Haem/Onc Flashcards
1
Q
Drugs in haem-onc?
A
2
Q
Chemotherapy extravasation points?
A
- Usually cold compress except vinca alkaloids –> heat compress
- Doxorubacin and daunorubicin extravasation tends to cause ulceration –> plastics referral, topical steroids
3
Q
General points with transfusion reactions?
A
- Bacterial contamination very rare with red cell transfusions, more common with platelet transfusions which are stored at room temp
- IgG antibodies cause delayed extravascular haemolytic reactions much more commonly than acute intravascular reactions
- IgM anti-A and anti-B antibodies cause acute haemolytic transfusion reactions
- Anti-O doesn’t exist
- ABO antigens present from birth, ABO antibodies acquired in first 6 months of life
4
Q
Delayed transfusion reactions?
A
Occurs 5-10 days post-transfusion due to development of red cell alloantibodies
- Unexplained pyrexia, jaundice or unexplained drop in heamoglobin
- Urinalysis shows urobilinogenuria and a blood shows fragile ballooned spherocytes
- Diagnosis is confirmed by Coombs test which is done by adding antihuman globulin (AHG) (anti-Ig G and anticomplement) to the patient’s washed RBCs. A positive test results in red cell agglutination.
5
Q
Intravascular vs Extravascular Haemolysis?
A
Intravascular
- Mismatched blood transfusion
- G6PD deficiency
- Red cell fragmentation: heart valves, TTP, DIC, HUS
- Paroxysmal nocturnal hemoglobinuria
- Cold autoimmune hemolytic anemia
Extravascular (usually abnormal RBC shape/RBC membrane disorders)
- Hemoglobinopathies: sickle cell, thalassemia
- Hereditary spherocytosis
- Hemolytic disease of newborn
- Warm autoimmune hemolytic anemia
6
Q
Autoimmune Haemolytic Anaemia? (Warm vs Cold)
A
Usually idiopathic but can be secondary to lymphoproliferative disorder, infection or drugs. Characterised by a positive direct antiglobulin test (Direct Coombs’ test)
Cold AIHA
- IgM
- Causes haemolysis at 4oC - mediated by complement and more commonly intravascular
- Features = Raynaud’s, acrocyanosis
- Causes = Neoplasia (e.g. Lymphoma), Infections (e.g. Mycoplasma, EBV
Warm AIHA
- IgG
- Casues haemolysis at body temperature - haemolysis occurs at extravascular sites (i.e. spleen)
- Management = steroids, immunosuppression, splenectomy
- Causes = Autoimmune disease (SLE), Neoplasia (Lymphoma, CLL), Drugs (Methyldopa)
7
Q
Difference between direct and indirect Coomb’s test?
A
Direct - detects antibodies or complement proteins that are bound to RBCs. Serum incubated with antihuman globulin –> if agglutination of RBCs then test is +ve.
Indirect - detects antiboides against RBCs that are unbound in the serum. Serum extracted and incubated with donor RBCs of known antigenicity. Antihuman globulin added –> if agglutination of RBCs then test is +ve
Indirect used in prenatal screening
8
Q
Hereditary spherocytosis?
A
- Most common hereditary hemolytic anemia in northern Europeans
- Autosomal Dominant defect of RBC cytoskeleton –> sphere shape instead of biconcave disc
- Reduced RBC survival, destroyed by the spleen
Presentation
- Chronic haemolysis and gallstone formation
- Failure to thrive
- Jaundice
- Splenomegaly
- Aplastic crisis preipitated by parvovirus infection
- MCV reduced, MCHC increased, Reticulocytes increased
Diagnosis
- Osmotic fragility test (spherocytes rupture in mildly hypotonic solution)
Mx
- Folate replacement
- Splenectomy
9
Q
Pathophysiology of sickle cell disease?
A
- Autosomal recessive
- Mutation in b-globin chain of Hb (chromosome 11) - glutamic acid replaced with valine at 6th position
- Two normal a-globin subunits with two mutant b-globin subunits –> HbS
Types
- Homozygotes - HbSS (sickle cell anaemia)
- Heterozygotes - 1 sickle gene and 1 normal gene –> HbAS (sickle cell trait)
- Rarer forms - compound heterozygous states where person has only one copy of HbS mutation and one copy of another abnormal Hb allele
10
Q
Types of sickle cell crisis?
