HAEM: Systemic disease Flashcards
What does a deficiency of FVIII cause?
Haemophilia A –> bleeding disorder
What does a deficiency of protein C cause?
Pro-thrombosis
What is the types of primary haematological disorders. Give examples of each.
1.Germline mutation/inherited
- FIX e.g. FIX deficiency = haemophilia B
- Erythrocytes e.g. beta globin chain deficiency causes beta-thalassaemia
2.Somatic/acquired
- Erythrocytes - JAK2 V617F mutation in polycythaemia vera
- Myeloid/granulocyte - BCR-ABL1 mutation in CML
What is the difference between a primary and secondary haematological disorder?
Secondary are changes in haematological parameters secondary to a non-haematological disease e.g. cyanotic heart disease causing polycythaemia or excess FVIII in inflammatory responses
What does VHL gene mutation cause?
Chuvash polycythaemia causing excess erythrocytes
When are soluble haematological components increased?
in inflammation - this increases thrombosis
When are erythrocytes raised/reduced?
Raised:
- EPO secreting tumour
- Altitude
- Hypoxia
Reduced:
- BM infiltration
- Deficiency disease e.g. B12 or Fe
- Shortened survival in haemolytic anaemia
When are platelets raised/reduced?
Raised:
- bleeding
- inflammation
- splenectomy
Reduced:
- BM infiltration
- Deficiency disease e.g. B12
- Shortened survival e.g. ITP, TTP
When are leukocytes raised/reduced?
Raised:
- Inflammation
- Infection
- Corticosteroids
Reduced:
- BM infiltration
- Deficiency disease e.g. B12
List 4 types of anaemia.
- Iron deficiency
- Autoimmune haemolytic
- Microangiopathic
- Leucoerythroblastic
What are the laboratory findings in Fe deficiency anaemia?
- Microcytic
- hypochronic
- Reduced ferritin
- Reduced TF saturation
- Raised TIBC
Which cancers can cause occult blood loss causing Fe deficiency anaemia?
- GI cancers - gastric, colorectal
- Urinary tract cancers (less common - renal cell carcinoma, bladder
NB: Fe deficiency is bleeding until proven otherwise
- Menorrhagia in pre-menopausal women
- GI blood loss in men and post-menopausal women
What is leucoerythroblastic anaemia? Why is it important?
- Red and white cell precursor anaemia of variable degree
- Usually the first manifestation of a bone marrow malignancy – breakdown in barrier from immature cells leaving the bone marrow
What is the morphology of a leucoerythroblastic anaemia on peripheral blood film?
- Teardrop RBCs – aniso and poikilocytosis
- Nucleated (normal in BM but should lose nucleus before they leave) RBCs (left purple cell)
- Immature myeloid cells (right purple cell)
What are 3 causes of a leucoerythroblastic film?
- Malignant – haematological (leukaemia/lymphoma/myeloma) or non-haematological (metastatic/breast/bronchus/prostate)
- Severe infection e.g. miliary TB or severe fungal infection
- Myelofibrosis
Define haemolytic anaemia.
Shortened RBC survival
What are the common lab features of all haemolytic anaemias? Which liver associated proteins are raised?
- Anaemia – may be compensated
- Reticulocytosis – immature red cell production in an attempt to compensate for some short cell survival
- Unconjugated bilirubin raised i.e. pre-hepatic
- LDH raised – intracellular enzyme released as a result of cell content release due to lysis
- Haptoglobins reduced
How are haemolytic anaemias classified?
- Inherited
- Acquired
Give 3 examples of inherited haemolytic anaemias.
Inherited = defects of the red cell /germline DNA mutation
- Membrane e.g. hereditary spherocytosis
- Cytoplasm/enzyme e.g. G6PD deficiency
- Haemoglobin e.g. SCD (structural) or thalassemia (quantitative)
Give 2 types of acquired haemolytic anaemias.
