Haematology Flashcards

Question

what is seen in blood tests in myeloma?

Answer 1

* normocytic normochromic anaemia * raised ESR * rouleaux formation on blood film

Answer 2

- high calcium - high alkaline phosphatase - Bence-jones protein in urine

Answer 3

``` • lytic ‘punched-out’ lesions: - pepper-pot skull - vertebral collapse • fractures • osteoporosis ```

Answer 4

CTD: Cyclophosphamide, Thalidomide and Dexamethsasone; max 8 cycles, for less fit people VAD: Vincristine, Adriamycine and Dexamethasone in fitter people; max 6 cycles

Answer 5

* lymphomas are disorders caused by malignant proliferations of B and T lymphocytes * these accumulate in the lymph nodes causing lymphadenopathy, may also be found in the peripheral blood or infiltrate organs * predominantly in lymph nodes but also blood, bone marrow, liver, spleen, anywhere

Answer 6

Hodgkins and Non-Hodgkins lymphoma

Answer 7

have characteristic cells with mirror-image nuclei called Reed-Sternberg cells

Answer 8

* do not have characteristic cells * low grade e.g. Follicular Lymphoma * high grade e.g. Diffuse Large B Cell Lymphoma * very high grade e.g. Burkitt’s Lymphoma

Answer 9

primary immunodeficiency: - ataxia telangiectasia - Wiscott-Aldrich syndrome - common variable immunodeficiency secondary immunodeficiency: - HIV - transplant recipients infection: - Epstein-Barr Virus (EBV) - Human T-lymphotropic virus - Helicobacter pylori autoimmune disorders e.g. SLE

Answer 10

- male predominance - majority of cases occur in teenagers e.g. 13-19 and elderly e.g. over 65 - 2 peaks of incidence; teenagers and elderly - Epstein-Barr Virus (EBV) has a suggested role in pathogenesis

Answer 11

- classical Hodgkins lymphoma (cHL) | - nodular lymphocyte predominant Hodgkins lymphoma (NLPHL)

Answer 12

- Reed-Sternberg cell with mirror image nuclei | - 90-95% of cases

Answer 13

the Reed-Sternberg variant, the popcorn cell

Answer 14

- affected sibling - Epstein-Barr virus (glandular fever) - ‘hide’ in white blood cells and can result in malignancy - SLE - obese - post-transplantation

Answer 15

- most commonly there is painless cervical lymphadenopathy, described on examination as ‘rubbery’ - a smaller proportion of patients (often young women) present with disease localised to the mediastinum with cough due to mediastinal lymphadenopathy - generalised disease including hepatosplenomegaly and constitutional B symptoms (weight loss, fever, night sweats) - other constitutional symptoms e.g. pruritus, fatigue, anorexia and alcohol-induced pain at the site of the enlarged lymph nodes also occur

Answer 16

weight loss, fever, night sweats

Answer 17

* infection * superior vena cava obstruction with increased jugular venous pressure (JVP) * sensation of fullness in the head * dyspnoea * blackouts * facial oedema

Answer 18

- CT/MRI of chest, abdomen and pelvis for staging (Ann Arbor); may show intrathoracic, abdominal and pelvic nodes - lymph node excision or bone marrow biopsy; shows mirror-image nuclei Reed-Sternberg cells or popcorn cells - liver biochemistry may be abnormal, with or without liver involvement - bloods film and bone marrow: • high ESR or Low Hb - indicate worse prognosis • high serum lactate dehydrogenase - immunophenotyping - cytogenetics - PET scan - molecular techniques (PCR)

Answer 19

Ann Arbor classification - 4 stages - each stage is either A, B, X or E

Answer 20

involvement of a single lymph node region or a single extralymphatic organ or site

Answer 21

involvement of two or more lymph node regions on the same side of the diaphragm, or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm

Answer 22

involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ (IIIE) or site or both (IIISE)

Answer 23

diffuse or disseminated involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement

Answer 24

* A: no systemic symptoms other than pruritus (severe itching of skin) * B: presence of B symptoms such as fever, weight loss and night sweats * X: bulky disease * E: involvement of a single extranodal site that is contiguous or proximal to the known nodal site

Answer 25

``` combination chemotherapy - ABVD: • A - Adriamycin • B - Bleomycin • V - Vinblastine • D - Dacarbazine ```

Answer 26

stages I-A to II-A (with less than 3 areas involved and no bulk): • short course of ABVD followed by involved field irradiation stages II-A to IV-B (with more than 3 areas involved): • longer course of ABVD • cyclical combination chemotherapy (8 cycles of AVBD) with irradiation at sites of bulk disease • PET/CT used to detect disease activity after treatment and to distinguish between active tumour (PET-positive) and necrosis or fibrosis (PET-negative) in residual masses - irradiation, with its attendant complications, can be omitted in PET-negative masses after chemotherapy

Answer 27

radiotherapy: - may increase risk of second malignancies - solid tumours especially in the lung, breast, melanoma, stomach, sarcoma and thyroid - increase risk of ischaemic heart disease, hypothyroidism and lung fibrosis due to radiation field chemotherapy: - myelosuppression, nausea, alopecia (hair loss) and infection - infertility

Answer 28

- includes all lymphomas without Reed-Sternberg cells - around 80% is of B-cell origin, diffuse large B-cell lymphoma (DLBCL) is commonest - around 20% is of T-cell origin - generally more varied in terms of presentation, sub-types, treatments and outcomes - presentation rare before 40yrs - not all centre on nodes - there is a strong link with Epstein-Barr virus and Burkitts lymphoma

Answer 29

- nodal disease (75%) e.g. superficial lymphadenopathy - extranodal disease (25%): skin (esp. T cell lymphomas and oropharynx, gut, small bowel, bone, CNS and lungs) - systemic B symptoms - pancytopenia

Answer 30

low/indolent grade and high grade

Answer 31

example is Follicular Lymphoma - slow growing - usually advanced at presentation - incurable - median survival 9-11 years

Answer 32

example is Diffuse Large B-cell Lymphoma - usually has nodal presentation - 1/3 cases have extranodal involvement

Answer 33

- raised lactate dehydrogenase reflects worse prognosis since its a sign of increased cell turnover and thus cell proliferation - blood count: may show anaemia, ESR may be raised, elevated WCC or thrombocytopenia suggests marrow involvement - liver biochemistry abnormal if liver involved - serum lactate dehydrogenase and beta2-microglobulin are prognostic indicators - CXR, CT, PET and gallium scans helpful in staging - lymph node excision or bone marrow biopsy; will not see mirror-image nuclei Reed-Sternberg cells or popcorn cells - marrow aspiration and trephine biopsy confirms marrow involvement - CT/MRI of chest, abdomen and pelvis for staging (Ann Arbor) - immunophenotyping - cytogenetics

