haem Flashcards

Question

what is Hereditary Eliptocytosis

Answer 1

Hereditary Eliptocytosis Autosomal dominant defect causes elliptical RBCs Most pts. are asymptomatic Rx: folate, rarely splenectomy

Answer 2

G6PD deficiency Pathophysiology X-linked disorder of pentose phosphate shunt decreased NADPH production causes RBC oxidative damage Affects mainly Mediterranean and Mid / Far East ``` Haemolysis Triggers Broad (Fava) beans Mothballs (naphthalene) Infection Drugs: antimalarials, henna, dapsone, sulphonamides ``` Ix Film Irregularly contracted cells Bite cells, ghost cells and blister cells Heinz bodies G6PD assay after 8wks (reticulocytes have high G6PD) Rx Treat underlying infection Stop and avoid precipitants Transfusion may be needed

Answer 3

Pyruvate Kinase Deficiency Autosomal recessive defect in ATP synthesis causes rigid red cells phagocytosed in the spleen Features: splenomegaly, anaemia ± jaundice Ix: PK enzyme assay Rx: often not needed or transfusion ± splenectomy

Answer 4

Pathogenesis Point mutation in beta globin gene: glu changes to val SCA: HbSS Trait: HbAS HbS insoluble when deoxygenated causes sickling Sickle cells have decreased life-span causes haemolysis Sickle cells get trapped in microvasc causes thrombosis

Answer 5

``` Presentation Clinical features manifest from 3-6mo due to HbF Triggers Infection Cold Hypoxia Dehydration Splenomegaly: may cause sequestration crisis Infarction: stroke, spleen, AVN, leg ulcers, BM Crises: pulmonary, mesenteric, pain Kidney disease Liver, Lung disease Erection Dactylitis ``` Complications Sequestration crisis: Splenic pooling causes shock + severe anaemia Splenic infarction: atrophy and hyposplenism increase infection: osteomyelitis Aplastic crisis: parvovirus B19 infection Gallstones

Answer 6

``` Ix Hb 6-9, increased retics, increased bilirubin Film: sickle cells and target cells Hb electrophoresis Dx at birth c¯ neonatal screening ```

Answer 7

Mx Chronic Disease Pen V BD + immunisations Folate Hydroxycarbamide if frequent crises ``` Mx Acute Crises General Analgesia: opioids IV Good hydration O2 Keep warm ``` Ix FBC, U+E, reticulocytes, cultures Urine dip CXR Rx Blind Abx: e.g. ceftriaxone Transfusion: exchange if severe Folate plus low dose penicillin (because they are ‘functionally asplenic’). Routine transfusion not usually required simply because of low Hb. Hydroxyurea - It is just not known exactly how does it, but what it does is increase the proportion of HbF in the red cell. The HbF does not carry the sickle substitution and this addition slows the rate of Hb polymerisation in sickling. Exchange transfusion. Best done on a plasmapheresis machine. Aim to reduce sickle percentage to less than 10%.

Answer 8

``` APTT: Intrinsic: 12, 11, 9, 8 Common: 10, 5, 2, 1 Increased in: Lupus anti-coagulant Haemophilia A or B vWD (carries factor 8) Unfractionated heparin DIC Hepatic failure ``` ``` PT: Extrinsic: 7 Common: 10, 5, 2, 1 Increased in Warfarin / Vit K deficiency Hepatic failure DIC ``` ``` Bleeding Time / PFA-100: Platelet function Increased in: decreased plats number or function vWD Aspirin DIC ``` ``` Thrombin Time: Fibrinogen function Increased in: Quantitative/ qualitative fibrinogen defect DIC, dysfibrinogenaemia Heparin ```

Answer 9

Vascular or Platelet Disorder Bleeding into skin: petechiae, purpura, echymoses Bleeding mucus mems: epistaxis, menorrhagia, gums Immediate, prolonged bleeding from cuts Coagulation Disorder Deep bleeding: muscles, joints, tissues Delayed but severe bleeding after injury

Answer 10

Congenital HHT Ehler’s Danlos (easy bruising) Pseudoxanthoma elasticum ``` Acquired Senile purpura Vitamin C deficiency Infection: e.g. meningococcus Steroids Vasculitis: e.g. HSP ```

Answer 11

Thrombocytopenia decreased production BM failure: aplastic, infiltration, drugs (EtOH, cyto) Megaloblastic anaemia increased destruction Immune: ITP, SLE, CLL, heparin, viruses Non-immune: DIC, TTP, HUS, PNH, antiphospholipid Splenic pooling Portal hypertension SCD ITP Children: commonly post-URTI, self-limiting Adults: F more than M, long-term Ix: Anti-platelet Abs present Rx: conservative, steroids, IVIg, splenectomy ``` Functional Defects Drugs: aspirin, clopidogrel 2O: paraproteinaemias, uraemia Hereditary Bernard-Soulier: GpIb deficiency Glanzmann’s: GpIIb/IIIa deficiency ```

Answer 12

1 - Acquired Severe liver disease Anticoagulants Vitamin K deficiency 2 - Haemophilia A: F8 Deficiency: X-linked, affects 1/5000 males Pres: haemoarthroses, bleeding after surgery/extraction Ix: increased APTT, normal PT, decreased F8 assay Mx Avoid NSAIDs and IM injections Minor bleeds: desmopressin + tranexamic acid Major bleeds: rhF8 3 - Haemophilia B: F9 deficiency: X-linked, 1/20,000 males 4 - VWD: Commonest inherited clotting disorder (mostly AD) vWF Stabilises F8 Binds plats via GpIb to damaged endothelium Ix If mild, APTT and bleeding time may be normal increased APTT, increased bleeding time, normal plat, decreased vWF AG Rx: desmopressin + tranexamic acid

Answer 13

DIC up PT, up APTT, up TT, down plats, down fibrinogen, up FDPs Schistocytes Thrombosis and bleeding Causes: sepsis, malignancy (esp. APML), trauma, obs Rx: FFP, plats, heparin

Answer 14

Coagulopathy predisposing to thrombosis, usually | venous.

Answer 15

Inherited Factor V Leiden / APC resistance Protein C deactivates F5 and F8 c¯ protein S and thrombomodulin cofactors Degradation resistance present in 5% of population Most don’t develop thrombosis Heterozygotes: 5x rise VTE Homozygotes: 50x rise VTE Prothrombin Gene Mutation increased prothrombin levels increased thrombosis due to decreased fibrinolysis by thrombin-activated fibrinolysis inhibitor Protein C and S Deficiency Heterozygotes for either have raised risk of thrombosis. Skin necrosis occurs – esp. c¯ warfarin Heterozygotes cause neonatal purpura fulminans Antithrombin III Deficiency AT is heparin co-factor cause thrombin inhibition Deficiency affects 1/500 Heterozygotes have huge raised thrombosis risk Homozygosity is incompatible c¯ life

Answer 16

Acquired Progesterones in OCPs Anti-phospholipid syndrome: CLOTs: venous and arterial: Coagulation defect: increased APTT Livido reticularis Obstetric complications: recurrent 1st trimester abortion Thrombocyotpenia

Answer 17

``` Indications Arterial thrombosis under50yrs (?APL) Venous thrombosis under40yrs c¯ no RFs Familial VTE Unexplained recurrent VTE Unusual site: portal, mesenteric Recurrent foetal loss Neonatal ``` Investigations FBC, clotting, fibrinogen concentration Factor V Leiden / APC resistance Lupus anticoagulant and anti-cardiolipin Abs Assays for AT, protein C and S deficiencies PCR for prothrombin gene mutation ``` Rx Rx acute thrombosis as per normal Anticoagulate to INR 2-3 Consider lifelong warfarin If recurrence occurs on warfarin increase INR to 3-4 ``` ``` Prevention Lifelong anticoagulation not needed if asymptomatic increased VTE risk c¯ OCP or HRT Prophylaxis in high risk situations Surgery Pregnancy ```

Answer 18

``` Immediate Transfusion Reactions: Haemolytic Bacterial Contamination Febrile non-Haemolytic Allergic TRALI Fluid Overload Massive Transfusion coagulopathies and imbalances ``` ``` Delayed Transfusion Reactions: Delayed Haemolytic Fe Overload Post-transfusion Purpura graft vs host disease ```

Answer 19

Congenital: Fanconi’s anaemia: aplastic anaemia ``` Acquired: Idiopathic aplastic anaemia BM infiltration Haematological: Leukaemia Lymphoma Myelofibrosis Myelodysplasia Megaloblastic anaemia ``` Infection: HIV Radiation ``` Drugs: Cytotoxic: cyclophos, azathioprine, methotrexate Abx: chloramphenicol, sulphonamides Diuretic: thiazides Anti-thyroid: carbimazole Anti-psychotic: clozapine Anti-epileptic: phenytoin ```

Answer 20

Aplastic Anaemia Rare stem cell disorder Key Features Pancytopenia Hypocellular marrow ``` Presentation: Pancytopenia Age: 15-24yrs and over 60yrs Anaemia Infections Bleeding ``` Causes Inherited: Fanconi’s anaemia: Ashkenazi, short, pigmented Dyskeratosis congenita: premature ageing Swachman-Diamond syn.: pancreatic exocrine dysfunction Acquired: Drugs Viruses: parvovirus, hepatitis Autoimmune: SLE Ix BM: Hypocellular marrow Mx Supportive: transfusion Immunosuppression: anti-thymocyte globulin Allogeneic BMT: may be curative

Answer 21

Pathophysiology Heterogeneous group of disorders causes BM failure Clone of stem cells c¯ abnormal development causes functional defects causes quantitative defects May be primary or secondary Chemo or radiotherapy ``` Characteristics Cytopenias Hypercellular BM Defective cells: e.g. ringed sideroblasts 30% causes AML ``` Clinical Features Elderly BM failure: anaemia, infection, bleeding, bruising Splenomegaly Ix Film: blasts, Pelger-Huet anomaly, dimorphic BM: Hypercellular, blasts, ringed sideroblasts Mx Supportive: transfusions, EPO, G-CSF Immunosuppression Allogeneic BMT: may be curative

Answer 22

``` Classification RBC cause Polycythaemia Vera WBC cause CML Platelets cause Essential thrombocythaemia Megakaryocytes cause Myelofibrosis ```

Answer 23

``` Features: Hyperviscosity Headaches Visual disturbances Tinnitus Thrombosis Arterial: strokes, TIA, peripheral emboli Venous: DVT, PE, Budd-Chiari ``` Histamine Release Aquagenic pruritus Erythromelalgia Sudden, severe burning in hands and feet c¯ redness of the skin Splenomegaly: 75% Hepatomegaly: 30% Gout ``` Ix 99% JAK2+ve increase RBC, Hb and Hct increase WCC and increase plats BM: hypercellular c¯ erythroid marrow decrease EPO increase red cell mass c¯ isotope studies ``` Rx Aim to keep Hct

Answer 24