Acquired = RBC is healthy but is due to defects in the environment where the RBC finds itself
- (1) Immune-mediated (DAT aka Coombs positive)
- (2) Non-immune mediated (DAT -ve)
What are the two types of immune-mediated haemolytic anaemia?
- Warm AIHA - IgG , extravascular haemolysis
- Cold AIHA - IgM (or IgG), intravascular haemolysis
List some causes of warm and cold AIHA.
- Warm - lymphoma, CLL, drug allergy, SLE, idiopathic
- Cold - M. pneumoniae, EBV, CMV
What are the laboratory findings in immune mediated haemolytic anaemia?
- DAT positive (direct antglobulin/Coomb’s test)
- Spherocytes (but not hereditary spherocytosis)
- Agglutination
Which conditions are associated with immune-mediated haemolytic anaemia?
- Malignancy e.g. lymphoma or CLL
- Auto immune e.g. SLE
- Infection e.g. mycoplasma
- Idiopathic
Describe the principles of the Coomb’s test.
Two types:
- Direct - tests for antibodies or complement on the surface of RBC e.g. in AIHA
- Indirect - tests for antibodies in the serum e.g. in pre-natal antibody screen
Positive test = agglutination
Give 3 examples of non-immune mediated haemolytic anaemias.
- Malaria (and other infections)
- Micro-angiopathic haemolytic anaemia (MAHA) e.g. due to HUS or underlying adenocarcinoma
- Paroxysmal nocturnal haemoglobinuria (Ham’s test +ve)
What are the laboratory features of non-immune mediated acquired haemolytic anaemia?
- DAT negative
- RBC fragments (schistocytes)
- thrombocytopenia
- hereditary spherocytosis (spherocytes with a negative Coomb’s test)
Why does malaria cause acquired haemolytic anaemia?
Parasite enters RBC and shortens RBC survival
List 3 causes of MAHA.
- Adenocarcinoma
- HUS e.g. E coli 0157
- TPP
How does adenocarcinoma cause MAHA?
- 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)
What is the triad of haemolytic uraemic syndrome?
- MAHA
- thrombocytopenia
- AKI
What is the pentad of thrombotic thrombocytopenia purpura? (TTP) What is the treatment?
- MAHA
- Thrombocytopenia
- AKI
- Neurological impairment
- Fever
Tx: plasma exchange
- Autoimmune; ADAMTS13 mutation –> deficiency in VWF cleaving protease
- High VWF acts like cheese wire in blood vessels
What % myeloblasts is abnormal in BM?
>5% myeloblasts is abnormal in BM
List 5 causes of neutrophilia.
- Corticosteroids
- Underlying neoplasia
- Tissue inflammation à colitis or pancreatitis
- Myeloproliferative or leukemic disorders
- PYOGENIC INFECTION (most likely)
List 3 infections that do not produce a neutrophilia.
- Brucella
- Typhoid
- Viral infections
What are the causes of abnormalities in neutrophils? Describe the profiles of how to differentiate these.
Reactive /infection - neutrophilia, toxic granulation +no immature cells
Malignant (massively raised neutrophils)
- CML - neutrophilia/basophilia + immature cells (myelocytes) + splenomegaly
- AML - neutropenia + myeloblasts
What are the causes of eosinophilia? Describe these.
Reactive
- Parasitic infection
- Allergic diseases –> asthma, rheumatoid, polyarteritis, pulmonary eosinophilia
- Underlying neoplasms esp. Hodgkin’s, T-cell NHL
- Drugs e.g. reaction erythema multiform
Chronic eosinophilic leukaemia
- Eosinophils part of “clone”
- FIP1L1-PDGFRa fusion gene
What are the causes of monocytosis?
(rare, seen in some chronic infections and primary haematological disorders)
- Bacterial: TB, brucella, typhoid
- Viral: CMV, varicella zoster
- Sarcoidosis
- Chronic myelomonocytic leukaemia (CMML, myelodysplastic syndrome)
List some causes of reactive lymphocytosis.
