Haematology

Question 1

Define what anaemia is?

Answer 1

A decrease in RBC mass that can be detected by haemoglobin (Hb) concentration, haematocrit (Hct), and RBC count.

Question 2

Describe an approach to classifying anaemia and there differential diagnoses?

Answer 2

Question 3

Describe the clinical features of anaemia on Hx and physical exam?

Answer 3

• History:
  
  • symptoms of anaemia: fatigue, malaise, weakness, dyspnea, decreased exercise tolerance, palpitations, headache, dizziness, tinnitus, syncope.
  • Acute vs chronic, bleeding, systemic illness, diet, alcohol, FHx
  • menstrual Hx: menorrhagia, menometrorrhagia, dysfunctional uterine bleeding
  • rule out pancytopaenia (recurrent infection, mucosal bleeding/easy bruising)
• Physical signs:
  
  • HEENT: pallor in mucous membranes, palmar creases and conjunctiva at Hb <90, ocular bruits at Hb <55, angular cheilosis, jaundice
  • Cardiac: tachycardia, orthostatic hypotension, systolic flow murmur, wide pulse pressure, signs of CHF
  • Dermatologic: pallor in palmar skin creases at Hb <75, jaundice (if due to haemolysis), nail changes, glossitis.

Question 4

How do you investigate anaemia and its causes?

Answer 4

• Rule out dilutional anaemia (low Hb due to increased effective circulating volume)
• FBC with differential (MCV, RDW, RBC count)
• reticulocyte count - very useful to evaluate for blood cell producion problems but must be corrected for anaemia
• Blood film
• rule out nutritional deficit, gastrointestinal and genitourinary disease in iron deficiency anaemia
• addition investigations as indicated by type of anaemia:
  
  • microcytic: iron studies, soluble transferrrin receptor/ferritin, haemoglobinopathy/thalassaemia screen, CRP, lead, bone marrow biopsy (gold standard)
  • normocytic: Iron studies, vitamin B12 and folate, LFT, protein electrophoresis, bone marrow biopsy
  • haemolytic: Bilirubin, lactate dehydrogenase, haptoglobinDirect and indirect coombs test
  • macrocytic: Vit B12 and folate, LFT, Thyroid stimulating hormone, proetin electrophoresis including free ligh chains, bone marrow biopsy.

Question 5

Define erythrocytosis and what might cause it?

Answer 5

An increase in the number of RBCs

• Relative/spurious erythrocytosis (decreased plasma volume): diurectics, severe dehydration, burns, ‘stress” (Gaisbock’s syndrome)
• Absolute erythrocytosis

Question 6

Define thrombocytopaenia and what casues it?

Answer 6

A low platelet count

Question 7

Define thrombocytosis.

Answer 7

High platelet count

Question 8

Define pancytopaenia and what are the causes?

Answer 8

A decrease in all haematopoietic cell lines

Question 9

Define neutrophilia and its causes?

Answer 9

• High neutrophil count
• Primary neutrophilia
  
  • chronic myeloid leukaemic (CML)
  • other myeloproliferative disorders: PV, essential thrombocytosis (ET), myelofibrosis
  • hereditary neutrophilia (autosomal dominant)
  • chronic idiopathic neutrophilia in otherwise health patients
  • leukocyte adhesion deficiency
• Secondary neutrophilia
  
  • smoking: most common cause of mild neutrophila
  • infection: leukocytosis with left shift ± toxic granulation, Döhle bodies (intra-cytoplasmic structures composed of agglutinated ribosomes)
  • inflammation: e.g. rheumatoid arthritis, IBD, hepatitis, MI, PE, burns
  • malignancy: haematologic (i.e. marrow invasion by tumour) and non-haemotaologic (especially large cell lung cancer)
  • stress/exercise/adrenaline: movement of neutrophils from marginated pool into circulating pool
  • medications: glucocorticoids, ß-agonists, lithium

Question 10

Define neutropenia and its causes?

Answer 10

A low neutrophil count

Question 11

Define lymphocytosis and its causes?

Answer 11

• High lymphocyte count
• Aetiology
  
  • Infection:
    
    • viral infection (majority); particularly mononucleosis
    • TB, pertussis, brucelosis, toxoplasmosis
  • physiologic response to stress (e.g. trauma, status epilepticus)
  • hypersentitivity (e.g. drugs, serum sickness)
  • autoimmune (e.g. rheumatoid arthritis)
  • neoplasm (e.g. ALL, CLL, lymphoma)

Question 12

Define lymphopenia and its causes?

Answer 12

• Low lymphocyte count
• Aetiology
  
  • idiopathic CD4+ lymphocytopenia
  • radiation
  • HIV/AIDS, hepatitis B, hepatitis C
  • malignancy/chemotherapeutic agents
  • malnutrition, alcoholism
  • autoimmune disease (SLE)

Question 13

Define eosinophilia and its causes.

Answer 13

• High eosinophil count
• Aetiology
  
  • primary: due to clonal bone marrow disorder
    
    • if no primary aetiologyidentified, classifies as hypereosinophilic syndrome
      
      • 6 mo of eosinophilia with no other detectable cuases (often with cloncal molecular abnormality)
      • can involve heart, bone marrow and CNS
  • secdary
    
    • most common causes are parastitic (usually heminth) infections and allergic reactions
    • less common
      
      • polyarteritis nodosa
      • respiratory causes (asthma, eosinophilic pneumonia, Churg-Strauss)
      • cholesterol emboli
      • haematologic malignancy
      • adrenal insufficiency
      • medications (penicillins)

Question 14

How are iron studies interpreted?
Serum ferritin, serum iron, TIBC, saturation and soluble transferrin receptor (sTfR)

Answer 14

• Serum ferritin: most important blood test for iron stores
  
  • decreased in iron deficiency anaemia
  • elevated in:
    
    • infection, inflammation, malignanct
    • liver disease, hyperthyroidism, and iron overload
• Serum iron: measure of all non-haeme iron present in blood
  
  • varies significantly daily
  • virtually all serum iron is bound to transferrin, only a trace is free or complexed in ferritin
• TIBC: total amount of transferrin present in blood
  
  • normally, one third of TIBC is saturated with iron
  • high specificity for decreased iron, low sensitivity
• Saturation:
  
  • serum Fe divided by TIBC, expressed as a proportion or a percentage
  • low in iron deficiency anaemia
• sTfR
  
  • reflects the availability of iron at the tissue level
  • the transferrin receptor is expressed on the surface of erythroblasts and is responsible for iron uptake-some is cleaved off and is present in circulation as sTfR
  • in iron deficient states more transferrin receptor is expressed on erythroblasts leading to an increase in sTfR
  • low in reduced erythropoiesis and iron overload
  • useful in determining iron deficiency in the setting of chronic inflammatory disorders.

Question 15

Describe how iron is absorbed, transported and stored within the body.

Answer 15

• Iron Absorption and Transport
  
  • dietary iron is absorbed in the duodenum (impaired by IBD, celiac disease, etc.)
  • in circulation the majority of non-heme iron is bound to transferrin which transfers iron from enterocytes and storage pool sites (macrophages of the reticuloendothelial system and hepatocytes) to RBC precursors in the bone marrow
• Iron Levels
  
  • hepcidin that regulates systemic iron levels
    
    • a hormone produced by hepatocytes
    • binds to iron exporter ferroportin on duodenal enterocytes and reticuloendothelial cells, and induces its degradation thereby inhibiting iron export into the circulation
    • hepcidin production is increased in states of inflammation (thereby mediating anemia of chronic inflammation) or iron overload, and decreased in states where erythropoiesis is increased (e.g. hemolysis) or oxygen tension is low
• Iron Storage
  
  • ferritin
    
    • ferric iron (Fe3+) complexed to a protein called apoferritin (hepatocytes are main ferritin storage site)
    • small quantities are present in plasma in equilibrium with intracellular ferritin
    • also an acute phase reactant – can be spuriously elevated despite low Fe stores in response to a stressor
  • hemosiderin
    
    • aggregates or crystals of ferritin with the apoferritin partially removed
    • macrophage-monocyte system is main source of hemosiderin storage

Question 16

Describe the aetiology of iron deficiency anaemia?

Answer 16

• increased demand
  
  • increased physiological need for iron in hte body (e.g. pregnancy)
• decreased supply: dietary deficiencies (rarely the only aetiology)
  
  • cow’s milk (infant diet)
  • “tea and toast” diet (elderly)
  • absorption imbalances
  • post-gastrectomy
  • malabsorption (IBD of duodenum, celiac disease, autoimmune atrophic gastritis)
• Increased losses
  
  • haemorrhage
    
    • obvious causes: menorrhagia, abnormal iterine bleeding, frank GI bleed
    • occult: peptic ulcer disease, GI cancer
  • haemolysis:
    
    • intravascular (e.g. PNH, cardiac valave RBC fragmentation)
    • extravascular (e.g. immune haemolytic anaemia)

Question 17

Describe the clinical features of iron deficiency anaemia?