Answer 34

``` R-CHOP regimen: • R - Rituximab (monoclonal antibody - minimal side effects) • C - Cyclophosphamide • H - Hydroxy-daunorubicin • O - Vincristine (Oncovin brand name) • P - Prednisolone ``` with field irradiation for those with bulky disease 60-70% of those with early-stage disease are cured with this regimen

Answer 35

- monoclonal antibody - targets CD20 expressed on cell surface B cells - chimeric mouse/human protein - minimal side effects

Answer 36

* none may be required | * radiotherapy may be curative in localised disease

Answer 37

early: - 3 months R-CHOP regimen with radiotherapy late: - 6 months R-CHOP regimen with radiotherapy

Answer 38

- endemic, sporadic and AIDS related types - occurs mainly in African children - associated with EBV infection - usually B cells with jaw lymphadenopathy in children, usually with gastrointestinal involvement - treatment with cyclical combination chemotherapy

Answer 39

- acute lymphoblastic leukaemia (ALL) - acute myeloid leukaemia (AML) - chronic myeloid leukaemia (CML) - chronic lymphocytic leukaemia (CLL)

Answer 40

- malignant neoplasms of haemopoietic stem cells (can be precursors of RBCs, platelets or white cells) in the bone marrow that are non functional - proliferate rapidly - characterised by diffuse replacement of bone marrow by neoplastic cells - leukaemic cells usually spill over into the blood, where they may be seen in large numbers - may also infiltrate the liver, spleen, lymph nodes and other tissues

Answer 41

- firstly, the leukaemia cells are dividing rapidly but serve no function and are wasting energy making useless cells and there is less energy available to make useful functional cells - secondly, due to rapid replication these cells take up a lot of space within the bone marrow meaning there is little space and food for other cells to grow • the bone marrow is unable to make as many normal functioning cells resulting in non-functional cells in the blood and symptoms of leukaemia • eventually when there is no longer space in the bone marrow, leukaemia cells will be present in the blood too

Answer 42

- most common between 2 and 4 years of age - the commonest cancer in childhood - thought to develop from a combination of genetic susceptibility and an environmental trigger - ionising radiation e.g. x-rays during pregnancy and Down’s syndrome (trisomy 21) are important associations - CNS involvement is common

Answer 43

- malignancy of immature lymphoid cells (give rise to T cells and B cells) - affects B or T lymphocyte cell lines, arrests the maturation and promotes uncontrolled proliferation of immature blast cells (immature precursor of myeloid cells (myeloblasts) or lymphoid cells (lymphoblast)) - majority of cases derive from B-cell precursors - there is increased proliferation of immature lymphoblast cells (B or T cell precursors) in the bone marrow: • if all B cells = children • if all T cells = adults

Answer 44

- marrow failure - organ infiltration - bone marrow infiltration resulting in bone pain and anaemia, bleeding and infection - liver/spleen infiltration resulting in hepatosplenomegaly - node infiltration resulting in lymphadenopathy - CNS infiltration resulting headache and cranial nerve palsies - mediastinum infiltration resulting in mediastinal masses with superior vena cava obstruction

Answer 45

anaemia - low Hb: - resulting in breathlessness, fatigue, angina and claudication - there is pallor and cardiac flow murmur infection - low WCC: - resulting in infections - there is fever and mouth ulcers bleeding - low platelets: - resulting in bleeding and bruising

Answer 46

- FBC and blood film: • WCC is usually high • blast cells on film and in bone marrow - CXR and CT scan to look for mediastinal and abdominal lymphadenopathy - lumbar puncture to look for CNS involvement

Answer 47

- blood and platelet transfusions - neutropenia may lead to deadly infections; treat with prophylactic antivirals, antibacterials and antifungals - allopurinol (prevents tumour lysis syndrome) - IV fluids - insert Hickman line (permanent cannula into main vessel, tunnelled under sub-cutaneous fat so harder for infection to arise) so can easily take blood for testing and administer drugs and fluids - remission induction with combination chemotherapy including vincristine, dexamethasone, asparaginase and daunorubicin - involves CNS, so prophylaxis of intrathecal drugs, methotrexate or cytosine arabinoside and occasionally cranial irradiation is used - marrow transplantation

Answer 48

the neoplastic proliferation of blast cells derived from marrow myeloid (gives rise to basophils, neutrophils and eosinophils) elements

Answer 49

- progresses rapidly with death in 2 months if untreated - affects mostly children - the commonest acute leukaemia of adults - associated with radiation and syndromes such as Down’s (trisomy 21) - complete remission is usually achieved in about 80% of patients under 60 years with no comorbidity, in whom treatment is offered with curative intent

Answer 50

- marrow failure - hepatomegaly and splenomegaly occur due to infiltration - gum hypertrophy - DIC occurs in a subtype of AML where there is release of thromboplastin

Answer 51

- WCC is often raised, but can be normal or even low - may be few blast cells in the peripheral blood so diagnosis depends on bone marrow biopsy - differentiation from acute lymphocytic leukaemia is based on microscopy, immunophenotyping and molecular methods

Answer 52

- infection is a major issue; be alert to septicaemia | - causes common organisms to present oddly, with few antibodies being made

Answer 53

- blood and platelet transfusions - neutropenia may lead to deadly infections; treat with prophylactic antivirals, antibacterial and antifungals - allopurinol (prevents tumour lysis syndrome) - IV fluids - insert Hickman line (permanent cannula into main vessel, tunnelled under sub-cutaneous fat so harder for infection to arise) so can easily take blood for testing and administer drugs and fluids - chemotherapy - marrow transplantation

Answer 54

- most exclusively a disease of adults - uncontrolled clonal proliferation of myeloid cells - occurs most often between 40-60 yrs - slight male predominance - rare in childhood - insidious onset - more than 80% have the Philadelphia chromosome which forms a fusion gene BCR/ABL on chromosome 22, which has tyrosine kinase activity: stimulates cell division

Answer 55

- chronic phase lasts 3-4 years, followed by blast transformation with development of acute leukaemia and rapid death - may also transform into myelofibrosis, with death from bone marrow failure - symptomatic anaemia e.g. shortness of breath - abdominal discomfort due to splenomegaly - weight loss - tiredness - pallor - fever and sweats in the absence of infection - may be features of gout due to purine breakdown - may be bleeding due to platelet dysfunction - 40-60yrs - metabolic features

Answer 56

- esp. CML - abnormality in chromosome 22 - defective and unusually short due to reciprocal translocation of genetic material between chromosome 9 and 22 - contains fusion gene called BCR-ABL1 - codes for a hybrid 210-kDa fusion protein: a tyrosine kinase signalling protein that is always on, causing the cell to divide uncontrollably by interrupting stability of the genome and impairing signalling pathways

Answer 57

blood count: • very high WCC, often > 100 × 109/L; with whole spectrum of myeloid cells i.e. increased neutrophils, myelocytes, basophils and eosinophils • low Hb (normochromic and normocytic anaemia) • platelets are low, normal or raised bone marrow aspirate: - hypercellular (increased myeloid progenitors)

Answer 58

- oral Imatinib (Glivec); specific BCR/ABL1 tyrosine kinase inhibitor; produces a complete haematological response in over 95% of patients - Nilotinib, Dasatinib, Ponatinib (tyrosine kinase inhibitors) - stem cell transplant

Answer 59

- the most common leukaemia - often incidental finding on FBC - occurs predominantly in later life - it is the uncontrolled proliferation and accumulation of mature B cells that have escaped programmed cell death and undergone cell-cycle arrest - mutations, trisomies and deletions influence risk - pneumonia may be a triggering event

Answer 60

chronic lymphocytic leukaemia

Answer 61

- often no symptoms, presenting as a surprise on a routine FBC (done pre-op) - may be anaemic (due to haemolysis or marrow infiltration) or infection prone - if severe then weight loss, sweats and anorexia - hepatosplenomegaly - enlarged, rubbery, non-tender nodes - indolent corse

Answer 62

blood count • normal or low Hb • raised WCC with lymphocytosis (> 5 × 109/L) • may be anaemia and thrombocytopenia blood film • smudge cells may be seen in vitro; these are small lymphocytes of mature appearance with are an artefactual finding due to cell rupture while the film is being made bone marrow • reflects peripheral blood usually heavily infiltrated with lymphocytes immunophenotyping and cytogenetics

Answer 63

- autoimmune haemolysis - increased infection risk due hypogammaglobulinaemia (low IgG); bacterial and viral especially herpes zoster - marrow failure

Answer 64

- many stay stable for years and may even regress - death is often due to complication of infection - may transform into aggressive lymphoma = Richter’s syndrome - the median survival from diagnosis is very variable and correlates closely with disease stage at diagnosis and cytogenetic findings, e.g. patients with either 11q or 17p deletions (the sites of two tumour suppressor genes) are at high risk of not responding to initial treatment and rapid progression. In other patients there is near-normal life expectancy.

Answer 65

- blood transfusions - combination therapy with fludarabine, cyclophosphamide and rituximab is standard first line therapy - chlorambucil usually reduces lymphocytosis, lymphadenopathy and splenomegaly in older patients - alemtuxumab used in patients where there is disease progression after treatment with Fludarabine - human IV immunoglobulins - chemotherapy or radiotherapy - monoclonal antibodies (e.g. anti-CD20: rituximab) - try stem cell/bone marrow transplant

Answer 66

* 1/3 will never progress * 1/3 progress slowly * 1/3 progress actively

Answer 67

- infertility - anthracyclines; cardiomyopathy - bleomycin; lung damage - vinca alkaloids; peripheral neuropathy - second cancers - psychological cancers

Answer 68

- alkylating agents - combination chemotherapy - purine analogues - monoclonal antibodies - radio-immunoconjugates - new oral targeted agents - radiotherapy - bone marrow transplant - do nothing

Answer 69

acute myeloid leukaemia = myeloblast chronic myeloid leukaemia = basophil, neutrophil, eosinophil acute lymphoblastic leukaemia = lymphoblast chronic lymphocytic leukaemia = B lymphocyte

Answer 70

- common myeloid progenitor | - common lymphoid progenitor

Answer 71

- megakaryocyte - erythrocyte - mast cell - myeloblast

Answer 72

- basophil - neutrophil - eosinophil - monocyte

Answer 73

macrophage (in tissues)

Answer 74

- natural killer cell (large granular lymphocyte) | - small lymphocyte

Answer 75

- T lymphocyte | - B lymphocyte

Answer 76

plasma cells

Answer 77

- preceeding haematological disorders - prior chemotherapy - exposure to ionising radiation

Answer 78

- HML - blood product support - prompt treatment of infectiosn - recognition of atypical/unusual infections

Answer 79

t(8;21), t(15;17), inv(16) | - t(15;17) = acute promyelocytic leukaemia

Answer 80

normal, +8, +21, +22, del(7q), del(9q), abnormal 11q23, all other structural or numerical changes

Answer 81

-5, -7, del(5q), abnormal 3q, complex cytogenetics

Answer 82

- 5-8% of AML in adults - t(15;17) – PML/RARA gene - blocks differentiation of promyelocyte to mature granulocyte - haematological emergency – DIC - 90% remission rate - targeted treatment = ATRA

Answer 83

- children majority cured - TYA (16-25yrs) most cured with Paediatric style treatment - adults up to ½ cured - depends critically on age and cytogenetics

Answer 84

Binet Stage Stage A: lymphocytosis (<3 nodal areas): survival 10-15yrs Stage B: nodes (3+ nodal areas): survival 5-7yrs Stage C: anaemia and/or thrombocytopenia: survival 2-3yrs

Answer 85

own - enables escalation of chemo with stem cell rescue - relatively straightforward - mortality 2%

Answer 86

- much more toxic - mortality 15-30% - stem cells attack residual tumour (GVL) - stem cells also attack recipient (GVHD) - used in acute and chronic leukaemias

Answer 87

present when there is a decrease of haemoglobin in the blood below the reference level for the age and sex of the individual

Answer 88

- may be due either to a low red cell mass (RCM) or increased plasma volume (e.g. in pregnancy where there is small increase in red cell mass as well as high plasma volume so concentration is decreased thus look anaemic) - may be due to reduced production from bone marrow or increased loss of RBC’s i.e. by the spleen, liver, bone marrow and blood loss and has many causes

Answer 89

- the test to determine if bone marrow production is the issue is to look at the reticulocyte count which is a count of immature RBC’s in the bone marrow - if production is the issue then the reticulocyte count will be low - if removal is the issue then the reticulocyte count will be high

Answer 90

reduction in plasma volume | - seen in dehydration

Answer 91

- a measure of the average volume of a red blood corpuscle (or red blood cell) - the measure is attained by multiplying a volume of blood by the proportion of blood that is cellular (the hematocrit), and dividing that product by the number of erythrocytes (red blood cells) in that volume

Answer 92

- low MCV <80fL - high MCV >96fL - normal MCV

Answer 93

- iron deficiency - Thalassaemia - anaemia of chronic disease - sideroblastic anaemia

Answer 94

- megaloblastic | - normoblastic

Answer 95

vitamin B12 or folate deficiency

Answer 96

- alcohol - increased reticulocytes (e.g. haemolysis or haemorrhage) - liver disease - hypothyroidism - drug therapy e.g. azathioprine

Answer 97

- acute blood loss - anaemia of chronic disease - CKD - combined deficiency, e.g. iron and folate - autoimmune rheumatic disease - marrow infiltration/fibrosis - endocrine disease - haemolytic anaemias

Answer 98

- reduced O2 transport - tissue hypoxia - compensatory changes

Answer 99

* increased tissue perfusion * increased O2 transfer to tissues * increased RBC production

Answer 100

- myocardial fatty change - fatty change in liver - aggravates angina and claudication - skin and nail atrophic changes - CNS cell death (cortex and basal ganglia)

Answer 101

* fatigue, headaches and faintness * dyspnoea and breathlessness * angina if there is pre-existing coronary disease * anorexia * intermittent claudication * palpitations

Answer 102

* may be absent even in severe anaemia - this is because a very slowly falling level of Hb allows for haemodynamic compensation and enhancement of oxygen-carrying capacity of the blood * pallor - skin and mucous membranes are pale * tachycardia * systolic flow murmur * cardiac failure

Answer 103

iron deficiency anaemia

Answer 104

average daily intake of iron is 15-20mg, although normally only 10% is absorbed in the duodenum

Answer 105

- actively transported into the duodenal intestinal epithelial cells by the intestinal haem transporter (HCP1) which is highly expressed in the duodenum - some is incorporated into ferritin (protein-iron complex) that acts as an intracellular store for iron

Answer 106

released into the blood where it is able to circulate around the body bound to the plasma protein transferrin

Answer 107

- is a plasma protein which binds to absorbed iron that doesn't bind to ferritin - allows iron to circulate around the body in the blood - transports iron in the blood plasma to the bone marrow to be incorporated into new erythrocytes - synthesised in the liver - normally about 1/3 saturated with iron

Answer 108

incorporated into haemoglobin in developing erythroid precursors and mature red cells

Answer 109

the rest is stored in reticuloendothelial cells, hepatocytes and skeletal muscle cells either as ferritin (majority; more easily mobilised than haemosiderin for Hb formation, found in small amounts in plasma and in most cells especially liver, spleen and bone marrow) or haemosiderin in hepatocytes, skeletal muscle and reticuloendothelial macrophages

Answer 110

- most common cause of anaemia worldwide - seen in 14% of menstruating women - develops when there is inadequate iron for haemoglobin synthesis

Answer 111

- blood loss - poor intake; rare in developed countries - increased demands e.g. in growth and pregnancy - malabsorption/decreased absorption, e.g. small bowel disease or post-gastrectomy

Answer 112

- menorrhagia (severe menstruation with heavy blood loss) - pregnancy and breast feeding - GI bleeding - hookworm - the leading cause of iron deficiency worldwide resulting in intestinal blood loss and iron deficiency

Answer 113

- undeveloped countries - high vegetable diet - premature infants - introduction of mixed feeding delayed, since breast milk contains low iron

Answer 114

less iron is available for haemoglobin synthesis; this is crucial for haemoglobin production, thus reduction in iron will result in a decrease in haemoglobin and smaller RBC’s resulting in microcytic anaemia

Answer 115

* fatigue, headaches and faintness * dyspnoea and breathlessness * angina if there is pre-existing coronary disease * anorexia * intermittent claudication * palpitations * may be absent even in severe anaemia * pallor * tachycardia * systolic flow murmur * cardiac failure * brittle nails and hair * spoon-shaped nails: koilonychia * atrophy of the papillae of the tongue: atrophic glossitis * angular stomatitis/cheilosis: ulceration of the corners of the mouth

Answer 116

- thalassaemia - sideroblastic anaemia - anaemia of chronic disease

Answer 117

- blood count and film - serum ferritin - serum iron - serum soluble transferrin receptors - further investigations into cause of blood loss e.g. GI tract examination - low reticulocyte count - bone marrow examination is generally unnecessary

Answer 118

* RBCs are microcytic (MCV <80fL) and hypochromic (MCH <27pg) (pale) * there is poikilocytosis (variation in RBC shape) and anisocytosis (variation in RBC size)

Answer 119

* the level of serum ferritin reflects the amount of stored iron * in simple iron deficiency this is low - confirms diagnosis * however may be normal in malignancy or infection (since it rises in these events i.e. inflammation)

Answer 120

* serum iron is low * total iron-binding capacity (TIBC) rises compared to normal, iron deficiency is present with the transferrin saturation (serum iron divided by TBIC) falls below 19%

Answer 121

- find and treat underlying cause - oral iron e.g. ferrous sulphate or ferrous gluconate - parenteral iron e.g IV iron or deep intramuscular iron in extreme cases e.g. severe malabsorption or when patients are intolerant

Answer 122

- oral iron e.g. ferrous sulphate or ferrous gluconate | - parenteral iron e.g. IV iron or deep intramuscular iron

Answer 123

- nausea, abdominal discomfort, diarrhoea/constipation, black stools - can give ferrous gluconate if side effects are bad

Answer 124

* anaemia that is secondary to a chronic disease; if the body is sick then the bone marrow will be too, resulting in anaemia * occurs in patients with chronic inflammatory disease (e.g. Crohn's and RA), chronic infections (e.g. TB), malignancy and CKD * RBC’s are often normocytic but they can be microcytic, especially in rheumatoid arthritis and Crohn’s disease, or can be normochromic

Answer 125

- the second most common anaemia - the commonest anaemia in hospital patients - occurs in individuals with chronic infections such as: • tuberculosis • Crohn’s • rheumatoid arthritis • SLE • malignant disease

Answer 126