``` Features: Hyperviscosity Headaches Visual disturbances Tinnitus Thrombosis Arterial: strokes, TIA, peripheral emboli Venous: DVT, PE, Budd-Chiari ``` Histamine Release Aquagenic pruritus Erythromelalgia Sudden, severe burning in hands and feet c¯ redness of the skin Splenomegaly: 75% Hepatomegaly: 30% Gout ``` Ix 99% JAK2+ve increase RBC, Hb and Hct increase WCC and increase plats BM: hypercellular c¯ erythroid marrow decrease EPO increase red cell mass c¯ isotope studies ``` Rx Aim to keep Hct

Answer 25

True Polycythaemia: increase total volume of red cells Primary: PV Secondary Hypoxia: altitude, COPD, smoking, cyanotic conditions of the heart EPO: renal cysts/tumours ``` Pseudopolycythaemia: decrease plasma volume Acute Dehydration Shock Burns ``` Chronic Diuretics Smoking

Answer 26

Features Thrombosis Arterial: strokes, TIA, peripheral emboli Venous: DVT, PE, Budd-Chiari Bleeding (abnormal plat function) E.g. mucus membranes Erythromelagia Ix Plats over 600 (often over 1000) BM: increase megakaryocytes 50% JAK2+ve ``` Rx Plats 400-1000: aspirin alone Thrombosis or plats over 1000: hydroxycarbamide Anagralide may be used Inhibits platelet maturation decreased plat count and function ``` Prognosis 5% causes AML/MF over 10yrs

Answer 27

Primary: ET ``` Secondary: Bleeding Infection Chronic inflammation: RA, IBD Trauma / surgery Hyposplenism / splenectomy ```

Answer 28

Clonal proliferation of megakaryocytes causes increase PDGF causes Myelofibrosis Acquired abnormal clone of haematopoietic cells causes fibrosis in the marrow. Extramedullary haematopoiesis: liver and spleen

Answer 29

Features Elderly Massive HSM Hypermetabolism: wt. loss, fever, night sweats BM failure: anaemia, infections, bleeding ``` Ix Film: leukoerythroblastic c¯ teardrop poikilocytes Cytopenias BM: dry tap (need trephine biopsy) 50% JAK2+ve ``` Rx Supportive: blood products Splenectomy Allogeneic BMT may be curative in younger pts. Prognosis 5yr median survival

Answer 30

Epidemiology Children 2-5yrs (commonest childhood Ca) Rare in adults Aetiology Arrest of maturation and proliferation of lymphoblasts 80% B lineage, 20% T lineage ``` Risk Factors Genetic susceptibility (often Chr translocations) Environmental trigger Radiation (e.g. during pregnancy) Down’s ``` ``` Features BM Failure: Anaemia Thrombocytopenia bleeding Leukopenia infection ``` ``` Infiltration: Lymphadenopathy Orchidomegaly Thymic enlargement HSM CNS: CN palsies, meningism Bone pain ```

Answer 31

``` Mx Supportive Blood products Allopurinol Hickman line or Portacath ``` Infections Gentamicin + tazocin Prophylaxis: e.g. co-timoxazole, ciprofloxacin Chemotherapy (recruited into national trials) 1. Remission induction 2. Consolidation + CNS Rx 3. Maintenance for 2-3yrs BMT Best option for younger adults Prognosis 85% survival in children Worse in adults

Answer 32

Acute Myeloid Leukaemia Epidemiology increases risk c¯ age: mean 65-70 Commonest acute leukaemia of adults Aetiology Neoplastic proliferation of myeloblasts (common progenitor for basophils, neutrophils, eosinophils and monocytes) ``` Risk Factors Chromosomal abnormalities Radiation Down’s Chemotherapy: e.g. for lymphoma Myelodysplastic and myeloproliferative syndromes ``` FAB Classification (based on cell type) M2: granulocyte maturation M3: acute promyelocytic leukaemia – t(15;17) M4: acute myelomonocytic leukaemia M7: megakaryoblastic leukaemia – trisomy 21

Answer 33

Features BM Failure: Cytopenias ``` Infiltration: Gum infiltration causes hypertrophy and bleeding (M4) HSM Skin involvement Bone pain ``` Blood: DIC: APML (M3) Hyperviscosity: massive increase WCC may cause thrombi ``` Ix: increase WCC blasts (occasionally normal) Anaemia and decrease plats BM aspirate: at least 20% blasts Auer rods are diagnostic ``` Dx: Made by immunological and molecular phenotyping Flow cytometry Cytogenetic analysis affects Rx and guides prognosis Mx: Supportive: as for ALL Infections: as for ALL Chemotherapy: V. intensive causes long periods of neutropenia and decrease plats ATRA for APML BMT: Allogeneic if poor prognosis Destroy BM and leukemic cells c¯ chemotherapy and total body irradiation. Repopulate marrow c¯ HLA-matched donor HSCs Autologous if intermediate prognosis HSCs taken from pt.

Answer 34

Chronic Lymphocytic Leukaemia Epidemiology Commonest leukaemia in Western World M>F=2:1 Elderly: 70s Aetiology Clone of mature B cells (memory cells). lymphoid haematopoeitic tree rather than myeloid like in CML. ``` Features Often asymptomatic incidental finding Symmetrical painless lymphadenopathy HSM Anaemia ``` 'B' symptoms also imply a poor prognosis weight loss over 10% in last 6 months fever over 38ºC night sweats ``` Complications Autoimmune haemolysis Evan’s = AIHA and ITP Infection (Ig): bacterial, zoster Marrow failure / infiltration ```

Answer 35

``` Ix increase WCC, lymphocytosis Smear cells decrease se Ig +ve DAT Rai or Binet staging ``` Dx Immunophenotyping to distinguish from NHL Natural Hx Some remain stable for years Nodes usually enlarge slowly (± lymphatic obstruction) Death often due to infection: e.g. encapsulates, fungi Richter Transformation: CLL then progress to large B cell lymphoma ``` Rx Indications Symptomatic Ig genes un-mutated (bad prognostic indicator) 17p deletions (bad prognostic indicator) Supportive care Chemotherapy Cylophosphamide Fludarabine Rituximab Radiotherapy Relieve LN or splenomegaly ``` Prognosis 1/3 never progress 1/3 progress c¯ time 1/3 are actively progressing

Answer 36

Chronic Myeloid Leukaemia Epidemiology 15% of leukaemia Middle-aged: 60-60yrs Aetiology Myeloproliferative disorder: clonal proliferation of myeloid cells. Features Systemic: wt. loss, fever, night sweats, lethargy Massive HSM abdo discomfort Bruising / bleeding (platelet dysfunction) Gout Hyperviscosity

Answer 37

``` Philadelphia Chromosome Reciprocal translocation: t(9;22) Formation of BCR-ABL fusion gene Constitutive tyrosine kinase activity Present in >80% of CML Discovered by Nowell and Hungerford in 1960 ```

Answer 38

``` Ix massive increase in WBC PMN and basophils Myelocytes ± decrease Hb and decrease plat (accelerated or blast phase) increase urate BM cytogenetic analysis: Ph+ve ``` Natural Hx Chronic phase: 90% haematological response 80% 5ys Allogeneic SCT Indicated if blast crisis or TK-refractory

Answer 39

The non-Hodgkin lymphomas (NHLs) are diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas.[1] Types of NHL vary significantly in their severity, from slow growing to very aggressive types.

Answer 40

Features ``` Lymphadenopathy: 75% @ presentation Painless Symmetric Multiple sites Spreads discontinuously ``` ``` Extranodal Skin: esp. T cell lymphomas CNS Oropharynx and GIT Splenomegaly ``` B Symptoms Fever Night sweats Wt. loss (>10% over 6mo) Blood Pancytopenia Hyperviscosity Ix FBC, U+E, LFT, LDH high LDH = worse prognosis Film Normal or circulating lymphoma cells ± pancytopenias Classification: LN and BM biopsy Staging: CT/MRI chest, abdomen, pelvis Stage c¯ Ann Arbor System

Answer 41

Classification ``` B Cell (commonest) Low Grade: usually indolent but often incurable Follicular Small cell lymphocytic (=CLL) Marginal Zone (inc. MALTomas) Lymphoplamsacytoid (e.g. Waldenstrom’s) ``` High Grade: aggressive but may be curable Diffuse large B cell (commonest NHL) Burkitt’s T Cell Adult T cell lymphoma: Caribs and Japs – HTLV-1 Enteropathy-assoc. T cell lymphoma: chronic coeliac Cutaneous T cell lymphoma: e.g. Sezary syn. Anaplastic large cell

Answer 42

Mx Diagnosis and management in an MDT High Grade (e.g. DLBCL) R-CHOP regimen BMT for relapse ~30% 5ys Low Grade (e.g. follicular) Rx when clinically indicated (e.g. chloambucil) >50% 5ys

Answer 43

Epidemiology M>F=2:1 (esp. in paeds) Bimodal age incidence: 20-29yrs and >60yrs May be assoc. c¯ EBV Features ``` Lymphadenopathy Painless Asymmetric Spreads contiguously to adjacent LNs Cervical nodes in 70% (also axillary and inguinal) May be alcohol-induced LN pain Mediastinal LN may mass effects SVC obstruction Bronchial obstruction ``` B Symptoms Fever Night sweats Wt. loss (>10% over 6mo) Other Itch Pel Ebstein Fever: cyclical fever Hepato- and/or spleno-megaly

Answer 44

Ix FBC, film, ESR, LFT, LDH, Ca ESR or Hb = worse prognosis LN excision biopsy or FNA Reed-Sternberg Cells (owl’s eye nucleus) Staging: CT/MRI chest, abdomen, pelvis BM biopsy if B symptoms or Stage 3/4 disease

Answer 45

Ann Arbor staging is the staging system for lymphomas, both in Hodgkin's lymphoma (previously called Hodgkin's disease) and Non-Hodgkin lymphoma (abbreviated NHL). It was initially developed for Hodgkin's, but has some use in NHL. It has roughly the same function as TNM staging in solid tumors. ``` Staging: Ann Arbor System 1. Single LN region 2. at least 2 nodal area on same side of diaphragm 3. Nodes on both sides of diaphragm 4. Spread byond nodes: e.g. liver, BM + B if constitutional symptoms ```

Answer 46

Mx Chemo, radio or both ABVD regimen BMT for relapse Prognosis Depends on stage and grade 1A: over 95% 5ys 4B: under 40% 5ys

Answer 47

Pathogenesis Clonal proliferation of plasma cells causes monoclonal massive rise in Ig Usually IgG or IgA Clones may also produce free light chain (lambda or kappa): ~2/3 Excreted by kidney causes urinary BJP Light chains only seen in plasma in renal failure Clones produce IL-6 which inhibits osteoblasts ( ALP) and activates osteoclasts.

