Haematology Flashcards
Favourable prognostic factors of AML
t(8;21)
t(15;17) - APML
Unfavourable prognostic factors of AML
FLT3-ITD
Translocations i.e. t(6;9), t(9;22)
Complex pattern of aberrations
Karyotype abnormalities (trisomy 8, monosomy 5 or 7/deletions of chromosome 5 or 7)
Targeted therapies for FLT-3 mutated disease
TKIs - midostaurin
Pathognomonic abnormality of APML
t(15;17); PML-RARa
Treatment for APML
Differentiation therapy -
Arsenic trioxide
All-trans retinoic acid (ATRA)
Induces maturation of malignant cells into WBCs
Treatment toxicities of ATRA therapy and clinical features
Differentiation syndrome
- Acute respiratory distress
- Fevers
- Shock
- Pleural/pericardial effusions
- Treatment with dexamethasone
QTc syndrome
Definition of myelodysplastic syndrome
Haematological cancers causing qualitative and quantitative defects in haematopoisis, resulting in malfunction of pleuripotent stem cells leading to hypercellularity and dysplasia of the bone marrow –> results in cytopenia of one or more cell lines (thrombocytopenia, erythrocytopenia, leukocytopenia).
Aetiology of MDS
- Primary MDS (idiopathic), more common in elderly
- Secondary MDS (caused by exogenous bone marrow damage) –> treatment-related following cytostatic therapy (alkylating agents, topoisomerase II inhibitors, azathioprine, etc.),
benzene and other organic solvents, radiation damage,
paroxysmal nocturnal hemoglobinuria
Treatment choice for del(5q)
Lenalidomide
Treatment for MDS
Dependent for severity, but largely supportive treatment i.e. blood/platelet transfusions, prophylactic antimicrobials, growth factors
Only curative treatment is allogenic bone marrow transplant for high risk patients
Lenalidomide for MDS with isolated del(5q)
Azacitadine for intermediate risk disease
Luspartercept mechanism of action
SMAD2/3 signalling inhibitor, promoting late-stage differentiation and correcting erythropoiesis
Used in MDS where there is increased SMAD2/3 signalling, causing ineffective erythropoiesis
Effective in patients with ring sideroblasts (SF3B1 mutation)
Chromosome and gene associated with CML
Philadelphia chromosome, associated with gene fusion of BCR-ABL1
Caused by t(9;22)
Clinical hallmark of CML
Uncontrolled production of granulocytes, primarily neutrophils, but could be basophils and eosinophils
Phases of CML
- Chronic CML (CP-CML) - can persist to up to 10 years and often subclinical
- Accelerated CML (AP-CML) - anaemia, signs of neutropenia, splenomegaly
PB myeloblasts 15-29%
PB myeloblasts and promyelocytes combined >/ 30%
PB basophils >/ 20%
Platelets </ 100 - Blast CML (BP-CML) - progression to myeloid blast crisis (i.e. AML) or lymphoid blast crisis (i.e. ALL)
>/ 30% myeloblasts in blood, bone marrow or both
CML treatment
Tyrosine kinase inhibitors
- First generation: Imatinib
- Second generation: Dasatinib, nilotinib
- Third generation: Ponatinib (Required if 315I mutation)
Hydroxyurea for patients with extreme leukocytosis or symptomatic splenomegaly
Interferon-alpha is an option for pregnant patients
Imatinib side effects
Diarrhoea, fluid retention, muscle pains
Dasatinib side effects
Pleural effusions, pulmonary HTN
Nilotinib
High BSLs, accelerated vascular disease, pancreatitis
Ponatinib
High risk of CVD events
MOA of asciminib
ABL1 inhibitor
Approved for CML resistant to 2 or more TKI agents including patients with T315I mutation
Side effects – pancreatitis, fatigue, nausea, headache
Clinical hallmark of polycythemia vera
Persistent erythyrocytosis, with increased haematocrit - resulting in hyperviscosity and increased risk of thrombosis/poor oxygenation
Can also have leukocytosis and thrombocytosis
Other signs - splenomegaly, aquagenic pruritis, thrombosis, vasomotor symptoms (e.g. erythromelalgia)
