Haematology - Study Notes

Haematology • • • • • • Anaemia WBC Platelets Haemostasis Transfusion Misc Haematology 2 7 13 14 19 21 Haem 1 of 22 Anaemia • List the typical symptoms of a patient with anaemia. Often asymptomatic Weakness, lethargy, tiredness Breathlessness, faintness, headaches Angina & intermittent claudication Palpitations Pallor Visual disturbances Also symptoms related to cause • Classify anaemia in terms of the red cell indices and list common causes of each type of anaemia RBCs can only be released from Microcytic hypochromic marrow once enough Hb is MCV < 80fl, MCH < 27pg produced. Defects in Hb synthesis Causes à more time for cell division à Iron deficiency– most common smaller cells Thalassaemia – fault in globin chain Sideroblastic anaemia – fault in tetrapyral ring (can be due to congenital, or post chemo / TB therapy / lead excess etc. Rx pyroxidine 10% of anaemia of chronic disease Normocytic normochromic MCV 80-90 fl, MCH > 26 pg Causes Acute blood loss à increased retic release Haemolytic / Aplastic anaemia – increased cell breakdown Chronic disease – cytokines downregulate the marrow response to EPO Renal failure à unable to produce EPO Macrocytic non-megaloblastic MCV > 95fl Causes B12 / Folate deficiency Bone marrow disease à reticulocytosis = larger cells Chemotherapy B12 is a co-factor for production of essential amino acids Folate is a source of AA precursors If unable to replicate DNA à fewer cell divisions à larger cells Increased serum cholesterol à increased cholesterol in cell membranes à larger surface area à large cells Pregnancy Alcohol abuse & liver disease Hypothyroidism Drugs (azothioprine) • Discuss the common causes of iron deficiency anaemia Inadequate iron intake – poor diet Malabsorption – gastrectomy, Coeliac disease Excess Iron loss – GI bleeds, CA, uterine bleeding Increased demands – infancy, adolescence, menstrual loss, pregnancy, lactation • Discuss appropriate investigations to confirm that a patient has iron deficiency & investigations for a patient with confirmed iron deficiency anaemia. Haem 2 of 22 Sx assoc with Fe def Koilonychia, atrophic glossitis, angular cheilosis Investigations Blood film – hypochromic, microcytic cells with poikilocytosis (shape variation) & anisocytosis (size variation) Decreased serum iron Increased total iron binding capacity (TIBC) Decreased serum ferritin Low / absent bone marrow iron à establish cause – GI, urine, self harm, poor diet, malabsorption Management Treat the cause if possible Oral FeSO4 200mg/8hr PO (se nausea, abdo discomfort, diarrhoea / constipation, black stools. Expect Hb to rise by 1g / dl / wk, continue for 3 months after normal to replace iron stores • Outline the physiological absorption, pathophysiology & diagnosis of vitamin B12 and folate deficiency B12 Found in liver, fish and dairy products – stores for 4 yrs Absorption Binds to intrinsic factor (from parietal cells) Pernicious anaemia Absorbed in terminal ileum 90% have Parietal cell Binds to transcobalamin à tissue Ab à kills cells à Deficiency underproduction of Low intake (vegan) intrinsic factor à can Impaired absorption – pernicious anaemia (Lack absorb B12 in of IF required to absorb B12), terminal ileum gastrectomy, IF deficiency, ileal disease, 50% also have IF Ab bacterial overgrowth Abnormal metabolism – transcobalamin deficiency Symptoms Anaemia, lemon tinge to skin (anaemia + haemolytic jaundice), glossitis, angular cheilosis Irritable / depression / psychosis / dementia Paraesthesia Sub acute degeneration of spinal cord (extensor plantars, absent knee jerk, absent ankle jerk) Ix – check parietal cell Ab & IF Ab. If non conclusive do schilling test (radio B12 uptake) Management Treat cause if possible If malabsorption then injection required (IM) Folate Found in green veg & offal – stores for 3-4 months Absorption Broken down in upper GI tract Polyglutamate à monoglutamate à methyl THF Absorbed in small intestine à THF à DNA synthesis Deficiency Poor intake – old age, alcohol excess, starvation, anorexia