Haem/Onc

Question 1

Drugs in haem-onc?

Answer 1

Question 2

Chemotherapy extravasation points?

Answer 2

• Usually cold compress except vinca alkaloids –> heat compress
• Doxorubacin and daunorubicin extravasation tends to cause ulceration –> plastics referral, topical steroids

Question 3

General points with transfusion reactions?

Answer 3

• 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

Question 4

Delayed transfusion reactions?

Answer 4

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.

Question 5

Intravascular vs Extravascular Haemolysis?

Answer 5

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

Question 6

Autoimmune Haemolytic Anaemia? (Warm vs Cold)

Answer 6

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 4^oC - 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)

Question 7

Difference between direct and indirect Coomb’s test?

Answer 7

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

Question 8

Hereditary spherocytosis?

Answer 8

• 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

Question 9

Pathophysiology of sickle cell disease?

Answer 9

• 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

Question 10

Types of sickle cell crisis?

Answer 10

1. 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
2. Aplastic
   
   • Caused by infection with parvovirus
   • Sudden fall in hemoglobin
3. 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)
4. Haemolytic
   
   • Rare - fall in Hb due to increased rate of haemolysis

Question 11

Pernicious anaemia?

Answer 11

• 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

Question 13

Sideroblastic anaemia?

Answer 13

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

Question 14

Pure red cell aplasia?

Answer 14

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

Question 15

Glucose-6-phosphate dhydrogenase (G6PD) deficiency?

Answer 15

• 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)

Question 16

Paroxysmal noctural haemoblobinuria (PNH)?

Answer 16

• 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

Question 17

Features, diagnosis and Mx of PNH?

Answer 17

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

Question 18

Causes of polycythaemia?

Answer 18

Relative

• Dehydration
• Stress: Gaisbock syndrome

Primary

• Polycythaemia Rubra Vera

Secondary

• COPD
• Altitude
• OSA
• Excessive erythropoietin: cerebellar hemangioma, hypernephroma, hepatoma, uterine fibroids

Question 19

How to differentiate between true (pimary or secondary) polycythaemia and relative polycythaemia?

Answer 19

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.

Question 21

Polycythaemia Rubra Vera?

Answer 21

• 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

Question 22

Features, investigation and management of PRV?

Answer 22

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

Question 23

Causes of neutropenia? Investigations?

Answer 23

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

Question 24

Leukemoid reaction?

Answer 24

• 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

Question 25

Leukemoid reaction vs CML?

Answer 25

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

Question 26

Myelofibrosis?

Answer 26

• 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)

Question 27

Myelodysplasia? (not enough cells)

Answer 27

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

Question 28

Philadelphia chromosome?

Answer 28

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

Question 29

CML?

Answer 29

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)

Question 30

AML?

Answer 30

• 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

Question 31

How to differentiate AML from ALL?

Answer 31

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

Question 32

Acute promyelocytic leukaemia?

Answer 32

• 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.

Question 34

Poor prognostic features for AML?

Answer 34

• > 60 years
• > 20% blasts after first course of chemo
• Cytogenics: deletions of chromosome 5 or 7

Question 35

Management of AML?

Answer 35

Chemo divided into two phases

1. Induction
   
   • All types (except M3) - cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin)
   • Regimen known as 7+3 - ara-C is given as a continuous IVI for 7 days while the anthracycline is given for 3 consecutive days as an IV push
2. Consolidation
   
   • Further therapy needed to eliminate non-detectable disease and prevent relapse
   • For good-prognosis leukemias [t(8;21), and t(15;17)], patients will typically undergo an additional 3–5 courses of intensive chemotherapy
   • For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related AML), allogeneic stem cell transplantation is usually recommended

Question 36

CLL?

Answer 36

Caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%)

Features

• Often none
• Constitutional: anorexia, weight loss
• Bleeding, infections
• Lymphadenopathy more marked than CML

Complications

• Hypogammaglobulinemia leading to recurrent infections most common cause of death
• Warm autoimmune hemolytic anemia in 10-15% of patients
• Transformation to high-grade lymphoma (Richter’s transformation)

Poor Prognostic Factors

• Male
• Age > 70 years
• Lymphocyte count > 50
• Prolymphocytes comprising > 10% of blood lymphocytes
• Lymphocyte doubling time < 12 months
• Raised LDH
• CD38 expression positive

Question 37

Investigations and Tx of CLL?

