Haematological Changes in Systemic Disease Flashcards
What haematological manifestations arise from altered function of soluble proteins?
Haemostasis: FVIII deficiency = bleeding tendency
Thrombophilia: Protein C deficiency = thrombotic tendency
What haematological disorders arise from abnormalities of cell number/ function?
WBC: Leukaemia, reactive leukocytosis, myeloma
RBC: Sickle cell, Thalassaemia
What are the other broad etiological groups of haematological disorders?
Immune: AI disorders
Transfusion associated
What conditions are caused by haematological deficiencies?
Factor VIII, IX, Protein C, Erythrocytes, Lymphocytes, Platelets
Factor VIII: Haemophilia A
Factor IX: Haemophilia B
Protein C: Pro-thrombotic
Erythrocytes: anaemia
Lymphocytes: Lymphopenia (HIV)
Platelets: ITP
What conditions are caused by haematological excesses?
Erythrocytes
Granulocytes
Lymphocytes
Platelets
Erythrocytes: Polycythaemia
Granulocytes: Leukaemia (CML), reactive eosinophilia
Lymphocytes: Leukaemia (CLL)
Platelets: Essential thrombocythemia
What are primary haematological disorders?
Inherited (germline gene mutated) or acquired (somatic gene mutated) DNA mutation(s)
What are most haematological malignancies due to?
Acquired (somatic) gene mutations
Give a primary and secondary condition causing raised erythrocytes
Primary: Polycythaemia Vera
Secondary: High altitude
Name 2 inherited mutations of FIX and erythrocytes that cause primary haematological disorders
FIX
Deficiency: Haemophilia B (bleeding)
Excess: FIX Padua (thrombosis)
Erythrocytes
Deficiency: Hb S
Excess: Polycythaemia
Name 2 ACQUIRED haematological mutations of erythrocytes that cause primary disorders
JAK2 V617F: Polycythaemia vera
PIG A: PNH Paroxysmal nocturnal haemoglobinuria
Why are there no acquired DNA mutations in soluble factors to cause primary haematological disorder?
Soluble factors are secreted by endothelial cells or hepatocytes
Not by rapidly dividing cells which have greater risk of mutation
Give a primary and secondary disorder causing reduced erythrocytes
Primary: Thalassaemia
Secondary: AI haemolytic anaemia
What are secondary haematological disorders?
Changes in haematological parameters in response to a non-haematological disease/ condition
What are the FVIII examples of secondary haematological disorders?
Excess: inflammatory response/ pregnancy
Deficiency: anti-FVIII auto-antibodies (acquired haemophilia A)
What systemic condition can cause increased FVIII? What is the consequence of this?
Chronic inflammation
Increases thrombosis risk
What systemic changes can cause increased or decreased erythrocytes?
Increased: Altitude/ hypoxia or EPO secreting tumour
Decreased: BM infiltration or deficiency disease (Vit B12 or Fe)
Shortened survival (Haemolytic anaemia)
What systemic changes can cause increased or decreased platelets?
Increased: Bleeding, Inflammation, splenectomy
Decreased: BM infiltration or deficiency disease (Vit B12)
Shortened survival (ITP, TTP)
What systemic changes can cause increased or decreased leucocytes?
Increased: Infection, Inflammation, corticosteroids
Decreased: BM infiltration or deficiency disease (Vit B12)
What systemic disease would you associate with folate deficiency, macrocytic anaemia and Howell Jolly bodies?
Coeliac
Give 2 examples of anomalous blood results that may be the first presentation of malignancy
Microcytic anaemia: GI cancer
Hypercalcaemia: Myeloma
What is the cause of iron deficiency unless proven otherwise?
Bleeding
What are the labratory findings in iron deficiency?
Microcytic hypochromic anaemia
Low ferritin
Low transferrin saturation
High TIBC
What are 2 classes of reasons for occult blood loss?
GI:
Peptic ulcer or Gastric cancer
IBD or Colonic cancer
Urinary tract:
Renal cell carcinoma
Bladder cancer
What is Leuco-erythroblastic anaemia and what are the signs in a blood film?
Variable degree of anaemia (mild-severe)
Teardrop RBCs (+aniso + poikilocytosis)
Nucleated RBCs
Immature myeloid cells
Why is leuco-erythroblastic anaemia an important finding? What can cause this?
It implies abnormal BM infiltration
Malignancy
Myelofibrosis
Severe infection (rarely)
What are the malignant causes of a leuco-erythroblastic anaemia?
Haematopoietic: Leukaemia, Lymphoma, Myeloma
Metastatic: Breast, Bronchus, Prostate
What features would indicate myelofibrosis being causative of a leuco-erythroblastic anaemia?
Massive splenomegaly
Dry tap on BM aspirate
Which infections could cause a leuco-erythroblastic anaemia?
Miliary TB
Severe fungal infection
What are common laboratory features of all haemolytic anaemias?
Anaemia (though may be compensated)
Reticulocytosis (high MCV)
HIGH Unconjugated BR (pre-hepatic, excess BR)
HIGH LDH (intracellular enzyme released)
LOW Haptoglobins
What are the two groups of haemolytic anaemia?
Primary (inherited)
Secondary (acquired)
What are the features of primary inherited haemolytic anaemia?