Excess use – pregnancy, lactation, haemolysis, CA) Malabsorption Haem 3 of 22 Antifolate drugs – methatrexate, trimethoprim Management Assess for underlying cause 5mg/dat folic acid for 4 months (+B12 unless normal) • Outline the clinical features and laboratory diagnosis of sickle cell anaemia. Outline the clinical management of a sickle cell crisis and the importance of sickle cell screening and surgery. Sickle cell disease= AR condition where B-globin chain is incorrectly produced à HbS (= SS). When HbS is deoxygenated the haemoglobin polymerises à distortion of red cells à sickle cell shape. The process is reversible if reoxygenated soon enough. Sickling is precipitated by hypoxia, acidosis, dyhydration and infection. Irreversibly sickled cells have a reduced life span and block micro-capillaries = crises Sickle cell trait = carriers produce ½ the B-globin chains abnormally (=AS) Carriers have increased resistance to falciparum malaria à high proportion of carriers in Africans Investigations Blood film – compensated anaemia – shows sickle cells, target cells and features of hyposplenism Emergency screening test – add sodium dithionite to blood. If turbid = prescence of HbS (but not specific to trait or disease) Definitive diagnosis – haemoglobin electrophoresis Management Daily folic acid and Penicillin V – as prophylaxis against pneumococcal infection Vaccinate against pneumococcus, HIB and Hep B Vaso-occlusive crisis – bony pain due to occlusion of flow to marrow (esp in hands, feet, femur, humerus, ribs, pelvis and vertebra). Assoc with tachycardia, sweating & fever Rx – aggressive rehydration, oxygen therapy, analgesia (often require opiates) and antibiotics. Transfusion may be required (where possible use fully genotyped blood) Sickle chest syndrome – following vaso-occlusive crisis – marrow infarcts à fat emboli to lungs à infarct & ventilatory failure. Commonest cause of death in adult sickle patients Sequestration crisis – thrombosis of venous outflow from organ à loss of function and painful enlargement. Spleen most common & can à severe anaemia & circulatory collapse. Recurrent infarction à loss of function Aplastic crisis – infection of adults with erythrovirus 19 à severe but self limiting red cell aplasia à low Hb à heart failure • Outline the clinical features and laboratory diagnosis of thalassaemia. Inherited impairment of haemoglobin production – partial or complete failure to produce either alpha or beta chains B-thalassaemia = failure to synthesise B-chains. Heterozygous = litte / no clinical disability. Mild anaemia (microcytic, hypochromic), some target cells, raised HbA Homozygous = thalassaemia major – very little production after 4 months old. à profound hypochromic anaemia, severe red cell dysplasia, erythroblastosis, absence or reduction of HbA, raised levels of HbF. Management – Transfusion to maintain Hb, folic acid supplementation, Allogenic bone marrow transplant will cure. Splenectomy if symptomatic splenomegaly Haem 4 of 22 A-thalassaemia = reduction or absence of A chain 1 gene deletion = little clinical effect 2 = mild hypochromic anaemia 3 = Heamoglobin H disease 4 = stillborn • Describe the laboratory features of haemolysis. Outline the causes of haemolytic anaemia and their treatment. Low Hb Raised MCV (reticulocytosis) Raised serum bilirubin Raised urine uribilinogen Raised LDH If intravascular haemolysis à free Hb in blood à toxic to renal tubules à ARF Free Hb will bind à increased haptoglobin Causes of intravascular haemolysis ABO incompatibility à IgM reaction G6PD deficiency + oxidative stress (e.g. flava beans) = haemolytic crisis Mechanical stress – marathon runners, leaky stitch in heart valve Clostridium perfingens infection Causes of extravascular haemolysis (due to macrophages (kupfer cells) in liver & spleen) Usually autoimmune (e.g. RA) or due to drugs (e.g. penicillin, mefenamic acid) • Outline the laboratory features of microangiopathic anaemia and list the common causes. The endothelial layer of small vessels are damaged with resulting fibrin deposition and platelet aggregation. As red blood cells travel through these damaged vessels, they are shredded. The result is red cell fragmentation and intravascular hemolysis Causes include aortic stenosis, HUS, TTP, DIC, Pre-eclampsia, Eclampsia and severe glomerulonephritis • Outline the features and causes of inherited red cell membrane defects and of red cell enzymopathies. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency Deficiency à vulnerable to oxidative stress à intravascular haemolysis X-linked (mainly seen in africal / middle east) Pyruvate Kinase deficiency AR Decreased ATP production à shortened RBC survival. Homozygotes have neonatal jaundice, later chronic haemolysis with splenomegaly & jaundice Rx – Usually well tolerated. splenectomy may help. Hereditary Spherocytosis AD RBC membrane defect à less deformable RBCs so get trapped in spleen à extravascular haemolysis. Ix – increased fragility with changes in osmolality • Outline the main causes of polycythaemia and their implications on health Haem 5 of 22 Polycythaemia = Raise in Hb or haematocrit Can be due to decrease in plasma volume (absolute), increase in red cell mass (relative) or neither (apparent) Decreased Plasma Volume Dehydration Diuretics Alcohol (diuretic effect) Smoking (CO à low PV for unknown reason) Increased Red Cell Mass Physiological Altitude Pathological End stage lung disease (e.g. cor pulmonale) Congenital cyanotic heart defects (e.g. downs) High affinity Hb variants (e.g. fetal Hb) Ectopic EPO production With increased Small cell lung CA EPO production Renal tumours Fibroids Cerebellomedullohaemangioblastoma Increased (aberrant) EPO with normal stimulus Polycyctic kidney disease Glomerulonephritis Post renal transplant Severe hydronephrosis Myeloproliferative disease – NB: Normal EPO levels Polycythaemia Rubro Vera (see later in notes) Familial forms – increased RBC production, normal WCC & Plts Significance Once haematocrit > 55% à Increased risk of DVT / Stroke / MI / PE due to decreased flow and increased velocity Haem 6 of 22 Cytosis / philia= increase Penia = decrease The white cell • Interpret a blood count showing a leucocytosis and list common causes for neutrophilia and neutropaenia, lymphocytosis and lymphopenia. Granulocytes Neutrophils – recognise, ingest and destroy particles and bacteria Eosinophils – phagocytic to protozoa and helminths. Also involved in allergy Basophils – bind IgG and release histamine, leucotrienes etc – involved in hypersensitivity Agranulocytes Monocytes – migrate to tissues à become macrophages / antigen presenting cells Lymphocytes – 80% T = mediate cellular immunity, 20% B = make Immunoglobulin Neutrophil leucocytosis (> 10 x 109 / l) Infection – bacteria / fungi Inflammation & necrosis (MI, vasculitis, trauma, RA) Metabolic disorders (uraemia, acidosis, gout) Neoplasm (CA, lymphoma, melanoma) Drugs (corticosteroids, lithium) Myeloproliferation (chronic myeloid leukaemia, myelosclerosis) Physiological (pregnancy, exercise) Neutropenia (< 1.5 x 109 / l) Viral infection & Severe bacterial infections (e.g. salmonella) Congenital (kostmann’s syndrome) Drugs (anti-inflammatories, antibacterials, anticonvulsants, antidepressants) Autoimmune neutropenia Can cause rapid progression (few hrs) of Marrow failure infection to sepsis if untreated Splenomegally Lymphoctosis (> 5 x 109 / l) Viral infection (EBV, CMV, HIV) Chronic infection (TB, Toxoplasmosis) Chronic lymphocytic leukaemia Some lymphomas Post splenectomy Lymphopenia Severe marrow failure Corticosteroid therapy Hodgkins disease Irradiation Immune deficiency (AIDS) Lymphadenopathy Infection – bacteria (strep, TB, brucellosis), Viral (EBV, HIV), Protozoal (toxoplasmosis), fungal (rare) Neoplasm – 1o (lymphoma, leukaemia), 2o (lung, breast, thyroid, stomach) Connective tissue disorders – rheumatoid, SLE Sarcoidosis Reactive nodes = painful Amyloidosis Haematological = painless Drugs – phenytoin • Describe the clinical features of acute leukaemia and