Answer 17

• iron deficiency may cause fatigue before clinical anemia develops
• signs/symptoms of anemia:fatigue, malaise, weakness, dyspnea, decreased exercise tolerance, palpitations, headache, dizziness, tinnitus, syncope
• brittle hair, nail changes (brittle, koilonychia)
• Plummer-Vinson syndrome: dysphagia (esophageal webs), glossitis, angular stomatitis (inflammation and fissuring at the corners of the mouth)
• pica (appetite for non-food substances e.g. ice, paint, dirt)

Question 18

What is the treatment for iron deficiency anaemia?

Answer 18

• treat underlying cause
• supplementation
  
  • Oral (tablets, syrup)
    
    • ferrous sulphate 325 mg tid, ferrous gluconate 300 mg tid, or ferrous fumarate 300 mg tid
    • supplement until anemia corrects, then continue for 3+ mo until serum ferritin returns to normal
    • oral iron should be taken with citrus juice to enhance absorption
  • IV (iron sucrose or dextran) can be used if patient cannot tolerate or absorb oral iron
• monitoring response
  
  • reticulocyte count will begin to increase after one wk
  • Hb normalizes by 10 g/L per wk (if no blood loss)
  • iron supplementation required for 4-6 mo to replenish stores

Question 19

Describe the aetiology and pathophysiology of anaemia of chronic disease?

Answer 19

• Aetiology:
  
  • Infection, malignancy, inflammatory and rheumatologic disease, chronic renal and liver disease, endocrine disorders (e.g. DM, hypothyroidism, hypogonadism, hypopituitarism)
• Pathophysiology:
  
  • an aemia of underproduction due to impaired iron utilisation (hepcidin is a key regulatory peptide)
    
    • enterocyte trapping of iron → increased hepcidin inhibits ferroportin (↓ iron into circulation)
    • macrophages trapping of iron → reduced plasma iron levels making iron relatively unavailable for new haemoglobin synthesis
    • marrow unresponsive to normal or slightly elevated EPO
  • Mild haemolytic component is often present
  • RBCs survival is modestly decreased.

Question 20

What is the treatment for anaemia of chronic disease?

Answer 20

• treat underlying disease
• only treat anaemia in patients who can benefit from a higher haemoglobin
• IV iron if no benefit from PO iron
• erythropoietin indicated in chronic renal failure; not to be used if patient has concommitant curative solid tumour malignancy; ensure Hb target <110

Question 21

Describe the definition, clinical features and treatment of lead poisoning?

Answer 21

• Definition/Etiology
  
  • blood lead levels greater than 80 μg/dL, possible symptomatology at 50 μg/dL
• Clinical Features
  
  • identify source: consider occupational history, exposures history
  • abdominal pain, constipation, irritability, difficulty concentrating
• Treatment
  
  • chelation therapy: dimercaprol and EDTA are first line agents

Question 22

What are sideroblasts?

Answer 22

• erythrocytes with iron-containing (basophilic) granules in the cytoplasm
• “normal”: granules are small, randomly spread in the cytoplasm
  
  • found in healthy individuals
• “ring”: iron deposits in mitochondria, forming a ring around the nucleus
  
  • abnormal, large granules
  • the hallmark of sideroblastic anemia

Question 23

What is the aetiology of sideroblastic anaemia?

Answer 23

• due to defects in heme biosynthesis in erythroid precursors
• hereditary (rare): X-linked; median survival 10 yr
• idiopathic (acquired)
  
  • refractory anemia with ringed sideroblasts: a subtype of myelodysplastic syndrome
  • may be a preleukemic phenomenon (10% transform to AML)
• reversible
  
  • drugs (isoniazid, chloramphenicol), alcohol, lead, copper deficiency, zinc toxicity, hypothyroidism

Question 24

What are the clinical features of sideroblastic anaemia?

Answer 24

• anemia symptoms
• hepatosplenomegaly, Fe2+ overload syndrome

Question 25

What is the treatment for sideroblastic anaemia?

Answer 25

• depends on aetiology
  
  • X-linked: high dose pyridoxine (vitamin B6) in some cases
  • acquired: EPO and G-CSF
  • reversible: remove precipitating cause
• supportive transfusions for severe anemia

Question 26

What is the definition and aetiology of aplastic anaemia?

Answer 26

• Definition
  
  • destruction of haematopoietic cells of the bone marrow leading to pancytopaenia hypocellular bone marrow
• Aetiology: see table

Question 27

What are the clinical features of aplastic anaemia?

Answer 27

• Can present acutely or insidiously
• symptoms of anaemia, thrombocytopaenia, and/or infection
• ± splenomegaly and lymphadenopathy (depending on the cause)

Question 28

Describe the treatment for aplastic anaemia?

Answer 28

• remove offending agents
• supportive care (red cell and platelet transfusions, antibiotics)
  
  • judicious use so as to not increase the risk of immune sensitization to blood products
• immunosuppression
  
  • anti-thymocyte globulin: 50-60% of patients respond
  • cyclosporine
• allogenic bone marrow transplant
• growth factors: e.g. Eltrombopag (TPO receptor agonist)

Question 29

Describe the aetiology of haemolytic anaemia?

Answer 29

• hereditary
  
  • abnormal membrane (spherocytosis, elliptocytosis)
  • abnormal enzymes (pyruvate kinase deficiency, G6PD deficiency)
  • abnormal hemoglobin synthesis (thalassemias, hemoglobinopathies)
• acquired
  
  • immune
  • autoimmune: warm vs. cold autoimmune hemolytic anemias (AIHA)
  • alloimmune: hemolytic disease of the fetus/newborn
• non-immune
  
  • Microangiopathic Haemolytic Anaemia (MAHA): thrombus in blood vessel causes RBCs to be sheared
    
    • associated with DIC, HUS/TTP, preeclampsia/HELLP, vasculitides, malignant HTN
    • other causes: PNH, hypersplenism, march hemoglobinuria (exertional hemolysis), infection (e.g. malaria), snake venoms, mechanical heart valves
• also classified as intravascular or extravascular
  
  • intravascular: G6PD deficiency, TTP, DIC, and PNH
  • extravascular: AIHA and hereditary spherocytosis

Question 30

What are the clinical features specific to haemolytic anaemia?

Answer 30

• jaundice
• dark urine (hemoglobinuria, bilirubin)
• cholelithiasis (pigment stones)
• potential for an aplastic crisis (i.e. BM suppression in overwhelming infection)
• iron overload with extravascular hemolysis
• iron deficiency with intravascular hemolysis

Question 31

Define thalassemia and its pathophysiology?

Answer 31

• Definition
  
  • defects in production of the α or β chains of hemoglobin
    
    • resulting imbalance in globin chains leads to ineffective erythropoiesis and hemolysis in then spleen or BM
  • clinical manifestations and treatment depends on specific gene and number of alleles affected
  • common features
    
    • increasing severity with increasing number of alleles involved
    • hypochromic microcytic anemia
    • basophilic stippling, abnormally shaped RBCs on blood film
• Pathophysiology
  
  • defect may be in any of the Hb genes
    
    • normally 4α genes in total; 2 on each copy of chromosome 16
    • normally 2β genes in total; 1 on each copy of chromosome 11
    • fetal hemoglobin, HbF (α2γ2), switches to adult forms HbA (α2β2) and HbA2 (α2δ2) at 3-6 mo of life
    • HbA constitutes 97% of adult hemoglobin
    • HbA2 constitutes 3% of adult hemoglobin

Question 32

Define microangiopathic haemolytic anaemia and its aetiology?

Answer 32

• Definition
  
  • haemolytic anemia due to intravascular fragmentation of RBCs
• Etiology
  
  • Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome
  • Disseminated Intravascular Coagulation
  • eclampsia, HELLP syndrome, AFLP
  • malignant HTN
  • vasculitis
  • malfunctioning heart valves
  • metastatic carcinoma
  • drugs (calcineurin inhibitors, quinine, simvastatin)
  • infections (severe CMV or meningococcus)
  • catastrophic antiphospholipid antibody syndrome

Question 33

Define glucose-6-phosphate dehydrogenase deficiency and it pathophysiology?

Answer 33

• Definition
  
  • deficiency in glucose-6-phosphate dehydrogenase (G6PD) leads to RBC sensitivity to oxidative stress due to a lack of reduced glutathione (GSH)
• Pathophysiology
  
  • X-linked recessive, prevalent in individuals of African, Asian, and Mediterranean descent

Question 34

What are the clinical features of G6PD?

Answer 34

• frequently presents as episodic hemolysis precipitated by
  
  • oxidative stress
  • drugs (e.g. sulfonamide, antimalarials, nitrofurantoin)
  • infection
  • food (fava beans)
• in neonates: can present as prolonged, pathologic neonatal jaundice

Question 35

What Ix need to be done in G6PD and what is seen on Ix?