Diagnostic criteria for PCV
Major critiera
- Hb > 165 or Hct > 49% (men) or 48% (women)
- BM biopsy - hypercellularity for age
- Presence of JAK2 or JAK2 exon 12 mutation
Minor criteria
- Subnormal serum erythropoietin level
3 major or 2 major and 1 minor
Treatment of PCV
Regular phlebotomy and aspirin
Cytoreductive therapy (hydroxyurea or peginterferon) if high risk PCR (age> 60 yrs, previous thrombotic event) or low risk PCV not responding to phlebotomy and aspirin
Target Hct for PCV
<0.45
Clinical hallmark of essential thrombocytosis
Persistent thrombocytosis with bone marrow changes of megakaryocyte proliferation
Splenomegaly, thrombosis, vasomotor symptoms
Diagnostic criteria of ET
Major criteria
- Thrombocytosis
- BM biopsy demonstrating megakaryocyte proliferation
- Exclusion of other differentials including CML, PCV, PMF, MDS
- Demonstration of genetic mutation (JAK2, CALR, MPL)
Minor criteria
- Demonstration of another clonal marker or no other identifiable cause of thrombocytosis found i.e. infection, inflammation, IDA
4 major or 3 major and 1 minor
Treatment of ET
Low risk patients - aspirin or observation only
High risk patients - aspirin + cytoreductive therapies
Cytoreductive therapies -
1st line: hydroxyurea, recombinant IFN alpha
2nd line: phosphodiesterase inhibitor (anagrelide), busulfan
Clinical hallmark of primary myelofibrosis
Disorder of megakaryocytes, with prominent cytokine release causing marrow fibrosis, extramedullary hematopoiesis, and splenomegaly
Treatment of primary myelofibrosis
Monitor for low risk patients
Symptomatic splenomegaly - ruxolitinib (JAK inhibitor), hydroxyurea
Symptomatic cytopenias - transfusions
Allogenic transplant is curative
Mutations in MPNs
JAK2, CALR2 exon 9, MPL
Features of mastocytosis
Abnormal mast cell proliferation and accumulation in tissues
Associated with mutations in c-Kit gene and elevated serum tryptase levels
Results in high histamine levels, leading to:
Pruritus, flushing, abdominal pain, diarrhea, hypotension
Gastric ulcers (due to increased gastric acid secretion)
Subtypes - cutaneous and systemic
Subtypes of mastocytosis
Cutaneous - skin manifestations i.e. urticaria
Systemic - symptoms of mast cell mediator release i.e. multisystem disorder, anaphylaxis without stimulus
Features of chronic myelomonocytic leukaemia
Overlap between MPN and MDS
Persistent monocytosis and features of dysplasia
Higher risk of transformation to AML
Clinical hallmark of CLL
Defined by >5x 10^9/L monoclonal cells, manifesting as lymphocytic leukocytosis
Pathophysiology of CLL
Acquired mutations in hematopoietic stem cells → increased proliferation of leukemic B cells with impaired maturation and differentiation in the bone marrow, resulting in:
- Suppression of the proliferation of normal blood cells
- Immunosuppression (Hypogammaglobulinemia,
Granulocytopenia)
- Thrombocytopenia
- Anemia
- Infiltration of the lymph nodes, liver, and spleen
Indications for treatment in CLL
- Significant cytopenias
- Bulky (symptomatic) lymph nodes or rapidly growing
- B symptoms
- Rapid lymphocyte doubling time
- Significant fatigue due to CLL
- Transformation to another histology
Definition of Richter’s transformation
CLL to DLBCL
Poor prognostic factors of CLL
17p deletion
TP53 mutation
IGHV UNmutated status
11q deletion
Treatment for CLL
First line treatment
- BTK inhibitor - ibrutinib, acalabrutinib
- BCL2 inhibitor- venetoclax
- PI3K inhibitor - idelalisib
Adjunctive therapies
- CD20 inhibitor - rituximab, obinutuzumab
- CD52 inhibitor - alemtuzumab
MOA of rituximab
CD20 inhibitor
MOA of alemtuzumab
CD52 inhibitor
Ibrutinib MOA/side effects
BTK inhibitor
- drastically spikes lymphocyte count, then slowly brings it down
Atrial fibrillation
Mild bruising - due to platelet dysfunction and impaired clot formation