- EBV, CMV, Toxoplasma
- Infectious hepatitis, rubella, herpes infections
- Autoimmune disorder
- Sarcoidosis
High WCC
List some causes of reactive lymphopenia.
Lymphopenia [LOW WCC]
- HIV
- Auto immune disorders
- Inherited immune deficiency syndromes
- Drugs (chemotherapy)
How can you evaluate whether the lymphocytosis is normal or abnormal using a blood film?
Look at morphology:
Mature lymphocytes (PB)
- Reactive/atypical lymphocytes (IM)
- Small lymphocytes and smear cells (CLL/NHL)
Immature lymphoid cells in PB
- Lymphoblasts (ALL)
How do you determine clonality in B-cell lymphocytosis? What is the difference between reactive and malignant lymphocytosis?
Use light chain restriction
Reactive = POLYCLONAL - kappa:lambda 60:40
Malignant = MONOCLONAL - kappa only or lambda only e.g. 99:1
What are the 4 stages that a tissue biopsy undergoes to establish a diagnosis?
See image.
Morphology - assess if mature/immature, small or large, if invasive or not.
Immunophenotype - assess if myeloid or lymphoid and if T or B cells, including stage of maturation.
Cytogenetics - check for philadelphia chromosome, prognostic info (e.g. 17p in CLL), translocations (e.g. t(8;14) in Burkitt’s)
Molecular genetics - check for JAK2 mutation in PV, BCR-ABL cDNA deetction and quantification
Where would you see:
- Primitive lymphoid blast cells expressing B cell marker?
- Mature lymphoid cells expressing T cell antigens and involving skin?
- Mature erythrocytes with JAK2 mutation?
- Primitive lymphoid blast cells expressing B cell marker = B cell Acute lymphoid leukaemia
- Mature lymphoid cells expressing T cell antigens and involving skin = cutaneous T cell lymphoma
- Mature erythrocytes with JAK2 mutation = polycythaemia vera
What are the 3 types of mutations causing leukaemia and lymphoma?
Give an example of conditions caused by the 3 types of mutations in leukaemias and lymphomas.
- Cellular proliferation (type 1) - BCR-ABL CML, JAK2 in MPD
- Impair/block cellular differentiation (type 2) - PML PARA in acute promyelocytic leukaemia
- Prolong cell survival (anti-apoptosis) - BCL2 and follicular lymphoma
Compare the morphology seen in myeloproliferative neoplasm (chronic) to acute myeloid leukaemia (acute).
Chronic - normal differentiation, just a lot of cells
Acute - not differentiated i.e. many blasts
What is the morphology and immunophenotype of B-cell lymphoblastic lymphoma? (3)
- TdT +ve (indicates immature** cells; used in **VDJ rearrangement)
- CD19 +ve (indicates B-cell lineage)
- Surface Ig -ve (abnormal)
What is the morphology and immunophenotype seen in multiple myeloma? (3)
- TdT -ve (normal)
- Surface Ig +ve (normal)
- CD138 +ve (abnormal)
What is the precise classification of haematological cancers used for generally?
- Predict likely course
- Choose appropriate treatment
What do the complications of leukaemias and lymphomas generally relate to?
-
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
-
Impaired organ function
- CNS lymphoma
- Skin lymphoma
- Other
What is the explanation for this anaemia?
- IDA
- Anaemia of chronic disease
- BM mets from breast Ca
- MAHA
- AIHA
BM mets from breast Ca
- IDA
- would not expect jaundice
- would not give nucleated red cells in PB
- Anaemia of chronic disease
- BM mets from breast Ca
- MAHA
- Not get leucoerythroblastic problems in blood as BM is healthy
- AIHA
- AIHA is DAT-positive
What is the likely diagnosis?
- B-cell ALL
- Mature B cell lymphoproliferative disorder
- Infectious mononucleosis
- T-cell acute leukaemic lymphoma
- B cell acute lymphoblastic leukaemia
-
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
- Would expect 60/40 proliferation of Kappa/Lambda
- T cell acute leukemic lymphoma