Answer 48

``` Symptoms Osteolytic Bone Lesions Backache and bone pain Pathological #s Vertebral collapse ``` BM Infiltration Anaemia, neutropenia or thrombocytopenia Recurrent Bacterial Infections Neutropenia Immunoparesis (= Ig) Chemotherapy Renal Impairment Light chains increased Ca AL-amyloid ``` Complications Hypercalcaemia Neurological: Ca, compression, amyloid AKI Hyperviscosity AL-amyloid (15%) ```

Answer 49

Ix NB. Do ESR and Se electrophoresis if >50 c¯ back pain Bloods FBC: normocytic normochromic anaemia Film: rouleaux ± plasma cells ± cytopenias massive rise ESR/PV, rise U+Cr, rise Ca, normal ALP Se electrophoresis and 2-microglobulin Urine Stix: rise specific gravity (BJP doesn’t show) Electrophoresis: BJP BM trephine biopsy ``` X-ray: Skeletal Survey Punched-out lytic lesions Pepper-pot skull Vertebral collapse Fractures ``` ``` Dx Clonal BM plasma cells 10% Presence of se and/or urinary monoclonal protein End-organ Damage: CRAB (1 or more) Ca rise (>2.6mM) Renal insufficiency Anaemia ( ```

Answer 50

Mx Supportive Bone pain: Analgesia (avoid NSAIDs) + bisphosphonates Anaemia: Transfusions and EPO Renal impairment: ensure good hydration ± dialysis Infections: broad spectrum Abx ± IVIg if recurrent Complications rise Ca: aggressive hydration, frusemide, bisphosphonates Cord compression: MRI, dexamethasone + local radio Hyperviscosity: Plasmapheresis (remove light chains) AKI: rehydration ± dialysis Specific Fit pts. Induction chemo: lenalidomide + low-dose dex Then allogeneic BMT Unfit pts. Chemo only: melphalan + pred + lenalidomide Bortezomib for relapse ``` Prognosis Mean survival: 3-5yrs Poor prognostic indicators up beta2-microglobulin down albumin ```

Answer 51

Smouldering / Asymptomatic Myeloma Se monoclonal protein and/or BM plasma cells at least 10% No CRAB MGUS Se monoclonal protein

Answer 52

Definition Group of disorders characterised by extracellular deposits of a protein in an abnormal fibrillar form that is resistant to degradation.

Answer 53

AL Amyloidosis AA Amyloidosis Familial Amyloidosis Others: non-Systemic Amyloidosis

Answer 54

AL Amyloidosis Clonal proliferation of plasma cells c¯ production of amyloidogenic light chains. 1O: occult plasma cell proliferation 2O: myeloma, Waldenstrom’s, MGUS, lymphoma Features Renal: proteinuria and nephrotic syndrome Heart: restrictive cardiomyopathy, arrhythmias, echo “Sparkling” appearance on echo Nerves: peripheral and autonomic neuropathy, carpal tunnel. GIT: macroglossia, malabsorption, perforation, haemorrhage, hepatomegaly, obstruction. Vascular: periorbital purpura (characteristic)

Answer 55

``` AA Amyloidosis Amyloid derived from serum amyloid A SAA is an acute phase protein Chronic inflammation RA IBD Chronic infection: TB, bronchiectasis ``` Features Renal: proteinuria and nephrotic syndrome Hepatosplenomegaly

Answer 56

Familial Amyloidosis Group of AD disorders caused by mutations in transthyretin (produced by liver) Features: sensory or autonomic neuropathy

Answer 57

non-Systemic Amyloidosis beta-amyloid: Alzheimer’s beta2 microglobulin: chronic dialysis Amylin: T2DM Dx Biopsy of affected tissue Rectum or subcut fat is relatively non-invasive Apple-green birefringence c¯ Congo Red stain under polarized light. Rx AA amyloid may improve c¯ underlying condition AL amyloid may respond to therapy for myeloma Liver Tx may be curative for familial amyloidosis Prognosis Median survival: 1-2yrs

Answer 58

Neutropenic Sepsis Hyperviscosity Syndrome DIC Tumour Lysis Syndrome

Answer 59

Neutropenic Sepsis Hyperviscosity Syndrome DIC Tumour Lysis Syndrome

Answer 60

``` Neutropenic Sepsis General Precautions Barrier nursing in a side room Avoid IM injections (may cause infected haematoma) Swabs + septic screen TPR 4hrly ``` Antimicrobials Start broad spectrum Abx: check local guidelines Consider G-CSF

Answer 61

Hyperviscosity Syndrome Causes massive rise RBC / Hct >0.5: e.g. PV massive rise WCC > 100: e.g. leukaemia massive rise plasma proteins: Myeloma, Waldenstrom’s Features CNS: headache, confusion, seizures, faints Visual: retinopathy cause visual disturbance Bleeding: mucus membranes, GI, GU Thrombosis Ix raise plasma viscosity (PV) FBC, film, clotting Se + urinary protein electrophoresis ``` Rx Polycythaemia: venesection Leukopheresis: leukaemia Avoid transfusing before lowering WCC Plasmapheresis: myeloma and Waldenstrom’s ```

Answer 62

DIC Widespread activation of coagulation from release of procoagulants into the circulation. Clotting factors and plats are consumed cause bleeding Fibrin strands cause haemolysis ``` Causes Malignancy: e.g. APML Sepsis Trauma Obstetric events: e.g. PET ``` Signs Bruising Bleeding Renal failure Ix down plats, down Hb, up APTT, up PT, up FDPs, down fibrinogen (therefore rise in TT) Rx Rx cause Replace: cryoprecipitate, FFP, vitamin K Consider heparin and APC

Answer 63

``` Tumour Lysis Syndrome Massive cell destruction High count leukaemia or bulky lymphoma up K, up urate causes renal failure Prevention: up fluid intake + allopurinol ```

Answer 64

``` Causes of Massive Splenomegaly: >20cm CML Myelofibrosis Malaria LeishManiasis Gaucher’s (AR, glucocerebrosidase deficiency) ```

Answer 65

``` All Causes of Splenomegaly Haematological Haemolysis: HS Myelproliferative disease: CML, MF, PV Leukaemia, lymphoma ``` Infective EBV, CMV, hepatitis, HIV, TB, infective endocarditis Malaria, leishmanias, hydatid disease Portal HTN: cirrhosis, Budd-Chiari Connective tissue: RA, SLE, Sjogrens ``` Other Sarcoid Amyloidosis Gaucher’s 1O Ab deficiency (e.g. CVID) ```

Answer 66

``` Indications Trauma Rupture (e.g. EBV infection) AIHA ITP HS Hypersplenism ```

Answer 67

Complications Redistributive thrombocytosis causes early VTE Gastric dilatation (ileus) Left lower lobe atelectasis: v. common susceptibility to infections Encapsulates: haemophilus, pneumo, meningo Film Howell-Jolly bodies Pappenheimer bodies Target cells Mx Immunisation: pneumovax, HiB, Men C, yrly flu Daily Abx: Pen V or erythromycin Warning: Alert Card and/or Bracelet Other Causes of Hyposplenism SCD Coeliac disease IBD

Answer 68

ESR How far RBCs fall through anti-coagulated blood in 1h Normal: ~20mm/h (M: age/2, F: (age+10)/2 high se proteins cover RBCs causes clumping causes rouleaux causes faster settling causes raised ESR. high ESR causes: Plasma factors high fibrinogen: inflammation high globulins: e.g. myeloma Red cell factors Anaemia causes high ESR ``` DD of ESR >100: Myeloma SLE GCA AAA Ca prostate ```

Answer 69

``` Neutrophilia Bacterial infection Left shift Toxic granulation Vacuolation ``` Stress: trauma, surgery, burns, haemorrhage Steroids Inflammation: MI, PAN Myeloproliferative disorders: e.g. CML in myeloproliferative disorders the other cells will be depressed, if just a neutrophilic most likely to be a bacterial infection. prednisolone can raise neutrophils whilst suppressing others.

Answer 70

``` Neutropenia Viral infection Drugs: chemo, cytotoxics, carbimazole, sulphonamides Severe sepsis Hypersplenism: e.g. Felty’s ```

Answer 71

``` Neutropenia Viral infection Drugs: chemo, cytotoxics, carbimazole, sulphonamides Severe sepsis Hypersplenism: e.g. Felty’s ``` leukaemias will present with other cell types depressed. lymphoma with no bone marrow invasion will preserve other cell types but raise the lympho.

Answer 72

Lymphopenia Drugs: steroids, chemo HIV

Answer 73

Monocytosis Chronic infection: TB, Brucella, Typhoid AML

Answer 74

``` Eosinophilia Parasitic infection Drug reactions: e.g. c¯ EM Allergies: asthma, atopy, Churg-Strauss Skin disease: eczema, psoriasis, pemphigus ``` for some reasons Hodgkins and churg-strauss have a high eosinophilia.

Answer 75

Basophilia Parasitic infection IgE-mediated hypersensitivity: urticarial, asthma CML

Answer 76

The Gell and Coombs classification divides hypersensitivity reactions into 4 types Type I - Anaphylactic antigen reacts with IgE bound to mast cells anaphylaxis, atopy (e.g. asthma, eczema and hayfever) Type II - Cell bound IgG or IgM binds to antigen on cell surface autoimmune haemolytic anaemia, ITP, Goodpasture's, pernicious anemia, acute hemolytic transfusion reactions, rheumatic fever, bullous pemphigoid, pemphigus vulgaris Type III - Immune complex free antigen and antibody (IgG, IgA) combine serum sickness, systemic lupus erythematosus, post-streptococcal glomerulonephritis, extrinsic allergic alveolitis (especially acute phase) Type IV - Delayed hypersensitivity T cell mediated tuberculosis, tuberculin skin reaction, graft versus host disease, allergic contact dermatitis, scabies, extrinsic allergic alveolitis (especially chronic phase), multiple sclerosis, Guillain-Barre syndrome In recent times a further category has been added: Type V antibodies that recognise and bind to the cell surface receptors, either stimulating them or blocking ligand binding Graves' disease, myasthenia gravis

Answer 77

moderate is 0.5-1 severe is under 0.5 x10^9 can result in life threatening neutropenic sepsis which can easily be missed as the inflamm/pus etc will be much less marked. so if they have neutropenia be on guard. broad spectrum abs within 30 minutes of diagnosing neutropenic sepsis/febrile neutropenia. do the sepsis 6. tazocin but check local guidelines.

Answer 78

Parathyroid hormone levels are useful as malignancy and primary hyperparathyroidism are the two most common causes of hypercalcaemia. A parathyroid hormone that is normal or raised suggests primary hyperparathyroidism. Hypercalcaemia: causes The most common causes of hypercalcaemia are malignancy (bone metastases, myeloma, PTHrP from squamous cell lung cancer) and primary hyperparathyroidism ``` Other causes include sarcoidosis* vitamin D intoxication acromegaly thyrotoxicosis Milk-alkali syndrome drugs: thiazides, calcium containing antacids dehydration Addison's disease Paget's disease of the bone** ``` *other causes of granulomas may lead to hypercalcaemia e.g. Tuberculosis and histoplasmosis **usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation

Answer 79

``` 10.6-28.3umol/L 41-77 umol/L 30-400 ug/L 0-20 umol/L 20-100 x109/L 0.6-2.6g/L ```

Answer 80

Key role as suppressor of iron in disease states - anaemia of chronic disease Lack of hepcidin gives iron overload A few genetic mutations Suppressed in thalassaemia Bolus doses of vitamin D2 decrease hepcidin, inerestingly it blocks iron absorption by blocking release of iron from enterocytes into the circulation - blocks ferroportin. excess iron is stored in the liver and released into the circulation, hepcidin blocks the ferroportins here too. blocking release.