``` have a chronic disease, e.g. • tuberculosis • Crohn’s • rheumatoid arthritis • SLE • malignant disease ```

Answer 127

- there is decreased release of iron from the bone marrow to developing erythroblasts (early RBC, before reticulocyte) - an inadequate erythropoietin response (cytokine which increases RBC production) to anaemia - high levels of hepcidin expression (binds to export transport protein, ferroportin, in the iron-absorbing cells in the duodenum, causing its degradation, with consequent reduction in trasnport of iron from duodenal cells into the plasma) - decreased RBC survival

Answer 128

* fatigue, headaches and faintness * dyspnoea and breathlessness * angina if there is pre-existing coronary disease * anorexia * intermittent claudication * palpitations

Answer 129

- serum iron and total iron-binding capacity (TIBC) are low - serum ferritin is normal or raised due to the inflammatory process - serum soluble transferrin receptor level is normal - blood count and film: • RBC’s are normocytic or microcytic and hypochromic as in rheumatoid arthritis and Crohn’s

Answer 130

RBC’s are normocytic or microcytic and hypochromic as in rheumatoid arthritis and Crohn’s

Answer 131

- treat underlying chronic cause - erythropoietin is effective in raising the haemoglobin level and is used in anaemia of renal disease and inflammatory disease e.g. rheumatoid arthritis and inflammatory bowel disease • side effects; flu-like symptoms, hypertension, mild rise in the platelet count and thromboembolism

Answer 132

flu-like symptoms, hypertension, mild rise in the platelet count and thromboembolism

Answer 133

- fatigue, headaches and faintness - dyspnoea and breathlessness - angina if there is pre-existing coronary disease - anorexia - intermittent claudication - palpitations

Answer 134

- normal B12 and folate - raised reticulocytes - Hb down - blood count and film: RBCs are normocytic

Answer 135

- treat underlying cause - improve diet with plenty of vitamins - erythropoietin injections

Answer 136

- erythroblasts with delayed nuclear maturation because of delayed DNA synthesis - they are large (i.e. high MCV) and have no nuclei - may also affect the white cells (causing hypersegmented neutrophil nuclei with six lobes, and sometimes leucopenia) and platelets (causing thrombocytopenia)

Answer 137

- B12 deficiency - type of megaloblastic anaemia - pernicious anaemia is an autoimmune disorder where the parietal cells of the stomach are attacked resulting in atrophic gastritis and the loss of intrinsic factor production and thus vitamin B12 malabsorption

Answer 138

meat, fish and dairy products but not plants

Answer 139

- B12 is absorbed by binding to intrinsic factor produced by the parietal cells of the stomach then being absorbed in the terminal ileum of the small intestines by carrier protein transcobalamin II - B12 is liberated from protein complexes in food by gastric acid and pepsin - binds to vitamin B12-binding protein (R binder) derived from saliva

Answer 140

- B12 is essential for thymidine and thus DNA synthesis - thus in B12 deficiency there is an impairment of DNA synthesis resulting in delayed nuclear maturation resulting in large RBCs as well as decreased RBC production in the bone marrow - this DNA impairment will affect all cells, but bone marrow is most affected since its the most active in terms of cell division

Answer 141

- dietary (vegans) - malabsorption (lack of intrinsic factor or terminal ileum removed/ileal resection) - pernicious anaemia (most common cause)

Answer 142

- the disease is common in the elderly (over 60) - seen in all races but more common in fair-haired, blue eyed individuals and those who have blood group A - more common in females than males - there is also an association with other autoimmune disease e.g. thyroid disease, Addison’s disease and vitiligo - many cases are undiagnosed

Answer 143

- elderly - female - fair-haired, blue eyes - blood group A - thyroid and Addison’s disease

Answer 144

- parietal cell antibodies are present in the serum in 90% of patients with pernicious anaemia, and also in 10% of normal individuals - intrinsic factor antibodies, although found in only 50% of patients with pernicious anaemia, are specific for diagnosis - atrophic gastritis (plasma and lymphoid cell infiltration in the fundus) - the parietal and chief cells are replaced by mucin-secreting cells - there is achlorhydria (reduced HCL acid production) and the absent secretion of intrinsic factor

Answer 145

reduced HCL acid production

Answer 146

- onset is insidious with progressively increasing symptoms of anaemia e.g. fatigue, headache, pallor, dyspnoea, anorexia, tachycardia and palpitations - may have a lemon-yellow skin colour due to the combination of pallor and mild jaundice caused by excess breakdown of haemoglobin (due to fact that body will try to remove defective large RBCs) - red sore tongue (glossitis) and angular stomatitis/cheilosis (ulceration of the corners of the mouth) may be present - neurological features can occur with very low levels of serum B12 and include a polyneuropathy caused by symmetrical damage to the peripheral nerves and posterior and lateral columns of the spinal cord (subacute combined degeneration of the cord). - the latter presents with progressive weakness, ataxia and eventually paraplegia if untreated. - dementia and visual disturbances due to optic atrophy may also occur. - there is a higher incidence of gastric carcinoma with pernicious anaemia than in the general population.

Answer 147

due to the combination of pallor and mild jaundice caused by excess breakdown of haemoglobin (due to fact that body will try to remove defective large RBCs)

Answer 148

* only occur with very low levels of B12 * symmetrical paresthesia (burning or prickling pain, tingling) in fingers and toes * early loss of vibration sense and proprioception * progressive weakness and ataxia * paraplegia may result * dementia, psychiatric problems, hallucinations, delusions and optic atrophy may occur from vitamin B12 deficiency

Answer 149

- must differentiate from the other cause of megaloblastic anaemia - folate deficiency - differentiate from other causes of B12 deficiency - any disease in the terminal ileum or bacterial overgrowth in the small bowel can result in B12 deficiency - gastrectomy

Answer 150

- blood count and film - serum bilirubin may be raised as a result of ineffective erythropoiesis resulting in increased RBC breakdown - serum B12 is low, frequently <50ng/L - red cell folate may be reduced because vitamin B12 is needed to convert serum folate to the active intracellular form - Hb is low - reticulocyte count is low - intrinsic factor antibodies are diagnostic but lower sensitivity i.e. not present in all patients - small bowel barium follow-through and distal duodenal biopsies may be needed - bone marrow examination shows hypercellular bone marrow with megaloblastic changes

Answer 151

* typical of megaloblastic anaemia * RBCs are macrocytic (MCV often >110fL) * peripheral film shows oval macrocytes (large RBC’s) with hypersegmented neutrophil polymorphs with six or more lobes in the nucleus * in severe cases, leucopenia and thrombocytopenia

Answer 152

- if not pernicious anaemia then treat cause - if a low B12 is due to malabsorption then injections are required - if cause is dietary then give oral B12 2mg per day - replenish B12 stores by giving IM hydroxocobalamin

Answer 153

green vegetables e.g. spinach and broccoli, nuts, yeast and offal e.g. liver and kidney

Answer 154

both poor intake and excess utilisation of folate e.g. in ICU

Answer 155

duodenum/proximal jejunum (upper small intestine)

Answer 156

- folate is essential for DNA synthesis - thus in folate deficiency there is an impairment of DNA synthesis resulting in delayed nuclear maturation and in large RBCs as well as decreased RBC production in the bone marrow - this DNA impairment will affect all cells, but bone marrow is most affected since it's the most active in terms of cell division - folate is also essential for fetal development; deficiency can result in neural tube defects

Answer 157

* main cause is poor intake e.g. poverty, alcoholics and elderly * increased demand/utilisation e.g. pregnancy or increased cell turnover i.e. haemolysis, malignancy, inflammatory disease and renal dialysis * malabsorption e.g. coeliac disease or Crohn’s disease * antifolate drugs e.g. methotrexate and trimethoprim

Answer 158

methotrexate and trimethoprim

Answer 159

- elderly - poverty - alcoholic - pregnant - Crohn’s or coeliac disease

Answer 160

- patients may be asymptomatic - may present with symptoms of anaemia e.g. pallor, fatigue, dyspnoea, anorexia and headache - glossitis (red sore tongue) can occur - no neuropathy/neurological defects unlike B12 deficiency

Answer 161

in folate deficiency there are no neuropathy/neurological problems, and in B12 deficiency there are

Answer 162

- blood count and film - serum and red cell folate is low; red cell is more accurate guide to tissue folate than serum folate, which is usually low - GI investigation e.g. small bowel biopsy to exclude occult GI disease - serum bilirubin may be raised due to ineffective erythropoiesis resulting in increased RBC breakdown - if the history does not suggest dietary deficiency as the cause, further investigations such as endoscopic small bowel biopsy should be performed to look for small bowel disease

Answer 163

* typical of megaloblastic anaemia * RBC’s are macrocytic * peripheral film shows oval macrocytes (large RBCs) with hypersegmented neutrophil polymorphs with six or more lobes in the nucleus

Answer 164

- treat underlying cause - give oral folic acid 5mg daily for 4 months; never without B12 as well (unless the patient is known to have normal B12) since in low B12 states it may precipitate/worsen subacute combined degeneration of the spinal cord - higher daily doses may be needed with malabsorption - prophylactic folic acid given to patients with chronic haemolysis (5mg weekly)

Answer 165

the premature breakdown of RBCs, before their normal lifespan of around 120 days

Answer 166

within the circulation (intravascular): • when RBCs are rapidly destroyed in circulation, haemoglobin is liberated • this is initially bound to haptoglobulin but these soon become saturated • excess free plasma haemoglobin is filtered by the renal glomerulus and enters the urine, although small amounts are reabsorbed by the renal tubules • in renal tubular cells, haemoglobin is broken down and becomes deposited in the cells as haemosiderin the reticuloendothelial system i.e. by macrophages of the liver, spleen (in particular) and bone marrow (extravascular)

Answer 167

haptoglobulin (soon becomes saturated)

Answer 168

broken down and becomes deposited in the cells as haemosiderin

Answer 169

- shortening of red cell survival does not always result in anaemia, as there is a compensatory increase in red cell production by the bone marrow - if the red cell loss can be contained within the marrow’s capacity for increased output, then a haemolytic state can exist with anaemia; known as compensated haemolytic disease - the bone marrow can increase its output by 6-8 times by increasing the proportion of cells committed to erythropoiesis (RBC production) (erythroid hyperplasia) and by expanding the volume of active marrow - additionally, reticulocytes (immature RBCs) are released prematurely - reticulocytes are larger than mature cells, hence macrocytic, and stain with light blue tinge on a peripheral blood stain (polychromasia)

Answer 170

reticulocytes are larger than mature cells, hence macrocytic, and stain with light blue tinge on a peripheral blood stain (polychromasia)

Answer 171

- RBC membrane defects: hereditary spherocytosis - enzyme defects: glucose-6-phosphate dehydrogenase (G6PD) deficiency - haemoglobinopathies: beta thalassaemia, alpha thalassaemia, sickle cell disease - autoimmune haemolytic anaemia

Answer 172

- high serum unconjugated bilirubin - high urinary urobilinogen - high faecal stercobilinogen - splenomegaly - bone marrow expansion - reticulocytosis

Answer 173

hormones, metals, iron, B12, folic acid, other vitamins

Answer 174

- the most common inherited haemolytic anaemia in Northern Europeans - autosomal dominant - however in 25% it can occur spontaneously with neither parent affected

Answer 175

family history

Answer 176

- caused by defects in the red cell membrane resulting in RBCs losing part of the cell membrane as they pass through the spleen, possibly because the lipid bilayer is inadequately supported by the membrane skeleton due to deficiency in the structural protein spectrin - the abnormal cell membrane is associated functionally with an increased permeability to Na+ requiring an increased rate of active transport of Na+ out of the cells, which is dependent on ATP produced by glycolysis - the surface to volume ratio decreases and the cells become spherocytic/spherical in shape - spherocytes are more rigid and less deformable than normal red cells - they are unable to pass through the splenic microcirculation so they become trapped in the spleen and thus have a shortened lifespan and are destroyed via extravascular haemolysis

Answer 177

more rigid and less deformable

Answer 178

- jaundice at birth - however the onset of jaundice can be delayed for many years and some patients may go through life with no symptoms and are detected only during family studies - varies from symptom-free carrier to severe haemolysis with anaemia, jaundice and splenomegaly - splenomegaly - ulcers on the leg - chronic haemolysis leads to the formation of pigment gallstones

Answer 179

* aplastic anaemia (sudden stop in RBC production) e.g. after infections, particularly with erythrovirus (parvovirus) * megaloblastic anaemia (result of folate depletion) caused by the hyperactivity of the bone marrow * haemolytic crises

Answer 180

- blood film - blood count - haemolysis - direct antiglobulin (Coomb's test) - diagnosis is usually straightforward and made on the basis of clinical features, family history, laboratory investigation and exclusion of other causes of haemolytic anaemia, particularly autoimmune haemolytic anaemia.