Answer 35

• neonatal screening - heel prick test
• G6PD assay (may not be useful if result is normal)
  
  • should not be done in acute crisis when reticulocyte count is high (reticulocytes have high G6PD levels)
• blood film
  
  • Heinz bodies (granules in RBCs due to oxidized Hb); passage through spleen results in the generation of bite cells
  • may have features of intravascular hemolysis (e.g. RBC fragments)

Question 36

What is the treatment for G6PD?

Answer 36

• Folic acid
• stop offending drugs and avoid triggers
• transfusion in severe cases

Question 37

What are the aetiologies of Vit B₁₂ deficiency?

Answer 37

Question 38

What is the pathophysiology of pernicious anaemia?

Answer 38

• auto-antibodies produced against gastric parietal cells leading to achlorhydria and lack of intrinsic factor secretion
• intrinsic factor is required to stabilize B12 as it passes through the bowel
• decreased intrinsic factor leads to decreased ileal absorption of B12
• may be associated with other autoimmune disorders (polyglandular endocrine insufficiency)
• F:M = 1.6:1; often >60 yr old

Question 39

What are the clinical features of vit B₁₂ deficiency?

Answer 39

• neurological
  
  • cerebral (common, reversible with B12 therapy)
    
    • confusion, delirium, dementia
  • cranial nerves (rare)
    
    • optic atrophy
  • cord (irreversible damage)
    
    • subacute combined degeneration
      
      • posterior columns: decreased vibration sense, proprioception, and 2-point discrimination
      • pyramidal tracts: spastic weakness, hyperactive reflexes
  • peripheral neuropathy (variable reversibility)
    
    • usually symmetrical, affecting lower limbs more than upper limbs

Question 40

What Ix should be order for Vit B12 deficiency anaemia and what is found on Ix?

Answer 40

• FBC, reticulocyte count
  
  • anemia often severe ± neutropenia ± thrombocytopenia
  • MCV >110 fL
  • low reticulocyte count relative to the degree of anemia (<2%)
• serum B12 and RBC folate
  
  • caution: low serum B12 leads to low RBC folate because of failure of folate polyglutamate synthesis in the absence of B12
  • alternatively, can measure urine metabolites (methylmalonate, homocysteine)
• blood film
  
  • oval macrocytes, hypersegmented neutrophils
• bone marrow
  
  • hypercellularity
  • nuclear-cytoplasmic asynchrony in RBC precursors (less mature nuclei than expected from the development of the cytoplasm)
• bilirubin and LDH
  
  • elevated unconjugated bilirubin and LDH due to breakdown of cells in BM
• Schilling test (see sidebar H24) to distinguish pernicious anemia from other causes
  
  • anti-intrinsic factor antibody, anti-parietal cell antibody

Question 41

What is the treatment for Vit B12 deficiency anaemia?

Answer 41

• vitamin B12 1,000 μg IM monthly for life or 1,000-1,200 μg PO daily if intestinal absorption intact
• less frequent, higher doses may be as effective (e.g. 1,000 μg IM q3mo)
• watch for hypokalemia and rebound thrombocytosis when treating severe megaloblastic anemia

Question 42

What are the aetiologies of folate deficiency?

Answer 42

Question 43

What are the clinical features of folate deficiency?

Answer 43

• mild jaundice due to hemolysis of RBCs secondary to ineffective hemoglobin synthesis
• glossitis and angular stomatitis
• melanin pigmentation (rare)
• purpura secondary to thrombocytopenia (rare)
• unlike B₁₂ deficiency, folate deficiency has no neurologic manifestations

Question 44

Define venous thromboembolism.

Answer 44

• thrombus formation and subsequent inflammatory response in a superficial or deep vein
• superficial thrombophlebitis, deep vein thrombosis (DVT), and pulmonary embolism (PE)
• thrombi propagate in the direction of blood flow (commonly originating in calf veins)
• more common in lower extremity than upper extremity
• incidence ~1% if age >60 yr
• most important sequelae are pulmonary embolism (~50% chance with proximal DVT) and chronic venous insufficiency

Question 45

What is the aetiology of VTE

Answer 45

• endothelial damage
  
  • exposes endothelium to prompt hemostasis
  • leads to decreased inhibition of coagulation and local fibrinolysis
• venous stasis
  
  • immobilization (post-MI, CHF, stroke, post-operative) inhibits clearance and dilution of coagulation factors
• hypercoagulability
  
  • inherited
  • acquired
    
    • age (risk increases with age)
    • surgery (especially orthopedic, thoracic, GI, and GU)
    • trauma (especially fractures of spine, pelvis, femur or tibia, spinal cord injury)
    • neoplasms (especially lung, pancreas, colon, rectum, kidney, and prostate)
    • blood dyscrasias (myeloproliferative neoplasms, especially PV, ET), PNH, hyperviscosity (multiple myeloma, polycythemia, leukemia, sickle cell disease)
    • prolonged immobilization (CHF, stroke, MI, leg injury)
    • hormone related (pregnancy, OCP, HRT, SERMs)
    • APS
    • heart failure (risk of DVT greatest with right heart failure and peripheral edema)
• idiopathic (10-20% are later found to have cancer)

Question 46

What are the clinical features of DVT?

Answer 46

• absence of physical findings does not rule out disease
• unilateral leg edema, erythema, warmth, and tenderness
• palpable cord (thrombosed vein)
• phlegmasia cerulea dolens and phlegmasia alba dolens with massive thrombosis
• Homan’s sign (pain with foot dorsiflexion) is unreliable

Question 47

What are the DDx of DVT?

Answer 47

• muscle strain or tear
• lymphangitis or lymph obstruction
• venous valvular insufficiency
• ruptured popliteal cysts
• cellulitis
• arterial occlusive disease

Question 48

What are the Ix for DVT?

Answer 48

• D-dimer test only useful to rule out DVT if negative with low clinical suspicion of disease and no other acute medical issues
• doppler ultrasound is most useful diagnostic test for DVT
  
  • sensitivity and specificity for proximal DVT ~95%
  • sensitivity for calf DVT ~70%
• other non-invasive tests include MRI and impedence plethysmography
• venography is the gold standard, but is expensive, invasive, and higher risk

Question 49

What is post-thrombotic syndrome?

Answer 49

• development of chronic venous stasis signs and symptoms secondary to a deep venous thrombosis
• symptoms: pain, venous dilatation, oedema, pigmentation, skin changes, venous ulcers
• clinical severity can be estimated based on the Villalta score
• large impact on quality of life following a DVT
• treatment: extremity elevation, exercise, continuous compression stockings, intermittent pneumatic compression therapy, skin/ulcer care

Question 50

What are the contraindications for the treatment of VTE?

Answer 50

Question 51

What is mucositis?

Answer 51

Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer.

Question 52

Define and classify non-hodgkin lymphoma.

Answer 52

• Definition
  
  • malignant proliferation of lymphoid cells of progenitor or mature B- or T-cells
• Classification
  
  • multiple classification systems exist at present and may be used at different centers
  • can originate from both B- (85%) and T- or NK- (15%) cell
    
    • B-cell NHL: e.g. diffuse large B-cell lymphoma, follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma
    • T-cell NHL: e.g. mycosis fungoides, anaplastic large cell lymphoma
• WHO/REAL classification system: 3 categories of NHLs based on natural history
  
  • indolent (35-40% of NHL): e.g. follicular lymphoma, small lymphocytic lymphoma/CLL
  • aggressive (~50% of NHL): e.g. diffuse large B-cell lymphoma
    
    • Note: mantle cell lymphoma (7% of NHL) may have features of aggressive or indolent lymphoma
  • highly aggressive (~5% of NHL): e.g. Burkitt’s lymphoma

Question 53

What are the clinical features of non-Hodgkin lymphoma?

Answer 53

• painless superficial lymphadenopathy, usually >1 lymph node region
• usually presents as widespread disease (exception is aggressive lymphoma)
• constitutional symptoms not as common as in Hodgkin lymphoma
• cytopenia: anemia ± neutropenia ± thrombocytopenia can occur when bone marrow is involved
• abdominal signs
  
  • hepatosplenomegaly
  • retroperitoneal and mesenteric involvement (second most common site of involvement)
• oropharyngeal involvement in 5-10% with sore throat and obstructive apnea
• extranodal involvement: most commonly GI tract; also testes, bone, kidney
• CNS involvement in 1% (often with HIV)

Question 54

Describe the pathophysiology of neurological complications of B₁₂ deficiency?

Answer 54

Vitamin B12 deficiency is known to adversely affect neuronal function, but the exact mechanism (or combination of mechanisms) remains elusive.

Reduced methylation of neuronal lipids and neuronal proteins, such as myelin basic protein, have been hypothesized to play a role in some of the neurologic deficits. Myelin basic protein makes up approximately one-third of myelin, and demyelination in the setting of vitamin B12 deficiency may explain many of the neurologic findings

Question 55

Describe the invesgitation and what is seen in non-hodgkins lymphoma?

