Haematology Flashcards
Pathophysiology of Anaemia of Chronic Disease
Reduced absorption of iron from GI Tract
Reduced EPO production
Sequestration of iron in macrophages
Increased Hepcidin
Causes of MAHA
DIC
HUS
TTP
Valve Related Haemolysis
What condition is the EMA Test for?
Hereditary Spherocytosis
What is the pathology in Hereditary Spherocytosis?
Mutations involving erythrocyte membrane proteins:
- Ankyrin
- Spectrin
- Band 3
Results in sequestration of spherocytes
What is the reason for/benefits of leukodepletion of donated blood?
Reduce dfebrile transfusion reactions
Reduced risk of CMV transmission
Reduced TRALI
Reduced Transfusion associated GVHD
What does Irradiation of donated red cells achieve?
Prevents proliferation of lymphocytes that haven’t been successfully filtered, which prevents transfusion associated GVHD
Which patients should receive irradiated RBCs?
Profoundly immunosuppressed patients
Stem cell transplants
Acute leukaemia
Which red cell surface antigen is most immunogenic?
ABO are the most immunogenic surface antigen group, followed by Rhesus antigens
Which blood group is the Universal Donor?
O
What is the cause of an acute haemolytic transfusion reaction?
ABO incompatibility.
Causes severe hypotension
Early suspension of transfusion → reduced mortality
What is the cause of delayed haemolytic transfusion reaction? What is the key risk factor?
Incompatibility of surface antigens other than ABO (i.e. less immunogenic antigens). Key risk factor is number of previous blood transfusions, as these sensitise immune system to these other antigens.
Transfusion Associated GFHD
Due to donor lymphocytes engrafting into recipient tissue. Extremely rare.
Causes fever, dermatitis and colitis, deranged LFTs and severe pancytopaenia. Management supportive
Febrile Non haemolytic reaction
Due to cytokines in transfusion product stimulating inflammatory response.
Starts either during or immediately after transfusion, presenting with fever, tachypnoea and tacycardia. Differentiated from acute haemolysis by appropriate Hb increment, lack of evidence of haemolysis
Transfusion Related Acute Lung Injury
Leading cause of transfusion related death. Mechanism not fully understood. Pregnancy is key risk factor (so plasma only comes from male donors). Donors who’ve caused it can’t donate again. Supportive management
What is the most common blood transfusion complication?
Transfusion related circulatory overload
What organism may be transmitted by blood products via its ability to survive refrigeration?
Yersinia
Indications for Platelet transfusion
Plt count <10
Plt count <50 and serious bleeding
Plt count <50 and needs surgery
Indications for Fresh Frozen Plasma
Severe bleeding
DIC
Hepatic Failure
Replenishes clotting factors
Anistocytes
Iron Deficiency
Target Cells
Haemoglobinopathy
Liver disease
Splenectomy
Schistocytes
Intravascular haemolysis
Spherocytes
Hereditary spherocytosis
Warm autoimmune haemolytic anaemia
Paroxysmal nocturnal haemolysis
Bite cells
G6pD
Tear Drop Cells
Myelofibrosis
Bone marrow infiltration
Spur Cells/Acanthocytes
Liver Disease
Burr Cells/Echinocytes
Renal Disease
Howell-Jolly Bodies
Hyposplenism
Iron Metabolism in acute inflammation
Hepcidin released as acute phase reactant → ferroportin breakdown → reduced iron absorption → contributes to anaemia of chronic disease
What conditions are type 1 cryoglobulinaemias associated with?
Waldenstrom’s macroglubulinaemia
Multiple Myeloma
Lymphoma
What are the Inherited Bone Marrow Failure Syndromes?