Inherited mutation of RBC
Membrane: Hereditary Spherocytosis
Cytoplasm/ enzymes: G6PD deficiency
Haemoglobin: Sickle cell disease (structural); Thalassaemia (quantitative)
What are the features of secondary acquired haemolytic anaemia?
Defects of RBCs environment (systemic disease):
Non Immune (DAT –ve)
Immune mediated (DAT +ve)
Direct Antiglobulin Test = DAT (aka Coombs test)
What are the features of DAT +ve haemolytic anaemia and what is it associated with?
Spherocytes
A/W systemic diseases
Malignancy: Lymphoma or CLL
AI: SLE
Infection: mycoplasma
Idiopathic
What is associated with DAT -ve haemolytic anaemia?
Infection: Malaria
Micro-angiopathic Haemolytic anaemia (MAHA): indicates underlying adenocarcinoma
or Haemolytic uraemic syndrome
What is microangiopathy associated with and what happens?
Adenocarcinomas, low grade DIC
- Platelet activation
- Fibrin deposition + degradation
- RBC fragmentation (microangiopathy, BP drives RBC through fibrin strands)
- Bleeding (low platelets + coag factor deficiency)
USUALLY a/w malignancy
What are 5 causes of neutrophilia?
PYOGENIC INFECTION
Corticosteroids
Underlying neoplasia
Tissue inflammation (e.g.colitis, pancreatitis, MI)
Myeloproliferative/ leukaemic disorders
What would you expect to see in a blood film for an infection?
Neutrophilia + toxic granulation no immature cells
What would you expect to see in a blood film for CML?
Neutrophilia PLUS Basophilia + Myelocytes
What would you expect to see in a blood film for AML?
Neutropenia plus Myeloblasts
4 causes of reactive eosinophilia?
Parasitic infestation
Allergic diseases: asthma, RA, polyarteritis, pulmonary eosinophilia.
Underlying Neoplasms, esp. Hodgkin’s, T-cell NHL
Drugs (reaction erythema multiforme)
What chronic infections and primary haematological disorders cause monocytosis?
RARE
TB, brucella, typhoid
CMV, VZV
Sarcoidosis
Chronic myelomonocytic leukaemia (MDS)
What are 4 causes of lymphocytosis?
EBV, CMV, Toxoplasma
Infectious hepatitis, rubella, herpes infections
AI disorders
Sarcoidosis
What are 4 causes lymphopenia?
Infection: HIV
AI disorders
Inherited immune deficiency syndromes
Drugs (chemotherapy)
What are the differentials for lymphocytosis with mature lymphocytes in the peripheral blood?
Reactive/ atypical lymphocytes: IM
Small lymphocytes + smear cells: CLL/ NHL
How do you determine if B-cell lymphocytosis is malignant or reactive?
Reactive: Polyclonal (Kappa + Lambda chain diversity, 60:40)
Malignant: Monoclonal (Kappa OR Lambda only, 99:1)
What are the three types of acquired somatic mutations?
Cellular proliferation (Type 1)
Impair/ block cellular differentiation (Type 2)
Prolong cell survival (Anti-apoptosis)
How do cellular proliferation mutations cause malignancy? Give 2 examples
Mutations in Tyrosine Kinase genes cause excess proliferation (no effect on differentiation)
BCR-ABL: CML
JAK2: MPD
How do mutations causing impaired/ blocked cellular differentiation lead to malignancy? Give an example
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
In which malignancies are there mutations that cause prolonged cell survival?
Mutations in apoptosis genes may occur in lymphomas
BCL2 + Follicular lymphoma
Which white cells are found in the bone marrow?
Myeloblasts
Lymphoblasts
Promyelocytes
Myelocytes
Which white cells are found in peripheral blood?
Phagocytes: Granulocytes + Monocytes
Immunocytes: T + B lymphocytes, NK cells
List 3 types of granulocyte
Neutrophils
Eosinophils
Basophils
What malignancy causes secondary eosinophilia?
Chronic eosinophilic leukaemia
Eosinophils part of the “clone”
FIP1L1-PDGFRa Fusion gene
What is the differential for lymphocytosis with immature lymphoid cells in the peripheral blood (PB)?
Acute Lymphoblastic Leukaemia
What investigations are performed on a tissue biopsy to establish haematological malignancy diagnosis?
- Morphology: architecture
- Immunophenotype: flow cytometry or immunohistology
- Cytogenetics: Translocations- fusion gene or de-regulated oncogene
- Molecular genetics: PCR
What is determined in immunophenotyping?
Myeloid or Lymphoid
T or B lineage
Stage of maturation
How does lympho-haemopoietic failure manifest and present in patients?
BM (Myeloid): Anaemia, Bacterial infection (neutrophils), Bleeding (platelets)
Immune system (Lymphoid): Recurrent viral or fungal infection
How does excess of malignant cells manifest and present in patients?
Erythrocytes/ Leukocytes: Impair blood flow- Stroke
Massively enlarged LN-lymphoma: compress hollow tubes- bowel, vena cava, uterus, bronchus
Which organs may be infiltrated and impaired in haematological malignancy?
CNS lymphoma
Skin lymphoma
Kidney failure (light chain deposition from myeloma)
Give 2 miscellaneous problems caused by haematological malignancy
Hypercalcaemia
Hypermetabolism