Answer 55

• FBC
  
  • normocytic normochromic anemia
  • autoimmune hemolytic anemia
  • advanced disease: thrombocytopenia, neutropenia, and leukoerythroblastic anemia
• peripheral blood film may show lymphoma cells
• flow cytometry of peripheral blood is valuable for low-grade NHL
• biochemistry
  
  • increase in uric acid
  • abnormal LFTs in liver metastases\
  • increased LDH (rapidly progressing disease, poor prognostic factor)
• CXR, CT neck, abdomen, pelvis for staging
• PET is useful for monitoring response to treatment and evaluation of residual tumor following therapy in aggressive histological disease
• diagnosed by
  
  • lymph node biopsy: excisional biopsy preferred, FNA unreliable
  • bone marrow biopsy: not optimal for diagnosis as BM may not be involved

Question 56

What is the treatment for non-Hodgkins lymphoma?

Answer 56

• localized disease (e.g. GI, brain, bone, head and neck)
  
  • radiotherapy to primary site and adjacent nodal areas
  • adjuvant chemotherapy
  • surgery: splenic marginal zone lymphoma
• indolent lymphoma: goal of treatment is symptom management
  
  • watchful waiting
  • radiation therapy for localized disease
  • bendamustine plus rituximab, an anti-CD20 antibody, is superior to CHOP + rituximab (CHOP-R) for advanced stage disease (StIL trial)
• aggressive lymphoma: goal of treatment is curative
  
  • combination chemotherapy: CHOP is mainstay, plus rituximab if B-cell lymphoma; different regimens for mantle cell lymphoma
  • radiation for localized/bulky disease
  • CNS prophylaxis with high-dose methotrexate if certain sites involved (testicular, nasopharyngeal)
  • relapse, resistant to therapy: high dose chemotherapy, BMt
• highly aggressive lymphoma
  
  • Burkitt lymphoma: short bursts of intensive chemotherapy
  • “CODOX-M” chemotherapy regimen also often used ± IVAC
  • CNS prophylaxis and tumor lysis syndrome prophylaxis

Question 57

Define chronic lymphocytic leukaemia and describe its pathophysiology?

Answer 57

• Definition
  
  • indolent disease characterized by clonal malignancy of mature B-cells
• Pathophysiology
  
  • accumulation of neoplastic lymphocytes in blood, bone marrow, lymph nodes, and spleen

Question 58

What are the clinical featres of CLL?

Answer 58

• 25% asymptomatic (incidental finding)
• 5-10% present with B-symptoms (≥1 of: unintentional weight loss ≥10% of body weight within previous 6 mo, temperature >38ºC or night sweats for ≥2 wk without evidence of infection, extreme fatigue)
• lymphadenopathy (50-90%), splenomegaly (25-55%), hepatomegaly (15-25%)
• immune dysregulation: autoimmune hemolytic anemia (Coombs positive), ITP, hypogammaglobulinemia ± neutropenia
• bone marrow failure: late, secondary to marrow involvement by CLL cells

Question 59

What Ix are done for CLL and what do the results look like?

Answer 59

• Bloods:
  
  • FBC: clonal population of CLL lymphocytes >5 x 109/L
  • LFTs: heptomegaly
• peripheral blood film
  
  • lymphocytes are small and matureƒ
  • smudge cells
• flow cytometry (CD5, CD20, CD23, etc.)
• Coombs test
• cytogenetics: FISH (dictates response therapy and prognosis)
• bone marrow biopsy
  
  • lymphocytes >30% of all nucleated cells
  • infiltration of marrow by lymphocytes in 4 patterns: nodular (10%), interstitial (30%), diffuse (35%, worse prognosis), or mixed (25%)
• Imaging:
  
  • CT abdo chest

Question 60

What is the natural history and treatment of CLL?

Answer 60

• natural history: indolent but incurable, with slow progression; thus select gentlest treatment that will control symptoms
  
  • observation if early, stable, asymptomatic
  • intermittent chlorambucil or fludarabine chemotherapy combined with rituximab, chlorambucil in the elderly
  • corticosteroids, IVIg: especially for autoimmune phenomena
  • radiotherapy
• small minority present with aggressive disease; usually associated with chromosomal abnormalities (e.g. p53 deletion)
• 9 yr median survival, but varies greatly
• prognosis predicted by Rai staging
  
  • low risk: lymphocytosis in blood and bone marrow only
  • intermediate risk: lymphocytosis with enlarged nodes in any site or splenomegaly, hepatomegaly
  • high risk: lymphocytosis with disease-related non-immune-mediated anemia (<11.0 g/dL) or thrombocytopenia (<100,000/mm3)
• molecular therapies
  
  • Idelalisib – PI3K inhibitor (not FDA-approved)
  • Ibrutinib – BTK (Bruton’s tyrosine kinase) inhibitor (FDA-approved in relapsed setting)

Question 61

What are the complications of CLL?

Answer 61

• bone marrow failure
• immune complications: AIHA, ITP, immune deficiency (hypogammaglobulinemia, impaired T-cell function)
• polyclonal or monoclonal gammopathy (often IgM)
• hyperuricemia with treatment
• 5% undergo Richter’s transformation: aggressive transformation to diffuse large B-cell lymphoma

Question 62

What is the clincial presentation of leukaemia in children?

Answer 62

• infiltration of leukemic cells into bone marrow results in bone pain and bone marrow failure (anemia, neutropenia, thrombocytopenia)
• infiltration into tissues results in lymphadenopathy, hepatosplenomegaly, CNS manifestations, testicular disease
• fever, fatigue, weight loss, bruising, and easy bleeding
• hyperleukocytosis (total WBC >10.0 x 109/dL) is a medical emergency
  
  • presents clinically with respiratory or neurological distress caused by hyperviscosity of blood and leukostasis
  • risk of ICH, pulmonary leukostasis syndrome, tumor lysis syndrome
  • management: fluids, allopurinol/rasburicase, fresh frozen plasma/platelets to correct thrombocytopenia, induction chemotherapy, avoid transfusing RBCs unless symptomatic (and then use very small volumes)

Question 63

What is the definition of febrile neutropenia? and the pathophysiology of it.

Answer 63

• Definition
  
  • fever (≥38.3ºC or ≥38.0ºC for ≥1 h) and one of:
    
    • ANC (absolute neutrophil count) <0.5 OR
  • ƒ ANC <1.0 but trending down to 0.5
• Pathophysiology
  
  • decreased neutrophil production
    
    • marrow: infection, aplastic/myelophthisic anemia, leukemia, lymphoma, myelodysplastic syndromes
    • iatrogenic: cancer chemotherapy, radiation, drugs
    • deficiencies: vitamin B12, folate
  • increased peripheral neutrophil destruction
    
    • autoimmune: Felty’s syndrome, SLE, antineutrophil antibodies
    • splenic sequestration

Question 64

What is the epidemiology and aetiology of febrile neutropenia?

Answer 64

• most common life-threatening complication of cancer therapy
• 8 cases per 1,000 cancer patients per year in the U.S.
• causative organism identified only 1/3 of the time
• Gram -ve (especially Pseudomonas) historically most common
• Gram +ve more common now
• fungal superinfection if neutropenia prolonged or if concurrent antibiotic use (especially Candida, Aspergillus)

Question 65

What Ix need to be done on a patient with febrile neutropenia?

Answer 65

• examine for potential sites of infection: mucositis and line infections are most common
• do NOT perform DRE; examine perianal region
• blood C&S (x2 sets), urine C&S, culture all indwelling catheter ports, ± sputum C&S and NP swab for respiratory viruses
• CBC and differential, Cr, BUN, electrolytes, AST/ALT, total bilirubin

Question 66

What is the treatment for febrile neutropenia?

Answer 66

• Piperacillin + tazobactam 4 + 0.5g IV, 6 hourly
• CAN add gentamicin 4-7mg/kg if resistant to piptaz or pt is in severe sepsis or septic shock
• IF MRSA ADD vancomycin IV

Question 67

Classify disorders of primary haemotstasis

Answer 67

• inability to form an adequate platelet plug due to:
  
  • disorders of blood vessels
  • disorders of platelets: abnormal function/numbers
  • disorders of vWF

Question 68

Describe the pathophysiology of von Willebrand disease.

Answer 68

• heterogeneous group of defects, usually mild in severity
• usually autosomal dominant (type 3 is autosomal recessive)
• qualitative or quantitative abnormality of vWF
  
  • vWF needed for platelet adhesion and acts as carrier for Factor VIII; abnormality of vWF can affect both primary and secondary hemostasis
  • vWF exists as a series of multimers ranging in size
    
    • largest multimers are most active in mediation of platelet adhesion, both large and small multimers complex with Factor VIII

Question 69

Describe the coagulation cascade.

Answer 69

Question 70

How is von Willebrand disease classified?

Answer 70

• type 1: mild quantitative defect (decreased amount of vWF and proportional decrease in vWF activity) – 75% of cases
• type 2: qualitative defect (vWF activity disproportionally lower than quantity) – 20-25% of cases
• type 3: severe total quantitative defect (no vWF produced) – rare

Question 71

What are the clinical features of von Willebrand disease?