Mild GI side effects
Venetoclax MOA/Side effects
BCL2 inhibitor
Very high risk of TLS
Definition of MGUS
Paraprotein < 30g/L
BM plasma cells < 10%
No CRAB or SLiM
Definition of smouldering myeloma
No CRAB or SLiM
Paraprotien > 30g/L and/or BM plasma cells 10-59%
Definition of active myeloma
BM plasma cells > 10%
Myeloma defining event
CRAB criteria
HyperCalcaemia
Renal failure
Anaemia
Bone lesions
SLiM criteria
Plasma cells> 60% (Sixty) in marrow
Light chain ration > 100
Multiple focal lesions on MRI
Risk of MGUS progression to myeloma
1% each year
Subtypes of myeloma
IgA and IgG
Pathophysiology of myeloma
- Neoplastic proliferation of plasma cells
Bone marrow infiltration by malignant plasma cells → suppression of hematopoiesis → leukopenia, thrombocytopenia, anemia
Cell proliferation → pro-osteoclastogenic factors (e.g., TNF-α, IL-1, RANK-L) → osteolytic lesions → hypercalcemia - Overproduction of monoclonal immunoglobulin and/or light chains → dysproteinemia (a state of pathologically increased synthesis of immunoglobulins and/or their subunits) → kidney damage (e.g., myeloma cast nephropathy) and/or paraprotein tissue deposition (may cause amyloidosis) [3][4]
Nonfunctioning antibodies → functional antibody deficiency
↑ Serum viscosity → hyperviscosity syndrome
MM treatment for transplant eligible patients
- Induction therapy (bortezomib, lenalidomide, dexamehtasone) - 3-6 cycles
- Stem cell transplant (high dose chemotherapy with stem cell reserve)
- Maintenance lenalidomide
MM treatment for NON-transplant eligible patients
- Bortezomib, cyclophosphamide, dexamethasone
- Lenalidomide, dexamethasone
- Lenalidomide, bortezomib, dexamethasone
Relapsed disease
- Daratumumab, lenalidomide
- Daratumumab, bortezomib, melphalan
Lenalidomide MOA/side effects
Immunomodulator (-lidomide)
Diarrhoea, muscle cramps, VTE risk
Thalidomide MOA/side effects
Immunomodulator (-lidomide)
Neuropathy, constipation, fatigue, VTE risk
Bortezomib MOA/side effects
Proteasome inhibitor (-zomib)
Neuropathy, thrombocytopenia
Carfilzomib MOA/side effects
Proteasome inhibitor (-zomib)
Idiosyncratic cardiac events, renal failure
Daratumumab MOA/Side effects
anti-CD38 antibody
URTI, neutropenia
Leads to non-specific positive antibody screen on routine transfusion testing
Pts should have extended phenotype performed prior to first infusion
Vincristine SE
Peripheral neuropathy
Doxorubicin SE
Cardiomyopathy
Follicular lymphoma treatment
First line
- Obinutuzumab-bendamustine or obinutuzumab-CHOP
Follicular lymphoma genetic abnormality
Translocation t(14;18), which involves the heavy-chain Ig (chromosome 14) and Bcl-2 gene (chromosome 18) → overexpression of Bcl-2 → dysregulation of apoptosis (normally inhibited by Bcl-2)
B cell lymphomas
Indolent:
- Follicular lymphoma
- Hairy cell lymphoma
- Marginal cell lymphoma
- Waldenstrom
- SLL
Aggressive:
- DLBCL
- Mantle cell lymphoma
- Burkitt
- Precursor B-cell lymphoblastic lymphoma
Hairy cell leukaemia pathology
Presence of mature lymphocytes with “hairy” border on blood film
Absolute monocytopenia, cytopenias and splenomegaly
High incidence of BRAFV600E mutation
Waldenstrom macroglobulinaemia definition
Lymphoplasmacytic lymphoma with associated IgM paraprotein
Genetic mutation in WM
MYD88 mutation
WM treatment and indications
Treatment for symptomatic patients i.e. anaemia, hyperviscocity
Anti-CD20 antibody (rituximab)
BTK inhibitors (venetoclax)
Chemotherapy - purine nucleoside analogs (fludarabine and cladribine), alkylating agents (e.g., cyclophosphamide)
Hyperviscocitiy syndrome (due to overproduction of IgM) - plasmapharesis
Marginal zone lymphoma features
- Associated with autoimmune diseases (e.g., Sjogren syndrome, Hashimoto thyroiditis)
Types
