Haematological Changes in Systemic Disease

Question 1

What can cause haematological disorders?

Answer 1

Haemostasis & Thrombophilia: Altered function of soluble proteins e.g. FVIII deficiency, Protein C deficiency, Platelet function & interaction with endothelial surfaces

Haematological oncology: Primary abnormalities of white cell production
and differentiation, leukaemia lymphoma myeloma

Red cell disorders: Inherited (sickle cell, thalassaemia) acquired

Immune haematology: Autoimmune cytopenias

Question 2

What can deficiencies cause?

Answer 2

Factor VIII: Haemophilia A
Factor IX: Haemophilia B

Protein C: Pro-thrombotic

Erythrocytes: anaemia

Lymphocytes: Lymphopenia (HIV)

Platelets: ITP

Question 3

What can excesses cause?

Answer 3

Erythrocytes: Polycythaemia

Granulocytes: Leukaemia (CML), reactive eosinophilia

Lymphocytes: Leukaemia(CLL)

Platelets: Essential thrombocythemia

Question 4

What are primary haematological disorders?

Answer 4

Primary disorders arise from DNA mutation(s)

Question 5

What are some examples of primary haematological disorders?

Answer 5

Germline/inherited (gene mutated)

• FIX
• Erythrocytes e.g. beta Thalassaemia or Chuvash polycythaemia

Somatic/acquired (gene mutated)

• Erythrocytes e.g. JAK2 V617F: Polycythaemia vera
• Myeloid/granulocytes e.g. BCR-ABL1: Chroinic myeloid leukaemia
• Soluble factors
• No acquired (somatic) DNA mutations, not rapidly dividing cells (hepatocytes /endothelial cells)

Question 6

What are secondary haematological disorders?

Answer 6

Secondary disorders are changes in haematological parameters secondary to a non-haematological disease

Question 7

What are some examples of secondary haematological disorders?

Answer 7

Erythrocytes

• Exces: cyanotic heart disease
• Deficiency: anti-RBC antibodies: Immune haemolysis

Factor VIII

• Excess: inflammatory response
• Deficiency: anti-FVIII auto-antibodies (acquired haemophilia A)

Question 8

What can cause increased FVIII?

Answer 8

Inflammation

Question 9

What can cause increased or decreased erythrocytes?

Answer 9

Raised - Altitude/hypoxia or Epo secreting tumour

Reduced - BM infiltration or deficiency disease (Vit B12 or Fe)
Shortened survival (Haemolytic anaemia)

Question 10

What can cause increased or decreased platelets?

Answer 10

Raised - Bleeding, Inflammation, splenectomy

Reduced - BM infiltration or deficiency disease (Vit B12)
Shortened survival (ITP, TTP)

Question 11

What can cause increased or decreased leucocytes?

Answer 11

Raised - Infection, Inflammation, corticosteroids

Reduced - BM infiltration or deficiency disease (Vit B12)

Question 12

What is the cause of iron deficiency unless proven otherwise?

Answer 12

Bleeding

Question 13

What are some reasons for occult blood loss?

Answer 13

GI cancers: Gastric, Colonic/rectal

Urinary tract cancers: Renal cell carcinoma, Bladder cancer

Question 14

What is Leuco-erythroblastic anaemia and what are the signs in a blood film?

Answer 14

Variable degree of anaemia

Teardrop RBCs (+aniso and poikilocytosis)
Nucleated RBCs
Immature myeloid cells

Question 15

What are causes of leucoerythroblastic film?

Answer 15

Malignant
Haemopoietic: leukaemia/lymphoma/myeloma
Non Haemopoietic: metastatic-breast/bronchus/prostate

Myelofibrosis
Massive splenomegaly
Dry tap on BM aspirate

Severe infection
Miliary TB
Severe fungal infection

Question 16

What are common laboratory features of all haemolytic anaemias?

Answer 16

Anaemia (though may be compensated)

Reticulocytosis

Unconjugated bilirubin raised (pre-hepatic)

LDH raised

Haptoglobins reduced

Question 17

What are the two groups of haemolytic anaemia?

Answer 17

Primary (inherited)

Secondary (acquired)

Question 18

What are the features of primary inherited haemolytic anaemia?

Answer 18

Defects of the red cell/Germline DNA mutation.