A
-
Thrombotic (painful)
- Vaso-occlusive
- Precipitated by infection, dehydration, deoxygenation
- Infarcts occur in various organs including the bones (e.g. avascular necrosis of hip), hand-foot syndrome in children, lungs, spleen and brain
-
Aplastic
- Caused by infection with parvovirus
- Sudden fall in hemoglobin
-
Sequestration (spleen, liver and kidney)
- Sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia
- Acute chest syndrome: dyspnea, chest pain, pulmonary infiltrates, low PO2 - the most common cause of death in adults (Hydroxyurea –> the incidence of acute chest syndrome)
- The most common cause of death in childhood: infraction and infection (Pneumococcus, Chlamydia, Mycoplasma)
-
Haemolytic
- Rare - fall in Hb due to increased rate of haemolysis
11
Q
Pernicious anaemia?
A
- Investigation
- Anti-gastric parietal cell antibodies in 90% (low specificity)
- Anti-intrinsic factor antibodies in 50% (specific for pernicious anaemia)
- Macrocytic anaemia, low WBC and platelets
- LDH may be raised due to ineffective erythropoiesis
- Hypersegmented polymorphs on film, megaloblasts in marrow
- Schilling test
- Radiolabelled B12 given on two occasions
- First on its own, second with oral Intrinsic Factor
- Urine B12 levels measured
12
Q
A
13
Q
Sideroblastic anaemia?
A
Condition where red cells fail to completely form heme, whose biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the mitochondria
that form a ring around the nucleus called a ring sideroblast. It may be congenital or acquired.
Causes
- Congenital = Delta-aminolevulinate synthase-2 deficiency
- Acquires = myelodysplasia, alcohol, lead, Chloramphenicol and Anti-TB medications (INH + Pyrazinamide)
Investigations
- Hypochromic microcytic anemia (more so in congenital)
- Bone marrow: sideroblasts and increased iron stores
Mx
- Supportive, treat underlying cause
- Pyridoxine may help
14
Q
Pure red cell aplasia?
A
Unexplained anaemia and reticulocytopenia, with a complete absence of red cell precursors in the bone marrow, but with preservation of other cell lines.
Associations
- Spontaneous
- Thymoma
- Autoimmune
- Lymphoproliferative disorders
- Can rarely occur where recombinant erythropoietin is administered, where antierythropoietin antibodies can be detected
Treatment
- Supportive with immunosuppression with ciclosporin or related compounds
- Withdrawal of erythropoietin –> subsequent falling of antibody levels
15
Q
Glucose-6-phosphate dhydrogenase (G6PD) deficiency?
A
- Commonest red cell enzyme defect - more common in people from the med/africa
- Pathway involves NADPH/reduced glutathione which usually protect RBCs from oxidative phosphorylation
- X-linked recessive inheritence
- Drugs can precipitated a crisis (as can Fava beans)
Features
- Neonatal jaundice is often seen
- Intravascular hemolysis
- Heinz bodies on blood films (indicates oxidative damage to the Hb)
Drugs causing haemolysis
- Anti-malarials: primaquine
- Ciprofloxacin
- Sulfonamides
- Co-trimoxazole (because it contains sulfa)
16
Q
Paroxysmal noctural haemoblobinuria (PNH)?
A
- Acquired disorder leaidng to haemolysis (intravascular)
- Caused by increased sensitivity of cell membranes to complement due to a lack of glycoprotein glycosyl-phosphatidylinositol (GPI)
- Also prone to venous thrombosis
- GPI = anchor which attaches surface proteins to cell membrane
- Complement-regulating surface proteins, e.g. decay-accelerating factor (DAF), are not properly bound to the cell membrane due a lack of GPI
- Thrombosis is thought to be caused by a lack of CD59 on platelet membranes predisposing to
platelet aggregation
17
Q
Features, diagnosis and Mx of PNH?