Answer 81

whether the blood is coombs test positive or negative. Positive ‘Coombs’’ or direct antiglobulin test. some causes of non-immune: Genetic Haemoglobinopathy (sickle, thalassaemia, many others) Membrane disorder (spherocytosis) Enzyme (pyruvate kinase) Acquired Paroxysmal nocturnal haemoglobinuria (severe malaria)

Answer 82

1 If there are enough red cells (eg haemochromatosis), venesection. Simple, safe, reasonably quick. 2 If the patient is already anaemic (eg severe congenital haemolytic anaemia such as thalassaemia major, already transfusion-dependent), drug treatment, which is no joke. 1 Desferrioxamine (‘Desferal’). Derived from a bacterial siderophore. Subcutaneous or iv administration, five or seven days per week. Eye plus ear checks. 1 Deferasirox (‘Exjade’), given orally. Nephrotoxic, causes diarrheoa, GI ulceration. Cytopenias. Liver dysfunction... it goes on. 2 Deferiprone (‘Ferriprox’). Oral, but even worse, rarely used, crosses blood-brain barrier

Answer 83

Blood removed from body and cells separated from plasma by centrifuge Cells replaced, antibody-containing plasma (serum) discarded Donor plasma infused

Answer 84

Idiopathic thrombocytopenic purpura (ITP), also known as primary immune thrombocytopenia, primary immune thrombocytopenic purpura or autoimmune thrombocytopenic purpura, is defined as isolated low platelet count (thrombocytopenia) with normal bone marrow and the absence of other causes of thrombocytopenia. It causes a characteristic purpuric rash and an increased tendency to bleed. Two distinct clinical syndromes manifest as an acute condition in children and a chronic condition in adults. The acute form often follows an infection and has a spontaneous resolution within 2 months. Chronic idiopathic thrombocytopenic purpura persists longer than 6 months with a specific cause being unknown. ITP is an autoimmune condition with antibodies detectable against several platelet surface antigens. ITP is diagnosed by a low platelet count in a complete blood count . However, since the diagnosis depends on the exclusion of other causes of a low platelet count, additional investigations (such as a bone marrow biopsy) may be necessary in some cases. In mild cases, only careful observation may be required but very low counts or significant bleeding may prompt treatment with corticosteroids, intravenous immunoglobulin, anti-D immunoglobulin, or immunosuppressive drugs. Refractory ITP may require splenectomy, the surgical removal of the spleen. Platelet transfusions may be used in severe bleeding together with a very low count. Sometimes the body may compensate by making abnormally large platelets. don't give platelets or thats fuel to the fire. steroids then IV IG. can use rituximab. the classic presentation is a young male with essentially no platelets, a viral infection, lymphocytosis due to the virus and nothing else wrong on the FBC. EBV HIV

Answer 85

``` "All Of My Blood Has Taken Some Poison": Aplastic anaemias Overwhelming sepsis Megaloblastic anaemias Bone marrow infiltration Hypersplenism TB SLE Paroxysmal nocturnal haemoglobinuria ```

Answer 86

``` NAACP: Neoplasm Allergy/ Asthma Addison's disease Collagen vascular diseases Parasites ```

Answer 87

``` ABCD: Acute blood loss Bone marrow failure Chronic disease Destruction (hemolysis) ```

Answer 88

Hodgkin's lymphoma is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distributions being most common in the third and seventh decades Histological classification Nodular sclerosing - Most common (around 70%) - Good prognosis - More common in women. Associated with lacunar cells Mixed cellularity - Around 20%- Good prognosis Associated with a large number of Reed-Sternberg cells Lymphocyte predominant Around 5% Best prognosis Lymphocyte depleted Rare Worst prognosis B' symptoms also imply a poor prognosis weight loss > 10% in last 6 months fever > 38ºC night sweats Other factors associated with a poor prognosis identified in a 1998 NEJM paper included: age > 45 years stage IV disease haemoglobin 15,000/µl *Reed-Sternberg cells with nuclei surrounded by a clear space

Answer 89

Platelets 150-400 * 109/l | White blood cells 4-11 * 109/l|

Answer 90

This patient almost certainly meets the diagnostic criteria for neutropenic sepsis given the blood result from two days ago. Empirical antibiotics need to be started immediately - you should not wait for the repeat neutrophil count. Tazocin is recommend as the first-line antibiotic by NICE. G-CSF is not used routinely in neutropenic sepsis. Neutropenic sepsis moderate is 0.5-1 severe is under 0.5 x10^9 can result in life threatening neutropenic sepsis which can easily be missed as the inflamm/pus etc will be much less marked. so if they have neutropenia be on guard. broad spectrum abs within 30 minutes of diagnosing neutropenic sepsis/febrile neutropenia. do the sepsis 6. tazocin but check local guidelines.

Answer 91

Spinal cord compression is an oncological emergency and affects up to 5% of cancer patients. Extradural compression accounts for the majority of cases, usually due to vertebral body metastases. It is more common in patients with lung, breast and prostate cancer Features back pain - the earliest and most common symptom - may be worse on lying down and coughing lower limb weakness sensory changes: sensory loss and numbness neurological signs depend on the level of the lesion. Lesions above L1 usually result in upper motor neuron signs in the legs and a sensory level. Lesions below L1 usually cause lower motor neuron signs in the legs and perianal numbness. Tendon reflexes tend to be increased below the level of the lesion and absent at the level of the lesion Management high-dose oral dexamethasone urgent oncological assessment for consideration of radiotherapy or surgery

Answer 92

Underlying causes of confusion need to be looked for and treated as appropriate, for example hypercalcaemia, infection, urinary retention and medication. If specific treatments fail then the following may be tried: first choice: haloperidol other options: chlorpromazine, levomepromazine In the terminal phase of the illness then agitation or restlessness is best treated with midazolam

Answer 93

Ovarian cancer

Answer 94

Pancreatic cancer

Answer 95

Breast cancer

Answer 96

Hepatocellular carcinoma, teratoma

Answer 97

Colorectal cancer

Answer 98

Melanoma, schwannomas

Answer 99

Small cell lung carcinoma, gastric cancer, neuroblastoma

Answer 100

mean corpuscular haemoglobin = the mean haemoglobin quantity within the blood cells, this affects their colour e.g. hypochromic most normocytic and microcytic anaemias are normochromic most microcytic anaemias are hypo chromic except in anaemia of chronic disease.

Answer 101

mean corpuscular haemoglobin concentration

Answer 102

RBC distribution width - a measure of the variation of RBC volumes. used in conjunction with MCV to see whether there is more than one cause for the anaemia raised RDW = antisocytosis

Answer 103

the mean volume of the RBC = -cytic e.g. microcytic | the main method used to classify anaemia

Answer 104

microcytic - sideroblastic, iron deficiency, thalassaemia, lead poisoning normocytic - acute blood loss, haemolytic anaemia, sickle cell, anaemia of chronic disease (can be microcytic) - hypothyroidism and bone marrow failure can be either normo or macrocytic in nature (aplastic anaemia, myelodysplasia, leukaemia, myelofibrosis.) macrocytic - megaloblastic - low B12 or folate - non-megaloblastic - alcolhol, reticulocytosis, liver disease, pregnancy

Answer 105

b12, folate ferritin

Answer 106

iron , transferrin/TIBC, ferritin

Answer 107

if bone marrow cause/haemolytic anaemia/ sideroblastic anaemia suspected

Answer 108

if thalassemia/sickle suspected

Answer 109

chronic blood loss - menstruation, GI (look at urea), other loss increase demand - pregnancy, growth decrease absorption - coeliacs, gastrectomy poor intake Ix - if no clear cause - endoscopy, colonoscopy, urine dip rx - treat cause, ferrous sulphate, transfusion if Hb under 70

Answer 110

Physiology: vitamin B12 is found in meat and dairy products. The stomach produces intrinsic factor which binds to B12, allowing it to be absorbed in the terminal ileum. Body stores last up to 4 years. Causes: pernicious anaemia, malabsorption (e.g. after gastrectomy or terminal ileum disease/resection) Investigations for pernicious anaemia: parietal cell antibodies, intrinsic factor antibodies, Schilling’s test Treatment: treat cause, hydroxocobalamin (B12) injections 3-monthly

Answer 111

Physiology: folate is found in green vegetables. Body stores only last 4 months (therefore deficiency develops earlier in malabsorption/pregnancy). Causes: Dietary (alcoholism, neglect) increased requirements (pregnancy, haematopoiesis) Malabsorption (coeliacs, pancreatic insufficiency, gastrectomy, crohns) Drugs interfere with metabolism (phenytoin, methotrexate, trimethoprim) Treatment: treat cause, oral folic acid supplements

Answer 112

Causes: any chronic disease Classically: iron ↓, TIBC ↓, ferritin normal (vs. iron deficiency anaemia: iron ↓, TIBC ↑, ferritin ↓) Treatment: treat cause, transfuse if Hb

Answer 113

When red cells are destroyed intravascularly (abnormal process) – free Hb follows one of three pathways: Some binds to hepatoglobulin (and is removed by liver) Some is filtered by the glomerulus and passed as haemoglobinuria or haemosiderinuria Some is oxidised to methaemoglobulin which dissociates to globin + ferrihaem (most ferrihaem then binds to albumin → methaemalbuminaemia)

Answer 114

Inherited causes: - Haemoglobinopathies: sickle cell, thalassaemia - Membrane defects: hereditary spherocytosis, elliptocytosis - Enzyme defects: G6PD deficiency, pyruvate kinase deficiency Acquired causes: - Immune mediated: autoimmune haemolytic anaemia, drug-induced haemolytic anaemia, alloimmune haemolytic anaemia - Non-immune mediated: DIC, TTP, physical damage by e.g. heart valves, toxins such as lead/uraemia/drugs, malaria, paroxysmal nocturnal haemoglobinuria

Answer 115

Investigations to confirm haemolysis: - Increased Hb breakdown: ↑unconjugated bilirubin, ↑LDH (from red cells), ↑urinary urobilinogen (on urine dipstick) - Increased Hb production: ↑reticulocytes - Intravascular haemolysis: ↓free hepatoglobulin, haemoglobinuria (on haematuric urine microscopy), ↑urinary haemosiderin

Answer 116

Investigations to find cause: - Blood film: sickle cells, schistocytes (microangiopathic haemolytic anaemia), inclusion bodies (malaria), spherocytes/ elliptocytes (hereditary spherocytosis/ elliptocytosis), Heinz bodies (G6PD), bite/blister cells (G6PD), distorted ‘prickle’ cells (pyruvate kinase deficiency) - Direct antiglobulin (Coombs’) test (for autoimmune haemolytic anaemia) - Osmotic fragility testing (for membrane abnormalities) - Hb electrophoresis (for haemoglobinopathies) - Enzyme assays (for enzyme defects)

Answer 117

Polycythaemia = “increased concentration of red blood cells within the blood”

Answer 118

Causes - Relative polycythaemia (i.e. ↓plasma volume) Acute dehydration Chronic (associated with obesity, hypertension, alcohol excess, smoking) - Absolute polycythaemia (i.e. ↑RBC mass) Primary = polycythaemia ruba vera Secondary = due to increased EPO (e.g. RCC) or chronic hypoxia (e.g. COPD, altitude, congenital cyanotic heart disease)

Answer 119

WCC and platelet count (both also raised in primary absolute polycythaemia, but not in secondary absolute polycythaemia) 51Cr Red cell mass study (normal red cell mass in relative polycythaemia; raised red cell mass in absolute polycythaemia) Erythropoietin level If polycythaemia ruba vera suspected: bone marrow biopsy, JAK-2 mutation

Answer 120