Answer 181

shows spherocytes (spherical RBCs) and reticulocytes

Answer 182

anaemia (Hb low) and increased reticulocytes

Answer 183

this is negative, virtually ruling out an autoimmune haemolytic anaemia in which spherocytes are also commonly present

Answer 184

splenectomy: • to relieve symptoms due to anaemia or splenomegaly, reverse growth failure and prevent recurrent gallstones • best to postpone until after childhood due to infection risk post-op • after operation do appropriate immunisations and life-long penicillin prophylaxis

Answer 185

- presents with haemolytic anaemia and affects millions of people worldwide, particularly in Africa, around the Mediterranean and in the Middle East and SE Asia - heterogenous X-linked; thus more common in males than females - however, female heterozygotes can also have clinical problems due to lyonisation whereby, because of random X-chromosome inactivation, female heterozygotes have two populations of red cells; a normal one and a G6PD deficient one - there are over 400 structural types of G6PD and mutations are mostly single amino acid substitutions (missense point mutations)

Answer 186

- G6PD is vital for a reaction that is necessary for RBCs by providing a NADPH which is used with glutathione to protect the RBC from oxidative damage from compounds such as hydrogen peroxide - this inherited enzyme deficiency thus results in reduced RBC lifespan due to oxidant damage - gene for G6PD is localised to chromosome Xq28 near the factor VIII gene

Answer 187

localised to chromosome Xq28 near the factor VIII gene

Answer 188

glucose-6-phosphate -> 6-phosphogluconate - catalyses this reaction - NADP+ -> NADPH - NADPH -> NADP+//GSSG -> GSH catalyesd by glutathione reductase

Answer 189

- most are asymptomatic but may get oxidative crisis due to reduction in glutathione production - chronic haemolytic anaemia - neonatal jaundice - acute haemolysis precipitated by ingestion of fava beans and drugs e.g. quinine, sulphonamides, quinolones and nitrofurantoin - clinical features are due to rapid intravascular haemolysis with symptoms of anaemia, jaundice and haemoglobinuria

Answer 190

- occurs due to reduction in glutathione production - acute drug-induced haemolysis - made worse by ingesting fava beans

Answer 191

- aspirin - antimalarials such as: primaquine, quinine and chloroquine - antibacterials such as; most sulphonamides, nitrofurantoin and chloramphenicol - dapsone - quinidine

Answer 192

- blood count is normal between attacks - blood film during attack: • irregularly contracted cells • bite cells (cells with an indentation in the membrane) • reticulocytosis - increased reticulocytes - G6PD enzyme levels - will be low (but note, immediately after attack the test may be normal since the oldest RBCs with the least G6PD activity are destroyed selectively, so results may show falsely high concentration of G6PD)

Answer 193

- stop offending drugs and/or fava beans - blood transfusion may be lifesaving - splenectomy is not usually helpful - avoid precipitating factors

Answer 194

HbA = haem + 2 alpha chains + 2 beta chains | - 97% of adult haemoglobin (Hb)

Answer 195

HbF = haem + 2 alpha chains + 2 gamma chains | - normal Hb in foetus from 3rd to 9th month; increased in beta-thalassaemia

Answer 196

HbA2 = haem + 2 alpha chains + 2 delta chains | - 2% of adult Hb; elevated in beta-thalassaemia