Fanconi Anaemia
Dyskeratosis Congenita
Shwachman-Diamond Syndrome
GATA2 Associated Syndrome
Myelodysplastic Syndrome
Clonal stem cell disorder leading to impaired production
One or more cytopaenias with morphological evidence of dysplasia in peripheral blood
Bone marrow blasts <20% for MDS
Genes: 5q minus syndrome, GATA2
Paroxysmal Nocturnal Haemoglobinuria
Acquired stem cell disorder, PIGA gene mutation → lack of GPI anchor → Cd55 and CD59 can’t adhere to red cells (These agents block C3 convertase and C3b) → complement mediated intravascular haemolysis
Haemolysis, pancytopaenia, thrombosis
Confirm with flow cytometry
Treat with Eclulizumab which inhibits C5
Diagnostic Criteria HLH
Either a molecular diagnosis of HLH, or 5 of the following:
- Fever
- Splenomegaly
- Cytopaenia affecting at least 2 lineages
- Hypertriglyceridaemia and/or hypofibrinogenaemia
- Fasting triglycerides ≥3, Fibrinogen ≤1.5
- Haemophagocytosis in bone marrow/spleen/nodes without evidence of malignancy
- Low or no NK cell activity
- Ferritin ≥500
- sCD25 ≥2400
What are the key mutations in Essential Thrombocytosis?
JAK2 (50%)
CALR (40%) - mostly type 2 insertion mutation
Both increase megakaryocyte activity → increased platelet synthesis
What is the management of Essential Thrombocytosis?
Monitor if Platelet count <600 and no additional thrombosis risks
Hydroxyurea first line to reduce thrombosis risk if required
What is the key mutation in Polycythaemia Rubra Vera?
JAK2 V617F mutation → neoplastic haematopoietic stem cell dysfunction → increased erythrocyte production (EPO independent)
Phases of Polycythaemia Rubra Vera
Latent: initial asymptomatic rise in RBC count
Proliferative: hyperviscosity, increased thrombosis risk
Spent: Fibrosis consumes marrow → pancytopaenia
What haematological condition can cause transient hand/foot pain and erythema?
Erythromelalgia due to Polycythaemia Rubra Vera
In what situation should correction of Iron Deficiency be avoided?
Polycythaemia Rubra Vera → worsens polycythaemia
Medications that can cause thrombocytopaenia
Valproate
Platinum chemotherapy
Isoretinoin
Interferon
Key diagnostic criteria/clinical features of HIT
Fall in platelet count >50% and nadir ≥20
Onset 5-10 days after commencement (or ≤1 day if used previously)
Proven arterial or venous thrombosis
Investigations for HIT
PF4 antibodies
Serotonin release assay → marker of platelet activation
Immunoassay + functional testing
Investigate if considering HIT as a possibility essentially
What is the risk of using Warfarin in thrombocytopaenia?
Skin necrosis, particularly with counts <150
Causes of ITP
Primary: Idiopathic (Most common)
Secondary: SLE< APLS, Lymphoma, Leukaemia (esp. CLL), HIV, HCV, Beta lactams, Heparin, Sulfonamides, Bactrim, quinine
What antibodies develop in ITP?
IgG against GpIIb/IIIa → promotion of opsonisation → splenic sequestration
Management of ITP
Stop medications that impair platelet function (NSAIDs, etc.)
Pulse MP
IVIg (induced rapid but transient recovery in counts to allow steroids to work)
What is Romiplostim, and what is its indication?
Thrombopoietin receptor agonist → for treatment resistant ITP. Similar to Eltrombopag.
A Plasmacytoma is a localised form of what?
And how is it differentiated?
Localised form of Myeloma
Differentiated by absence of:
- Anaemia
- Hypercalcaemia
- Other bony deposits
- Renal failure
Normal bone marrow biopsy, or <10% clonal plasma cells.
Where do Plasmacytomas occur?
Marrow containing bones such as vertebrae, soft tissue including upper respiratory tract. Can present with bone pain or pathological fracture.