- Extranodal MZL: gastric MALT lymphoma (most common) and nongastric MALT lymphoma (e.g., thyroid, salivary gland)
- Nodal MZL (or monocytoid B-cell lymphoma)
- Splenic MZL
Gastric MALT lymphoma: associated with translocation t(11;18)(q21;q21) and H. pylori infection
Mantle Cell lymphoma features
- Translocation t(11;14) involving cyclin D1 (chromosome 11) and heavy-chain Ig (chromosome 14) → increased levels of cyclin D1 → promotes the transition of cells to S phase
CD5+ - Spreads rapidly; most patients are diagnosed with advanced disease (stage IV)
Burkitt leukaemia/lymphoma features
Extremely aggressive
Associated with translocation in myc and immunodeficiency
High risk of CNS involvement
Translocation t(8;14) in 75% of cases: reciprocal translocation involving the c-myc gene (chromosome 8) and heavy-chain Ig locus (chromosome 14) → overactivation of c-myc proto-oncogene → activation of transcription
Types:
- Sporadic (located in abdomen or pelvis)
- Endemic (associated with EBV, located in maxillary and mandibular bones)
Starry sky pattern
Brentuximab MOA/SE
Anti-CD30 antibody drug conjugate
peripheral neuropathy
Hairy cell leukaemia treatment
1st line - cladribine or pentostatin
Intrinsic pathway factors and measurement
APTT
Factors 8, 9, 11, 12
Extrinsic pathway factors and measurement
PT
Factors 7, tissue factor
Common pathway factors and measurement
APTT and PT
Factors 2, 5, 10
Cell based model of coagulation phases
Initiation phase
- exposure of TF, factor 7 and initial platelet activation
Amplication phase
- Production of thrombin (2a)
- Activates factor 5, 8, and 9
- Accelerates 10a production and further thrombin generation
Propagation phase
- Conversion of prothrombin (2) to thrombin (2a)
- Allows conversion of fibrinogen to fibrin, and activation of factor 13
Fibrinolysis initiators
Plasminogen activators
- tPA and urokinase
Cleared by liver
Fibrinolysis regulators
Prevents excessive fibrinolysis
- Plasminogen activator inhibitors (PAIs)
PAI-1: inactivates tPA and urokinase. Released from endothelium and activated platelets.
PAI-2: from placenta - Plasmin inhibitor
a2-antiplasmin: free or clot bound - TAFI
Thrombin activatable fibrinolysis inhibitor
Removes lysine residues from fibrin
MOA of transexamic acid
Antifibrinolytic
Competitively inhibits binding of plasmin and plasminogen to fibrin by blocking lysine binding sites of plasminogen
Renally cleared
PT measurement and abnormalities
Extrinsic and common pathway
Vitamin K deficiency
Warfarin +/- rivaroxaban
Liver disease
Factor 7 deficiency/inhibitor
Common pathway if APTT also abnormal
APTT measurement and abnormalities
Intrinsic and common pathway
Factor 8, 9, 11 or 12 deficiency or inhibitors
LAC
Common pathway if PT also abnormal
UFH +/- dabigatran
Fibrinogen abnormalities
Decreased
- DIC
- Liver disease
- Congenital abnormality
Increased
- Thrombosis
- Infection
- Inflammation
- Pregnancy
Thrombin time abnormalities
Increased
- Thrombin problem (heparin, dabigatran, amyloid)
- Fibrinogen/fibrin problem (paraprotein)
Anti-Xa measurement and abnormalities
Measures extent an anticoagulant inhibits factor Xa function
UFH, LMWH, rivaroxaban, apixaban
Mixing test interpretation
Correction - factor deficiency
No correction - factor inhibitor
Immediate: lupus inhibitor, factor 9 inhibitor
Delayed: factor 8 inhibitor
MOA of warfarin
Oral vitamin K antagonist
Prevents vitamin-dependent y carboxylation of glutamate residues on factor 2, 7, 9, 10
Depletes protein C and S
Warfarin reversal
Urgent: prothrombin complex concentrate, FFP
Semi-urgent: Vitamin K
Elective: Withhold doses +/- bridging heparin
Heparin MOA and monitoring
Potentiates anti 10a +/- anti 2a effect on antithrombin III
APTT for UFH
Anti-Xa for enoxaparin or UFH
Heparin reversal