Membrane: e.g. Hereditary Spherocytosis

Cytoplasm/enzymes: e.g. G6PD deficiency

Haemoglobin: Sickle cell disease (structural); Thalassaemia (quantitative)

Question 19

What are the features of secondary acquired haemolytic anaemia?

Answer 19

Defects of the environment (systemic disease) in which the red cell finds itself:

Non Immune (DAT –ve)

Immune mediated (Direct Antiglobulin Test (DAT) (aka Coombs
test) +ve)

Question 20

What are the features of DAT +ve haemolytic anaemia and what is it associated with?

Answer 20

Spherocytes

Associated with systemic diseases involving Immune system

• Malignancy: e.g. Lymphoma or CLL
• Autoimmune: e.g. SLE
• Infection: e.g. mycoplasma
• Idiopathic

Question 21

What is associated with DAT -ve haemolytic anaemia?

Answer 21

Infection: Malaria

Micro-angiopathic Haemolytic anaemia (MAHA)

• Underlying adenocarcinoma
• Haemolytic uraemic syndrome

Question 22

What is microangiopathy associated with and what happens?

Answer 22

Adenocarcinomas, low grade DIC

• Platelet activation
• Fibrin deposition and degradation
• Red cell fragmentation (microangiopathy)
• Bleeding (low platelets and coag factor deficiency)

USUALLY associated with malignancy

Question 23

What are some causes of neutrophilia?

Answer 23

Corticosteroids

Underlying neoplasia

Tissue inflammation (e.g.colitis, pancreatitis)

Myeloproliferative/leukaemic disorders

PYOGENIC INFECTION

Question 24

What would you expect to see in a blood film for an infection?

Answer 24

Neutrophilia + toxic granulation no immature cells

Question 25

What would you expect to see in a blood film for CML?

Answer 25

Neutrophilia plus basophilia & immature cells myelocytes

Question 26

What would you expect to see in a blood film for AML?

Answer 26

Neutropenia plus myeloblasts suggests acute leukaemia (AML)

Question 27

What are some causes of eosinophilia?

Answer 27

**Reactive eosinophilia** - Parasitic infestation Allergic diseases e.g. asthma, rheumatoid, polyarteritis,pulmonary eosinophilia. Underlying Neoplasms, esp. Hodgkin’s, T-cell NHL (reactive eosinophilia) Drugs (reaction erythema multiforme) **Chronic eosinophilic leukaemia** Eosinophils part of the “clone” FIP1L1-PDGFRa Fusion gene

Question 28

What is monocytosis?

Answer 28

Rare but seen in certain chronic infections and primary haematological disorders. - TB, brucella, typhoid - Viral; CMV, varicella zoster - Sarcoidosis - Chronic myelomonocytic leukaemia (MDS)

Question 29

What are some causes of increased lymphocytes?

Answer 29

EBV, CMV, Toxoplasma Infectious hepatitis, rubella, herpes infections Autoimmune disorders Sarcoidosis

Question 30

What are some causes of decreased lymphocytes?

Answer 30

Infection HIV Auto immune disorders Inherited immune deficiency syndromes Drugs (chemotherapy)

Question 31

What are differentials for unusual blood films with lymphocytosis?

Answer 31

Mature lymphocytes (PB) - Reactive/atypical lymphocytes (IM) - Small lymphocytes and smear cells (CLL/NHL) Immature Lymphoid cells in PB - Lymphoblasts (Acute Lymphoblastic Leukaemia)

Question 32

How do you determine if B-cell lymphocytosis is malignant or reactive?

Answer 32

If it is polyclonal (Kappa and Lambda chain diversity) then it is reactive, if it is monoclonal, then it is malignant.

Question 33

What are the three types of acquired somatic mutations?

Answer 33

Cellular proliferation (type 1) Impair/block cellular differentiation (type 2) Prolong cell survival (anti-apoptosis)

Question 34

What are examples of cellular proliferation?

Answer 34

Mutations in Tyrosine Kinase genes cause excess proliferation (no effect on differentiation) - BCR-ABL1 CML - JAK2 MPD

Question 35

What are examples of impaired/blocked cellular differentiation?

Answer 35

Mutations in nuclear transcription factors may block differentiation. If present along with a proliferation mutation can cause acute leukaemia PML-RARA in acute promyelocytic leukaemia

Question 36

What are examples of prolonged cell survival?

Answer 36

Mutations in apoptosis genes may occur in lymphomas - BCL2 and Follicular lymphoma