Answer 197

``` HbA = 97% HbA2 = 2% HbF = 1% ```

Answer 198

- disorders of quantity (reduced production) • normally, there is balanced 1:1 production of alpha and beta chains • these are genetic diseases of unbalanced Hb synthesis, with under production (or no production) of one globin chain. arise from one or multiple gene defects • the precipitation of the imbalanced globin chains within red cell precursors results in cell damage and death of precursors in bone marrow i.e ineffective erythropoiesis • the precipitation of these imbalanced globin chains in mature red cells leads to haemolysis • these are common in areas from the Mediterranean to the Far East

Answer 199

- little or no beta chain production resulting in excess alpha chains - these excess alpha chains combine with whatever delta and gamma chains are produced - resulting in increased HbA2 (Hb delta) and HbF (Hb gamma) - caused by over 200 genetic defects

Answer 200

- unlike alpha-thalassaemia, the defects are normally point mutations as opposed to gene deletions - the mutations result in defects in transcription, RNA splicing and modification, translation via frame shifts and nonsense codons producing highly unstable beta globulin which cannot be utilised - in heterozygous beta-thalassaemia there is usually asymptomatic microcytosis with or without mild haemolysis

Answer 201

- B thalassaemia minor (trait carrier) - B thalassaemia intermedia - B thalassaemia major

Answer 202

- common carrier state: heterozygous beta thalassaemia - asymptomatic - anaemia is mild or absent - RBCs are hypochromic (pale) and microcytic with a low MCV and MCH - can be confused with iron deficiency but can be distinguished since serum ferritin and the iron stores are normal - Hb electrophoresis shows a raised HbA2 and often a raised HbF

Answer 203

has normal serum ferritin and iron stores

Answer 204

- includes those who are symptomatic with moderate anaemia (Hb 70-100g/L) that do not require regular transfusions - splenomegaly - bone deformities - recurrent leg ulcers - gallstones - infections - may be caused by combination of homozygous beta and alpha thalassaemias

Answer 205

- presents in children with homozygous beta thalassaemia in the first year of life with severe anaemia (Cooley's anaemia), failure to thrive and recurrent infections - life-long transfusion dependant - hypertrophy of ineffective bone marrow leads to bone abnormalities: the thalassaemic facies, with an enlarged maxilla and prominent frontal and parietal bones - skull X-ray shows ‘hair on end’ sign due to increased marrow activity - blood results: MCV very low; microcytic - blood film: large and small irregular hypochromic RBCs - serum ferritin is normal

Answer 206

- in homozygous disease; blood count and film show: • hypochromic/microcytic anaemia • raised reticulocyte count • nucleated RBC in peripheral circulation - haemoglobin electrophoresis shows increased HbF (gamma) and absent or reduced HbA (normal)

Answer 207

- regular (every 2-4 weeks) life-long transfusions to keep Hb above 100g/L and to suppress the ineffective extramedullary haematopoiesis and to allow normal growth - long-term folic acid supplements - iron overload by repeated blood transfusions may lead to damage of endocrine glands, liver, pancreas and heart, with death in the second decade from cardiac failure - iron-chelating agents to prevent iron overload; oral deferiprone and SC desderrioxamine - 200mg daily ascorbic acid to increase urinary excretion of iron - splenectomy if hypersplenism persists with increasing transfusion requirements, but do after childhood to reduce infection risks - bone marrow transplant

Answer 208

pain, deafness, cataracts and retinal damage

Answer 209

to increase urinary excretion of iron

Answer 210

- keep Hb above 90g/L - suppress ineffective extramedullary haematopoiesis - allow normal growth

Answer 211

* progressive increase in body iron load * mainly deposited in the liver and spleen resulting in liver fibrosis and cirrhosis * also deposited in the endocrine glands and heart resulting in diabetes, hypothyroidism, hypocalcaemia and premature death

Answer 212

- in contrast to beta-thalassaemia, alpha-thalassaemia is often caused by gene deletions - there are four alpha-globin genes per cell - the gene for alpha-globin chains is duplicated on both chromosomes 16 - the deletion of one alpha chain or both alpha-chain genes on each chromosome 16 may occur (deletion of one alpha chain is most common)

Answer 213

four, three, two and one gene deletion and whether a chain synthesis is partial or completely absent

Answer 214

- deletion of both genes on both chromosomes • there is no alpha chain synthesis • only Hb Barts (4 gamma chains) is present • Hb Barts cannot carry O2 and is incompatible with life • infants are either stillborn or die very shortly after birth • they are pale and oedematous and have enormous livers and spleens; known as hydrops fetalis

Answer 215

- 4 gamma chains present - occurs in 4 gene deletion alpha thalassaemia - cannot carry O2 and is incompatible with life

Answer 216

* severe reduction in alpha chain synthesis results in HbH disease, which is common in parts of Asia * HbH has 4 beta-chains * moderate anaemia and splenomegaly * patient is usually not transfusion dependent

Answer 217

4 beta chains | - found in alpha thalassaemia, biologically useless

Answer 218

- microcytosis with or without mild anaemia | - carrier

Answer 219

usually a normal blood picture

Answer 220

a disorder of quality (abnormal molecule or variant haemoglobins) where the sickle beta-globin gene is inherited

Answer 221

- commonest in Africans but also in India, Middle East and southern Europe - autosomal recessive disorder causing the production of abnormal beta globin chains - 1 in 4 chance of disease - 50% chance of being a carrier - 1 in 4 chance of being disease free

Answer 222

- African | - family history

Answer 223

- sickle cell haemoglobin (HbS) results from a single-base mutation of adenine to thymine which produces a substitution of valine for glutamic acid at the sixth codon of the beta-globin chain - in the heterozygous state (sickle cell trait), only one chromosome carries the gene; these are carriers of the disease - in the homozygous state (sickle cell anaemia), both genes are abnormal - since the synthesis of HbF (gamma or fetal) is normal, the disease does not manifest itself until the HbF decreases to adult levels at about 6 months of age - sickle cell haemoglobin (HbS) is insoluble and polymerises when deoxygenated - the flexibility of the cells is decreased and they become rigid and take up their characteristic sickle appearance - process is initially reversible but, with repeated sickling, the cells eventually lose their membrane flexibility and become irreversibly sickled - irreversibly sickled cells are dehydrated and dense, and will not return to normal when oxygenated

Answer 224

* a shortened RBC survival resulting in haemolysis * impaired passage of cells through the microcirculation (vasoocclusion), leading to obstruction of small vessels and tissue infarction and thus intense pain

Answer 225

infection, dehydration, cold, acidosis or hypoxia

Answer 226

- HbS releases its oxygen to the tissues more readily than normal RBCs - except in crises or complications

Answer 227

* symptom free with no disability expect in hypoxia e.g. in unpressurised aircraft or anaesthesia when vaso-occlusive events may occur * carriage offers protection against falciparum malaria

Answer 228

Falciparum malaria

Answer 229

- vaso occlusive crises - acute chest syndrome - pulmonary hypertension - anaemia

Answer 230

- acute pain in the hands and feet (dactylitis) owing to vaso-occlusion of the small vessels and avascular necrosis of the bone marrow in children - in adults there is pain in the long bones such as the femur, spine, ribs and pelvis due to avascular necrosis of the bone marrow - possible to have CNS infarction in children leading to stroke, seizures and cognitive defects - attacks vary in frequency and can occur as much as every day to once a year depending on patient

Answer 231

pulmonary hypertension and chronic lung disease

Answer 232

- a vaso-occlusive crisis of the pulmonary vasculature - occurs in 30% - pulmonary hypertension and chronic lung disease are the most common causes of death in adults with sickle cell disease - caused by infection (due to Chlamydia, mycoplasma and Streptococcus pneumoniae), fat embolism from necrotic bone marrow or pulmonary infarction due to sequestration of sickle cells (where sickle cells get trapped in the pulmonary vasculature) - results in shortness of breath, chest pain, hypoxia, fever, cough, dyspnoea and pulmonary infiltrates on CXR

Answer 233

- defined as a mean pulmonary artery pressure greater than 25mmHg by right heart catheterisation - occurs in 10% of patients - most probably caused by damage from repeated chest crises and repeated thromboembolism and intravascular haemolysis - increases the risk of hypoxaemia and worsening sickle cell crises

Answer 234

chronic haemolysis produces a stable haemoglobin level (60-80g/L) with a high reticulocyte count (10-20%) however an acute fall in the haemoglobin level can occur

Answer 235

splenic sequestration (where sickle cells get trapped in the spleen due to their shape): - resulting in the acute painful enlargement of spleen and an acute fall in Hb - can eventually lead to a fibrotic, non-functioning spleen - liver sequestration can also occur bone marrow aplasia: - most commonly follows infection with erythrovirus B19, which invades proliferating erythroid progenitors - there is a rapid fall in haemoglobin with no reticulocytes in the peripheral blood because of the failure of erythropoiesis in the marrow - aplastic crisis further haemolysis due to drugs or acute infection

Answer 236

- growth and development - avascular necrosis of bones results in shortened, deformed bones in children - infection in bones, lungs and kidneys (most susceptible to vaso-occlusive crisis) - splenic atrophy (resulting in susceptibility to infection with pneumococcus, salmonella species and haemophilus) - cardiac - neurological (fits and strokes) - liver: chronic hepatomegaly and liver dysfunction due to trapping of sickle cells - sequestration of red cells within corpora cavernosa causes priapism (prolonged painful erections) and eventual impotence - renal: chronic tubulointerstitial nephritis, CKD - eye: retinopathy, vitreous haemorrhage and retinal detachments - pregnancy: impaired placental blood flow can result in spontaneous abortion

Answer 237

- these are common sites for vaso-occlusive crises resulting in chronic infarcts - avascular necrosis of the hips and shoulders, compression of vertebrae and shortening of bones in the hands and feet occur - osteomyelitis can occur due to Staphylococcus Aureus, Staph. pneumoniae and salmonella

Answer 238

blood count: • level of Hb is in the range of 60-80 g/L • raised reticulocyte count blood films: • sickled erythrocytes shown sickle solubility test will be positive Hb electrophoresis: • confirms diagnosis • shows 80-95% HbS and absent HbA • aim for diagnosis at birth (cord blood) to aid prompt pneumococcal prophylaxis sickling can be induced in vitro with sodium dithionite

Answer 239

- precipitating factors such as infection, cold and dehydration should be avoided or treated quickly e.g prophylaxis vaccines - transfusion are not routinely given in steady-state anaemia - pneumococcal and influenza vaccination given routinely and daily penicillin 500mg orally - folic acid for all haemolysis patients - hospital admission when pain not controlled by non-opiate analgesia or if there are complications

Answer 240

* IV fluids * analgesia: morphine, codeine, paracetamol and NSAIDs * oxygen and antibiotics if required

Answer 241

- acute chest syndrome - acute anaemia due to acute splenic sequestration - aplastic crisis - stroke - heart failure - note: increased risk of iron overload

Answer 242

* oral hydroxycarbamide: increases HbF concentrations | * stem cell transplant

Answer 243

- rare but serious stem cell disorder - defined as pancocytopenia (this is a reduction in all the major cell lines; red cells, white cells and platelets) with hypocellularity (aplasia) of the bone marrow (marrow stops making cells) - it is usually an acquired condition but may be inherited

Answer 244

* congenital e.g. Fanconi’s anaemia * idiopathic acquired (67% of cases) * benzene, toluene, insecticides and glue sniffing * cytotoxic drugs and radiation * chemotherapeutic drugs * antibiotics such as chloramphenicol, carbamazepine and azathioprine * infections such as Epstein-Barr virus, HIV, hepatitis and TB * paroxysmal nocturnal haemoglobinuria * miscellaneous, e.g. pregnancy

Answer 245

- caused by a reduction in the number of pluripotent stem cells, together with a fault in those remaining or an immune reaction against them so that they are unable to repopulate the bone marrow - failure of only one cell line may also occur, resulting in isolated deficiencies, e.g. red cell aplasia

Answer 246

symptoms result because of RBC, WBC and platelet deficiency: • anaemia • increased susceptibility to infection • bleeding • bleeding gums, epitaxis, mouth infections, bruising with minimal trauma and blood blisters in mouth

Answer 247

must be differentiated from other causes of pancocytopenia: - aplastic anaemia - drugs - megaloblastic anaemia - bone marrow infiltration or replacement: lymphoma, acute leukaemia, myeloma, secondary carcinoma, myelofibrosis - hypersplenism - SLE - disseminated TB - paroxysmal nocturnal haemoglobinuria - overwhelming sepsis

Answer 248

blood count: • pancocytopenia with low or absent reticulocyte count bone marrow examination: • hypocellular marrow with increased fat spaces

Answer 249

- treatment of cause - withdrawal of offending agent, supportive care and some form of definitive therapy - main concern is infection thus any patient with severe neutropenia with a fever needs to be given broad-spectrum parenteral antibiotics urgently - give red cell transfusion and platelets - bone marrow transplant: • from HLA identical sibling or donor treatment of choice in those under 40 • blood and platelet transfusion used cautiously in patients who are candidates for bone marrow transplant to avoid sensitisation - immunosuppressive therapy with antithymocyte globulin (ATG) and ciclosporin in those: • over 40 • below 40 with severe disease who do not have a HLA identical sibling donor • those who are transfusion dependent

Answer 250

antithymocyte globulin (ATG) and ciclosporin

Answer 251

* over 40 * below 40 with severe disease who do not have a HLA identical sibling donor * those who are transfusion dependent

Answer 252

* can also be referred to erythrocytosis, which is essentially is an increased red blood cell mass, whereas polycythaemia refers to any increase in RBCs * defined as an increase in haemoglobin, packed cell volume (PCV) aka haematocrit and RCC - these measurements are all concentrations and are directly dependent on plasma volume as well as RBC mass * PCV is a more reliable indicator of polycythaemia than Hb, which may be disproportionally low in iron deficiency

Answer 253

- absolute (i.e. due to increase in RBC mass; primary or secondary) - relative (i.e. decreased plasma volume and normal RBC mass; apparent polycythaemia or dehydration)

Answer 254

due to an increase in RBC mass primary: - polycthaemia vera (PV) or - mutations in erythropoietin receptor - high oxygen affinity haemoglobins secondary: - hypoxia e.g. high altitude, chronic lung disease, cyanotic congenital heart disease or heavy smoking (appropriate increase in EPO) - inappropriately high erythropoietin secretion e.g. in renal carcinoma and hepatocellular carcinoma

Answer 255

- arises from a single haematopoietic progenitor cell and leads to excessive proliferation of red cells and variable increase in platelets and myeloid cells - over 95% of patients have acquired mutations of the gene Janus kinase 2 (JAK2) - in the vast majority of cases there is a point mutation that causes the substitution of phenylalanine for valine at position 617 - JAK2 is a cytoplasmic tyrosine kinase that transduces signals, especially those triggered by haemopoietic growth factors such as erythropoietin - commoner if over 60

Answer 256

Janus Kinase 2 | - cytoplasmic tyrosine kinase that tranduces signals, especially those triggered by haemopoietic growth factors e.g. EPO

Answer 257

- a clonal stem cell disorder resulting in a malignant proliferation of a clone derived from a single haematopoietic progenitor cell - the erythroid progenitor offspring are unusual in not needing erythropoietin to avoid apoptosis - this results in the excess proliferation of RBCs, white blood cells and platelets which causes a raised haematocrit (PCV) resulting in hyperviscosity and thrombosis - major complications are thrombosis and haemorrhage

Answer 258

a clonal stem cell disorder resulting in a malignant proliferation of a clone derived from a single haematopoietic progenitor cell

Answer 259

- symptoms and signs are due to hypervolaemia and hyperviscosity - may be asymptomatic and only detected on FBC - usually presents in patients over 60 - headache, vertigo, tinnitus, visual disturbance, angina pectoris, intermittent claudication, pruritus and venous thrombosis - severe itching after a hot bath or when the patient is warm - erythromelalgia; burning sensation in fingers and toes - increased risk of gout due to increased cell turnover and uric acid production - intermittent claudication - plethoric complexion; congested or swollen with blood in facial skin - hepatosplenomegaly; due to extramedullary haemopoiesis - distinguishes PV from secondary polycythaemia - risk of thrombosis and haemorrhage due to friable haemostatic plugs

Answer 260

``` • headaches • itching • tiredness • dizziness • tinnitus • visual disturbance note: these symptoms are common in those over 60 hence why PV is often missed ```

Answer 261

blood count showing raised WCC and platelet counts suggests PV as opposed to other causes of polycythaemia - demonstrating evidence of increased red cell volume (Hb >185g/L in men and >165g/L in women) and a gain of function mutation in JAK2 with at least one of: - erythroid hyperplasia, with increased numbers of megakaryocytes and granulocytes on bone marrow examination - serum erythropoietin levels below normal - erythroid colony formation in vitro in the absence of exogenous erythropoietin.

Answer 262

- no cure - treatment aims to maintain a normal blood count and to prevent complications of the disease, particularly thrombosis and haemorrhage - venesection to maintain PCV<0.45L/L - chemotherapy: hydroxycarbamide and busulfan used to reduce platelet count - low dose aspirin alongside above treatments - anagrelide inhibits megakaryocyte differentiation and is useful for thrombolysis - radioactive phosphorus but only in those over 70 due to increased risk of acute leukaemia - allopurinol to block uric acid production and reduce gout

Answer 263

* aims to lower PCV and platelet count * removal of 400-500mL of blood weekly to relieve symptoms * often used as sole treatment

Answer 264

hydroxycarbamide and low-dose busulfan for those who do not tolerate venesection or have poorly controlled features of the disease e.g. thrombocytosis (too many platelets)

Answer 265

to block uric acid production and reduce gout

Answer 266

coronary circulation = MI cerebral circulation = TIA or stroke peripheral circulation = peripheral vascular disease

Answer 267

- smoking - hypertension - diabetes - hyperlipidaemia - obesity/sedentary lifestyle - stress

Answer 268

- result of an atheroma that forms in areas of turbulent blood flow such as the bifurcation of arteries - platelets adhere to the damaged vascular endothelium and aggregate in response to ADP and thromboxane A2 - plaque rupture leads to the exposure of blood containing factor VIIa to tissue factor within the plaque which may trigger blood coagulation and lead to thrombus formation - this can result in complete occlusion of the vessel or embolisation that produces distal obstruction

Answer 269

• COX inhibitor e.g. aspirin which inhibits platelet aggregation • P2Y12 inhibitor e.g. clopidogrel which inhibits ADP from binding to the P2Y12 receptor • dipyramidole inhibits phosphordiesterase-mediated breakdown of cyclic AMP which prevents platelet activation • antibodies, peptides and non-peptide antagonists block GpIIb/IIIa receptor, inhibiting the final common pathway of platelet aggregation - epoprostenol is a prostacyclin which is used to inhibit platelet aggregation during renal dialysis (with or without heparin) and is used in primary pulmonary hypertension

Answer 270

- deep vein thrombosis (DVT) occurs in 25-50% of surgical patients and many non-surgical patients - 65% of below-knee DVTs are asymptomatic and these rarely embolise to the lung - commonly occurs after periods of immobilisation but it can occur in normal individuals for no obvious reasons

Answer 271

- Factor V Leiden (5%) - common in caucasians, increase risk of thrombus - PT20210A (3%) - common in caucasians, increase risk of thrombus rare: • antithrombin deficiency • Protein C or Protein S deficiency