Answer 71

• mild
  
  • asymptomatic
  • mucosal and cutaneous bleeding, easy bruising, epistaxis, menorrhagia
• moderate to severe
  
  • as above but more severe, occasionally soft-tissue haematomas, petechiae (rare), GI bleeding, haemarthroses

Question 72

What Ix is done for von Willebrand disease and the expected results?

Answer 72

Question 73

What is the treatment for von Willebrand disease?

Answer 73

• desmopressin (DDAVP®) is treatment of choice for type 1 vWD
  
  • causes release of vWF and Factor VIII from endothelial cells
  • variable efficacy depending on disease type; tachyphylaxis occurs
  • need good response before using with further bleeding
  • caution in children due to hyponatremia
• tranexamic acid (Cyklokapron®, antifibrinolytic) to stabilize clot formation
• high-purity Factor VIII concentrate containing vWF (Hemate P®) in select cases and type
  
  • frozen plasma (FP) is not useful
  • need to monitor vWF and factor VIII levels (very high factor VIII level can cause thrombosis)
• conjugated estrogens (increase vWF levels)

Question 74

Classify disorders of secondary haemostasis.

Answer 74

• inability to form an adequate fibrin clot
  
  • disorders of clotting factors or co-factors
  • disorders of proteins associated with fibrinolysis
• characterized by delayed bleeding, deep muscular bleeding, spontaneous joint bleeding

Question 75

What are the 5 Hs of haemophilia A?

Answer 75

1. Haemarthroses
2. Haematomas
3. Haematochezia
4. Haematuria
5. Head Haemorrhage

Question 76

Describe the pathophysiology, clinical features, Ix, and Rx for haemophilia A (Factor VIII deficiency)?

Answer 76

• Pathophysiology
  
  • X-linked recessive, 1/5,000 males
  • mild (>5% of normal factor level), moderate (1-5%), severe (<1%
• Clinical Features
  
  • Surface cuts: normal/slightly prolonged bleeding
  • haemostasis onset after injury is delayed
  • site of bleeding: deep i.e. joints, muscles, GI tract, GU tract, excessive post-traumatic bleeding
  • haemarthroses and haematomas
  • older patients may also have HIV or HCV from contaminated blood products
• Investigations
  
  • prolonged aPTT, normal INR (PT)
  • decreased Factor VIII (<40% of normal)
  • vWF usually normal or increased
• Treatment
  
  • desmopressin (DDAVP®) in mild hemophilia A
  • recombinant Factor VIII concentrate for
    
    • prophylaxis (2-3x/wk at home)
    • minor but not trivial bleeding (e.g. hemarthroses)
    • major potentially life-threatening bleeding (e.g. multiple trauma)
  • anti-fibrinolytic agents (e.g. tranexamic acid)

Question 77

Describe haemophilia B (factor IX deficiency)

Answer 77

• i.e. Christmas disease
• X-linked recessive, 1/30,000 males
• clinical and laboratory features identical to hemophilia A (except decreased Factor IX)
• treatment: recombinant Factor IX concentrate, anti-fibrinolytic agents

Question 78

Define tumour lysis syndrome.

Answer 78

• group of metabolic complications that result from spontaneous or treatment-related breakdown of cancer cells
• more common in diseases with large tumor burden and high proliferative rate (high grade lymphoma, leukemia)

Question 79

What are the metabolic abnormalities that are seen in tumour lysis syndrome and the complications of them?

Answer 79

• metabolic abnormalities
  
  • cells lyse, releasing K⁺, uric acid, PO₄^3- (increased levels)
  • PO₄^3- binds Ca²⁺ (decreased Ca²⁺)
• complications
  
  • lethal cardiac arrhythmia (increased K⁺)
  • acute renal failure (urate nephropathy)

Question 80

What is the Rx for tumour lysis syndrome?

Answer 80

• prevention
  
  • aggressive IV hydration
  • alkalinization of the urine
  • allopurinol or rasburicase
  • correction of pre-existing metabolic abnormalities
• dialysis

Question 81

Define hyperviscosity syndrome.

Answer 81

• refers to clinical sequelae of increased blood viscosity (when relative serum viscosity >5-6 units), resulting from increased circulating serum Igs or from increased cellular blood components in hyperproliferative disorders (e.g. multiple myeloma, leukemia, PV)
• Waldenstrom’s macroglobulinemia accounts for 85% of cases

Question 82

What are the clincial features of hyperviscosity syndrome?

Answer 82

• hypervolaemia causing: CHF, headache, lethargy, dilutional anaemia
• CNS symptoms due to decreased cerebral blood flow: headache, vertigo, ataxia, stroke
• retina shows venous engorgement and hemorrhages
• bleeding diathesis
  
  • due to impaired platelet function, absorption of soluble coagulation factors (e.g. nasal bleeding, oozing gums)
• ESR usually very low

Question 83

Define acute myeloid leukaemia and describe its epidemiology?

Answer 83

• Definition:
  
  • rapidly progressive malignancy characterized by failure of myeloid cells to differentiate beyond blast stage
• Epidemiology
  
  • incidence increases with age; median age of onset is 65 yr old
  • accounts for 10-15% of childhood leukemias

Question 84

What are the risks factors for developing AML?

Answer 84

Myelodysplastic syndromes (MDS), benzene, radiation, alkylating agents as treatment for previous malignancy

Question 85

Describe the pathophysiology of AML.

Answer 85

• etiology subdivided into
  
  • primary: de novo
  • secondary: hematologic malignancies (e.g. myeloproliferative disorders and MDS) or previous chemotherapeutic agents (e.g. alkylating agents)
• uncontrolled growth of blasts in marrow leads to
  
  • suppression of normal hematopoietic cells
  • appearance of blasts in peripheral blood
  • accumulation of blasts in other sites (e.g. skin, gums)
  • metabolic consequences; tumor lysis syndrome

Question 86

What are the clinical features of AML?

Answer 86

• anemia, thrombocytopenia (associated with DIC in PML), neutropenia (even with normal WBC), leads to infections, fever
• thrombocytopenia (associated with DIC in promyelocytic leukemia)
• accumulation of blast cells in marrow
  
  • skeletal pain, bony tenderness (especially sternum)
• organ infiltration
  
  • gingival hypertrophy (particularly myelomonocytic leukemia) – may present to dentist first
  • hepatosplenomegaly (in ALL)
  • lymphadenopathy (not marked)
  • skin: leukemia cutis
  • gonads (in ALL)
  • eyes: Roth spots, cotton wool spots, vision changes (uncommon)
• leukostasis/hyperleukosis syndrome (medical emergency)
  
  • large numbers of blasts interfere with circulation and lead to hypoxia and hemorrhage – can cause diffuse pulmonary infiltrates, CNS bleeding, respiratory distress, altered mental status, priapism
• metabolic effects; aggravated by treatment (rare)
  
  • increased uric acid → nephropathy, gout
  • release of phosphate → decreased Ca²⁺, decreased Mg²⁺
  • release of procoagulants → DIC (higher risk in acute promyelocytic leukemia)
• decreased or normal K⁺ before treatment, increased K⁺ after treatment (from lysed cells)

Question 87

What Ix would be ordered for AML and what are the expected results?

Answer 87

• blood work
  
  • FBC: anemia, thrombocytopenia, variable WBC
  • ƒ INR, aPTT, fibrin degradation products (FDP), fibrinogen (in case of DIC)
  • increased LDH, increased uric acid, increased PO₄^3- (released by leukemic blasts), decreased Ca²⁺
  • baseline renal and liver function tests
• peripheral blood film – circulating blasts with Auer rods (azurophilic granules) are pathognomonic for AML
• Bone marrow aspirate
  
  • blast count: AML >20% (normal is <5%)
  • morphologic, cytochemical, and/or immunotypic features are used to establish lineage and maturation
• CXR to rule out pneumonia, ECG, MUGA scan prior to chemotherapy (cardiotoxic)

Question 88

What is the Rx for AML?

Answer 88

• mainstay of treatment is chemotherapy (rapidly fatal without treatment)
  
  • all AML subtypes treated similarly except promyelocytic variant with t(15:17) translocation
    
    • all-trans-retinoic acid (ATRA) added to induce differentiation; arsenic trioxide + ATRA combination therapy for APL is non-inferior to traditional chemotherapy
• treatment strategy
  
  • 1. Induction: chemotherapy to induce complete remission of AML
       * several possible regimens (e.g. cytarabine with anthracycline [daunorubicin])
       * patients with poor response to initial induction therapy – worse prognosis
       * must ensure reversal of DIC, platelet transfusions if <10
  • 2. Consolidation: to prevent recurrence
       * intensive consolidation chemotherapy
       * stem cell transplantation – autologous or allogeneic (younger patients with better performance status)
• consider acceleration with hematopoietic growth factors (e.g. G-CSF) if severe infection develops
• supportive care
  
  • screening for infection via regular C&S of urine, stool, sputum, oropharynx, catheter sites, perianal area
  • fever: C&S of all orifices, CXR, start antibiotics
  • platelet and RBC transfusions (irradiated to prevent transfusion-related GVHD) ± EPO
  • prevention and treatment of metabolic abnormalities
    
    • allopurinol, rasburicase for prevention of hyperuricemia

Question 89

What is the prognosis for AML?

