1. Systemic Disease Flashcards
3 types of anaemia
- iron deficiency
- leukoerythoblasgtic
- haemolytic = immune, non-immune-mediated
- anaemia of inflammation (chronic disease)
Fe deficiency anaemia: causes, biochemical/lab findings
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
Leucoerythroblastic anaemia: what is it, blood film, causes
red and white cell precursor anaemia
blood film
- poikilocytosis (teardrop RBCs) and anisocytosis
- nucleated RBCs
- immature myeloid cells
Leucoerythroblastic anaemia: what is it, blood film, causes
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
Haemolytic anaemia: common lab features
shortened RBC survival
2 types of haemolytic anaemias
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),
Warm vs Cold AIHA
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
DAT vs iDAT
DAT vs iDAT
Paroxysmal Cold Haemoglobinuria (PCH)
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)
Non-immune mediated anaemia features
DAT -ve
Schistocytes, thrombocytopenia, DAT-ve, hereditary spherocytosis
Non-immune mediated anaemia: infection
MALARIA (commonest WW)
parasite enters RBC, causes it to die, shortening survival of RBC
PNH = paroxysmal nocturnal haemoglobinuria
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
3 types of MAHA
Adenocarcinoma, HUS, TTP
Adenocarcinoma
- 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)
HUS
E. coli toxin O157
triad: MAHA, thrombocytopenia, AKI
TTP
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)
Types of white blood cells in peripheral blood and bone marrow
What do we ix when abnormal WBC
FBC = Hb, MCV, platelet count, WBC
Blood film = count, pancytopaenia?, which lineages abnormal?, morphology?
Causes of neutrophilia
infections that don’t produce a neutrophilia
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
Reactive/infection vs malignant (e.g. CML and ALL) neutrophilia
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
Reactive vs chronic eosinophilic leukaemia
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
Monocytosis: chronic infections and primary haematological disorders
- TB, brucella, typhoid
- vira, CMV, varcella zoster
- sarcoidosis
- CMML, myelodysplastic syndrome
Summary of increased phagocyte count
Summary of increased phagocyte count
Lymphocytosis and lymphpaenia causes
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)
Evaluating lymphocytosis morphology
Mature lymphocytes (PB)
- Reactive/atypical lymphocytes (IM)
- Small lymphocytes and smear cells (CLL/NHL)
Immature lymphoid cells (PB)
- Lymphoblasts (ALL)
Mature lymphocytes (PB)
- Reactive/atypical lymphocytes (IM)
- Small lymphocytes and smear cells (CLL/NHL)
Immature lymphoid cells (PB)
- Lymphoblasts (ALL)
Clonality in B-cell lymphocytosis (light chain restriction)
- Polyclonal = kappa and lambda (reactive)
- Monoclonal (kappa ONLY or lambda ONLY (malignant)
leukaemia vs lymphoma
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
Myeloid differentiation
Myeloid differentiation
What are the 3 acquired somatic mutations that cause leukaemia and lymphoma?
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
What parts of tissue biopsy do we look at to establish a diagnosis (4)
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
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)
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)
Clinical problems with systemic disease
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
Summary
Which is it? IDA, ACD, BM mets from breast Ca, MAHA, AIHA
What is the likely diagnosis?
B cell ALL
Mature B cell lymphoproliferative disorder (e.g. CLL)
Infectious mononucleosis (e.g. EBV)
T cell acute leukaemia lymphoma
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