Answer 37

Ix

• Immunophenotyping (flow cytmetry)
  
  • Immunophenotyping will demonstrate the cells to be B-cells (CD19 positive). CD5 and CD23 are also characteristically positive in CLL
• Blood film: smear or smudge cells

Mx

• None early on
• Chlorambucil to reduce lymphocyte count
• Fludarabine
  
  • causes profound lymphopenia –> increases the risk of opportunistic infections significantly,
  • Give co-trimoxazole or to use monthly nebulised pentamidine to prevent PCP pneumonia

Question 38

Indications for treatment in CLL?

Answer 38

• Progressive marrow failure: the development or worsening of anemia and/or thrombocytopenia
• Massive (>10 cm) or progressive lymphadenopathy
• Massive (>6 cm) or progressive splenomegaly
• Progressive lymphocytosis: > 50% raised over 2 months or lymphocyte doubling time < 6 months
• Systemic symptoms: weight loss > 10% in previous 6 months, fever >38ºc for > 2 weeks, extreme fatigue, night sweats
• Autoimmune cytopenias e.g. ITP

Question 39

Hairy cell leukaemia?

Answer 39

Rare malignant proliferation disorder of B cells lymphocytes

Classified as a sub-type of chronic lymphoid leukemia

Hairy cells = abnormal WBCs with hair-like projections of cytoplasm.

Features

• Pancytopenia (Monocytopenia is classical)
• Splenomegaly
• Skin vasculitis in 1/3 patients
• ‘Dry tap’ despite bone marrow hypercellularity (also seen in myelofibrrosis)
• Bone marrow biopsy migh show “fried egg appearance”
• Tartrate resistant acid phosphotase (TRAP) stain positive

Management

• Chemotherapy is first-line: cladribine, pentostatin
• Immunotherapy is second-line: rituximab, interferon-
• Splenectomy sometimes required

Question 40

ALL?

Answer 40

Causes problems by crowding out normal cells in the bone marrow, and metastasising

2 peaks - 2-5 years, and old age

• t(12:21) = most common translocation –> good prognosis.
• Philadelphia chromosome t(9:22) –> bad prognosis.
• t(4:11) is the most common in children under 12 months and portends a poor prognosis.

Question 41

Presentation of ALL?

Answer 41

Presentation

• Generalized weakness and fatigue, anaemia
• Frequent or unexplained fever and infections
• Weight loss and/or loss of appetite
• Excessive and unexplained bruising; Petechiae due to thrombocytopenia
• Bone pain, arthralgia.
• Dyspnea due to lung infiltration.
• Lymphandeopathy, hepatosplenomegaly.
• Pitting edema in the lower limbs and/or abdomen

Question 42

Dx of ALL?

Answer 42

• Leukocytosis.
• Blast cells are seen on blood smear in 90% of cases
• Bone marrow biopsy is conclusive proof of ALL
• LP to detect CNS involvement.
• CXR: to look for mediastinal mass (common in ALL)
• U&E to look for Tumor Lysis Syndrome.
• Immunophenotyping, establish whether the “blast” cells origin is B or T lymphocytes
• DNA testing; different mutations reflect prognosis.

Terminal deoxynucleotide transferase (TdT) present in 95% of ALL

Question 43

Good and bad prognostic factors of ALL?

Answer 43

Good

• Common ALL
• Pre-B phenotype
• Low initial WBC
• FAB L1 type

Bad

• FAB L3 type
• T or B cell surface markers
• Philadelphia translocation, t(9;22)
• Age < 2 years or > 10 years
• Male Sex.
• CNS involvement
• High initial WBC (e.g. > 100 * 109/l)
• Non-Caucasian

Question 44

Leukoerythroblastic Anemia?

Answer 44

• Left-shifted granulocytic series and nucleated red blood cells) with pancytopaenia
• Also defined when there are immature cells (e.g myelocytes, and nucleated red blood cells) seen on the peripheral blood film

Associations

• Increased Bone marrow turnover e.g. in severe hemolytic anemia (in which case the reticulocyte count would be high).
• Myelofibrosis and Chronic Myeloid Leukaemia (where there would be splenomegaly, and the white cell and platelet count would usually be raised).
• Bone marrow invasion. Often in bone marrow invasion the invading malignancy will already have been diagnosed previously.
• Myeloma
• Polycythaemia Rubra Vera
• Osteopetrosis
• Tuberculous infiltration of the bone marrow
• Sarcoidosis

Question 45

Hodgkin’s lymphoma?