``` Bacterial infection Inflammation Necrosis Corticosteroids Malignancy/ myeloproliferative disorder Stress (trauma, surgery, burns) ```

Answer 121

``` Post-chemotherapy Agranulocytosis causing drugs (4C’s: Carbamazepine, Clozapine, Colchicine, Carbimazole) Viral infection Hypersplenism Bone marrow failure (e.g. in leukaemia) Felty’s syndrome ```

Answer 122

Viral infection Chronic infections CLL/ lymphoma

Answer 123

``` Viral infection HIV Post-chemotherapy Bone marrow failure (e.g. in leukaemia) Whole body radiation ```

Answer 124

Bacterial infection Autoimmune diseases Leukaemias/ Hodgkin’s disease

Answer 125

Acute infections Corticosteroids Leukaemias

Answer 126

``` Allergy (inc. eczema, ABPA) Parasite infection Drug reactions Hypereosinophilic syndrome Skin diseases Malignancy e.g. Hodgkin’s disease ```

Answer 127

``` Some leukaemias/ lymphomas IgE mediated hypersensitivity Inflammatory disorders Myeloproliferative disorders Viral infection ```

Answer 128

Thrombocytopenia Causes 1 - Decreased production: bone marrow failure, aplastic anaemia, megaloblastic anaemia, myelosuppression 2 - Increased destruction/ consumption - Non-immune: DIC, TTP, HUS, sequestration in hypersplenism - Primary immune: ITP - Secondary immune: SLE, CLL, viruses, drugs, alloimmune Treatment Treat cause Immunosuppresants e.g. prednisolone, azathioprine, cyclophosphamide Platelet concentrate transfusion Splenectomy

Answer 129

Thrombocythemia Causes 1- Primary: essential thrombocythaemia, other myeloproliferative disorders 2 - Secondary: bleeding eg reactive, inflammation, infection, malignancy, post-splenectomy Treatment Aspirin (to prevent thromboembolic disease) Hydroxycarbamide (if primary cause)

Answer 130

dark centre to red cells thalassaemia, liver disease, iron deficiency, Hb C (Afro-Caribbeans)

Answer 131

nuclear remnants in red cells | post-splenectomy, hyposplenism

Answer 132

``` denatured haemoglobin oxidative haemolysis (e.g. G6PD deficiency) ```

Answer 133

red cell fragments | mechanical e.g. prosthetic heart valves, DIC

Answer 134

irregularly crenated red cells | renal failure, hypothyroidism

Answer 135

dark centre to red cells thalassaemia, liver disease, iron deficiency, Hb C (Afro-Caribbeans)

Answer 136

nuclear remnants in red cells | post-splenectomy, hyposplenism

Answer 137

``` denatured haemoglobin oxidative haemolysis (e.g. G6PD deficiency) ```

Answer 138

red cell fragments | mechanical e.g. prosthetic heart valves, DIC

Answer 139

irregularly crenated red cells | renal failure, hypothyroidism

Answer 140

INTRINSIC: Damaged surface → factor 7 → 11 → 9 → 8 EXTRINSIC: Tissue damage → Thromboplastin → factor 7 factor 7 and 8 both convert prothrombin to thrombin thrombin converts fibrinogen to fibrin

Answer 141

tPA converts plasminogen to plasmin. In circulation, plasminogen adopts a closed, activation resistant conformation. Upon binding to clots, or to the cell surface, plasminogen adopts an open form that can be converted into active plasmin by a variety of enzymes, including tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), kallikrein, and factor XII (Hageman factor). Fibrin is a cofactor for plasminogen activation by tissue plasminogen activator.

Answer 142

Vitamin K dependant clotting factors: 2, 7, 9, 10 (+ protein C&S)

Answer 143

PT and INR = EXTRINSIC Thromboplastin is added to blood to activate the extrinsic pathway. Clotting time is measured in seconds (PT). This is compared to the normal value (12-13s) to get the INR for ease of comparison (normal 0.8-1.2). Aid to memoire: WEPT Warfarin Extrinsic Prothrombin Time Only factors 7 and 10 involved (of which isolated deficiencies are rare) so PT/INR is only really affected by reduced clotting factor synthesis or increased consumption: Warfarin/vitamin K deficiency Liver disease DIC

Answer 144

APTT = INTRINSIC Phospholipid, a contact activator and calcium are added to blood to activate the intrinsic pathway. Clotting time is measured in seconds (normal = 30-50s) Involves the same clotting factors as the extrinsic pathway PLUS some others (8, 9, 11) so affected by: Warfarin/vitamin K deficiency Liver disease DIC PLUS anything which affects factors 8 (haemophilia A/Von Willebrands), factor 9 (haemophilia B), factor 11 (haemophilia C)

Answer 145

Bleeding time = PLATELET FUNCTION involves making a patient bleed and timing how long it takes to stop Measures platelet plug formation so only affected by conditions involving platelet quantity/function

Answer 146

Thrombin time = FIBRINOGEN TEST Thrombin is added to blood to test the conversion of fibrinogen to fibrin to form a clot This tests the level and function of fibrinogen

Answer 147

DIC: in a severe systemic illness dying cells release procoagulant agents that activate coagulation, resulting in fibrin generation that occludes small vessels. Platelets and clotting factors are used up and result in bleeding elsewhere. Blood tests reveal thrombocytopenia, increased PT/INT and APTT, and raised D-dimer and fibrin degradation products. Treat by removing cause and supportive therapies (blood, platelets, FFP, cryoprecipitate).

Answer 148

Heparin: heparin is a natural anticoagulant that potentiates antithrombin (which inactivates factors 2, 9, 10, 11, 12) and inactivates thrombin. Types of heparin that are commonly used include: - Subcutaneous LMWH (e.g. enoxiparin) – most commonly used for prophylactic and therapeutic anticoagulation. Consists of only short chain heparins and, therefore, only binds to a specific part of antithrombin, which results in inhibition of factor 10A only. This means the effects are more predictable than standard (unfractionated) heparin. Monitoring is not required but effect can be measured by anti-factor 10A. - IV or subcutaneous unfractionated (standard) heparin – consists of heparin chains with a variety of molecular lengths and, therefore, has more and less predictable effects. Subcutaneous therapy may be used for prophylactic anticoagulation in patients with reduced renal function (unfractionated heparin is partially cleared by the liver, whereas LMWH is not). IV therapy may be used for therapeutic anticoagulation pre-op or if there is significant risk of bleeding, due to its short half-life (effect stops within 4 hours of infusion stopping). It must be monitored regularly using APTT and dose adjusted (as per hospital guidelines). Heparin can be reversed with protamine sulphate if required.

Answer 149

``` Haemophilia A (factor 8 deficiency), B (factor 9 deficiency), C (factor 11 deficiency): clinical features depend on level of affected factor but characteristically include haemarthroses and muscly haematomas ```

Answer 150

``` Von Willebrands disease: deficiency of von Willebrand factor which is involved in platelet aggregation and adhesion, and binds factor 8 preventing it from destruction. Hence von Willebrands disease produced a platelet disorder picture of bleeding (petichiae, menorrhagia, contact bleeding (e.g. gums) ```

Answer 151

Warfarin therapy is monitored using the INR Aims: INR 2-3: DVT/PE, hypercoagulable states, AF INR 2.5-3.5: aortic metallic heart valves (higher pressure blood flow reduced embolic risk) INR 3-4: mitral metallic heart valves

Answer 152

Ferritin is an intra-cellular storage protein with the capacity to store up to 4000 iron atoms. The concentration of ferritin in serum correlates well with the amount of storage iron as proven by phle- botomy trials. Hence, serum ferritin is a good marker of total body iron stores. A low serum ferritin is almost only seen in iron deficiency. In the presence of conditions such as inflamma- tion, infection, malignancy (haematological and solid tumours), or liver or kidney disease, serum ferritin concentrations do not reflect iron stores alone and are typically higher than otherwise expected. In addition, higher ferritin levels are seen with increasing BMI and post-menopause. In all these set- tings, a normal or elevated serum ferritin level does not exclude iron deficiency nor diagnose iron overload. Serum iron concentration is a poor measure of iron status in the body. In an individual, levels fluctuate significantly due to diurnal variation and fasting status. Even when blood collection is standardised to morn- ing samples in fasting patients, iron is an acute phase reactant and low levels may be seen as a consequence of acute inflammation.

Answer 153

Transferrin is often referred to as the circulating car- rier protein for iron. In fact, this describes apotransfer- rin, which, when bound to either one or two atoms of iron, is then named transferrin. Monoferric or diferric transferrin has high affinity for the transferrin receptor allowing cellular uptake by endocytosis. Iron is then utilised or stored by the cell and apotransferrin returned to the circulation. Liver synthesis further contributes to apotransferrin levels so that high serum transferrin concentrations may be induced in iron deficiency or high oestrogen states (eg, pregnancy, oral contraceptive pill use). Low levels may be in response to iron loading or due to liver disease with poor synthetic function. Like serum iron, transferrin is also a negative acute phase reactant. Transferrin saturation is a calculated ratio between serum iron and TIBC. Because of this, it is influenced by the analytical, physiological and pathological fac- tors that affect these components. TIBC may be measured directly or derived from measuring unsaturated iron binding capacity (UIBC) or transferrin. Measuring transferrin is generally more expensive for laboratories compared with TIBC or UIBC, but there is less variation in results between dif- ferent assays. Hepcidin, despite its importance in iron metabolism, is yet to have an established role in diagnostic testing and is not routinely available.

Answer 154

Key Points Both with have low iron Iron deficiency anaemia will have high TIBC - this is because is iron deficiency anaemia, as iron stores are depleted, the body tries to compensate by increasing the serum's ability to carry iron. In Anaemia of chronic disease, the low serum iron is a result of low TIBC. Iron deficiency will have low ferritin - ferritin is a measure of iron stores. In iron deficiency anaemia these are depleted. In anaemia of chronic disease, there is a not a problem with iron stores, but instead with iron utilisation / transfer, so ferritin levels will be normal or high. *WARNING* Iron level are not a always a reliable indicator - iron is also an acute phase biochemical marker Take iron levels with a pinch of salt. Loads of things can alter serum iron levels: False normal - if a patient is taking supplements False low - acute or chronic inflammation, ongoing infection, post-operatively, malignancy, hypoalbuminaemia

Answer 155

philadelpia chromosome ab for CML

Answer 156

agranulocytosis - BM suppression specifically of granulocytes.