Answer 89

• achievement of first remission
  
  • 70-80% if ≤60 yr old, 50% if >60 yr old
  • median survival 12-24 mo
  • 5 yr survival 40%
  • prognosis related to cytogenetics (favorable, intermediate, or adverse)

Question 90

Define chronic myeloid leukaemia and its epidemiology.

Answer 90

• Definition
  
  • myeloproliferative disorder characterized by increased proliferation of the granulocytic cell line without the loss of their capacity to differentiate
• Epidemiology
  
  • occurs in any age group (mostly middle age to elderly) with a median age of 65 yr

Question 91

Describe hte pathophysiology of chronic myeloid leukaemia.

Answer 91

• Philadelphia chromosome (Ph)
  
  • translocation between chromosomes 9 and 22
  • the c-abl proto-oncogene is translocated from chromosome 9 to “breakpoint cluster region” (bcr) of chromosome 22 to produce bcr-abl fusion gene, an active tyrosine kinase

Question 92

What are the clinical features of chronic myeloid leukaemia?

Answer 92

• 3 clinical phases
  
  • chronic phase: 85% diagnosed here
    
    • few blasts (<10%) in peripheral film
    • ± slightly elevated eosinophils and basophils
    • no significant symptoms other than leukostasis
  • accelerated phase: impaired neutrophil differentiation
    
    • circulating blasts (10-19%) with increasing peripheral basophils (pruritus)
    • FBC: thrombocytopenia <100,000/mm3
    • cytogenetic evidence of clonal evolution
    • worsening constitutional symptoms and splenomegaly (extramedullary hematopoiesis)
  • blast crisis: more aggressive course, blasts fail to differentiate
    
    • blasts (>20%) in peripheral blood or bone marrow; reflective of acute leukemia (1/3 ALL, 2/3 AML)
• clinical presentation
  
  • 20-50% of patients are asymptomatic when diagnosed (incidental lab finding)
  • nonspecific symptoms
    
    • fatigue, weight loss, malaise, excessive sweating, fever
  • secondary to splenic involvement
    
    • early satiety, LUQ pain/fullness, shoulder tip pain (referred)
    • splenomegaly (most common physical finding)
  • anemia
  • bleeding: secondary to platelet dysfunction
  • pruritus, PUD: secondary to increased blood histamine
  • leukostasis, priapism, encephalopathy (rare): secondary to very elevated WBC (rare)

Question 93

What Ix are needed for CML and what results are expected?

Answer 93

• high increase in WBC, decreased/normal RBC, increased/decreased platelets, increased basophils
  
  • WBC differential shows a bimodal distribution, with predominance of myelocytes and neutrophils
• peripheral blood film
  
  • leukoerythroblastic picture (immature red cells and granulocytes present, e.g. myelocytes and normoblasts)
  • presence of different mid-stage progenitor cells differentiates it from AML
• bone marrow
  
  • myeloid hyperplasia with left shift, increased megakaryocytes, mild fibrosis
• molecular and cytogenetic studies of bone marrow or peripheral blood for Philadelphia chromosome
• abdominal imaging for spleen size

Question 94

What is the Rx for CML?

Answer 94

• symptomatic
  
  • allopurinol and antihistamines
• chronic phase
  
  • imatinib mesylate inhibits proliferation and induces apoptosis by inhibiting tyrosine kinase activity in cells positive for bcr-abl
    
    • if loss of response or intolerance (~25%), trial of 2nd (dasatinib, nilotinib) or 3rd generation inhibitors
    • dasatinib may be considered for first line management (see sidebar)
  • interferon-α: may improve response to tyrosine kinase inhibitors
  • hydroxyurea in palliative setting
  • bone marrow transplantation if progression to accelerated or blast phases: CML (curative)
• accelerated phase or blast phase
  
  • refer for clinical trial or 2nd/3rd generation (ponatinib only for T315I-mutated CML) TKI and prepare for allogeneic stem cell transplant patients, in blast phase typically get standard AML induction
• stem cell transplantation may be curative: to be considered in young patients who do not meet therapeutic milestones
• treatment success is monitored based on therapeutic milestones
  
  • haematologic: improved WBC and platelet counts, reduced basophils
  • cytogenetic: undetectable Philadelphia-chromosome in the bone marrow
  • molecular: reduction/absence of bcr-abl transcripts in periphery and marrow

Question 95

What is the prognosis for CML?

Answer 95

• survival dependent on response
  
  • those achieving complete cytogenetic response (CCR) on imatinib by 18 mo of therapy: 6 yr overall survival >90%
  • those who do NOT achieve CCR on imatinib: 6 yr overall survival of 66%
• acute phase (blast crisis – usually within 3-5 yr)
  
  • 2/3 develop a picture similar to AML
    
    • unresponsive to remission induction
  • 1/3 develop a picture similar to ALL
    
    • remission induction (return to chronic phase) achievable

Question 96

Define polycythemia vera.

Answer 96

Stem cell disorder characterized by elevated RBC mass (erythrocytosis) ± increased white cell and platelet production.

Question 97

What are the clinical features of polycythaemia vera?

Answer 97

• symptoms are secondary to high red cell mass and hyperviscosity
• bleeding complications: epistaxis, gingival bleeding, ecchymoses, and GI bleeding
  
  • due to platelet abnormalities
• thrombotic complications: DVT, PE, thrombophlebitis, increased incidence of stroke, MI
  
  • due to increased blood viscosity, increased platelet number and/or activity
• erythromelalgia (burning pain in hands and feet and erythema of the skin)
  
  • associated with platelets >400,000/mm3
  • pathognomonic microvascular thrombotic complication in PV and ET
• pruritus, especially after warm bath or shower (40%)
  
  • due to cutaneous mast cell degranulation and histamine release
• epigastric distress, PUD
  
  • due to increased histamine from tissue basophils, alterations in gastric mucosal blood flow due to increased blood viscosity
• gout (hyperuricemia)
  
  • due to increased cell turnover
• characteristic physical findings
  
  • plethora (ruddy complexion) of face (70%), palms
  • splenomegaly (70%), hepatomegaly (40%)

Question 98

What Ix need to be ordered for polycythaemia vera and what are the expected results?

Answer 98

• serum erythropoietin (EPO): increased EPO suggests autonomous production or hypoxia, and is used to rule out PV
• must rule out secondary polycythemia
• diagnosis (WHO 2008) requires either both major criteria plus one minor criteria OR the first major criterion plus 2 minor criteria
  
  • Major Criteria
    
    • 1. hemoglobin >18.5 g/dL in men, 16.5 g/dL in women or other evidence of increased red cell volume
    • 2. presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation
  • Minor Criteria
    
    • 1. bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation
    • 2. serum erythropoietin level below the reference range for normal
    • 3. endogenous erythroid colony formation in vitro
         *

Question 99

What is the Rx for polycythaemia vera?

Answer 99

• phlebotomy to keep hematocrit <45%
• hydroxyurea (prior thrombosis or symptoms, severe coronary artery disease, refractory to phlebotomy)
• low-dose Aspirin® (for antithrombotic prophylaxis, will also treat erythromelalgia)
• allopurinol: as needed
• antihistamines: as needed

Question 100

What is the prognosis of polycythaemia vera?

Answer 100

• 10-20 yr survival with treatment
• complicated by thrombosis, hemorrhage, leukemia transformation (AML)

Question 101

Define idiopathic myelofibrosis and its epidemiology?

Answer 101

• Definition
  
  • excessive bone marrow fibrosis leading to marrow failure
  • characterised by anaemia, extramedullary haematopoiesis, leukoerythroblastosis, teardrop red cells in peripheral blood and hepatosplenomegaly
• Epidemiology
  
  • rare, median age at presentation is 65 yr

Question 102

Describe the pathophysiology of idiopathic myelofibrosis?

Answer 102

• abnormal myeloid precursor postulated to produce dysplastic megakaryocytes that secrete fibroblast growth factors
  
  • stimulates fibroblasts and stroma to deposit collagen in marrow
• increasing fibrosis causes early release of haematopoietic precursors leading to:
  
  • leukoerythroblastic blood film (primitive RBCs and WBCs present in blood)
  • migration of precursors to other sites: extramedullary haematopoiesis (leading to hepatosplenomegaly)
  • mutations in JAK2, c-mpl, and calreticulin define the clone

Question 103

What are the clinical features of idiopathic myelofibrosis?

Answer 103

• anaemia (severe fatigue is most common presenting complaint, pallor on exam in >60%)
• weight loss, fever, night sweats → secondary to hypermetabolic state
• splenomegaly (90%) → secondary to extramedullary haematopoiesis; may cause early satiety
• hepatomegaly (70%) → may get portal HTN
• bone and joint pain → secondary to osteosclerosis, gout
• signs of extramedullary haematopoiesis (depends on organ involved)

Question 104

What Ix need to be order for idiopathic myelofibrosis and what are the expected results?