discuss the laboratory diagnosis. Leukaemia = malignancy of haemopoietic stem cells assoc with raised WBC in marrow or blood Causes / Associations Ionising radiation Cytotoxic drugs (can induce myeloid) Genetic – esp downs Immune deficiency Haem 7 of 22 Acute leukaemia M:F = 3:2 AML > ALL in adults by 4:1 (in children ALL > AML Pathology Proliferation of the primative stem cells à Very rapid cell growth of blast cells (blast cells don’t mature so don’t produce normal blood components) Can fill the marrow before spilling out into the blood High WBC (but not always present) Presentation - bone marrow failure Anaemia – tiredness, fatigue, pallor – with normal or raised MCV Thrombocytopenia – bleeding, bruising Neutropenia – infections – can vary from 1 to > 500 (most cases < 100) Investigations Blood films may show the abnormal blast cells Otherwise à marrow aspirate (wet sample) or trephine biopsy (dry tap if no aspirate obtained) Can follow on from pre-existing conditions e.g. myelodysplasia • Distinguish between myeloid and lymphoid cell lineages in the classification of acute leukaemia; highlight differences between childhood leukaemia and adult onset disease. Myeloid – includes myeloproliferative disorders and myelodysplasia Myeloproliferative includes Essential thrombocytopenia Polycythaemia rubra vera Myelofibrosis Hypereosinophilic syndrome Systemic mastocytosis Myelodysplasia Disordered maturation of blood cells in marrow Any cell line can be affected Rx is supportive – transfusions, tranexamic acid (antifibrinolytic to stabilise blood clots), platelet transfusions for active bleeds, Abx for severe infection Acute myeloid leukaemia Older patients have worse prognosis Different chromosomal markers can indicate prognosis – multiple markers = poorer prognosis Chronic myeloid leukaemia See later Lymphoid – includes immunosecretory disorders Acute lymphocytic leukaemia commonest malignancy in children (peak 4-5 yrs) 90% can be brought to remission with induction chemo, 85% cured! Higher relapses in boys and older children Chronic lymphocytic leukaemia (M:F = 2:1) See later Plasma cell disorders – e.g. myeloma Hodgkin’s disease Non Hodgkin’s disease (inc follicular, burkitts etc) T cell lymphomas • Outline the general principles of treatment of acute leukaemias. Once diagnosis available then (if patient suitable) give aggressive treatment Haem 8 of 22 Before treatment… Treat any current infections Correct anaemia with red cell transfusions Control bleeding with thrombocytopenia Ideally fit central line – e.g. Hickman line to administer therapy Aim of treatment is to destroy clone cells but to leave enough stem cells for marrow to repopulate from. Treatment is split into 3 stages Induce remission – combination chemo to destroy the bulk of cells à severe bone marrow hypoplasia requiring intensive care Remission consolidation – chemotherapy to destroy any remaining areas of disease. If extensive deposits remaining then extensive therapy may à need for stem cell transplant Maintainence of remission – continuing outpatient treatment to ensure no relapse ALL – also require prophylactic treatment for CNS as drugs don’t penetrate BBB – use radiotherapy, intrathecal chemotherapy and high dose methatrexate NB: Patients must report any fever > 38oc lasting over 1 hour as immune response will be compromised à need for Abx treatment Prophylaxis for fungal infections is often given during treatment Bone marrow transplant Usually donor from HLA matched relative or unrelated donor from register Stem cells are infused IV to the recipient who has been conditioned with ablation of all haemopoietic tissue. After 3-4 weeks the cells have established in the bone marrow and differentiated to produce sufficient blood for the patient. The new WBCs also recognise and destroy any remaining malignant cells (graft v disease reaction) NB: Graft V Host disease can occur if donor T lymphocytes sensitise to new host. Prognosis Untreated is approx 5 weeks Extended to 3 months with supportive treatment (transfusions