Protamine sulfate for UFH (limited utility for LMWH)
Stop infusion
Dabigatran MOA
Direct thrombin inhibitors
Inhibits circulating and clot bound thrombin
Apixaban and rivaroxaban MOA
Direct factor Xa inhibitor
Dabigatran reversal
Idarucizumab (Praxbind)
Monoclonal antibody fragment
Binds dabigatran with higher affinity than thrombin
Binds free and thrombin-bound dabigatran and neutralises its activity
Approved for lifethreatening bleeding and emergency procedures
Apixaban/rivaroxaban reversal
Andexanet alfa
Recombinant modified factor Xa decoy
Binds and neutralises anticoagulants effects of direct and indirect Xa inhibitors
Factors that alter D-dimer level
Trauma, inflammation, age, pregnancy
APLS criteria
Revised Sapporo/Sydney criteria
>/ 1 clinical and >/ 1 lab criteria
Clinical criteria
- Vascular thrombosis (arterial, venous or small vessel)
- Pregnancy morbidity (unexplained foetal death, premature birth or >/ 3 consecutive spontaneous miscarriages)
Lab criteria (presence on >/ 2 occasions at least 12 weeks apart)
- Lupus anticoagulant
- Anticardiolipin antibody
- Anti beta-2 glycoprotein-I antibody of IgG and/or IgM
Warfarin anticoagulation indications
Mechanical heart valve
Renal impairment
APLS
Breast feeding
LMWH anticoagulation indications
Malignancy (though accumulating evidence for DOACs)
Pregnancy
Indications for IVC filter
Consider in pts with acute BTE and contraindication to anticoagulation i.e. active bleeding
Therapeutic targets and MOA of clopidogrel
Thienopyridine inhibitor (including prasugrel)
Targets substance ADP which acts on receptor P2Y1 and P2Y32
Causes platelet shape change and aggregation
Ticagrelor MOA
Non-thienopyridine inhibitor
Targets substance ADP which acts on receptor P2Y1 and P2Y32
Causes platelet shape change and aggregation
Examples of fibrinogen inhibitors
Abciximab, eptifibatide, tirofiban
Acts on GPIIb/IIIa receptor
ITP causes
Idiopathic
Secondary causes
- Viruses i.e. HIV, HCV
- Malignancy, particularly CLL
- Antigen stimulation i.e. H. pylori
- AI conditions i.e. APLS, SLE
ITP pathophysiology
Antiplatelet antibodies (mostly IgG directed against, e.g., GpIIb/IIIa, GpIb/IX) bind to surface proteins on platelets → splenic and liver sequestration → ↓ platelet count → bone marrow megakaryocytes and platelet production increase in response (in most cases)
DDx for ITP
Peripheral destruction
- TTP, DIC, HITS
Marrow causes
- MDS
Splenic sequestration
Artefactual - platelet clumping
Gestational thrombocytopenia - more likely in second/third trimesters
ITP Management
Treatment of underlying cause
Avoid antiplatelets/NSAIDs - drugs that impair platelet function
Prednisone
IVIg (use whilst awaiting effects of prednisone)
Splenectomy (6-80% long term remission) + asplenic prophylaxis
Thrombopoietin receptor agonists
- Romiplostim 1-2mcg/kg/weekly SC
- Eltrombopag 50mg daily PO
- Avatrombopag
TTP causes
Primary
- Congenital ADAMTS13 deficiency (Upshaw-Schulman syndrome)
Secondary
- Antibodies against ADAMTS13 due to drugs (quinidine, gemcitabine), malignancy, infection, HIV, pregnancy
TTP pathophysiology
ADAMTS13 deficiency → decrease in vWF breakdown → accumulation of vWF on endothelial cell surfaces → platelet adhesion and microthrombosis → MAHA
TTP clinical pentad
MAHA
Fever
Renal impairment
Thrombocytopenia
Neurological impairment
Do not wait for pentad to occur
TTP DDx
HUS - Shiga toxin producing E Coli
atypical HUS - Complement dysregulation → treat with eculuzimab
DIC
ITP
HITS
TTP management
Urgent plasma exchange
FFP/cryodeplete plasma
Steroids
Other specialist therapies
- Caplacizumab - immunoglobulin fragment targeting A1 domain of vWF - preventing interaction between vWF and platelet glycoprotein Ib-Ix-V receptor
MOA of caplacizumab
Antibody targeting A1 domain of vWF - prevents interaction between glycoprotein Ib-IX-V receptor and vWF