Answer 272

- anti-phospholipid syndrome - lupus anticoagulant - hyperhomocysteinaemia - high levels are reduced by taking folate

Answer 273

- can occur in any vein of the leg or pelvis, but is particularly found in the veins of the calf - unlike arterial thrombosis, venous thrombosis usually occurs in normal vessels, often in the deep veins of the leg. - originates around the valves as red thrombi consisting of red cells and fibrin. - propagation occurs, inducing a risk of embolization to the pulmonary vessels. - chronic venous obstruction in the leg results in a permanently swollen leg - below the calf there are 6 veins, from the popliteal fossa upwards they merge into one - a DVT in the calf below the knee is not too much of a concern - a DVT in above the knee is potentially fatal and usually occurs in the proximal leg vein

Answer 274

- increased age - pregnancy - synthetic oestrogen - trauma - surgery (especially pelvic or orthopaedic) - past DVT - cancer - obesity - immobility - family history - varicose veins with phlebitis - thrombophilia - IBD - nephrotic syndrome

Answer 275

- may be asymptomatic - pain in the calf, often with swelling, redness and engorged superficial veins - the affected calf is often warmer and there may be ankle oedema - with complete occlusion, particularly in a large vein can result in cyanotic discolouration of the limb and severe oedema - pulmonary embolism can occur with any DVT but is more frequent from an iliofemoral thrombosis and is rare with thrombosis confined to the veins below the knee

Answer 276

- plasma D-dimer - compression ultrasound - venography - Doppler ultrasound

Answer 277

* type of fibrinogen degradation product that is released into the circulation when a clot begins to dissolve * D-dimers are elevated in other conditions e.g. cancer, pregnancy and post-operatively and a positive result is not diagnostic of DVT and requires further imaging * a normal result excludes DVT

Answer 278

- low molecular weight heparin for a minimum of 5 days (at first) - oral warfarin with a target INR of 2.5 (2-3) for 6 months after - direct acting oral anti-Coagulants (DOAC) similar to warfarin but do not need monitoring - compression stockings - inferior vena cava filters to reduce risk of pulmonary emboli

Answer 279

* early mobilisation post-op * compression stockings * thrombophylaxis for both low risk and high risk * assess risk of patients on admission * recent long distance, sedentary travel

Answer 280

* platelets are anucleate cells formed by fragmentation of megakaryocytic (MK) cytoplasm in bone marrow * disc shape allows them to flow close to the endothelium * play an important role in primary haemostasis (stopping of bleeding) * life span of 7-10 days * old platelets are phagocytosed by splenic macrophages in red pulp * have surface glycoproteins

Answer 281

thrombopoietin (TPO) • produced mainly by the liver thus if liver damage then there will be reduced thrombopoietin and thus decreased platelets • stimulates the production of platelets by megakaryocytes (MKs) • binds to platelet and MK receptors • decrease in platelets = less bound TPO = more TPO able to bind to MK = increased platelet production

Answer 282

- thromboxane A2 (TXA2) - P2Y12 - glycoprotein IIb/IIIa

Answer 283

- platelet receptor • synthesised from arachidonic acid in platelets via cyclooxygenase (COX-1) • induces platelet aggregation and vasoconstriction

Answer 284

* receptor on platelets that is activated by ADP | * amplifies activation of platelets and helps activate glycoprotein IIb/IIIa

Answer 285

* acts as a receptor for fibrinogen and von Willebrand Factor (vWF) * vWF is a clotting factor that is essential for platelets to adhere to damaged blood vessels * aids platelet adherence and aggregation

Answer 286

* congenital abnormality in platelet function * medication e.g. aspirin * von Willebrand disease resulting in reduced vWF activity meaning platelets are unable to bind to damaged blood vessels resulting in platelet dysfunction and thus muco-cutaneous bleeding * uraemia (raised urea levels in blood)

Answer 287

- this is a deficiency of platelets in the blood | - can either be due to decreased production or increased destruction

Answer 288

- congenital thrombocytopenia: absent/reduced/malfunctioning megakaryocytes (form platelets) in bone marrow - infiltration of bone marrow: leukaemia, metastatic malignancy (breast and prostate), lymphoma, myeloma, myelofibrosis - reduced platelet production by bone marrow - dysfunctional production of platelets in bone marrow: myelodysplasia

Answer 289

- low B12/folate - reduced thrombopoietin (TPO) e.g. in liver disease - medication: methotrexate and chemotherapy - toxins e.g. alcohol - infections e.g. viral (HIV) or TB - aplastic anaemia (autoimmune)

Answer 290

* autoimmune: immune thrombocytopenia purpura (ITP); primary or secondary * hypersplenism: portal hypertension and splenomegaly * drug related immune destruction: e.g. heparin induced thrombocytopenia * consumption of platelets: disseminated intravascular coagulopathy (DIC) or thrombotic thrombocytopenic purpura (TTP)

Answer 291

* thrombocytopenia due to immune destruction of platelets * the antibody-coated platelets are removed following binding to Fc receptors on macrophages * IgG antibodies form to platelets and megakaryocytes

Answer 292

- primary, acute - occurs most commonly in the 2-6 year age group - has an acute onset with muco-cutaneous bleeding and there may be a history or recent viral infection including varicella zoster (chickenpox) or measles - may also follow immunisation - although bleeding may be severe, life-threatening haemorrhage is rare - sudden self-limiting purpura

Answer 293

- secondary, chronic - usually is less acute than in children - characteristically seen in women and may be associated with other autoimmune disorders such as SLE, thyroid disease and autoimmune haemolytic anaemia - it is also seen in patients with chronic lymphocytic leukaemia (CLL) and solid tumours, and after infections with viruses like HIV or Hep C - platelet autoantibodies are detected in about 60-70% of patients, and are presumed to be present, although not detectable in the remaining patients; the antibodies often have specificity for platelet membrane glycoproteins IIb/IIIa and/or Ib

Answer 294

- easy bruising - epistaxis (nose bleed) - menorrhagia (heavy menstruation) - purpura (red or purple spots on the skin caused by bleeding underneath skin) - gum bleeding - major haemorrhage is rare - splenomegaly is rare

Answer 295

- bone marrow examination: shows thrombocytopenia with increased or normal megakaryocytes in the marrow - platelet autoantibodies (present in 60-70%); not needed for diagnosis

Answer 296

* oral corticosteroids 1mg/kg body weight produces a response in 2/3rds of patients but relapse is common when dose is reduced. * IV immunoglobulin - raises platelet count more rapidly than steroids, thus useful for surgery

Answer 297

* splenectomy * if splenectomy fails then high dose corticosteroids and immunosuppressive agents * thrombopoietin receptor agonists, e.g. romiplostim and eltrobopag, drive increased platelet production and may be used in refractory ITP

Answer 298

Immune Thrombocytopenia Purpura - defined as an isolated low platelet count with a normal bone marrow in absence of other causes of low platelets - causes a characteristic bruise-like rash and an increased tendency to bleed

Answer 299

Thrombotic Thrombocytopenic Purpura • widespread adhesion and aggregation of platelets leads to microvascular thrombosis and thus consumption of platelets and thus profound thrombocytopenia, low RBCs and often kidney, heart and brain dysfunction • occurs due to a reduction in ADAMTS-13 (which is attacked by the immune system) - a protease that is normally responsible for the degradation of vWF • large multimers of vWF form resulting in platelet aggregation and fibrin deposition in small vessels leading to microthrombi

Answer 300

- idiopathic - autoimmune e.g. SLE - cancer - pregnancy - drug associated e.g. quinine

Answer 301

- florid purpura - fever - fluctuating cerebral dysfunction - haemolytic anaemia with red cell fragmentation, often accompanied by acute kidney injury

Answer 302

- coagulation screen is normal | - lactate dehydrogenase is raised as a result of haemolysis

Answer 303

- plasma exchange to remove the antibody to ADAMTS-13 as well as providing a source of ADAMTS-13 - IV methylprednisolone - IV rituximab - platelet concentrates are contraindicated

Answer 304

disseminated intravascular coagulation - widespread generation of fibrin within blood vessels, caused by initiation of the coagulation pathway - consumption of platelets and coagulation factors occurs, as well as secondary activation of fibrinolysis, leading to production of FDPs, which contribute to bleeding by inhibiting fibrin polymerisation

Answer 305

- never occurs in isolation - recognition that the patient has a clinical disorder that may result in DIC is the key to investigation and management - DIC arises because of systemic activation of coagulation either by release of procoagulant material, such as tissue factor or via cytokine pathways as part of the inflammatory response - such systemic activation leads to widespread generation of fibrin and depositing in the blood vessels, leading to thrombosis and multiorgan failure - also results in the consumption of platelets and clotting factors with increased risk of bleeding

Answer 306

• massive activation of the coagulation cascade • initiating factors are: - extensive damage to vascular endothelium thereby exposing tissue factor - enhance expression of tissue factor by monocytes in response to cytokines • sepsis • major trauma and tissue destruction • advanced cancer • obstetric complications

Answer 307

- cytokine release in response to SIRS (systemic inflammatory response syndrome); usually caused by sepsis, trauma, pancreatitis, obstetric emergency or malignancy - widespread systemic generation of fibrin within blood vessels caused by the initiation of the coagulation pathway - either causes microvascular thrombosis and thus organ failure OR - the consumption of platelets and coagulation factors, leading to bleeding by inhibiting fibrin polymerisation (thus fibrin cannot polymerise)

Answer 308

- patient is often acutely ill and shocked - bleeding may occur from the mouth, nose and venepuncture sites and there may be widespread ecchymoses (discolouration of skin due to bleeding caused by bruising) - confusion - bruising - thrombotic events occur as a result of vessel occlusion by fibrin and platelets; any organ may be involved but the skin, brain and kidneys are most affected

Answer 309

- severe thrombocytopenia - diagnosis can be suggested from history e.g severe sepsis, trauma or malignancy, clinical presentation and thrombocytopenia - decreased fibrinogen - elevated FDPs (fibrin degradation products) e.g. D-dimer due to the intense fibrinolytic activity that is stimulated by the presence of fibrin in the circulation - blood film shows fragmented RBCs - prolonged prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT)

Answer 310

- treat underlying condition - replace platelets if they are very low via transfusion - maintain count > 50 x 10^9/L - fresh frozen plasma (FFP) to replace the coagulation factors - cryoprecipitate to replace fibrinogen and some coagulation factors - red cell transfusion in patients who are bleeding

Answer 311

development of an IgG antibody against a complex formed between platelets and heparin

Answer 312

* heparin binds to a protein in the blood called platelet factor 4 (PF4), forming a complex - PF4/Heparin * IgG then binds to this complex forming IgG/PF4/heparin which in turn then binds and activates platelets * this results in platelet consumption and thus thrombocytopenia * also results in thrombosis (arterial or venous) as well as skin necrosis

Answer 313

cardiac bypass surgery (since lots of heparin is used) and those on unfractioned heparin treatment

Answer 314

typically seen as a sharp fall in platelets around 5-10 days starting heparin treatment

Answer 315

* can be life-threatening and need to stop heparin immediately and try alternative anticoagulation even if platelets are low * never reexpose patient to heparin

Answer 316

temperature recorded as above 38°C in a patient with absolute neutrophil count <1.0x109/L • emergency since if not recognised or acted on quickly then patients can rapidly deteriorate and some will die

Answer 317

- any patient that has had chemotherapy less than 6 weeks ago - any patient who has had a stem cell transplant or high dose chemotherapy within the last year - any haematological condition resulting in neutropenia: • aplastic anaemia - bone marrow failure syndrome • autoimmune disease • leukaemia - people on methotrexate, carbimazole and clozapine

Answer 318

- pyrexia > 38°C - generally unwell with malaise - sweats/rigors - cough, sore throat, abdominal pain or diarrhoea - pain or erythema around central venous catheter - tachycardia, hypotension and raised respiratory rate - may not always have temperature/rigors due to inability to amount immune response

Answer 319

- start broad spectrum IV antibiotics without waiting for results ideally within 1 hour of admission - do not catheterise if neutropenic due to increased infection risk