Answer 157

``` HbA = 2alpha 2 beta chains = normal HbA2 = 2alpha chains and 2 delta chains (normally up to 2.5% but increased in beta thalassemias and sickle cell) ``` HbF = 2 alpha and 2 gamma - raised in sickle HbH = 4 beta chains so seen in alpha thalassemia as they don't make alpha chains

Answer 158

``` very unwell low Hb - bleeding v low platelets - clotting clotting tests e.g. APTT shot to hell. elevated WBC likely due to the trigger e.g. infection or burns ```

Answer 159

peptic ulcers

Answer 160

low Hb low WBC low platelets can be caused by leukaemia amongst others.

Answer 161

moderate is 0.5-1 severe is under 0.5 x10^9 can result in life threatening neutropenic sepsis which can easily be missed as the inflamm/pus etc will be much less marked. so if they have neutropenia be on guard. broad spectrum abs within 30 minutes of diagnosing neutropenic sepsis/febrile neutropenia. do the sepsis 6. tazocin but check local guidelines.

Answer 162

1 - microangiopathic autoimmune haemolytic anaemia MAHA - have to gauge this from the clinical picture (do they get worse after giving the platelets and blood) 2 - thrombocytopenia 3 - fluctuating neurological signs (neurovascular) 4 - fever (SIRS) 5 - renal failure basically blockage of any and all small vessels. if you think they might have TTP then look for the risk/precipitating factors

Answer 163

1 - pregnancy 2 - viral illness (causes antibody to ADAMST13 so use plasma exchange) 3 - infection 4 - malignancy 5 - sytemic illness such as lupus 6 - drugs such as cyclosporin (stop the drug)

Answer 164

plasma exchange with FFP plasmapheresis to replace the ADAMST13 further immunosuppression e.g. methylpred and rituximab

Answer 165

both cause a drop in Hb and platelets in TTP the clotting tests will be largely normal as the factors are not being consumed, in DIC the will be very deranged however. never give platelets in TTP, you can give them in DIC though

Answer 166

Burkitt's lymphoma is a common cause of tumour lysis syndrome. Tumour lysis syndrome occurs as a result of cell breakdown following chemotherapy. This releases a large quantity of intracellular components such as potassium, phosphate and uric acid. Burkitt's lymphoma is a high-grade B-cell neoplasm. There are two major forms: endemic (African) form: typically involves maxilla or mandible sporadic form: abdominal (e.g. ileo-caecal) tumours are the most common form. More common in patients with HIV Burkitt's lymphoma is associated with the c-myc gene translocation, usually t(8:14). The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of Burkitt's lymphoma and to a lesser extent the sporadic form. Microscopy findings 'starry sky' appearance: lymphocyte sheets interspersed with macrophages containing dead apoptotic tumour cells ``` Management is with chemotherapy. This tends to produce a rapid response which may cause 'tumour lysis syndrome'. Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses the conversion of uric acid to allantoin*) is often given before the chemotherapy to reduce the risk of this occurring. Complications of tumour lysis syndrome include: hyperkalaemia hyperphosphataemia hypocalcaemia hyperuricaemia acute renal failure ``` *allantoin is 5-10 times more soluble than uric acid, so renal excretion is more effective

Answer 167

transfuse if the Hb is below 70 or if it is below 100 and their have certain risk factors e.g. previous ischaemic event, ischaemic sounding symptoms such as chest pain.

Answer 168

Point mutation in beta globin gene: glu changes to val

Answer 169

likely a thalassaemia as its pretty difficult to get this low with iron deficiency

Answer 170

parvovirus B19 - fine in normal people but causes aplastic anaemia in sickle cell and HIV. fine marrow failure

Answer 171

sequestration crisis in children with a giant spleen, get acute ischaemic symptoms e.g. chest pain. in adults the spleen is already infarcted so less likely to have a sequestration crisis, more likely thrombotic. give fluids, oxygen, morphine, sickle train = malaria resistance full sickle disease = worse malaria as no spleen

Answer 172

in both the RBC is big but in megaloblastic the nucleus is big and hypersegmented = caused by low B12, low folate or antifolate drugs. non-megaloblastic caused by v chronic bad ETOH abuse.

Answer 173

there will be lots of blasts in an acute disorder, not in a chronic disorder. so really high lymphocytes but no blasts = CLL, really high neutrophils but no blasts = CML.

Answer 174

Churg–Strauss syndrome (CSS, also known as eosinophilic granulomatosis with polyangiitis [EGPA] or allergic granulomatosis[1]) is an autoimmune condition that causes inflammation of small and medium-sized blood vessels (vasculitis) in persons with a history of airway allergic hypersensitivity (atopy)

Answer 175

Thrombotic thrombocytopenic purpura

Answer 176

lymphopenia is low lymphocytes | leukopenia is low WCC overall.

Answer 177

if you're sure its urticarial and not anaphylactic then slow the rate and add chlorphenamine 10mg IM/IV and monitor closely.

Answer 178

B12 folate reticulocytes LFTs and thyroid function tests.

Answer 179

a common scenario. 1- remove the cause 2 - if not bleeding and the INR is below 8 then withhold warfarin and monitor. restart once under 5 3 - if the INR is over 8 and or there is minor bleeding then reverse with vitamin K 0.5mg IV or 5mg PO. 4 - major bleeding - vitamin k 5-10mg IV

Answer 180

ciprofloxacin and erythromycin are enzyme inhibitors | rifampicin in an enzyme inducer.

Answer 181

under the data protection act 1998 a PT has a right of access to their medical notes so you give them to them. however it is important to consider the Caldecott principles which were put in place to ensure maximum safety of confidential information. to do so the doctor should contact the hospital's designated Caldicott guardian to discuss the situation, but also reassure the patient that their right to access will be respected.

Answer 182

malabsorption - eg coeliac disease. look for anti-endomyseal antibodies.

Answer 183

polymorphs are found to be large and have a hyperhsegmented nucleus because the rate at which the nucleus developed is slower than the rage at which the cytoplasm developed. this delay is due to lack of folate or b12 which are needed in DNA synthesis. pernicious anaemia is the most common cause of macrocytosis with megaloblastic bone marrow and treatment is to replenish the vitamin stores via IM injection.

Answer 184

gum bleeding, nose bleeds. microvascular occlusion causing pain in the hands and feet, esp fingers and toes. and headache. this is due to high levels of platelets that are derived from a clonal proliferation of megakaryocytic and so do not function properly.

Answer 185

waldenstrom's macroglobulinaemia. a rare type of slow growing non-hodgkin's lymphoma

Answer 186

it is very common to find a monoclonal protein in the serum of a person over 50 years old. if there is no evidence of end organ damage e.g. anaemia or renal failure etc, and if the concentration is low (under 30g/L) then it is described as an asymptomatic plasma cell dyscrasia and labelled as MGUS. MGUS can transform into something more malignant however. if the conc is high and the conc of monoclonal plasma cells in the bone marrow is over 10%, or end organ damage appears, then it is becoming malignant. depending on the type of protein involved this will either be multiple myeloma, amyloid, or waldenstrom's macroglobulinaemia. thus MGUS ought to be followed up by serial measurements of the monoclonal protein but is benign for now.

Answer 187

fever night sweats weight loss. found in malignancies of lymphocytes. e.g. lymphoma, CLL and usually involves B rather than T cells.

Answer 188

the oxygen dissociation curve (which illustrates the relationship between PaO2 and SaO2) is shifted to the right indicating that sickle cell Hb has a lower affinity for oxygen and thus can release it easier in the tissues.

Answer 189

basically the inverse of each other. the bohr effect states that hemoglobin's oxygen binding affinity (see Oxygen–haemoglobin dissociation curve) is inversely related both to acidity and to the concentration of carbon dioxide and thus to allows it to desaturate in the periphery. right shift of oxygen dissociation curve. the haldane effect describes how Deoxygenation of the blood increases its ability to carry carbon dioxide and conversely, oxygenated blood has a reduced capacity for carbon dioxide. this is what happens in the periphery to pick up Co2 and in the lungs to dump it. left shift of oxygen dissociation curve

Answer 190

needs to be formally recorded. needs to be signed and witnessed by a responsible healthcare professional. is so this overrides any change in a patient's capacity or any desire of the medical team to treat a pt in their best interests, it is legally binding. the example given is of a jehovah's witness refusing life saving blood transfusions with an AD.

Answer 191

mycoplasma and EBV. most commonly the autoantibodies are idiopathic though. causes an extravascular haemolysis and spherocytosis. coombs direct anti-globulin test will identify the RBCs covered in Ab or complement.

Answer 192

looks at ability of the body to absorb B12. used in megaloblastic macrocytic anaemias to determine whether a low serum vitamin B12 is due to reduced absorption at the terminal lieum or due to decreased secretion of intrinsic factor.

Answer 193

paroxysmal nocturnal haemoglobinuria. causes a chronic intravascular haemolysis with pancytopenia and an increased risk of thrombosis. now you use flow cytometry but previously you could use HAM's test in which serum is acidified to activate complement which induces the erythrocyte lysis.

Answer 194

first a peripheral blood film then bone marrow aspirate and immunophenotyping as there is possibly a leukaemia.

Answer 195

APTT goes up paradoxically and platelets are depleted.

Answer 196

low Hb high LDh and high bilirubin.

Answer 197

heparin-induced thrombocytopenia occurs in 1-5% of patients on heparin. antibodies against heparin are produced over a few days which bind to it and cause platelet activation and thrombosis. this causes the platelet count to fall and the PT develops blood clots or an existing one will enlarge. take serial FBC over the first week to 10 days of the initiation of heparin to check for this in PTs. if suspected 1 - stop heparin immediately 2 - treat with non-heparin anticoagulants that don't cross react with the HIT antibodies to damped the storm of thrombin. 3 - a protracted course 2-3months of warfarin to prevent thrombosis recurrence.

Answer 198

has been shown to be able to both inhibit and induce.

Answer 199

enzyme inhibitor.

Answer 200

pancytopenia is either due to reduced cell production or increased cell destruction. increased destruction = hypersplenism decreased production = e.g. aplastic anaemia, myelodysplasia, AML, myeloma.

Answer 201

only need to remember one thing: if there are any uncertainties about whether a dose of warfarin has been given, no further doses should be given on that occasion and an INR should be taken the next day. taking an INR on the same night would not leave long enough for any doses that had been given earlier that evening to be evident and as result an extra dose may be given by accident .

Answer 202

platelets are coated with autoantibody and are removed from the reticuloendothelial system thus reducing their lifespan to a few hours. the purpuric rash is due to thrombocytopenia causing the breakdown of capillaries and bleeding into the skin. coagulation disorders are more iikely to cause bleeding into the joints or muscles.

Answer 203

more than 1.5 degrees above baseline. should think either acute haemolytic reaction or bacterial contamination. contamination is more common in platelets as they are stored at 22degrees but it can occur with blood. stop the transfusion and send the unit back to the lab with FBC/u and E / clotting and culture.

Answer 204

transfusion related acute lung injury increase in resp rate, resp distress. non cardiogenic pulmonary oedema of uncertain cause associated with hypoxia and pulmonary infiltrates.

Answer 205

non-megaloblastic macrocytic anaemia.