Answer 104

• FBC: anemia, variable platelets, variable WBC
• biochemistry: increased ALP (liver involvement, bone disease), increased LDH (2^o to ineffective haematopoiesis), increased uric acid (increased cell turnover), increased B₁₂ (2^o to increased neutrophil mass)
• blood film: leukoerythroblastosis with teardrop RBCs, nucleated RBCs, variable polychromasia, large platelets, and megakaryocyte fragments
• JAK2 PCR
• bone marrow aspirate: “dry tap” in as many as 50% of patients (no blood cells espirated)
• bone marrow biopsy (essential for diagnosis): fibrosis, atypical megakaryocytic hyperplasia, thickening and distortion of the bony trabeculae (osteosclerosis)

Question 105

What is the RX for idiopathic myelofibrosis?

Answer 105

• allogeneic stem cell transplant is potentially curative
• JAK2 inhibitors
• symptomatic treatment
  
  • transfusion for anaemia
  • erythropoietin: 30-50% of patients respond
  • androgens (e.g. danazol has shown transient response with response rates of <30%)
  • hydroxyurea for splenomegaly, thrombocytosis, leukocytosis, systemic symptoms
    
    • α-interferon (as second line therapy)
    • splenectomy (as third line therapy; associated with high mortality and morbidity)
  • radiation therapy for symptomatic extramedullary haematopoiesis, symptomatic splenomegaly
  • thalidomide, and etanercept may improve quality of life and spleen size, but not survival

Question 106

What is the prognosis for idiopathic myelofibrosis?

Answer 106

• International Prognostic Scoring System (IPSS) for IMF uses 5 factors to determine mean survival
  
  • presence of constitutional symptoms; age >65; hemoglobin <10.0 g/dL; leukocyte count >25,000/mm3; circulating blast cells ≥1%
  • based on the calculated score, a patient’s IMF is categorized as “low”, “intermediate 1”, “intermediate 2”, or “high” with a mean survival of 135, 95, 48, and 27 mo respectively
• risk of transformation to AML (8-10%)

Question 107

Define essential thrombocythemia and describe the epidemiology?

Answer 107

• Definition
  
  • overproduction of platelets in the absence of recognizable stimulus
  • must rule out secondary thrombocythaemia
• Epidemiology
  
  • increases with age; F:M = 2:1, but F=M at older age

Question 108

What is the aetiology of secondary thrombocythaemia?

Answer 108

• Infection
• Inflammation (IBD, arthritis)
• Malignancy
• Hemorrhage
• Iron deficiency
• Hemolytic anemia
• Post splenectomy
• Post chemotherapy

Question 109

How is essential thrombocythaemia diagnosed?

Answer 109

(2008 WHO Criteria) requires meeting all four criteria

1. sustained platelet count >450,000/mm³
2. bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased number of enlarged, mature megakaryocytes; no significant increase or left shift of neutrophil granulopoiesis or erythropoiesis
3. not meeting WHO criteria for PV, primary myelofibrosis, bcr-abl CML, or myelodysplastic syndrome or other myeloid neoplasms
4. demonstration of JAK2 V617F (or in its absence another clonal marker), no evidence for reactive thrombocytosis

Question 110

What are the clinical features of essential thrombocythaemia?

Answer 110

• often asymptomatic
• vasomotor symptoms (40%)
  
  • headache (common), dizziness, syncope
  • erythromelalgia (burning pain of hands and feet, dusky color, usually worse with heat, caused by platelet activation g microvascular thrombosis)
• thrombosis (arterial and venous)
• bleeding (often GI; associated with platelets >1,000,000/mm³)
• constitutional symptoms, splenomegaly
• pregnancy complications; increased risk of spontaneous abortion
• risk of transformation to AML (0.6-5%), myelofibrosis

Question 111

What Ix are used for essential thrombocythaemia and what are the expected results?

Answer 111

• FBC: increased platelets; may have abnormal platelet aggregation studies
• JAK2 PCR assay
• bone marrow hypercellularity, megakaryocytic hyperplasia, giant megakaryocytes
• increased K+, increased PO₄^3- (2^o to release of platelet cytoplasmic contents)
• diagnosis: exclude other myeloproliferative disorders and reactive thrombocytosis

Question 112

What is the Rx for essential thrombocythaemia?

Answer 112

• low dose ASA if previous history of thrombotic event, ≥1 cardiovascular risk factors, older, or symptomatic
• cytoreductive therapy if thrombosis or thrombotic symptoms: hydroxyurea (HU) (1st line therapy), anagrelide, interferon-α, or ³²P (age >80 or lifespan <10 yr)
• splenectomy not recommended (increased risk of bleeding episodes, thrombosis)

Question 113

Define acute lymphoblastic leukaemia.

Answer 113

• malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow
• WHO subdivides ALL into two types depending on cell of origi
  
  • 1. B-cell: precursor B lymphoblastic leukemi
  • 2. T-cell: precursor T lymphoblastic leukemia
• The French-American-British (FAB) classification (L1, L2, L3) is no longer encouraged, as morphology is not prognostic and inferior to immunophenotying and cytogenetics

Question 114

What are the clinical featuresof acute lymphoblastic leukaemia?

Answer 114

• Same as AML
• clinical symptoms usually secondary to:
  
  • bone marrow failure: anemia, neutropenia (50% present with fever; also infections of oropharynx, lungs, perianal region), thrombocytopaenia
  • ƒorgan infiltration: tender bones, lymphadenopathy,hepatosplenomegaly, meningeal signs (headache, N/V, visual symptoms; especially in ALL relapse)

Question 115

Describe the differences between AML and ALL?

Answer 115

Question 116

What Ix are used in ALL?

Answer 116

• FBC: increased leukocytes >10 x 10⁹/L (occurs in 50% of patients); neutropenia, anemia, or thrombocytopenia
• may have increased uric acid, K⁺, PO₄^3-, Ca²⁺, LDH
• PT, aPTT, fibrinogen, D-dimers for DIC
• leukaemic lymphoblasts lack specific morphological (no granules) or cytochemical features, therefore diagnosis depends on immunophenotyping
• cytogenetics: Philadelphia (Ph) chromosome in _~25% of adult ALL cases
• CXR: patients with ALL may have a mediastinal mass
• LP prior to systemic chemotherapy to assess for CNS involvement (ensure adequate platelet count and PT/PTT)

Question 117

What is the Rx for ALL?

Answer 117

• eliminate abnormal cloned cells
  
  • 1. Induction: to induce complete remission (undetectable leukemic blasts, restore normal haematopoiesis)
  • 2. Consolidation and/or intensification chemotherapy
       * consolidation: continuing same chemotherapy to eliminate subclinical leukemic cells
       * intensification: high doses of different (non-cross-reactive) chemotherapy drugs to eliminate cells with resistance to primary treatment
  • 3. Maintenance chemotherapy: low dose intermittent chemotherapy over prolonged period (2-3 yr) to prevent relapse
  • 4. Prophylaxis: Methotrexate (intrathecal or systemic) or CNS radiation therapy
• haematopoietic stem cell transplantation: potentially curative (due to pre-implant myeloablative chemoradiation and post-implant graft-versus-leukemia effect) but relapse rates and non-relapse mortality high

Question 118

What is the prognosis for ALL?

Answer 118

• depends on response to initial induction or if remission is achieved following relapse
• good prognostic factors: young, WBC <30 x 10⁹/L, T-cell phenotype, absence of Ph chromosome, early attainment of complete remission
• achievement of first remission: 60-90%
• childhood ALL: 80% long-term remission (>5 yr)
  
  • higher cure rates in children because of better chemotherapy tolerance, lower prevalence of bcr-abl fusion gene (associated with chemotherapeutic resistance)
• adult ALL: 30-40% 5 yr survival

Question 119

Define multiple myeloma and describe its epidemiology.

Answer 119

• Definition
  
  • neoplastic clonal proliferation of plasma cells producing a monoclonal immunoglobulin resulting in end organ dysfunction
  • usually single clone of plasma cells, although biclonal myeloma also occurs; rarely non-secretory
• Epidemiology
  
  • incidence 3 per 100,000, most common plasma cell malignancy
  • increased frequency with age; median age of diagnosis is 68 yr; M>F

Question 120

First thought multiple myeloma?

Answer 120

CRAB

• Increased Calcium
• Renal failure
• Anaemia
• Bony lesions (lytic leasion or osteoporosis felt to be caused by myeloma)

Question 121

What is the pathophysiology of multiple myeloma?

Answer 121

• malignant plasma cells secrete monoclonal antibody
  
  • 95% produce M protein (monoclonal Ig = identical heavy chain + identical light chain, or light chains only)
    
    • IgG 50%, IgA 20%, IgD 2%, IgM 0.5%
    • 15-20% produce free light chains or light chains alone found in either:
      
      • serum as an increase in the quantity of either kappa or lambda light chain (with an abnormal kappa:lambda ratio)
      • urine has Bence-Jones protein
• <5% are non-secretory

Question 122

What are the clinical features and complications of these for multiple myeloma?