Answer 45

• Malignant proliferation of lymphocytes characterized by the presence of the Reed-Sternberg cell.
• Bimodal age distributions being most common in the third and seventh decades.
• Associated with EBV
• 25% have constitutional symptoms (night sweats, weight loss, fever, pruritus and lethargy)

Diagnosis

• Hodgkin results in patchy bone marrow infiltration, an isolated bone marrow biopsy may yield non-specific results.
• Bone marrow biopsy is more useful for staging of advanced disease.
• Lymph node biopsy would be more likely to be positive, Reed-Sternberg cell is evident on microscopy

Question 46

Staging of Hodgkin’s Lymphoma?

Answer 46

Ann-Arbor

• I: single lymph node
• II: 2 or more lymph nodes/regions on same side of diaphragm
• III: nodes on both sides of diaphragm
• IV: spread beyond lymph nodes

Each stage may be subdivided into A or B

• A = no systemic symptoms other than pruritus
• B = weight loss > 10% in last 6 months, fever > 38c, night sweats (poor prognosis)

Question 47

Poor prognostic factors in Hodgkin’s lymphoma?

Answer 47

• Age = 45 years
• Stage IV disease
• Hemoglobin < 10.5 g/dl
• Lymphocyte count < 600/μl or < 8%
• Male
• Albumin < 40 g/l
• White blood count = 15,000/μl

Question 48

Management of Hodgkin’s Lymphoma?

Answer 48

IA/IIA

• Radiation therapy AND chemotherapy.
• The choice of treatment depends on the age, sex, bulk and the histological subtype of the disease.

III, IVA or IVB

• Combination chemotherapy alone

Large mass in the chest (regardless of stage)

• Treated with combined chemotherapy and radiation therap.
• Chemo includes: Doxorubicin, Bleomycin, Vincristine, Cyclophosphamide and other cytotoxic drugs.

Question 49

Hodgkin’s lymphoma types?

Answer 49

Question 50

Non-Hodgkin’s Lymphomas?

Answer 50

• Diverse group of lymphomas that include any kind of lymphoma except Hodgkin’s lymphomas
• Low-grade lymphoma is predominantly a disease of older people.
• Most non-Hodgkin’s lymphomas are of B cell phenotype, though T cell tumours are recognised

Presentation

• Most present with advanced disease, bone marrow infiltration being almost invariable.
• Extra-nodal presentation is more common than Hodgkin’s disease.
• Renal impairment in non-Hodgkin’s lymphomas usually occurs as a consequence of ureteric obstruction secondary to intra-abdominal or pelvic lymph node enlargement.
• Anaemia, an elevated white cell count and/or thrombocytopaenia are suggestive of bone marrow infiltration.

Question 51

Management of NHL?

Answer 51

• Lymph node biopsy is sufficient for a definitive diagnosis –> immuno-phenotyping and cytogenetic/molecular analysis.
• High-grade lymphomas are responsive to chemotherapy and potentially curable,
• Low-grade lymphomas are incurable with conventional therapy.
• Chemotherapy is the mainstay of treatment in most cases

Question 52

Burkitt’s Lymphoma?

Answer 52

High grade B cell neoplasm (NHL)

Two forms

• Endemic (African) form: typically involves maxilla or mandible
• Sporadic form: abdominal (ileo-caecal) tumors are the most common form. More common in patients with HIV

Associated with the c-myc gene translocation, usually t(8:14)

EBV strongly implicated in African form but not so much sporadic

Common cause of Tumour Lysis Syndrome

Question 53

Tumour Lysis Syndrome?

Answer 53

Occurs after the initiation of a chemotherapeutic. TLS tends to occur in patients with bulky, rapidly proliferating, treatment-responsive tumors

Associations

• Acute leukemia
• High-grade non-Hodgkin’s lymphomas.
• Pre-treatment raised LDH (levels of LDH correspond with tumor bulk)

Manifestation (rapid 48-72 hours after initiation)

• Hyperkalaemia
• Hyperuricaemia
• Hyperphosphataemia
• Hypocalcaemia
• Acute renal failure

Management

• Prevention is with good hydration before starting chemotherapy.
• Hyperuricemia –> urine alkalinisation and allopurinol
• Osmotic diuretics are NOT first line therapy and may contribute to the precipitation of uric acid in the renal tubules.
• Dietary modifications include restricting dietary potassium.
• Further chemotherapy should be withheld until the patient has fully recovered

Question 54

Haem malignancies genetics?