Answer 320

- any malignancy can cause spinal cord compression: • bone metastasis and vertebral collapse • local tumour extension • deposition of malignant cells within cord - commonly seen in: • myeloma • lymphoma

Answer 321

- back pain - weakness/numbness in legs - inability to control bladder/bowel - saddle paraesthesia - uni/bilateral leg weakness - decreased perineal sensation - decreased anal tone - in acute cord compression, tone and reflexes will be reduced

Answer 322

- strict bed rest - high dose steroid e.g. oral dexamethosone - analgesia - urgent MRI of whole spine

Answer 323

tumour cell breakdown - > hyperkalaemia -> cardiac instability and muscle cramps - > nucleic acid catabolism -> high uric acid -> uric acid crystal formation -> acute renal failure -> hyperkalaemia - > hyperphosphataemia -> precipitation calcium phosphate -> acute renal failure - > hyperphosphataemia -> hypocalcaemia -> tetany, muscle cramps, irritability, seizures

Answer 324

- high tumour burden - high grade disease i.e. rapid cell turnover - pre-existing renal impairment - increasing age - on drugs that increase uric acid formation

Answer 325

- increase in blood viscosity - usually due to high levels of immunoglobulins: • seen in multiple myeloma and waldenstrom macroglobulinemia - can be due to high cell numbers e.g. leukaemia or polycythaemia - hyperviscosity results in vascular stasis and hypoperfusion

Answer 326

- mucosal bleeding - visual change due to hypoperfusion to retina - neurological disturbance due to brain hypoperfusion: vertigo, hearing loss, paraesthesia, ataxia, headache, seizure or stupor - shortness of breath - fatigue/anorexia - bruises/gum bleeding - dilated retinal veins/retinal haemorrhages on fundoscopy - ataxia/nystagmus - evidence of volume overload

Answer 327

- plasma viscosity level - CT head to exclude other causes of neurological signs - immunoglobulin levels - FBC

Answer 328

- keep hydrated - avoid blood transfusion since this will only make blood thicker - plasmapheresis; removes circulating immunoglobulins (paraprotein) to decrease serum viscosity, symptoms will improve

Answer 329

- confusion - bone pain - constipation - nausea - polyuria - abdominal pain - anorexia - renal stones - patients can get shortening QT interval and suffer cardiac arrest

Answer 330

- IV hydration, 3-4L a day | - bisphosphonates e.g. zolendronate, reduces Ca2+ production but takes a few days to come into effect

Answer 331

- anti-emetic drug | - is a 5HT3 antagonist

Answer 332

- often used in bypass surgery IV - glycoaminoglycan - binds to antithrombin and increases its activity - indirect thrombin inhibitor - monitor with Activated Partial Thromboplastin Time (APTT) - given by continuous IV infusions - easily reversed by proteamine

Answer 333

- smaller molecule - less variation in dose - renally excreted - given once daily, weight-adjusted dose given sub-cutaneously (SC) - used for treatment and prophylaxis

Answer 334

- inhibits cyclo-oxygenase (COX) IRREVERSIBLY - acts for the lifetime of platelets which is around 7-10 days - inhibits thromboxane formation and hence platelet aggregation - used in arterial thrombosis given orally once daily - Clopidogrel is similar but inhibits ADP induced platelet aggregation - need to stop aspirin 5 days before surgery so platelets can recover

Answer 335

- orally active - prevents the synthesis of active factors II, VII, IX, X (1972) - antagonist/blocker of Vitamin K (required for II, VII, IX X factor synthesis since it makes post-translational changes on them to make them active) - long half life (36 hours) - prolongs the prothrombin time - can reverse with Vitamin K but takes time to produce new active factors - difficult to use - due to the presence of Vitamin K in the diet so if vitamin K increases then your warfarin requirement will also need to increase - thus need to monitor using INR (international normalised ratio which standardises prothrombin time) - usual target range = 2-3 - higher range = 3-4.5

Answer 336

International Normalised Ratio - standardises prothrombin time - usual target range = 2-3 - higher target range = 3-4.5

Answer 337

- orally active - like aspirin and warfarin - direct action on factor II or X - no blood tests or monitoring required - has a shorter half life so given twice/once daily - used for extended thromboprophylaxis and treatment of atrial fibrillation and DVT and pulmonary embolism - effect is equivalent to INR 2-3, not higher, thus cannot be used with heart valves - not used in pregnancy

Answer 338

an alkylator (cyclophosphamide or melphalan), steroid (prednisolone or dexamethasone) and novel agent (bortezomib or thalidomide)

Answer 339

- by lymph node biopsy and histological examination - shows Reed-Sternberg cells (binucleate or multinucleate malignant B lymphocytes) in a background rich in benign small lymphocytes and histiocytes

Answer 340

- local infection - pyogenic infection, e.g. tonsillitis - tuberculosis - lymphoma - secondary carcinoma

Answer 341

- infection - EBV - cytomegalovirus - Toxoplasma sp. - tuberculosis - HIV infection - lymphoma - leukaemia - systemic disease: systemic lupus erythematosus, sarcoidosis, rheumatoid arthritis - drug reaction e.g. phenytoin

Answer 342

prognosis is related to the stage of disease at presentation, with a 5-year survival rate of over 90% in stage I declining to 60% in stage IV. the presence of B symptoms indicates more severe disease with a worse prognosis

Answer 343

- PET/CT is used to detect disease activity after treatment and to distinguish between active tumour (PET-positive) and necrosis or fibrosis (PET-negative) in residual masses - irradiation, with its attendant complications, can be omitted in PET-negative masses after chemotherapy

Answer 344

- malignant clonal expansion of lymphocytes, occurring at different stages of lymphocyte development - 80% of B cell origin - neoplasms of non-dividing mature lymphocytes are indolent, whereas those of proliferating cells (e.g. lymphoblasts, immunoblasts) are much more aggressive - B and T/natural killer cell lymphomas are further divided on this basis, e.g. precursor B cell lymphoma - then again subdivided based on cytogenetics and immunophenotyping

Answer 345

- rare before 40yrs - painless peripheral lymph node enlargement - systemic symptoms may occur - extranodal involvement more common than in Hodgkin's lymphoma; almost any organ in body can be involved - bone marrow infiltration -> anaemia, recurrent infections and bleeding - skin involvement with T cell lymphoma presents as mycosis fungoides and Sezary syndrome

Answer 346

- may show anaemia - elevated WCC or thrombocytopenia suggests bone marrow involvement - ESR may be raised

Answer 347

the term used for treatment that employs high-dose chemotherapy or chemotherapy plus radiation, with the aim of clearing the bone marrow completely of both benign and malignant cells. without bone marrow replacement or ‘transplantation’, the patient would die of bone marrow failure

Answer 348

- bone marrow or peripheral blood stem cells from another individual, usually a human leucocyte antigen (HLA)-identical sibling, are infused intravenously following myeloablative therapy - immunosuppression is required to prevent host rejection and graft-versus-host disease (GVHD) - blood count usually recovers within 3-4 weeks - mortality rate is 20-40% depending on age, often due to infection of GVHD

Answer 349

- neutropenic sepsis - superior vena cava syndrome - acute tumour lysis syndrome - spinal cord compression - hypercalcaemia - PE - raised intracranial pressure

Answer 350

- can arise from any upper mediastinal mass but is most commonly associated with lung cancer and lymphoma. - presentation is with difficulty breathing and/or swallowing, oedematous facies and arms, and venous congestion in the neck with dilated veins in the upper chest and arms. - treatment is with immediate steroids, vascular stents, radiotherapy and chemotherapy for sensitive tumours.

Answer 351

- occurs as a result of treatment producing massive and rapid breakdown of tumour cells, leading to increased serum level of urate, potassium and phosphate with secondary hypocalcaemia - it is most commonly seen as a complication of treatment of acute leukaemia and high-grade lymphoma unless preventive measures are taken. - hyperuricaemia and hyperphosphataemia result in acute kidney injury through urate and calcium phosphate deposition in the renal tubules

Answer 352

- prevention and treatment is with allopurinol, rasburicase (urate oxidase) - high fluid loads, e.g. 4–5 L daily by intravenous (i.v.) infusion prior to, and continuing during, chemotherapy - allopurinol (xanthine oxidase inhibitor) or rascurbicase (recombinant urate oxidase) both work to reduce uric acid production - monitor electrolytes - refer for dialysis if required

Answer 353

- have the translocation t(15;17) involving the retinoic acid receptor alpha (RARa) on chromosome 17 and the promyelocytic leukaemia gene (PML) on chromosome 15 - resulting PML-RARa fusion protein shows reduced sensitivity to retinoic acid and prevents differentiation of myeloid cells

Answer 354

- associated with APML - retinoic acid receptor alpha (RARa) on chromosome 17 - promyelocytic leukaemia gene (PML) on chromosome 15 - resulting PML-RARa fusion protein shows reduced sensitivity to retinoic acid and prevents differentiation of myeloid cells

Answer 355

Auer rods (a rod-like conglomeration of granules in the cytoplasm) within blast cells are pathognomonic of AML

Answer 356

increased cellularity, with high percentage of abnormal lymphoid or myeloid blast cells

Answer 357

1. AML with recurrent cytogenetic abnormalities (including acute promyelocytic leukaemia with t(15;17) or variants) 2. AML with multilineage dysplasia (often secondary to pre-existing MDS) 3. AML and MDS, therapy related, occurring after chemotherapy or radiotherapy 4. AML - not otherwise categorised

Answer 358

1. precursor B cell ALL 2. Burkitt cell leukaemia 3. precursor T cell ALL

Answer 359

- the initial requirement of therapy is to return the peripheral blood and bone marrow to normal (complete remission) with ‘induction chemotherapy’ tailored to the particular leukaemia and the individual patient’s risk factors. - the risk of failure of treatment is based on the cytogenetic pattern. - successful remission induction is always followed by further treatment (consolidation), the details being determined by the type of leukaemia and the patient’s risk factors (and the patient’s tolerance of treatment). - recurrence is almost invariable if ‘consolidation’ therapy is not given.

Answer 360

- correction of anaemia, thrombocytopenia and coagulation abnormalities by administration of blood, platelets and blood products - treatment of infection with IV antibiotics - prevention of acute tumour lysis syndrome

Answer 361

a moderately intensive combination of i.v. chemotherapy, e.g. cytosine arabinoside (cytarabine) and daunorubicin, is given at intervals to allow marrow recovery in between. this is followed by consolidation therapy with a minimum of four cycles of treatment given at 3–4-week intervals.

Answer 362

consolidating chemotherapy to induce remission followed by sibling-matched allogeneic bone marrow transplantation, despite its attendant risks.

Answer 363

this is only curable with allogeneic transplantation but unfortunately ‘high risk’ is more common with advancing age when the toxicity of this treatment increases greatly.

Answer 364

- APML is a variant of AML that is specifically associated with DIC which may worsen when treatment is started - combine chemotherapy with all-trans-retinoid acid (ATRA) which causes differentiation of promyelocytes and rapid reversal of bleeding tendency caused by DIC - successful remission induction followed with maintenance ATRA

Answer 365

all-trans-retinoic acid - combined with chemotherapy - causes differentiation of promyelocytes and rapid reversal of bleeding tendency caused by DIC (which is associated with APML)

Answer 366

- the prognosis in children with ALL is excellent, with almost all achieving complete remission and with 80% being alive and disease free at 5 years. - the results in adults are not as good, the prognosis getting worse with advancing years. - overall, about 70–80% achieve complete remission with only about 30% being cured.

Answer 367

- combination chemotherapy including vincristine, dexamethasone, asparaginase and daunorubicin. - details of consolidation will be determined by the anticipated risk of failure but is usually with intensive chemotherapy and then maintenance therapy for 2 years to reduce the risk of disease recurrence. - unlike AML, ALL has a propensity to involve the CNS, so treatment also includes prophylactic intrathecal drugs, methotrexate or cytosine arabinoside (cytarabine). - cranial irradiation is used in those at very high risk or in those with symptoms.

Answer 368

- CML occurs most commonly in middle age and is characterized by the presence of the Ph chromosome. - there is an insidious onset, with fever, weight loss, sweating and symptoms of anaemia. - massive splenomegaly is characteristic.