Answer 122

• bone disease: pain (usually back), bony tenderness, pathologic fractures
  
  • lytic lesions are classical (skull, spine, proximal long bones, ribs)
  • increased bone resorption secondary to osteoclast activating factors such as PTHrP
• anemia: weakness, fatigue, pallor
  
  • secondary to bone marrow suppression
• weight loss
• infections
  
  • usually S. pneumoniae and Gram-negatives
  • secondary to suppression of normal plasma cell function
• hypercalcemia: N/V, confusion, constipation, polyuria, polydipsia
  
  • secondary to increased bone turnover
• renal disease/renal failure
  
  • most frequently causes cast nephropathy
• bleeding
  
  • secondary to thrombocytopaenia, may see petechiae, purpura
  • can also be caused by acquired von Willebrand disease
• extramedullary plasmacytoma
  
  • soft tissue mass composed of monoclonal plasma cells, purplish colour
• hyperviscosity: may manifest as headaches, stroke, angina, MI
  
  • secondary to increased viscosity caused by M protein
• amyloidosis
  
  • accumulation of insoluble fibrillar protein (Ig light chain) in tissues; can cause infiltration of any organ system: cardiac infiltration – diastolic dysfunction, cardiac arrhythmias, syncope, sudden death; GI involvement – malabsorption, beefy large or laterally scalloped tongue; neurologic involvement – orthostatic hypotension, carpal tunnel syndrome
  • may cause Factor X deficiency if fibrils bind Factor X → bleeding (raccoon eyes)
• neurologic disease: muscle weakness, pain, paresthesias
  
  • radiculopathy caused by vertebral fracture, extramedullary plasmacytoma
  • spinal cord compression (10-20% of patients) is a medical emergency

Question 123

What Ix are used in multiple myeloma and what are the expected results?

Answer 123

• FBC
  
  • normocytic anemia, thrombocytopenia, leukopenia
  • rouleaux formation on peripheral film
• biochemistry
  
  • increased Ca²⁺, increased ESR, decreased anion gap, increased Cr, albumin, β2-microglobulin (as part of staging), proteinuria (24 h urine collection)
• monoclonal proteins
  
  • serum protein electrophoresis (SPEP): demonstrates monoclonal protein spike in serum in 80% (i.e. M protein)
  • urine protein electrophoresis (UPEP): demonstrates light chains in urine = Bence-Jones protein (15% secrete only light chains)
  • immunofixation: demonstrates M protein and identifies Ig type; also identifies light chains
  • serum free light chain quantification: kappa and lambda light chains, calculated ratio
• bone marrow aspirate and biopsy
  
  • often focal abnormality, greater than 10% plasma cells, abnormal morphology, clonal plasma cells; send for FISH or cytogenetics (prognostic implications)
• skeletal series (x-rays), MRI if symptoms of cord compression
  
  • presence of lytic lesions and areas at risk of pathologic fracture
  • bone scans are not useful since they detect osteoblast activity
• β2-microglobulin, LDH, and CRP are poor prognosticators

Question 124

How is multiple myeloma diagnosed?

Answer 124

International Myeloma Working Group Criteria

1. serum or urinary monoclonal protein
2. presence of clonal plasma cells in bone marrow or a plasmacytoma
3. presence of end-organ damage related to plasma cell dyscrasia, such as
   
   1. increased serum Ca2+
   2. lytic bone lesions or osteoporosis
   3. anaemia
   4. renal failure

Question 125

What is the Rx for multiple myeloma?

Answer 125

• treatment is non-curative
• treatment goals
  
  • improvement in quality of life (improve anaemia, reverse renal failure, bony pain)
  • prevention of progression and complications
  • increase overall survival
• autologous stem cell transplant as consolidation therapy
  
  • usually preceded by 4-6 mo of cytoreductive therapy: steroid based with novel agents
  • (i.e. immunomodulatory drugs or proteosome inhibitors)
• chemotherapy if >65 yr old or transplant-ineligible
  
  • melphalan, prednisone, and novel agent (i.e. bortezomib)
• dexamethasone and bortezomib if ARF; bortezomib ± dexamethasone in light chain amyloidosis
• supportive management
  
  • bisphosphonates for those with osteopenia or lytic bone lesions (requires renal dosing)
  • local XRT for bone pain, spinal cord compression
  • kyphoplasty for vertebral fractures to improve pain relief and regain height
  • treat complications: hydration for hypercalcemia and renal failure, bisphosphonates for severe hypercalcaemia, prophylactic antibiotics, erythropoietin for anaemia, DVT prophylaxis
• all patients will relapse; choice of retreatment regimen depends on duration of remission, organ involvement, patient’s comorbidities, and preferences

Question 126

What is the prognosis for multiple myeloma?

Answer 126

• International Staging System (β2-microglobulin and albumin) used to stage and estimate prognosis
  
  • cytogenetic profile (i.e. p53 mutation associated with poor survival and resistance to chemotherapy)
• median survival based on stage, usually 16-70 mo

Question 127

Define monoclonal gammopathy of unknown significance?

Answer 127

• presence of M protein in serum in absence of any clinical or laboratory evidence of a plasma cell dyscrasia or lymphoproliferative disorders
  
  • ƒ incidence: 0.15% in general population, 5% of people >70 yr of age
  • asymptomatic

Question 128

How is monoclonal gammopathy of unknown significance diagnosed?

Answer 128

• presence of a serum monoclonal protein (M protein) at a concentration <3.0 g/dL
• <10% plasma cells in bone marrow
• absence of hyperCalcaemia, Renal insufficiency, Anaemia, Bony disease related to the plasma cell proliferative process (absence of “CRAB”)
• 0.3-1% of patients develop a hematologic malignancy each year
  
  • patients with M protein peak ≥1.5 g/dL or patients with IgA or IgM MGUS are at higher risk of malignant transformation
  • patients with abnormal serum free light chains ratio are at increased risk of malignant transformation
• monitor with annual history, physical, FBC, Cr, calcium, albumin, serum protein electrophoresis (considered pre-malignant)

Question 129

Define typhlitis.

Answer 129

Neutropenic enterocolitis (typhlitis) is a life-threatening, necrotizing enterocolitis occurring primarily in neutropenic patients. Neutropenic enterocolitis occurs most commonly in individuals with hematologic malignancies who are neutropenic and have breakdown of gut mucosal integrity as a result of cytotoxic chemotherapy.

Question 130

Describe the pathogenesis of typhlitis.

Answer 130

• The pathogenesis of neutropenic enterocolitis is incompletely understood.
• It probably involves a combination of factors, including mucosal injury by cytotoxic drugs or other means, profound neutropenia, and impaired host defense to invasion by microorganisms.
• The microbial infection leads to necrosis of various layers of the bowel wall.
• The cecum is usually affected, and the process often extends into the ascending colon and terminal ileum.
• The preference for the cecum is possibly related to its distensibility and its diminished vascularization relative to the rest of the colon.

Question 131

Which microbes are mostly involved in typhlitis?

Answer 131

• Various bacterial and/or fungal organisms, including:
  
  • gram-negative bacilli
  • gram-positive cocci
  • anaerobes (eg, Clostridium septicum)
  • Candida spp.
  • polymicrobial infection is frequent
• Bacteremia or fungemia is also common; pathogens include:
  
  • Pseudomonas aeruginosa
  • Escherichia coli
  • Klebsiella spp
  • viridans group streptococci
  • enterococci
  • Bacteroides spp, Clostridium spp, and Candida spp

Question 132

What are the signs and symptoms of typhlitis?

Answer 132

• Neutropenia, fever and abdominal pain
• location on pain depends on the location of the neutropenic colitis - common the RLQ
• Symptoms:
  
  • abdo distension
  • cramping
  • tenderness
  • N/V
  • watery or bloody diarrhea
  • and frank haematochezia (fresh blood out the anus)
  • peritoneal signs and shock

Question 133

How is typhlitis managed?

Answer 133

• Supportive
  
  • Bowel rest
  • NG suction
  • IV fluids and nutritional support
• Medical:
  
  • Blood products support (pack red cells)
  • Abx - Pip/Taz
• Surgical:
  
  • surgery usually avoided in patient with neutropenia or thrombocytopenia.
  • BUT recommended if free perforation or another process that cannot be controlled medically (e.g. persistent bleeding despite adequate medical treatment)

Question 134

What are barr bodies and in which condictions are they found?

Answer 134

Barr bodies are the inactivated X chromosome seen in the nucleus in females (XX).

• Females of genotype XXX - have 2
• Klinefelter’s syndrome XXY
• Anyone who has XX karyotyping

Question 135

c-myc proto-oncogene is assoacited with which carcinomas?

Answer 135

• breast, colon, cervix, lung and stomach.
• Burkitt lymphoma