etc) With treatment remission rates can reach 80% although remission is high (so followup is required) • Describe the clinical features and laboratory diagnosis of chronic myeloid leukaemia and outline the principles of management. Mainly granulocytic cell line Usually occurs between 30 and 80 yrs 95% of patients have Philadelphia chromosome The disease has 3 phases Chronic – responsive to treatment and easy to control (usually 3-5 years) Accelerated phase – disease becomes more difficult (can be very short) Blast crisis – disease transforms into AML (70%) or ALL (30%) à poor response to treatment & short prognosis Presentation Anorexia Tiredness (37%) Sweating Weight loss (26%) Abdominal fullness Breathlessness (21%) Bruising Abdominal pain & discomfort (21%) Vague ill health Lethargy NB: 90% have splenomegaly at presentation, 50% have hepatomegaly Ix & Dx Haem 9 of 22 Normocytic, normochromic anaemia Increased platelets Blood film shows abnormal range of granulocyte precursors Rx Imatinib – suppresses white cell proliferation Hydroxycarbide – suppresses production – more used palliatively Bone marrow transplant if available • Describe the clinical features and laboratory diagnosis of chronic lymphatic leukaemia and outline the principles of treatment. Most common type of leukaemia M:F = 2:1 Reproductive rate of cells is LOWER than normal cells BUT defective apoptosis means cells don’t die. B Lymphocytes are unable to respond to antigens (so unable to produce Ab) Presentation Onset very insidious – many picked up on routine FBC Can present with anaemia, infections, painless lymphadenopathy, night sweats or weight loss (all usually occur later in the disease) Ix & Dx Mature lymphocytosis à characteristic morphology & surface markers Retic count – high Direct coombs test – autoimmune haemolytic anaemia is common Assess serum immunoglobulins – indicates degree of immunosupression Staging – based on blood abnormalities and number of areas of lymphoid enlargement Rx Only required in evidence of marrow failure, massive lymphadenopathy / splenomegaly or systemic sx – e.g. weight loss or night sweats Chlorambucil à reduction of lymphocyte mass à symptomatic improvement in most cases • Describe the clinical features and laboratory diagnosis of multiple myeloma. Outline the associated laboratory abnormalities including changes in blood viscosity, renal function and serum calcium. Malignant proliferation of plasma cells Normal Ig is polyclonal (variation in heavy chains) In myeloma the malignant cells only produce 1 heavy and 1 light chain = paraprotein If only the light protein is produced = Bence Jones protein in urine Disease of the elderly – always consider if anaemia / high ESR (with normal CRP) / Back pain Multisystem disorder Marrow - anaemia, thrombocytopenia Skeletal – pathological # from lytic lesions, general osteoporosis (due to maliganant cells producing cytokines à stimulate osteoclasts à lysis & hyper Ca2+) Blood / CVS – high paraprotein à hyperviscosity Neuro – hypercalcaemia, spinal cord compression Infection – due to suppression of normal Ig Renal – increased UTI (immune suppression), dehydration (due to hypercalceamia from bone lysis), Bence Jones proteins are toxic to renal tubules, urate nephropathy, Ca2+ based stones, NSAID nephropathy from # pain, plasma cell infiltration of kidney Diagnosis Plasma cells in marrow > 10% Detectable paraprotein in blood / urine Need all 3 to diagnose myeloma Lytic lesions on skeletal survey Haem 10 of 22 Treatment In elderly – gentle chemo (steroids, cyclophosphamide) In young & fit – induce remission with chemo Lytic bone lesions respond well to radiotherapy High fluid intake to dilute Ca2+ & reduce renal damage Allopurinol – prevents urate nephropathy Bisphosphonates reduce hypercalcaemia and slow lysis Analgesia for bone pain Plasmaphoresis for hyperviscosity if required • Describe the clinical features of lymphoma. Lymphoma = 1o neoplastic disease of lymphoid cells. Divided to: Hodgkins Enlarged, painless, rubbery LNs – typically cervical (60-70%), axillary or inguinal 25% have systemic sx - weight loss, night sweats, pruritis or lethargy Can have effects due to pressure on other structures (SVC obstruction etc) Non-Hodgkins 75% enlarged nodes at presentation Also affects bone, gut, skin, lung Less systemic sx than hodgkins (systemic = disseminated disease) If ? Lymphoma à Scan to look for extent & identify accessible LNs Biopsy for diagnosis • Classify lymphomas into Hodgkin's disease and Non-Hodgkin's type and to high and low grade. Outline the principles of treatment. Hodgkin’s disease – atypical lymphoid cells (Reed-Sternberg cells) ?? related to EBV infection (some clinical evidence) Presentation Enlargement of a single / group of Ann-Arbor staging nodes I One node group OR one Weight loss (> 10% in 6 months) extranodal site Drenching night sweats (enough to II Several node groups on same change linen) o side of diaphragm OR limited Fevers (> 38 C) involvement of adjacent site 2 age peaks – teens/20s or elderly III Groups on both sides of Macroscopic diaphragm OR limited involvement Nodes enlarged to approx 2cm of adjacent extranodal site OR & replaced with firm, rubbery, involvement of the spleen pinkish/white tissue IV Disseminated involvement of one Course or more tissues (liver, bone or Untreated will spread to adjacent marrow) with or without nodes node groups à spleen, liver & bone marrow A Asymptomatic Diagnosis B Symptoms (fever, night sweats, Lymph node biopsy weight loss) Extent staged by CT / MR to check other nodes, liver & spleen Staging system is the “Ann Arbor system” Check renal function before starting treatments LFT and LDH abnormality indicates more severe disease 5 subtypes based on histology Haem 11 of 22 Nodular lyphocyte predominant – mainly in young adult males. Surrounding cells are B-cell origin. Most present in stage I or II Mixed cellularity – mainly in later life. Classid RS cells. Over 50% present in stage III or IV Nodular sclerosis – most common type. Mainly in young adults. Mediastinal nodes usually involved at presentation. Nodular due to bands of fibrosis Lymphocyte risk – different to nodular lymphocyte predominant because not B cell surrounding Lymphocyte depleated – mainly in elderly. Many pleiomorphic cells. Most present in stage III or IV disease & has poorest prognosis Overall prognosis - 10 yr survival > 80% for nodular lymphocyte predominant 75% for nodular sclerosis (type I) 60% for mixed cellularity 55% for nodular sclerosis (Type II) 5% for lymphocyte depleted (40% have 5 yr survival) Treatment Usually a combination of chemotherapy and radiotherapy Non-Hodgkin’s disease – neoplastic proliferation of B/T lyphocytes (rarely histiocytic cells) Nodal = orginiate in lymph nodes (majority of cases) Extranodal = arise in specialised groups of lymphoid cells (usually epithelial related Non-Hodgkins can be B or T cell in origin Small nuclei = low rate of proliferation à slow growth Large nuclei = rapid proliferation à aggressive behaviour 4 Main types of Non-Hodgkin’s disease: Slow growing, indolent B cell lymphoma (50%) Rapid growing, aggressive B cell lymphoma (30%) Slow growing T cell lymphoma (10%) Rapid growing aggressive T cell lymphoma (10%) Investigations As for hodgkins but also add … Bone marrow aspiration & trephine Immunophenotyping of cells (to distinguish T or B cell) Immunoglobulin determination (indicator of treatment response) Uric acid levels (high grade = high à renal failure on starting treatment Management A combination of radio, chemo, and monoclonal Ab therapy. Some cases required stem cell transplant Haem 12 of 22 The platelet • Discuss the role of platelets in the pathophysiology of vascular disease including vascular thrombosis and platelet emboli. Factors V & X join to complex with Ca2+ à prothrombin à thrombin Thrombosis Clot formation in a blood vessel, usually prevented by flow & PGI2 Endothelial damage à exposes collagen & vWF à Aggregation & adhesion à TXA2 from platelets & ADP à Further platelet activation Platelet