Answer 54

Question 55

Infections related to haem malignancies?

Answer 55

Viruses

• EBV: Hodgkin’s and Burkitt’s lymphoma, nasopharyngeal carcinoma
• HTLV-1 (Human T-lymphotropic virus Type I): Adult T-cell leukemia/lymphoma
• HIV-1: High-grade B-cell lymphoma

Bacteria

• Helicobacter pylori: gastric lymphoma (MALT)

Protozoa

• Malaria: Burkitt’s lymphoma

Question 56

Stem cell transplants?

Answer 56

• Not used in first complete remission in most haematological malignancies - reserved for first relapse/second complete remission (high treatment related morbidity/mortality)
• Transplants from matched sibling donors are used as first line therapy in certain circumstances, including CML
• If no siblings, then imatinib to induce remission is first choice
• Blood Products
  
  • Irradiated blood - patients receiving a bone marrow transplant, patients with previous purine analogue exposure and a diagnosis of Hodgkin’s disease
  • CMV-negative blood - atients who may need a bone marrow transplant in the future (CMV carriage increases transplant mortality

Question 57

Causes of eosinophilia?

Answer 57

NAACCP

• Neoplasia
• Addison’s
• Allergy/Asthma
• Collagen vascular diseases
• Cholesterol emboli
• Parasites

Question 58

Bleeding times with diseases?

Answer 58

Question 59

Acquired factor VIII deficiency

Answer 59

Results from the development of inhibitors against factor VIII. Occurs mainly in the elderly.

Associations

• Malignancy
• Psoriasis
• Pemphigus
• Drugs: cephalosporins, penicillins

Diagnosis

• Bleeding tendencies
• APTT: is prolonged (intrinsic pathway).
• APTT doesn’t correct/will only correct slightly with the adding of normal plasma.
• Bethesda titre can quantify the inhibitor. There is a 20% mortality rate from acquired factor VIII deficiency.

Treat with recominant factor VIIa or factor VIII bypassing agent (latter is prothrombotic –> MI/DIC)

Question 60

Clotting pathways - intrinsic/extrinsic, PT/aPTT?

Answer 60

Question 61

Haemophilias?

Answer 61

Haemophilia A

• X-linked; factor VIII (most common - 90%)

Haemophilia B

• X-linked; factor IX (more severe but less common)

Haemophilia C

• Autosomal; factor XI - not completely recessive, some heterozygotes show increased bleeding tendencies.

Question 62

Acquired haemophilia?

Answer 62

Associated with anti-factor VIII IgG antibodies and is idiopathic in the majority of cases.

Associations

• Autoimmune diseases: (Rheumatoid Arthritis or IBD)
• Drugs such as phenytoin

Mx

• Sometimes replacement of factor VIII is all that is needed
• Immunosupression with corticosteroids +/- steroid sparing agents such as cyclosporine may be required.

Question 63

Von Willebrand’s disease?

Answer 63

Most common inherited bleeding disorder. Mostly AD inheritence. Behaves like a platelet disorder.

Types

• Type 1 - partial reduction in vWF (80% of patients)
• Type 2: abnormal form of vWF
• Type 3: total lack of vWF (autosomal recessive) most severe

Ix

• PFA-100 has >95% sensitivity to diagnose vWD
• Prolonged bleeding time
• Slightly prolonged APTT
• Decreased factor VIII levels
• Defective platelet aggregation with ristocetin

Mx

• TXA for mild bleeding
• Desmopressin raises levels of vWF by inducing release of vWF from Weibel Palade bodies in endothelial cells. Used as prohyplaxis prior to procedures.
• Factor VIII concentrate

Question 64

Role of vWF?

Answer 64

• Promotes platelet adhesion to damaged endothelium
• Carrier molecule for factor VIII

Question 65

Causes for severe and moderate thrombocytopenia?

