells)

Question 2

Give examples of primary inherited disorders of the blood

Answer 2

FIX deficiency: haemophilia B
FIX excess: FIX padua

Erythrocyte deficiency: HbS
Erythrocyte excess: polycythaemia

Question 3

Give examples of primary acquired disorders of the blood

Answer 3

Erythrocyte excess: JAK2 → polcythaemia vera
Erythrocyte deficiency: PIG A → PNH paroxysmal nocturnal haemoglobinuria

Question 4

Give examples of secondary disorders of the blood involving the following: FVIII, erythrocytes, platelets, leucocytes

Answer 4

FVIII excess: inflammatory response/pregnancy
FVIII deficiency: anti-VFIII auto-antibodies (acquired haemophilia A)

Erythrocyte excess: Raised altitude, EPO secreting tumour
Erythrocyte deficiency: vitamin B12/folate deficiency, haemolytic anaemia

Platelet excess: bleeding, splenectomy, inflammation
Platelets low: vitamin B12/folate deficiency, ITP, TTP

Leucocyte excess: infection, inflammation, steroid use
Leucocytes low: BM infiltration, vitamin B12/folate deficiency

Question 5

What is often the first sign of systemic disease in the blood and give examples where this might be the case

Answer 5

Anaemia

Folate deficiency and Howell Jolly bodies → Coeliac
Fe deficiency → after delivery - PPH
Leucoerythroblastic anaemia → leukaemia
Haemolytic anaemia → immune haemolytic anaemia

Question 6

What are the laboratory findings in iron deficiency anaemia

Answer 6

Microcytic hypochromic anaemia
Reduced ferritin, transferrin saturation
Raised TIBC

Question 7

What are the causes of iron deficiency anaemia

Answer 7

Blood loss
GI: Peptic ulcer or gastric cancer, IBD,Colonic cancer
Urinary tract: Renal cell carcinoma, Bladder cancer

Question 8

What are the morphological features of leuco-erythroblastic anaemia

Answer 8

Teardrop RBCs (+Aniso and poikilocytosis)
Nucleated RBCs (should not leave the bone marrow)
Immature myeloid cells/myelocytes (should not leave the bone marrow)

Question 9

What does leuco-erythroblastic leukaemia imply

Answer 9

Implies bone marrow infiltration
Haemopoietic malignancy: leukaemia, lymphoma myeloma
Metastatic malignancy: breast, bronchus, prostate
Myelofibrosis
Severe infection: miliary TB, severe fungal infectin

Question 10

What are the types of haemolytic anaemia

Answer 10

Acquired:
- Immune mediated
- Non-immune mediated
Inherited
- membrane disorders
- cytoplasm/enzyme disorders
- Hb disorders

Question 11

What are the laboratory findings in haemolytic anaemia

Answer 11

Anaemia (though may be compensated)
Reticulocytosis (may cause modest elevation of MCV )
Bilirubinaemia (unconjugated/pre-hepatic cause)
LDH raised
Haptoglobins reduced

Question 12

What is the most common group of acquired haemolytic anaemias

Answer 12

Immune haemolytic anaemia

Question 13

What are the causes of immune haemolytic anaemia

Answer 13

Lymphoma, chronic lymphocytic leukaemia
Auto-immune: SLE
Infection e.g. mycoplasma
Idiopathic

Question 14

What are the laboratory features of immune haemolytic anaemia

Answer 14

Spherocytes
Positive Coombs DAT (direct antiglobulin test)

Anaemia (though may be compensated)
Reticulocytosis (may cause modest elevation of MCV )
Bilirubinaemia (unconjugated/pre-hepatic cause)
LDH raised
Haptoglobins reduced

Question 15

What are the causes of non-immune haemolytic anaemia

Answer 15

Micro-angiopathic haemolytic anaemia (MAHA):
Underlying adenocarcinoma
Haemolytic uraemic syndrome
Low grade DIC

Question 16

What are the laboratory features of non-immune haemolytic anaemia

Answer 16

RBC fragments
Thrombocytopenia

Anaemia (though may be compensated)
Reticulocytosis (may cause modest elevation of MCV )
Bilirubinaemia (unconjugated/pre-hepatic cause)
LDH raised
Haptoglobins reduced

Question 17

Describe the pathogenesis of Micro-angiopathic haemolytic anaemia (MAHA)