emboli Break off from thrombus = thromboembolism • Describe the mechanism of action of aspirin and outline its role in cardiovascular disease prevention. Cox inhibition à impairs TXA2 à decreased aggregation • Outline the clinical features, investigation and treatment of immune thrombocytopaenia. Usually presents as autoimmune thrombocytopenic purpura ?? Reticular endothelial system à immune destruction NOT a clotting problem but is a differential for low platelets Acute AITP Usually in children, post viral infection due to immune platelet Ab Chronic AITP Usually adult women Usually idiopathic (can be SLE, thyroid, haemolytic anaemia, leukaemia, solid tumours, post viral infections) Platelet AutoAb in 60-70% of patients Symptoms Easy bruising, purpura, epistaxis, menorrhagia, major haemorrhage Investigations Thrombocytopenia (otherwise normal) Increased megakaryoblasts in marrow Should prove that clotting, marrow, liver function and autoimmune serology are all normal Treatment Acute – steroids, high dose IVIG, (2nd line is azathioprine, splenectomy or ciclosporin) Chronic – prednisolone, splenectomy Haem 13 of 22 Haemostasis • Describe the laboratory tests that are used to assess the clotting system and recognise patterns of abnormality. Intrinsic pathway Extrinsic pathway Prothrombin Time (PT) è INR APTT PT Normal = 9-12 sec. (normal INR = 1) Measure of the extrinsic pathway (factors II, VII, IX and X) Prolonged in liver disease, Warfarin, Vit K Common pathway deficiency, infection, DIC and factor VII def TT Used to monitor warfarin doses Activated partial thromboplastin time (APTT) Normal = 22-23 sec Measure of the intrinsic pathway Prolonged in heparin use, liver disease, vitamin deficiencies, infection, DIC, haemophilia and lupus Used to monitor heparin Thrombin Time (TT) Normal = 13-20 sec Measures final common pathway Prolonged by heparin, dysfibrinogenaemia, DIC & liver disease, • Outline a plan of investigation for a patient complaining of easy bruising. FBC – esp platelets Clotting screen LFT’s • Describe the role of the liver in normal clotting, including the part played by vitamin K in the synthesis of some clotting factors. Normal liver roles Synthesis of clotting factors (esp the vitamin K dependent factors) Synthesis of fibrinogen Production of bile (required for Vit K absorption) Effects in Liver disease Decreased circulating platelets Decreased clotting factor production (esp Vit K dependent factors) Dysfunctional clotting factors (dysfibrinogenaemia) Can à consumption of factors à DIC • Discuss the clinical features, diagnosis and management of clotting factor deficiencies including haemophilia and Christmas disease. Haemophilia A – Factor VIII deficiency X linked (males affected, women carriers) Usually presents 12-24 months as buttock / large joint haemarthrosis à mobility problems Ix – APTT = prolonged at approx 120s Rx – DDAVP (mild) or factor VIII concentrate (severe) Haemophilia B (aka Christmas disease) – factor IX deficiency X linked (males affected, women carriers) Haem 14 of 22 Usually presents 12-24 months as buttock / large joint haemarthrosis à mobility problems Ix – APTT = prolonged at approx 120s Rx – DDAVP (mild) or factor IX concentrate (severe) Von Willebrand’s disease VWF carries VIII in circulation and attaches platelets & fibrinogen to endothelium AD – tends to be milder than haemophilia Presents at any stage in life with post-traumatic bleeds (dental work, menorrhagia) Ix – APTT = prolonged Rx – DDAVP (mild) or VIII concentrate • Discuss the pharmacokinetics, and clinical use of warfarin including the laboratory tests used to monitor clinical effect. Outline the clinical management of over anticoagulation with warfarin. Warfarin = 4-hydroxycoumarin Blocks regeneration of Vit K Vit K is a cofactor for gamma carboxylation of factors II, VII, IX & X Clotting factors are still produced but not in active form Dosing Takes 48-72 hours to take effect – should be on LMWH until then ONLY comes in 3mg tablets in Notts area Starting regime = 9, 