Diagnostic Criteria for MGUS
M protein <30g/L
Clonal Plasma cells in Bone Marrow <10%
No myeloma defining events
Diagnostic Criteria for Smouldering MGUS
M protein ≥30g/L in serum or ≥500mg/24hr in urine
Clonal plasma cells in Bone Marrow 10-60%
No myeloma defining events
Diagnostic Criteria for Multiple Myeloma
Clonal bone marrow plasma cells ≥10 or ≥ 1 biopsy proven plasmacytoma
AND 1 or more myeloma defining events:
CRAB features:
- Hypercalcaemia >11mg/dL
- Renal impairment CrCl <40
- Anaemia Hb <100
- Bone disease ≥1 lytic lesion on imaging
Biomarkers of malignancy
- Clonal plasma cells in Bone marrow ≥60%
- Serum free light chain ratio ≥100
- >1 MRI focal lesion ≥5mm
What cut off for Beta-2 Microglobulin indicates stage III disease for Multiple Myeloma?
> 5.5 mg/L
Bortezomib
Proteasome inhibitor
Used for Multiple Myeloma treatment induction
Key side effects: peripheral neuropathy, thrombocytopaenia
With which Immunoglobulin class is the risk of Hyperviscosity highest?
IgM
What is the key cause of hyperviscosity?
Waldenstrom’s Macroglobulinaemia (because it leads to excessive IgM)
What thresholds raise concern for hyperviscosity?
IgM >50g/L
IgA >70
IgG >100
Waldenstrom Macroglobulinaemia
Low grade non hodgkin lymphoma involving B lymphocytes and plasma cells
Blood: IgM monoclonal gammopathy
Marrow: Lymphoplasmacytic lymphoma
MYD88 gene point mutations, CXCR4 has worse prognosis
Causes of Macroglobulinaemia
IgM MGUS (>10% progress to Waldenstrom)
Smouldering Waldenstrom
Waldenstrom
CLL
Primary AL Amyloidosis
What is the mechanism of neuropathy in Waldenstrom Macroglobulinaemia?
Paraprotein binding to myelin sheath → demyelination (IgM antiganglioside antibody). Sensorimotor, glove and stocking distribution, slowly progressive lower > upper limbs
What antigen is a potential target for CAR-T Cell therapy in Multiple Myeloma?
BCMA
What is the classic histology of AL Amyloidosis?
Positive Congo Red tissue staining
“apple green birefringence under polarised light”
Pathology of TTR Amyloidosis
Abnormal tissue deposition of excess, misfolded TTR protein either due to TTR gene mutation or with age → heart failure.
Classic Echo finding: Reduced Global Longitudinal Strain (GLS)
Bone Scan shows cardiac uptake
Treatment for TTR Amyloidosis
Tafamidis: prevents TTR synthesis → reduced tissue deposition. Improves overall survival
Pathology/Pathophysiology of AL Amyloidosis
Most common form of amyloid. Related to plasma cell dycrasias (mostly multiple myeloma). Plasma cells form abnormal proteins, often in sheets, which don’t readily break down and are instead deposited in tissues including heart, nerves, kidney, thyroid.
Infiltrative, restrictive cardiomyopathy
Heart block due to conduction defects
Autonomic neuropathy
Carpal Tunnel syndrome
Nephrotic syndrome
Management of AL Amyloidosis
Treat the underlying haematological malignancy
MDS-5q Syndrome
Key subgroup of MDS/AML
Deletion on long arm of Chromosome 5
Responds very well to low dose Lenalidomide
What are the favourable genetic mutations/markers in AML?
- t(8;21)
- inv16
- Biallelic CEBPA mutation
- NPM1 mutation without FLT3
What mutation has a particularly poor prognosis in AML?
TP53
AML Blood film
Auer rods within blasts
Azacitidine
MoA: DNA hypomethylation → cytotoxic effect on cells
Indications: AML, high risk MDS
Can cause significant myelosuppression, and small risk of TLS particularly in first cycle, risk of toxicity higher in renal impairment
What mutations in AML have targeted therapies available in Australia?
FLT3 mutations
Midostaurin and Gilteritinib are both FLT3 inhibitors, and improve overall survival added to chemotherapy
What condition should be suspected in a patient initially thought to have AML but has marked coagulopathy?
APML
Platelet count threshold for DAPT
> 50
Platelet count threshold for single agent antiplatelet therapy
> 30
Platelet count thresholds for anticoagulation
Therapeutic: >50
Prophylactic: >30
Can also give reduced dose DOAC at platelet counts 30-50