Answer 17

1. Inappropriate/unfocussed activation of coagulation
2. Platelets are activated and they adhere to the vessel wall
3. Platelets deposit fibrin, which degrades
4. Red cells become fragmented as they pass through (microangiopathy)
5. Leads to bleeding with low platelets and coagulation factor consumption

Question 18

What cells are found in the bone marrow

Answer 18

1. Blasts (myeloid and lymphoid) (<5% of BM cells)
2. Promyelocytes
3. Myelocytes

Question 19

What are the causes of neutrophilia

Answer 19

Pyogenic infection: steroids, underlying neoplasia, tissue inflammation (colitis, pancreatitis, myocarditis, MI)
Reactive neutrophilia i.e. to infection
Malignancy

Question 20

What is the difference in appearance of the blood/neutrophils in reactive neutrophilia and malignant neutrophilia

Answer 20

Reactive: heavy toxic granulation, vacuoles seen, no immature cells

Malignant:
- CML: neutrophilia + basophilia + myelocytes
- AML: neutrophilia + myeloblasts

Question 21

What are the causes of eosinophilia (reactive and chronic)

Answer 21

Reactive eosinophilia
- Parasitic infestation
- Allergic diseases e.g. asthma, rheumatoid, polyarteritis, pulmonary eosinophilia.
- Neoplasms, esp. Hodgkin’s, T-cell NHL (reactive eosinophilia)
- Drugs (reaction erythema multiforme)

Chronic eosinophilic leukaemia (Malignant)
- Eosinophils part of the “clone”
- FIP1L1-PDGFRa Fusion gene

Question 22

What are the causes of monocytosis

Answer 22

Chronic infections and primary haematological disorders:

TB, brucella, typhoid
Viral; CMV, varicella zoster
sarcoidosis
chronic myelomonocytic leukaemia (MDS)

Question 23

What are the causes of lymphocytosis

Answer 23

EBV, CMV, Toxoplasma (Infectious mononucleosis IM)
infectious hepatitis, rubella, herpes infections
autoimmune disorders
Sarcoidosis

Question 24

What are the causes of lymphopenia

Answer 24

Untreated infection HIV
Auto immune disorders
Inherited immune deficiency syndromes
Drugs (chemotherapy)

Question 25

What does the morphology of lymphocytes tell you in lymphocytosis

Answer 25

Mature lymphocytes (PB)
- reactive/atypical lymphocytes (IM)
- small lymphocytes and smear cells (CLL/NHL)

Immature Lymphoid cells in PB
- Lymphoblasts; Acute Lymphoblastic Leukaemia (ALL)

Question 26

Describe immunophenotyping of B cell lymphocytosis

Answer 26

Mature B cells express Immunoglobulin (usually IgM or IgG). The light chains will be either kappa or lambda expressing
- Polyclonal = kappa and lambda (reactive)
- Monoclonal = kappa ONLY or lambda ONLY (malignant)

Question 27

What can mutations in tyrosine kinase cause and give an example

Answer 27

Excess proliferation (but no effect on differentiation)
BCR ABL → CML
JAK2 → MPD

Question 28

What can mutations in nuclear transcription factors cause and give an example

Answer 28

Blocks differentiation
May cause acute leukaemia in conjunction with a proliferation mutation
PML RARA → acute promyelocytic leukaemia

Question 29

What may mutations in apoptosis genes cause and give an example

Answer 29

Lymphoma
BCL2 → follicular lymphoma

Question 30

What should be assessed when diagnosing blood cancers

Answer 30

1. Morphology (cytology, cytochemistry)
2. Immunophenotype (flow cytometry, immunohistology)
3. Cytogenetics
4. Molecular genetics (PCR, pyro-sequencing)

Question 31

What are the common blood cancer presentations or problems

Answer 31

Lympho-haemopoietic failure
- Bone marrow (myeloid): anaemia, bacterial infection (neutrophils) bleeding (platelets)
- Immune system (lymphoid): recurrent viral or fungal infection

Excess of malignant cells
- Erythrocytes or leucocytes: impair blood flow >stroke or TIA
- Massively enlarged lymph nodes (lymphoma)> compress hollow tubes: bowel, vena cava, ureters, bronchus.

Infiltrate and impair other organ function
- CNS lymphoma
- Skin lymphoma
- Kidney failure (light chain deposition from myeloma)

Miscellaneous problems e.g. hypercalcaemia, hypermetabolism