Answer 65

Severe

• ITP
• TT
• DIC
• Hematological malignancy

Moderate

• Heparin induced thrombocytopenia (HIT)
• Drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)
• Alcohol and Vitamin B12 deficiency
• Liver disease
• Hypersplenism
• Viral infection (EBV, HIV, hepatitis)
• Pregnancy
• SLE/antiphospholipid syndrome

Question 66

Idiopathic thrombocytopenic purpura (ITP)?

Answer 66

Immune mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb-IIIa or Ib complex.

• Acute - mostly children - M=F. May follow infection/vaccination, self-limiting over 1-2 weeks.
• Chronic - young/middle aged women, relapsing-remitting course.

Ix

• Antiplatelet autoantibodies (usually IgG)
• Bone marrow aspiration shows megakaryocytes in the marrow. This should be carried out prior to the commencement of steroids in order to rule out leukemia

Mx

• Oral prednisolone (80% of patients respond)
• Splenectomy if platelets < 30 after 3 months of steroid therapy
• IV immunoglobulins
• Immunosuppressive drugs e.g. Cyclophosphamide

Question 67

Evans’ syndrome?

Answer 67

ITP in association with autoimmune haemolytic anaemia

Question 68

Thrombotic thrombocytopenic purpura mechanism?

Answer 68

Neurological features, renal failure, pyrexia and thrombocytopenia point towards a
diagnosis of TTP - difference from HUS = neuro signs and purpura.

• Abnormally large and sticky multimers of vWF cause platelets to clump within vessels
• Autoantibody-mediated inhibition of the enzyme ADAMTS13, which normally cleaves the multimers into smaller units
• Increased platelet adhesion –> thrombi –> decreased numbers of circulating platelets
• Overlaps with hemolytic uraemic syndrome (HUS)

Question 69

TTP features, causes, management?

Answer 69

Features

• Rare, typically adult females
• Fever
• Fluctuating neuro signs (microemboli)
• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Renal failure

Causes

• Post-infection e.g. Urinary, gastrointestinal
• Pregnancy
• Drugs: cyclosporin, oral contraceptive pill, penicillin, clopidogrel, aciclovir
• Tumors
• SLE
• HIV

Management

• No antibiotics - may worsen outcome
• Plasma exchange is the treatment of choice
• Steroids, immunosuppressants
• Vincristine

Question 70

Drug causes of pancytopenia?

Answer 70

• Cytotoxics
• Antibiotics: trimethoprim, chloramphenicol
• Anti-rheumatoid: gold, penicillamine
• Carbimazole*
• Anti-epileptics: carbamazepine
• Sulphonylureas: tolbutamide

Question 71

Heparin induced thrombocytopenia (HIT)?

Answer 71

Immune mediated (IgG) drug reaction. Usually takes about 5 days to manifest.

Presentation

• Bleeding is rare, more strongly associated with thrombosis (antibodies initiate platelet activation –> clots)
• Both venous and arterial thrombosis

Dx (clinical)

• Thrombocytopenia: PLT < 100 or <50% from the patient’s baseline
• The exclusion of other causes of thrombocytopenia
• The resolution of thrombocytopenia after cessation of heparin
• HIT antibodies can be demonstrated using lab tests and assays (HIPA, SRA)

Management

• Stop all forms of Heparin
• Start alternative anticoagulant which do not cross-react with HIT antibodies, such as: Danaparoid, Lepirudin, Argatroban.
• Oral anticoagulation with warfarin should NOT be initiated for longer-term protection from further events until substantial platelet count recovery has occurred
  
  • HIT patients who are switched to warfarin alone after the discontinuation of heparin may paradoxically have worsening thrombosis and develop venous limb gangrene and skin necrosis

Question 72

Hyposplenism blood film? e.g. post-splenectomy

Answer 72

• Target cells
• Howell-Jolly bodies
• Cabot’s rings
• Siderotic granules
• Acanthocytes
• Schizocytes

Question 73

Iron deficiency anaemia blood film?

Answer 73

• Target cells
• ‘Pencil’ poikilocytes
• If combined with B12/folate deficiency a ‘dimorphic’ film
• occurs with mixed microcytic and macrocytic cells

Question 74

Typical blood films for: G6PD deficiency, Myelofibrosis, Intravascular haemolysis, Megaloblastic anaemia?