MOA of eculizumab and indications
Anti-C5 humanised chimeric monoclonal antibody
Targets terminal component of complement cascade (reduces haemolysis)
Vulnerability to infection by encapsulated organisms
Uses:
- Atypical HUS
- PNH
Causes for reduced Hb
Reduced production
- Iron deficiency
- Vitamin B12 deficiency
- Renal failure
- BM disorder
Increased destruction
- Haemolysis
- Thalassaemia
Causes for increased Hb
Reactive
- Respiratory (hypoxia)
- Renal disease
- Increase EPO (tumour, illicit)
- High affinity Hb
Clonal
- Polycythaemia vera
Causes for microcytic anaemia
Iron deficiency
Thalassaemia
Anaemia of chronic disease
Myelodysplasia - usually macrocytic
Sideroblastic anaemia
Hyperthyroidism
Heavy metal poisoning
Blood film features of IDA
Microcytic, hypochromic red cells
Increased central pallor
Reduced haemoglobinisation
Mechanisms of anaemia of chronic disease
Altered/abnormal iron homeostasis
Reduced red cell production by bone marrow
Blunted response to erythropoietin
Shortened red cell survival
Iron studies for IDA
Iron reduced
Transferrin increased
Tsats reduced
Ferritin reduced
Iron studies for anaemia of chronic disease
Iron reduced
Transferrin reduced to normal
Tsats reduced
Ferritin normal to increased
Blood film features of B12/folate deficiency
Macrocytes, oral macrocytes, megaloblastic anaemia
Differential diagnosis of macrocytic anaemia
Megaloblastic erythropoiesis
- B12/folate deficiency
- Drugs: anti-folate drugs (MTX, pentamidine, trimethoprim), DNA synthesis (azathioprine, hydroxyurea, zidovudine, phenytoin)
Reticulocytosis
- Haemolysis
- Bleeding
Others
- BM pathology (MDS, myeloma, aplastic anaemia)
- Liver disease
- Copper deficiency, arsenic poisoning
- Down syndrome
B12 deficiency causes
- Pernicious anaemia - autoimmune destruction of gastric mucosa/parietal cells
- Nutrition
- Intestinal pathology (CD, ileal resection, tapeworm infection)
- Gastrectomy
- Congenital deficiency
- TCII deficiency
- Nitrous oxide poisoning
- Congenital pernicious anaemia (lack of IF)
Diagnosis of pernicious anaemia
IF antibodies (very specific, 50% sensitive)
Parietal cell antibodies (sensitive but non-specific)
Clinical findings of B12 deficiency
Insidious onset, macrocytic anaemia
Glossitis, angular stomatitis
Neural tube defects
Subacute combined degeneration of spinal cord
Blood films of B12 deficiency
Macrocytic anaemia
Hypersegmented neutrophils
Oral macrocytes
Low reticulocyte count
Drugs that can cause megaloblastic anaemia
Metabolic
- Azathioprine
- Mycophenolate
- MTX
- Gemcitabine
- Hydroxyurea
- Leflunomide
Reduced absorption
- Metformin
- PPI
- Alcohol
- Phenytoin
- Isoniazid
Blood test results of haemolysis
Increased reticulocytes
- immature RBC containing RNA polychromasia on film
Increased LDH
- increased cell turnover
Decreased haptoglobin
- glycoprotein from lifer, binds free Hb
Increased unconjugated bilirubin
Causes of haemolysis
Intravascular
- Fragmentation
- PNH
- PCH
Extravascular
- Immune mediated
- RBC membrane
- RBC enzymes
- Metabolic defects
- Bacterial and parasitic infections
Findings of intravascular haemolysis
Very reduced haptoglobin
Positive urinary haemosiderin (if chronic)
Findings of extravascular haemolysis
Reduced haptoglobin
Negative urinary haemosiderin
Blood film finding of haemolysis
Red cell fragmentation - schistocyte, fragments, Helmut cells
Causes for microangiopathic haemolytic anaemia (MAHA)
TTP
HUS
Pre-eclampsia, HELLP, malignant HTN, renal allograft rejection
Atypical HUS
Causes for red blood cell fragmentation
- MAHA
- DIC
- Mechanical haemolytic anaemia - prosthetic heart valves, severe cardiac valvular disease
- Vascular malformations - hemangiomas
- Direct damage by heat, venoms, toxins etc.
