Haematology Flashcards

Question

What is the treatment for sideroblastic anaemia?

Answer 1

* 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

Answer 2

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

Answer 3

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

Answer 4

* 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)

Answer 5

* 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

Answer 6

* 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

Answer 7

* 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

Answer 8

* 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

Answer 9

* 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

Answer 10

* 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

Answer 11

* 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)

Answer 12

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

Answer 13

* 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

Answer 14

* 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

Answer 15

* 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

Answer 16

* 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

Answer 17

* 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

Answer 18

* 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

Answer 19

* 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)

Answer 20

* 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

Answer 21

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

Answer 22

* 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

Answer 23

* 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

Answer 24

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.

Answer 25

* 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

Answer 26

* 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)

Answer 27

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

Answer 28

* 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

Answer 29

* 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

Answer 30

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

Answer 31

* 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

Answer 32

* Bloods: * FBC: clonal population of CLL lymphocytes \>5 x 109/L * LFTs: heptomegaly * peripheral blood film * lymphocytes are small and mature * 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

Answer 33

* 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)

Answer 34

* 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

Answer 35

* 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)

Answer 36

* Definition * fever (≥38.3ºC or ≥38.0ºC for ≥1 h) and one of: * ANC (absolute neutrophil count) \<0.5 OR * 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

Answer 37

* 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)

Answer 38

* 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

Answer 39

* 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

Answer 40

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

Answer 41

* 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

Answer 42

* 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

Answer 43

* 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

Answer 44

* 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)

Answer 45

* 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

Answer 46

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

Answer 47

* 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)

Answer 48

* 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

Answer 49

* 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)

Answer 50

* 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)

Answer 51

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

Answer 52

* 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

Answer 53

* 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

Answer 54

* 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

Answer 55

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

Answer 56

* 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

Answer 57

* 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)

Answer 58

* blood work * FBC: anemia, thrombocytopenia, variable WBC * 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)

Answer 59

* 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

Answer 60

* 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)

Answer 61

* 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

Answer 62

* 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

Answer 63

* 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)

Answer 64

* 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

Answer 65

* 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

Answer 66

* 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

Answer 67

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

Answer 68

* 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%)

Answer 69

* 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 *

Answer 70

* 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

Answer 71

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

Answer 72

* 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

Answer 73

* 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

Answer 74

* 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)

Answer 75

* 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)

Answer 76

* 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

Answer 77

* 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%)

Answer 78

* 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

Answer 79

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

Answer 80

(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

Answer 81

* 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

Answer 82

* 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

Answer 83

* 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)

Answer 84

* 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

Answer 85

* 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 * organ infiltration: tender bones, lymphadenopathy,hepatosplenomegaly, meningeal signs (headache, N/V, visual symptoms; especially in ALL relapse)

Answer 86

* 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)

Answer 87

* 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

Answer 88

* 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

Answer 89

* 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

Answer 90

**CRAB** * Increased **C**alcium * **R**enal failure * **A**naemia * **B**ony lesions (lytic leasion or osteoporosis felt to be caused by myeloma)

Answer 91

* 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

Answer 92

* 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

Answer 93

* 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

Answer 94

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

Answer 95

* 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

Answer 96

* 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

Answer 97

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

Answer 98

* presence of a serum monoclonal protein (M protein) at a concentration \<3.0 g/dL * \<10% plasma cells in bone marrow * absence of hyper**C**alcaemia, **R**enal insufficiency, **A**naemia, **B**ony 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)

Answer 99

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.

Answer 100

* 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.

Answer 101

* 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

Answer 102

* 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

Answer 103

* 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)

Answer 104

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

Answer 105

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