Answer 369

- untreated, this chronic phase lasts 3–4 years. - this is usually followed by blast transformation, with the development of acute leukaemia (usually acute myeloid) and, commonly, rapid death. - less frequently, CML transforms into myelofibrosis, death ensuing from bone marrow failure.

Answer 370

- blood count usually shows anaemia and a raised white cell count (often > 100 × 109/L). the platelet count may be low, normal or raised. - bone marrow aspirate shows a hypercellular marrow with an increase in myeloid progenitors. - the Ph chromosome and the BCR-ABL oncogene are shown by cytogenetics and reverse transcriptase polymerase chain reaction (RT-PCR).

Answer 371

- imatinib, a tyrosine kinase inhibitor that specifically blocks the enzymatic action of the BCR-ABL fusion protein, is first-line treatment for the chronic phase. - imatinib produces a complete haematological response in over 95% of patients, and 70–80% of these have no detectable BCR-ABL transcripts in the blood. - event-free, and overall, survival appear to be better than for other treatments - imatinib can be continued indefinitely. - in the acute phase (blast transformation) most patients have only a short-lived response to imatinib, and other chemotherapy as for acute leukaemia is used in the hope of achieving a second chronic phase.

Answer 372

CLL, the most common form of leukaemia, is an incurable disease of older people, characterized by an uncontrolled proliferation and accumulation of mature B lymphocytes.

Answer 373

- CLL usually follows an indolent course. - early CLL is generally asymptomatic and isolated peripheral blood lymphocytosis is frequent. - symptoms are a consequence of bone marrow failure: anaemia, infections and bleeding. - an autoimmune haemolysis contributes to the anaemia. - some patients may be asymptomatic, the diagnosis being a chance finding on the basis of a blood count performed for a different reason. - there may be lymphadenopathy and, in advanced disease, hepatosplenomegaly.

Answer 374

- blood count shows a raised white cell count with lymphocytosis (> 5 × 109/L). there may be anaemia and thrombocytopenia. - blood film shows small lymphocytes of mature appearance with ‘smear or smudge cells’, an artefactual finding due to cell rupture while the film is being made. - bone marrow reflects peripheral blood usually heavily infiltrated with lymphocytes. - immunophenotyping is essential to exclude reactive lymphocytosis and other lymphoid neoplasms. - cytogenetics to characterize the specific mutation can be helpful in assessing prognosis.

Answer 375

- combination therapy with fludarabine, cyclophosphamide and rituximab has become standard first-line therapy and can induce complete remission. - for older patients, chlorambucil usually reduces lymphocytosis, lymphadenopathy and splenomegaly to palliate the disease. - alemtuzumab is used in patients in whom there is disease progression after treatment with fludarabine. - new generation anti-CD20 monoclonal antibodies, such as ofatumumab and obinutuzumab, are also used in fludarabine- or alemtuzumab-refractory CLL or in combination with chlorambucil.

Answer 376

ofatumunab and obinutuzumab | - can be used in fludarabine or alemtuzumab-refractory CLL or in combination with chlorambucil

Answer 377

- the median survival from diagnosis is very variable and correlates closely with disease stage at diagnosis and cytogenetic findings, e.g. patients with either 11q or 17p deletions (the sites of two tumour suppressor genes) are at high risk of not responding to initial treatment and rapid progression. - in other patients there is near-normal life expectancy.

Answer 378

- blood consists of red cells, white cells, platelets and plasma. - plasma is the liquid component of blood which contains soluble fibrinogen and in which the other components are suspended. - serum is what remains after the formation of the fibrin clot.

Answer 379

stimulatory - erythropoietin (red cells) - thrombopoietin (platelets) - neutrophils (G-CSF0) - interleukin-5 (eosinophils) inhibitory - TNF

Answer 380

- reticulocytes are young red cells recently released from the bone marrow and still contain RNA. - they are larger than mature red cells and normally represent 0.5–2.5% of total circulating red blood cells. - the reticulocyte count gives a guide to the erythroid activity in the bone marrow and there is normally an increase with haemorrhage, haemolysis and after treatment with specific haematinics in deficiency states.

Answer 381

- haemorrhage - haemolysis - after treatment with specific haematinics in deficiency states

Answer 382

- the principal function of haemoglobin (Hb) is to deliver oxygen to the tissues from the lungs. - Hb is a tetramer consisting of two pairs of globin polypeptide chains. - a haem group, consisting of a single molecule of protoporphyrin IX bound to a single ferrous ion (Fe2+) is linked covalently at a specific site to each globin chain. - oxygenation and deoxygenation of Hb occur at the haem iron.

Answer 383

gastric acid, iron deficiency and increased erythropoietic activity

Answer 384

- fixed at 1mg/day - occurs through shedding of skin and mucosal cells and excretion in sweat, urine and faeces - loss during menses in women

Answer 385

- non-haem iron forms the main part of dietary iron and is derived from fortified cereals and vegetables. it is dissolved in the low pH of the stomach and reduced from the ferric to the ferrous form by a brush border ferrireductase before transportation across the mucosal cells. - haem iron is derived from Hb and myoglobin in red or organ meats. haem iron is better absorbed than non-haem iron.

Answer 386

fortified cereals and vegetables

Answer 387

it is dissolved in the low pH of the stomach and reduced from the ferric to the ferrous form by a brush border ferrireductase before transportation across the mucosal cells

Answer 388

Hb and myoglobin in red or organ meats

Answer 389

a response to iron treatment is characterized by an increase in the reticulocyte count followed by an increase in Hb at a rate of about 10 g/L every week until the Hb concentration is normal

Answer 390

hepcidin binds to the export transport protein, ferroportin, in the iron-absorbing cells in the duodenum, thereby causing its degradation, with a consequent reduction in the transport of iron from duodenal cells into the plasma

Answer 391

- sideroblastic anaemia is a rare disorder of haem synthesis characterized by a refractory anaemia with hypochromic cells in the peripheral blood and ring sideroblasts in the bone marrow. - ring sideroblasts are erythroblasts with iron deposited in mitochondria and reflect impaired utilization of iron delivered to the developing erythroblast. - it may be inherited or acquired (secondary to myelodysplasia, alcohol excess, lead toxicity, isoniazid). - treatment is to withdraw the causative agents and some cases respond to pyridoxine (vitamin B6).

Answer 392

1mg, which is easily supplied by balanced Western diet (containing 5-30μg daily)

Answer 393

- liberated by gastric acid and pepsin | - binds to a vitamin B12-binding protein (R binder) derived from saliva

Answer 394

- released by pancreatic enzymes - becomes bound to intrinsic factor, which, along with H+ ions, is secreted from gastric parietal cells - complex is delivered to terminal ileum, where vitamin B12 is absorbed and transported to tissues

Answer 395

carrier protein transcobalamin II

Answer 396

about 1% of an oral dose of B12 is absorbed passively without the need for intrinsic factor, mainly through the duodenum and ileum

Answer 397

- low dietary intake - impaired absorption - abnormal utilisation

Answer 398

- pernicious anaemia - gastrectomy - congenital deficiency of intrinsic factor

Answer 399

- ileal disease or resection, e.g. Crohn’s disease - coeliac disease - tropical sprue - bacterial overgrowth - fish tapeworm (Diphyllobothrium latum)

Answer 400

- congenital transcobalamin II deficiency (rare) | - nitrous oxide (inactivates B12)

Answer 401

- old age - poverty - alcohol excess - anorexia

Answer 402

- Coeliac disease - Crohn's disease - tropical sprue

Answer 403

physiological: pregnancy, lactation, prematurity pathological: chronic haemolytic anaemia, malignant and inflammatory diseases, renal dialysis

Answer 404

- phenytoin - trimethoprim - sulfasalazine - methotrexate

Answer 405

- to prevent first occurrence of neural tube defects, women should be advised to take folate supplements (at least 400 μg/day) before conception and during pregnancy. - larger doses (5 mg daily) are recommended for mothers who already have an infant with a neural tube defect.

Answer 406

- pregnancy | - newborn

Answer 407

- alcohol excess - liver disease - reticulocytosis (e.g. due to haemolysis) - hypothyroidism - haematological disorders: myelodysplastic syndrome, sideroblastic anaemia and aplastic anaemia - drugs: hydroxycarbamide (hydroxyurea) and azathioprine - cold agglutinins

Answer 408

- aplastic anaemia - drugs - megaloblastic anaemia - bone marrow infiltration or replacement: lymphoma, acute leukaemia, myeloma, secondary carcinoma, myelofibrosis - hypersplenism - systemic lupus erythematosus - disseminated tuberculosis - paroxysmal nocturnal haemoglobinuria - overwhelming sepsis

Answer 409

suspect neutropenic sepsis in a neutropenic patient (neutrophil count < 1 × 10^9/L) who is pyrexial or has new-onset confusion, tachycardia, hypotension, dyspnoea or hypothermia.

Answer 410

history and physical examination including mucous membranes, oropharynx (?thrush, erythema), surgical sites and intravenous lines

Answer 411

* bloods: full blood count and differential white cell count, C-reactive protein, urea and electrolytes, liver biochemistry, clotting, blood cultures * radiology: chest X-ray. consider further imaging if localizing signs, e.g. computed tomography (CT) scan of abdomen and pelvis * microbiology: microscopy and culture of peripheral blood and taken from central lines, sputum, urine, stool (if diarrhoea)

Answer 412

- red cell membrane defect - hereditary spherocytosis - hereditary elliptocytosis - Hb abnormalities - thalassaemia - sickle cell disease - metabolic defects - G6PD deficiency - pyruvate kinase deficiency - pyrimidine kinase deficiency

Answer 413

- G6PD deficeincy - pyruvate kinase deficiency - pyrimidine kinase deficiency

Answer 414

immune - autoantibodies - alloimmune - drug-induced antibodies non-immune - paroxysmal nocturnal haemoglobulinuria - mechanical destruction: microangiopathic - haemolytic anaemia, damaged artificial heart valves, march haemoglobulinuria - secondary to systemic disease, e.g. liver failure - infections - drugs/chemicals - hypersplenism

Answer 415

- increased reticulocytosis/polychromasia | - erythroid hyperplasia of bone marrow

Answer 416

- anaemia - increased serum bilirubin - increased LDH - increased urobilinogen - positive urinary haemosiderin - decreased plasma haptoglobulin

Answer 417

- abnormal red cells - spherocytes - bite cells, blister cells, Heinz bodies - fragmentation

Answer 418

haemoglobin electrophoresis - thalassaemia - sickle cell diseae - HB C, D, E, H

Answer 419

- drugs e.g. methyldopa, quinine, NSAIDs, interferon, ribavarin - autoimmune haemolytic anaemia: IgG warm or cold

Answer 420

- hereditary spherocytosis | - malaria, Clostridium welchii

Answer 421

enzyme defects, e.g.: - decreased G6PD - decreased pyruvate kinase - decreased pyrimidine 5' nucleotidase

Answer 422

microangiopathic haemolytic anaemia e.g.: - eclampsia - haemolytic uraemic syndrome - thrombotic thrombocytopenic purpura - DIC

Answer 423

hereditary elliptocytosis is similar to spherocytosis, but the red cells are elliptical in shape. it is milder clinically and usually does not require splenectomy.

Answer 424

HbS = alpha2beta2 | - substitution of valine for glutamic acid in position 6 of beta chain

Answer 425

HbC = alpha2beta2 | - substitution of lysine for glutamic acid in position 6 of beta chain

Answer 426

inheritance of the HbS gene from one parent and HbC from the other parent gives rise to Hb SC disease, which tends to run a milder clinical course than sickle cell disease but with more thromboses

Answer 427

- pain – uncontrolled by non-opiate analgesia - swollen painful joints - acute sickle chest syndrome or pneumonia - mesenteric sickling and bowel ischaemia - splenic or hepatic sequestration - central nervous system deficit - cholecystitis (pigment stones) - cardiac arrhythmias - renal papillary necrosis resulting in colic or severe haematuria - hyphema (layer of red cells in anterior chamber of eye) or retinal detachment - priapism

Answer 428

- after TIAs and stroke - acute chest syndrome - splenic sequestration crisis and aplastic crises - before elective operation - during pregnancy

Haematology Flashcards

(461 cards)