- Malignant HTN
Blood film findings of hereditary spherocytosis
Polychromasia, prominent spherocytes
Clinical findings of hereditary spherocytosis
Jaundice
Cholelithiasis
Splenomegaly
Diagnostic findings of hereditary spherocytosis
Family history
Film - polychromasia, prominent spherocytes
FBC - increased MCHC, RDW, reticulocytes
DAT - NEGATIVE
Flow cytometry - eosin-5-maleimide (EMA) binding
Blood film findings of G6PD deficiency
Bite cells and blister cells
Pyruvate kinase deficiency
“Prickle” cell, nucleated red cell
Features of G6PD deficiency
Hexose-monophosphate pathway
Acute haemolytic crisis
Susceptibility to oxidative stress
X linked
Features of pyruvate kinase pathway
Glycolytic pathway
Chronic haemolysis
Reduced ATP formation –> RBC rigidity
Autosomal recessive
Reactions G6PD are involved in
Production of NADPH for protection against oxidative stress
Oxidation of glucose-6-phosphate
Survival advantage of G6PD deficiency
Against P falciparum infections
Features of G6PD deficiency
Precipitant induced haemolytic crisis - rapid development
Blood film - bite cells, blister cells
Severe disease resulting in chronic haemolysis
Definition of haemoglobinopathy
Synthesis of abnormal haemoglobin
Definition of thalassaemia
Reduced rate of synthesis of normal haemoglobins
Normal haemoglobin structures
Haemoglobin A (a2B2) - main haemoglobin in adults (97%)
Haemoglobin A2 (α2δ2) - minor haemoglobin (2-3%)
Haemoglobin F (a2y2) - primary form in neonates, minor haemoglobin in adults (<1%)
Abnormality in a-thalassaemia
Reduced a-globin production (reduced Hb A, A2, F)
Types of a-thalassaemia
a0 thal: deletion or inactivation of both alleles on single chromosome
a+ thal: one allele inactivated on same chromosome
Abnormality in B-thalssaemia
Reduced B-globin production (reduced HbA)
Genetic abnormality - deletions
Types of B-thalassaemia
B0: Abnormal gene is not expressed
B+: Reduced expression of abnormal gene
Genetic abnormality - small deletions/mutations (>200)
Definition of HbH disease
(–/-a)
Chronic haemolysis, splenomegaly, HbH inclusions
FBC findings of HbH disease
Reduced Hb
Very reduced MCH/MCV
Many HbH cells
Definition of Hydrops foetalis
(–/–)
Incompatible with extra-uterine life
B-thalassaemia trait/minor pathophysiology
Results in reduced B-globin synthesis, therefore reducing HbA (a2B2)and compensatory increase in HbA2 (α2δ2)
Results in haemolysis and ineffective erythropoiesis
Features of B-thalassaemia trait/minor
Clinically asymptomatic/mild anaemia
FBC - reduced MCV (<72) and MCH (<27), poikilocytosis, basophilic stippling, target cells
HPLC - increased HbA2, increased HbF
Pathophysiology of B-thalassamia major
Homozygous or compound heterozygotes for B-thalassaemia with absent of severe deficiency of B-globin production
Features of B-thalassaemia major
Severe anaemia
Developmental delay
Skeletal abnormalities
Iron overload
Marked anisopoikilocytosis, stippling, NRBCs
Elevated HbA2 and HbF
Reduced or absent HbA
Management of B-thalassaemia major
Transfusion support
Supportive care - endocrine failure, bone disease, risk of VTE
Stem cell transplant
Iron chelation therapy - desferrioxamine, deferiprone, exjade
Sickle cell haemoglobin pathophysiology
Synthesis of abnormal haemoglobin
Due to GAG to GTG; B globin gene
Substitutes valine for glutamic acid (HbS)
HbS polymerises into long fibres on deoxygenation
Sickle cell disease Hb
Hb S/S, C/S, B/S
Management of sickle cell disease
Hydroxyurea - foetal haemoglobin induction
Transfusion
Monitor HbS levels
Risk of infections (due to hyposplenism)
Voxeleter (HbS polymerisation inhibitor) - phase 3 clinical trials showed increased Hb and reduced haemolysis