Answer 74

• G6PD = Heinz bodies
• Myelofibrosis = ‘Tear drop’ poikilocytes
• Intravascular Haemolysis = Schistocytes
• Megaloblastic anaemia = Hypersegmented neutrophils

Question 75

Haem cancers blood films

Answer 75

Question 76

Stains and reagents used in haematology?

Answer 76

Question 77

Hereditary haemorrhagic telangectasia?

Answer 77

AD inheritence

Types

• HHT1: chromosome 9, associated with AVM (cerebral and pulmonary)
• HHT2: chromosome 12.

Features

• Epistaxis
• Telangiectasia develop on skin, mucous membranes and internal organs
• Associated with pulmonary and other AV malformations in 10%
• May present as iron-deficiency anemia secondary to bleeding in the GI tract or nasal mucosa

Question 78

Waldenstrom’s Macroglobulinemia?

Answer 78

• Older men
• Lymphoplasmacytoid malignancy characterized by the secretion of a monoclonal IgM paraprotein

Features

• Monoclonal IgM paraproteinemia
• Systemic upset: weight loss, lethargy
• Hyperviscosity syndrome e.g. Visual disturbance
• Hepatosplenomegaly
• Lymphadenopathy
• Cryoglobulinemia e.g. Raynaud’s
• Raised ESR

Mx

• Monoclonal antibody rituximab, sometimes in combination with
  chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or Vincristine or with thalidomide.
• Steroids
• Plasmaphoresis can be used to address the hyperviscosity

Question 79

Differences between MGUS and myeloma?

Answer 79

• Normal immune function
• Normal beta-2 microglobulin levels
• Lower level of paraproteinemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA)
• Stable level of paraproteinemia
• No clinical features of myeloma (e.g. Lytic lesions on x-rays or renal disease)

Question 80

Features and diagnostic criteria for MGUS?

Answer 80

Features

• Usually asymptomatic
• No bone pain or increased risk of infections
• Around 10-30% of patients have a demyelinating neuropath
• M protein level < 30gm/l
• No end-organ damage.

Diagnostic Criteria

• Serum paraprotein <30 g/L AND
• Clonal plasma cells <10% on bone marrow biopsy AND
• NO myeloma-related organ or tissue impairment

Question 81

Methaemoglobulinaemia?

Answer 81

Oxidation of Fe²⁺ to Fe³⁺ by NADH methemoglobin reductase

Results in tissue hypoxia as Fe³⁺ cannot bind oxygen –> dissociation curve moved to the left

Causes

• Congenital - Hb chain variants (HbM, HbH), deficiency of the enzyme
• Acquired - drugs (sulphonamides, nitrates, dapsone, sodium nitroprusside, primaquine), chemicals (alanine dyes)

Features

• ‘Chocolate’ cyanosis
• Dyspnoea, anxiety, headache
• Severe - acidosis, arrhythmias, seizures, coma
• Normal PO₂ but decreased sats

Management

• Ascorbic acid if enzyme deficiency
• IV methylene blue

Question 82

Fanconi’s anaemia?

Answer 82

• Autosomal recessive
• Aplastic anemia
• Increased risk of AML
• Neurological manifestation
• Skeletal abnormalities
• Skin pigmentation (café-au-lait spots)

Question 83

Haemochromatosis?

Answer 83

Autossomal Recessive - HFE gene, chromosome 6

Typical Tests

• Transferrin saturation > 55% in men or > 50% in women
• Raised ferritin (e.g. > 500 ug/l) and iron
• Low TIBC

Diagnostic Tests

• Molecular genetic testing for the C282Y and H63D mutations
• Liver biopsy: Perl’s stain

Monitoring Venesection

• ‘transferrin saturation should be kept below 50% and the serum ferritin
  concentration below 50 ug/l’

Question 84

Presentation and complications of haemochromatosis?

Answer 84

Presentation

• Early symptoms include fatigue, erectile dysfunction and arthralgia (often of the hands)
• ‘Bronze’ skin pigmentation
• Diabetes Mellitus
• Liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition.
• Cardiac failure (2nd to dilated cardiomyopathy)
• Hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)
• Arthritis (especially of the hands) - joint X rays show chondrocalcinosis

Complications

• Reversible - cardiomyopathy, skin pigmentation
• Irreversible - cirrhosis, DM, hypogonadism, arthropathy