A
Features
- Hemolytic anemia
- Red blood cells, white blood cells, platelets or stem cells may be affected therefore pancytopenia may be present
- Haemoglobinuria: classically dark-colored urine in the morning
- Thrombosis e.g. Budd-Chiari syndrome
- Aplastic anemia may develop in some patients
Diagnosis
- Flow cytometry of blood to detect low levels of CD59 and CD55
- Ham’s test was previously gold standard - acid-induced hemolysis (normal red cells would not)
Mx
- Blood product replacement
- Anticoagulation
- Eculizumab, a monoclonal antibody directed against terminal protein C5
- Stem cell transplantation
18
Q
Causes of polycythaemia?
A
Relative
- Dehydration
- Stress: Gaisbock syndrome
Primary
- Polycythaemia Rubra Vera
Secondary
- COPD
- Altitude
- OSA
- Excessive erythropoietin: cerebellar hemangioma, hypernephroma, hepatoma, uterine fibroids
19
Q
How to differentiate between true (pimary or secondary) polycythaemia and relative polycythaemia?
A
Red Cell Mass Studies
- In true polycythaemia
- males > 35 ml/kg
- women > 32 ml/kg
Erythroid colony studies
- Autonomous growth of erythroid colonies is taken as a sign of primary
polycythaemia, where erythropoiesis has escaped the control of erythropoietin - Arythroid colony studies are thought to have high specificity for detecting primary versus secondary polycythaemia.
20
Q
A
21
Q
Polycythaemia Rubra Vera?
A
- Myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to raised RBCs, often accompanied by raised WBC (neutrophils) and raised platelets.
- JAK2 +ve in 95%
- 50-60 yrs
- Association with Budd-Chiari syndrome
- About 30% progress to myelofibrosis; 5-15% develop an acute leukaemia
22
Q
Features, investigation and management of PRV?
A
Features
- Hyperviscosity (headaches, tinnitus, visual disturbance, cyanosis, joint pain)
- Pruritus, typically after a hot bath
- Splenomegaly ± Hepatomegaly
- Thrombotic events
- Hemorrhage (secondary to abnormal platelet function not number)
- Plethoric appearance
- Low ESR
- Hypertension in a third of patients
Investigations
- Raised Hemoglobin and hematocrit
- Raised Leucocyte alkaline phosphatase (LAP)
- ± raised WBC and raised PLT
- ± raised Plasma volume
- Raised vitamin B12
- Raised Red cell mass
- Reduced Erythropoietin level
Mx
- Venesection - first line treatment
- Hydroxyurea -slight increased risk of secondary leukemia
- Allopurinol & Phosphorus-32 therapy
23
Q
Causes of neutropenia? Investigations?
A
Congenital
- Kostmann’s syndrome
- Chediak–Higashi
- Schwachmann–Diamond syndrome
- Cyclical neutropenia
Acquired
- Infection: viral e.g. influenza, HIV, hepatitis, bacterial sepsis.
- Drugs: anticonvulsants (phenytoin) – anti-thyroid (carbimazole) – phenothiazines (chlorpromazine) – antibacterial agents (cotrimoxazole) – ACE-inhibitors (ramipril)
- Immune-mediated: SLE, Felty’s syndrome (Rheumatoid Arthritis + Neutropenia + Splenomegaly)
- Bone marrow failure: leukaemia, lymphoma, Hematinic deficiency
- Splenomegaly: any cause
Investigations
- Blood film
- Hematinics: factors that increase Hb (Iron, TIBC, Vit B12, Folic Acid, Vit D)
- Autoimmune profile bone marrow aspirate/trephine are indicated if there are severe or prolonged neutropenia or features suggestive of marrow failure
24
Q
Leukemoid reaction?
A
- Presence of immature cells such as myeloblasts, promyelocytes and nucleated red cells in the peripheral blood
- May be due to infiltration of the bone marrow causing the immature cells to be ‘pushed out’ or sudden demand for new cells
Causes
- Severe infection
- Severe hemolysis
- Massive hemorrhage
- Metastatic cancer with bone marrow infiltration
25
Q
Leukemoid reaction vs CML?
A
Leukemoid Reaction
- High leukocyte alkaline phosphatase score
- Toxic granulation (Dohle bodies) in the white cells
- ‘Left shift’ of neutrophils i.e. increased neutrophils or 3 segments of the nucleus
CML
- Low leukocyte alkaline phosphatase score
26
Q
Myelofibrosis?