Answer 206

a) This man has G6PD deficiency which is the commonest enzyme deficiency in the world. It is due to an inability to regulate NADPH and has X-linked recessive inheritance. The commonest complications are; 1) neonatal jaundice 2) haemolytic anaemia In this patient haemolysis has been triggered by dapsone (which he has been prescribed for dermatitis herpetiformis) and primaquine (which he took for malaria prophylaxis when he went to Africa). Intravascular haemolysis (RBCs destroyed in circulation) causes a triad of; 1) Anaemia; 2) Jaundice; 3) Haemoglobinuria Deficient glutathione leads to oxidized methemoglobin which precipitates out as Heinz bodies. Bite cells and blister cells can be seen on the blood film.

Answer 207

Intravascular haemolysis (RBCs destroyed in circulation) causes a triad of; 1) Anaemia; 2) Jaundice; 3) Haemoglobinuria Deficient glutathione leads to oxidized methemoglobin which precipitates out as Heinz bodies. Bite cells and blister cells can be seen on the blood film.

Answer 208

1) Haemolysis; 2) Thrombosis; 3) Pancytopenia

Answer 209

1) Jaundice ; 2) Anaemia 3) Splenomegaly (NO haemoglobinuria)

Answer 210

``` Hyposplenism e.g. post-splenectomy target cells Howell-Jolly bodies Pappenheimer bodies siderotic granules acanthocytes ``` Iron-deficiency anaemia target cells 'pencil' poikilocytes if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed microcytic and macrocytic cells Myelofibrosis 'tear-drop' poikilocytes Intravascular haemolysis schistocytes Megaloblastic anaemia hypersegmented neutrophils

Answer 211

Von Willebrand's disease is the most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare Role of von Willebrand factor large glycoprotein which forms massive multimers up to 1,000,000 Da in size promotes platelet adhesion to damaged endothelium carrier molecule for factor VIII Types type 1: partial reduction in vWF (80% of patients) type 2: abnormal form of vWF type 3: total lack of vWF (autosomal recessive) *type 3 von Willebrand's disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients have type 1 disease

Answer 212

Management tranexamic acid for mild bleeding desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells factor VIII concentrate

Answer 213

Investigation prolonged bleeding time APTT may be prolonged factor VIII levels may be moderately reduced defective platelet aggregation with ristocetin

Answer 214

The sudden fall in haemoglobin without an appropriate reticulocytosis (3% is just above the normal range) is typical of an aplastic crisis, usually secondary to parvovirus infection Sickle-cell crises Sickle cell anaemia is characterised by periods of good health with intervening crises ``` Four main types of crises are recognised: thrombotic, 'painful crises' sequestration aplastic haemolytic ``` Thrombotic crises also known as painful crises or vaso-occlusive crises precipitated by infection, dehydration, deoxygenation infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-foot syndrome in children, lungs, spleen and brain Sequestration crises sickling within organs such as the spleen or lungs causes pooling of blood with worsening of the anaemia acute chest syndrome: dyspnoea, chest pain, pulmonary infiltrates, low pO2 - the most common cause of death after childhood Aplastic crises caused by infection with parvovirus sudden fall in haemoglobin Haemolytic crises rare fall in haemoglobin due an increased rate of haemolysis

Answer 215

t(9;22) - Philadelphia chromosome present in > 95% of patients with CML this results in part of the Abelson proto-oncogene being moved to the BCR gene on chromosome 22 the resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal poor prognostic indicator in ALL The Philadelphia translocation is seen in around 95% of patients with chronic myeloid leukaemia. Around 25% of adult acute lymphoblastic leukaemia cases also have this translocation.

Answer 216

There are two main types of heparin - unfractionated, 'standard' heparin or low molecular weight heparin (LMWH). Heparins generally act by activating antithrombin III. Unfractionated heparin forms a complex which inhibits thrombin, factors Xa, IXa, XIa and XIIa. LMWH however only increases the action of antithrombin III on factor Xa

Answer 217

Monitoring Activated partial thromboplastin time (APTT) Anti-Factor Xa (although routine monitoring is not required)

Answer 218

Heparin-induced thrombocytopaenia (HIT) immune mediated - antibodies form which cause the activation of platelets usually does not develop until after 5-10 days of treatment despite being associated with low platelets HIT is actually a prothrombotic condition features include a greater than 50% reduction in platelets, thrombosis and skin allergy treatment options include alternative anticoagulants such as lepirudin and danaparoid Both unfractionated and low-molecular weight heparin can cause hyperkalaemia. This is thought to be caused by inhibition of aldosterone secretion. Heparin overdose may be reversed by protamine sulphate, although this only partially reverses the effect of LMWH.

Answer 219

Diagnosis NICE published guidelines in 2012 relating to the investigation and management of deep vein thrombosis (DVT). If a patient is suspected of having a DVT a two-level DVT Wells score should be performed: Clinical probability simplified score DVT likely: 2 points or more DVT unlikely: 1 point or less If a DVT is 'likely' (2 points or more) a proximal leg vein ultrasound scan should be carried out within 4 hours and, if the result is negative, a D-dimer test if a proximal leg vein ultrasound scan cannot be carried out within 4 hours a D-dimer test should be performed and low-molecular weight heparin administered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours) If a DVT is 'unlikely' (1 point or less) perform a D-dimer test and if it is positive arrange: a proximal leg vein ultrasound scan within 4 hours if a proximal leg vein ultrasound scan cannot be carried out within 4 hours low-molecular weight heparin should be administered whilst waiting for the proximal leg vein ultrasound scan (which should be performed within 24 hours) Clinical feature Points Active cancer (treatment ongoing, within 6 months, or palliative) 1 Paralysis, paresis or recent plaster immobilisation of the lower extremities 1 Recently bedridden for 3 days or more or major surgery within 12 weeks requiring general or regional anaesthesia 1 Localised tenderness along the distribution of the deep venous system 1 Entire leg swollen 1 Calf swelling at least 3 cm larger than asymptomatic side 1 Pitting oedema confined to the symptomatic leg 1 Collateral superficial veins (non-varicose) 1 Previously documented DVT 1 An alternative diagnosis is at least as likely as DVT -2

Answer 220

Venous thromoboembolism - length of warfarin treatment provoked (e.g. recent surgery): 3 months unprovoked: 6 months Management Low molecular weight heparin (LMWH) or fondaparinux should be given initially after a DVT is diagnosed. a vitamin K antagonist (i.e. warfarin) should be given within 24 hours of the diagnosis the LMWH or fondaparinux should be continued for at least 5 days or until the international normalised ratio (INR) is 2.0 or above for at least 24 hours, whichever is longer, i.e. LMWH or fondaparinux is given at the same time as warfarin until the INR is in the therapeutic range warfarin should be continued for at least 3 months. At 3 months, NICE advise that clinicians should 'assess the risks and benefits of extending treatment' NICE add 'consider extending warfarin beyond 3 months for patients with unprovoked proximal DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding'. This essentially means that if there was no obvious cause or provoking factor (surgery, trauma, significant immobility) it may imply the patient has a tendency to thrombosis and should be given treatment longer than the norm of 3 months. In practice most clinicians give 6 months of warfarin for patients with an unprovoked DVT/PE for patients with active cancer NICE recommend using LMWH for 6 months Further investigations and thrombophilia screening As both malignancy and thrombophilia are obvious risk factors for deep vein thrombosis NICE make recommendations on how to investigate patients with unprovoked clots. Offer all patients diagnosed with unprovoked DVT or PE who are not already known to have cancer the following investigations for cancer: a physical examination (guided by the patient's full history) and a chest X-ray and blood tests (full blood count, serum calcium and liver function tests) and urinalysis. Consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or PE Thrombophilia screening not offered if patients will be on lifelong warfarin (i.e. won't alter management) consider testing for antiphospholipid antibodies if unprovoked DVT or PE consider testing for hereditary thrombophilia in patients who have had unprovoked DVT or PE and who have a first-degree relative who has had DVT or PE

Answer 221

The nub of this question is emergency management of haemorrhage in patients on warfarin. This patient has an INR greater than 8 and is actively bleeding. Therefore the answer is 4. Patients on warfarin have reduced levels of Factor X, IX, VII and II. Rapid correction is most effectively achieved through administration of prothrombin complex concentrates. The British Journal of Haematology states that: 'Emergency anticoagulation reversal in patients with major bleeding should be with 2550 u/kg four-factor prothrombin complex concentrate and 5 mg intrave- nous vitamin K' Follow this link for more information http://www.bcshguidelines.com/documents/warfarin4thed.pdf Warfarin: management of high INR The following is based on the BNF guidelines, which in turn take into account the British Committee for Standards in Haematology (BCSH) guidelines. A 2005 update of the BCSH guidelines emphasised the preference of prothrombin complex concentrate over FFP in major bleeding. Situation Management Major bleeding Stop warfarin Give intravenous vitamin K 5mg Prothrombin complex concentrate - if not available then FFP* ``` INR over 8.0 Minor bleeding Stop warfarin Give intravenous vitamin K 1-3mg Repeat dose of vitamin K if INR still too high after 24 hours Restart warfarin when INR under 5.0 ``` INR over 8.0 No bleeding Stop warfarin Give vitamin K 1-5mg by mouth, using the intravenous preparation orally Repeat dose of vitamin K if INR still too high after 24 hours Restart when INR under 5.0 INR 5.0-8.0 Minor bleeding Stop warfarin Give intravenous vitamin K 1-3mg Restart when INR under 5.0 INR 5.0-8.0 No bleeding Withhold 1 or 2 doses of warfarin Reduce subsequent maintenance dose *as FFP can take time to defrost prothrombin complex concentrate should be considered in cases of intracranial haemorrhage

Answer 222

The discovery of the JAK2 mutation has made red cell mass a second-line investigation for patients with suspected JAK2-negative polycythaemia rubra vera Polycythaemia rubra vera: features Polycythaemia rubra vera (PRV) is a myeloproliferative disorder caused by clonal proliferation of a marrow stem cell leading to an increase in red cell volume, often accompanied by overproduction of neutrophils and platelets. It has recently been established that a mutation in JAK2 is present in approximately 95% of patients with PRV and this has resulted in significant changes to the diagnostic criteria. The incidence of PRV peaks in the sixth decade. ``` Features hyperviscosity pruritus, typically after a hot bath splenomegaly haemorrhage (secondary to abnormal platelet function) plethoric appearance hypertension in a third of patients ```

Answer 223

Polycythaemia rubra vera - JAK2 mutation The discovery of the JAK2 mutation has made red cell mass a second-line investigation for patients with suspected JAK2-negative polycythaemia rubra vera Following history and examination, the British Committee for Standards in Haematology (BCSH) recommend the following tests are performed full blood count/film (raised haematocrit; neutrophils, basophils, platelets raised in half of patients) JAK2 mutation serum ferritin renal and liver function tests ``` If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH suggest the following tests: red cell mass arterial oxygen saturation abdominal ultrasound serum erythropoietin level bone marrow aspirate and trephine cytogenetic analysis erythroid burst-forming unit (BFU-E) culture ``` Other features that may be seen in PRV include a low ESR and a raised leukocyte alkaline phosphotase The diagnostic criteria for PRV have recently been updated by the BCSH. This replaces the previous PRV Study Group criteria. JAK2-positive PRV - diagnosis requires both criteria to be present Criteria Notes A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted) A2 Mutation in JAK2 JAK2-negative PRV - diagnosis requires A1 + A2 + A3 + either another A or two B criteria Criteria Notes A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women A2 Absence of mutation in JAK2 A3 No cause of secondary erythrocytosis A4 Palpable splenomegaly A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells B1 Thrombocytosis (platelet count >450 * 109/l) B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 12.5*109/l in smokers) B3 Radiological evidence of splenomegaly B4 Endogenous erythroid colonies or low serum erythropoietin

Answer 224

Common predisposing factors include malignancy, pregnancy and the period following an operation. The comprehensive list below is partly based on the 2010 SIGN venous thromboembolism (VTE) guidelines: ``` General increased risk with advancing age obesity family history of VTE pregnancy (especially puerperium) immobility hospitalisation anaesthesia central venous catheter: femoral >> subclavian ``` ``` Underlying conditions malignancy thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency heart failure antiphospholipid syndrome Behcet's polycythaemia nephrotic syndrome sickle cell disease paroxysmal nocturnal haemoglobinuria hyperviscosity syndrome homocystinuria ``` Medication combined oral contraceptive pill: 3rd generation more than 2nd generation hormone replacement therapy: the risk of VTE is higher in women taking oestrogen + progestogen preparations compared to those taking oestrogen only preparations raloxifene and tamoxifen antipsychotics (especially olanzapine) have recently been shown to be a risk factor It should be remembered however that around 40% of patients diagnosed with a PE have no major risk factors.

Answer 225

The slowly progressive symptoms of pruritus and pain accompanied by the examination findings are strongly suggestive of post-thrombotic syndrome. Post-thrombotic syndrome ``` It is increasingly recognised that patients may develop complications following a DVT. Venous outflow obstruction and venous insufficiency result in chronic venous hypertension. The resulting clinical syndrome is known as post thrombotic syndrome. The following features maybe seen: painful, heavy calves pruritus swelling varicose veins venous ulceration ```

Answer 226

Compression stockings should be offered to all patients with deep vein thrombosis to help reduce the risk of post-thrombotic syndrome. NICE state the following: Offer below-knee graduated compression stockings with an ankle pressure greater than 23 mmHg to patients with proximal DVT a week after diagnosis or when swelling is reduced sufficiently and if there are no contraindications, and: advise patients to continue wearing the stockings for at least 2 years ensure that the stockings are replaced two or three times per year or according to the manufacturer's instructions advise patients that the stockings need to be worn only on the affected leg or legs.

Answer 227