A
- Myeloproliferative disorder caused by hyperplasia of abnormal megakaryocytes responsible for the production of platelets
- Resultant release of platelet derived growth factor is thought to stimulate fibroblasts
- Hematopoiesis develops in the liver and spleen
Features
- E.g. Elderly person with symptoms of anemia e.g. Fatigue (the most common presenting symptom)
- Massive splenomegaly
- Hypermetabolic symptoms: weight loss, night sweats etc
Ix
- Anemia
- High WBC and platelet count early in the disease
- ‘Tear-drop’ poikilocytes on blood film
- Unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
- High urate and LDH (reflect increased cell turnover)
27
Q
Myelodysplasia? (not enough cells)
A
30% progress to AML
Presentation
- Pancytopenia –> anaemia, infection, bleeding
Investigations
- Serial blood counts –> evidence of increasing bone marrow failure
- Bone marrow shows increased cellularity
Management
- < 5% blasts in the bone marrow –> manage conservatively.
- Raised WBC –> gentle chemotherapy.
- < 60 years old –> Intensive chemotherapy
28
Q
Philadelphia chromosome?
A
Philadelphia chromosome
- translocation between the long arm of chromosome 9 and 22 -
t(9:22)(q34:q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. - The resulting BCR-ABL gene codes for a fusion protein which
has tyrosine kinase activity in excess of normal - Good prognostic sign in CML
- Poor prognostic sign in AML + ALL
29
Q
CML?
A
Presentation
- Middle-age
- Anemia, weight loss
- Splenomegaly may be marked (lethargy, anorexia, abdominal discomfort – 75% palpable spleen)
- Hepatomegaly and lymphadenopathy are uncommon
- Spectrum of myeloid cells seen in peripheral blood
- Reduced neutrophil alkaline phosphatase
- May undergo blast transformation (AML in 80%, ALL in 20%)
Diagnosis
- Philadelphia is confirmatory
- Peripheral blood film: (leukocytosis in all stages of differentiation within the myeloid linage)
- Basophilia is important diagnostic marker especially when Philadelphia is absent
- Monocytopenia
- Bone-marrow hypercellularity with increased myloid-erythroid ratio
Management
- Hydroxyurea (also used in PRV, painful attacks in sicklers and as antiretroviral in HIV)
- Interferon- a
- Imatinib (inhibitor of tyrosine kinase)
- Allogenic bone marrow transplant (optimum management)
30
Q
AML?
A
- Most common form of acute leukemia in adults
- May occur as a primary disease or following a secondary transformation of a myeloproliferative disorder (e.g CML, myelofibrosis)
- > 30% blasts are almost diagnostic of AML
Presentation (pancytopenia)
- Early signs are vague and non-specific (influenza-like)
- Persistent or frequent infections (due to low WBC)
- Bruising and petechiae (due to low PLT)
- Splenomegaly may occur but typically mild and asymptomatic. Lymph node swelling is rare
31
Q
How to differentiate AML from ALL?
A
Combination of a myeloperoxidase or Sudan black stain and a non-specific esterase (NSE) stain will provide distinction of AML from ALL and in subclassification of AML in most cases
32
Q
Acute promyelocytic leukaemia?
A
- M3 subtype of AML
- Presents younger than other types of AML (25 yrs)
- Classical presentation = rasied WCC, DIC or thrombocytopenia
- Associated with t(15:17) translocation which causes fusion of the PML and RAR-a genes.
- Good prognosis
- Treated with the ATRA in addition to induction chemotherapy.
- All-trans-retinoic acid - activates the RAR-a gene thus helps the WBCs to differentiate (i.e mature) but it will not eliminate the leukemia.
33
Q
A
34
Q
Poor prognostic features for AML?
A
- > 60 years
- > 20% blasts after first course of chemo
- Cytogenics: deletions of chromosome 5 or 7
49
Q
Hodgkin’s lymphoma types?
A
54
Q
Haem malignancies genetics?
A
57
Q
Causes of eosinophilia?
A
NAACCP
- Neoplasia
- Addison’s
- Allergy/Asthma
- Collagen vascular diseases
- Cholesterol emboli
- Parasites
58
Q
Bleeding times with diseases?
A
60
Q
Clotting pathways - intrinsic/extrinsic, PT/aPTT?
A
75
Q
Haem cancers blood films
A
76
Q
Stains and reagents used in haematology?
A