``` Inherited activated protein C resistance (factor V Leiden): most common cause antithrombin III deficiency protein C deficiency protein S deficiency ``` Acquired antiphospholipid syndrome the Pill

Answer 228

Diagnosis is based on: monoclonal proteins (usually IgG or IgA) in the serum and urine (Bence Jones proteins) increased plasma cells in the bone marrow bone lesions on the skeletal survey

Answer 229

G6PD deficiency Hereditary spherocytosis Gender Male (X-linked recessive) Male + female (autosomal dominant) Ethnicity African + Mediterranean descent Northern European descent Typical history • Neonatal jaundice • Infection/drugs precipitate haemolysis • Gallstones * Neonatal jaundice * Chronic symptoms although haemolytic crises may be precipitated by infection * Gallstones * Splenomegaly is common Blood film Heinz bodies Spherocytes (round, lack of central pallor) Diagnostic test Measure enzyme activity of G6PD Osmotic fragility test

Answer 230

The isolated thrombocytopenia in a well patient points to a diagnosis of ITP. The combined oral contraceptive pill does not commonly cause blood dyscrasias ITP Idiopathic thrombocytopenic purpura (ITP) is an immune mediated reduction in the platelet count. Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex. ITP can be divided into acute and chronic forms: ``` Acute ITP more commonly seen in children equal sex incidence may follow an infection or vaccination usually runs a self-limiting course over 1-2 weeks ``` Chronic ITP more common in young/middle-aged women tends to run a relapsing-remitting course Evan's syndrome ITP in association with autoimmune haemolytic anaemia (AIHA)

Answer 231

The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML). It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in excess of normal Presentation (40-50 years) middle-age anaemia, weight loss, abdo discomfort splenomegaly may be marked spectrum of myeloid cells seen in peripheral blood decreased leukocyte alkaline phosphatase may undergo blast transformation (AML in 80%, ALL in 20%)

Answer 232

``` Management imatinib is now considered first-line treatment hydroxyurea interferon-alpha allogenic bone marrow transplant ``` Imatinib inhibitor of the tyrosine kinase associated with the BCR-ABL defect very high response rate in chronic phase CML

Answer 233

``` The causes of massive splenomegaly are as follows: myelofibrosis chronic myeloid leukaemia visceral leishmaniasis (kala-azar) malaria Gaucher's syndrome ```

Answer 234

Such a lymphocytosis in an elderly patient is very likely to be caused by chronic lymphocytic leukaemia. Steroids tend to cause a neutrophilia. It would be unusual for a viral illness to cause such a marked lymphocytosis in an elderly person. Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia (CLL) is caused by a monoclonal proliferation of well-differentiated lymphocytes which are almost always B-cells (99%) ``` Features often none constitutional: anorexia, weight loss bleeding, infections lymphadenopathy more marked than CML ``` Complications hypogammaglobulinaemia leading to recurrent infections warm autoimmune haemolytic anaemia in 10-15% of patients transformation to high-grade lymphoma (Richter's transformation) Investigations blood film: smudge cells (also known as smear cells), these look like well stained squashed bugs immunophenotyping

Answer 235

Activated protein C resistance Activated protein C resistance is the most common inherited thrombophilia. It is due to a mutation in the Factor V Leiden mutation. Heterozygotes have a 5-fold risk of venous thrombosis whilst homozygotes have a 50-fold increased risk

Answer 236

Hereditary spherocytosis Basics most common hereditary haemolytic anaemia in people of northern European descent autosomal dominant defect of red blood cell cytoskeleton the normal biconcave disc shape is replaced by a sphere-shaped red blood cell red blood cell survival reduced as destroyed by the spleen ``` Presentation failure to thrive jaundice, gallstones splenomegaly aplastic crisis precipitated by parvovirus infection degree of haemolysis variable MCHC elevated ```

Answer 237

Side-effects haemorrhage teratogenic, although can be used in breast-feeding mothers skin necrosis: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis purple toes

Answer 238

liver disease P450 enzyme inhibitors, e.g.: amiodarone, ciprofloxacin cranberry juice drugs which displace warfarin from plasma albumin, e.g. NSAIDs inhibit platelet function: NSAIDs

Answer 239

A microcytic anaemia in a female should raise the possibility of either gastrointestinal blood loss or menorrhagia. However, there is no history to suggest this and the microcytosis is disproportionately low for the haemoglobin level. This combined with a raised HbA2 points to a diagnosis of beta-thalassaemia trait Beta-thalassaemia trait The thalassaemias are a group of genetic disorders characterised by a reduced production rate of either alpha or beta chains. Beta-thalassaemia trait is an autosomal recessive condition characterised by a mild hypochromic, microcytic anaemia. It is usually asymptomatic ``` Features mild hypochromic, microcytic anaemia - microcytosis is characteristically disproportionate to the anaemia HbA2 raised (> 3.5%) ```

Answer 240

Dabigatran Rivaroxaban Apixaban UK brand name Pradaxa Xarelto Eliquis Mechanism of action Direct thrombin inhibitor Direct factor Xa inhibitor Direct factor Xa inhibitor Route Oral Oral Oral Excretion Majority renal Majority liver Majority faecal NICE indications Prevention of VTE following hip/knee surgery Prevention of stroke in non-valvular AF* Prevention of VTE following hip/knee surgery Treatment of DVT and PE Prevention of stroke in non-valvular AF* Prevention of VTE following hip/knee surgery Prevention of stroke in non-valvular AF* *NICE stipulate that certain other risk factors should be present. These are complicated and differ between the NOACs but generally require one of the following to be present: prior stroke or transient ischaemic attack age 75 years or older hypertension diabetes mellitus heart failure

Answer 241

This man is most likely to have haemophilia A, which accounts for 90% of cases of haemophilia. Haemophilia Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition. Haemophilia A is due to a deficiency of factor VIII whilst in haemophilia B (Christmas disease) there is a lack of factor IX Features haemoarthroses, haematomas prolonged bleeding after surgery or trauma Blood tests prolonged APTT bleeding time, thrombin time, prothrombin time normal Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment

Answer 242

Blood product transfusion complications ``` Complications haemolytic: immediate or delayed febrile reactions transmission of viruses, bacteria, parasites hyperkalaemia iron overload ARDS clotting abnormalities ``` Immediate haemolytic reaction e.g. ABO mismatch massive intravascular haemolysis Febrile reactions due to white blood cell HLA antibodies often the result of sensitization by previous pregnancies or transfusions Causes a degree of immunosuppression e.g. patients with colorectal cancer who have blood transfusions have a worse outcome than those who do not

Answer 243

Tear-drop poikilocytes = myelofibrosis RBCs that look a bit like tear drops

Answer 244

Tamoxifen increases the risk of VTE + endometrial cancer

Answer 245

Burkitt's lymphoma - c-myc gene translocation

Answer 246

Factor V Leiden is the most common inherited thrombophilia NICE would recommend testing for thrombophilia given the unprovoked venous thromboembolism and family history. Activated protein C resistance is due a point mutation in the Factor V gene, encoding for the Leiden allele. Heterozygotes have a 5-fold risk of venous thrombosis whilst homozygotes have a 50-fold increased risk Von Willebrand's disease is the most common inherited bleeding disorder

Answer 247

Neutropenic sepsis is a relatively common complication of cancer therapy, usually as a consequence of chemotherapy. It may be defined as a neutrophil count of under 0.5 * 109 in a patient who is having anticancer treatment and has one of the following: a temperature higher than 38ºC or other signs or symptoms consistent with clinically significant sepsis Prophylaxis if it is anticipated that patients are likely to have a neutrophil count of less than 0.5 * 109 as a consequence of their treatment they should be offered a fluoroquinolone Management antibiotics must be started immediately, do not wait for the WBC NICE recommend starting empirical antibiotic therapy with piperacillin with tazobactam (Tazocin) immediately many units add vancomycin if the patient has central venous access but NICE do not support this approach following this initial treatment patients are usually assessed by a specialist and risk-stratified to see if they may be able to have outpatient treatment if patients are still febrile and unwell after 48 hours an alternative antibiotic such as meropenem is often prescribed +/- vancomycin if patients are not responding after 4-6 days the Christie guidelines suggest ordering investigations for fungal infections (e.g. HRCT), rather than just starting therapy antifungal therapy blindly there may be a role for G-CSF in selected patients

Answer 248

It is important in a patient who is also deficient in both vitamin B12 and folic acid to treat the B12 deficiency first to avoid precipitating subacute combined degeneration of the cord. Consideration in this case should also be given to secondary care referral to identify the underlying cause