9, 6 and check INR on day 3 Check INR weekly until stable then 2-weekly or more as appropriate Target INR based on reason for treatment: 2.5 for DVT / PE 3.0 for AF & mechanical aortic valves 3.5 for recurrent DVT / PE & mechanical mitral valves Cautions / Contraindications Caution – recent surgery, hepatic & renal impairment, breast feeding Contraindications – active peptic ulcer, severe hypertension, bacterial endocarditis NB: contraindicated in pregnancy due to teratogenic effects 6-12 weeks gestation MUST stop warfarin 4 days before surgery (convert to heparin) AVOID – Vit K containing foods (leafy green veg) and enzyme inducers (alcohol, cranberry juice) Side effects – haemorrhage, hypersensitivity, rash, allopecia, diarrhoea Key interactions – erythromycin, coproxamol, amidoarone, antoconvulsants, NSAIDs Emergency reversal – Immediate with FFP (but will only last 8 hrs so give Vit K as well) Normal reversal = 12 hrs. IV or PO Vit K 10mg for complete reversal • Discuss the pharmacokinetics and clinical use of heparin including the laboratory tests used in monitoring heparin therapy. Outline the clinical management of over anticoagulation with heparin. Heparin = Glycosaminoglycan (GAG) = Polysaccharide Naturally present in mast cells – Lung or gut Clinically used unfractionated heparin isolated from lung of pigs or cows Action Potentiates Antithrobin 3 (NB wont work in rare state of antithrombin 3 deficiency) à Inhibition IIa and Xa Haem 15 of 22 Pharmacokinetics Destroyed in the gut – Parenteral administration required T1/2 60 mins – Increases with dose (longer in LMWH than standard heparin) Should monitor APTT if on heparin infusion Renal clearance Uses Rapid anticoagulation in PE/DVT until warfarin is started During thrombolysis for MI Before surgery in place of warfarin (shorter action & easier to control) Anticoagulation / DVT/PE prophylaxis during pregnancy (warfarin is teratogenic) Side effects Longterm can à osteoporosis Heparin induced thrombocytopenia / Thrombosis (HITT) Develops after 4-5 days treatment Causes reduction in platelets (can be complicated by thrombus) Hyperkalaemia Aldosterone secretion is reduced by heparin can à high K+ (esp if on K+ sparing diuretics) Reversing heparin Emergency – Protamine sulphate (binds heparin) NB: FFP wont work due to inhibition of clotting Routine - T1/2 of unfractionated heparin is 90mins – so just switch off! • Discuss the clinical use of thrombolysis, including monitoring and complications. Streptokinase – for life threatening venous thrombosis Alteplase – acute ischaemic stroke Both (+ reteplase) – can be used in pulmonary embolus For AMI - Of greatest benefit <12hrs (can be used upto 24hrs) Indications (within 12 hrs) • ST elevation >2mm in > chest leads • ST elevation >1mm in > limb leads • Posterior infarct (dominant R & ST depression in V1-V3) • New LBBB • Continuing chest pain or ST elevation (12-24hrs) Contraindications • Internal bleeding (inc prolonged CPR) • Suspected aortic dissection • Previous allergic reaction • Heavy PV bleed / Pregnant / <18 weeks PN • Acute Pancreatitis • Severe lung disease / active lung disease with cavitation • Oesophageal varices • Recent trauma/surgery (<2 weeks) • Cerebral neoplasm • Severe hypertension (>200/120 Relative contraindications • Peptic ulcer • History of CVA • Bleeding diathesis Haem 16 of 22 • Anticoagulated Side effects • Mainly nausea, vomiting and bleeding • Reperfusion arrhythmias & hypotension can occur with AMI • Outline the clinical indications for screening for thrombophilia and how this should be done. Indications for thrombophilia screen Venous thrombosis at a “young age” Recurrent venous thrombosis Family history of venous thrombosis Unusual site of thrombosis Recurrent miscarriage Arterial thrombosis at a young age Inherited thrombophilias - Detectable in approx. 30% of cases of VTE Factor V leiden - 5% popn An Abnormal factor V that is resistant to cleavage by APC = APC resistance Main cause of VTE in Caucasians Heterozygous FVL = 3% of Europeans = 7 fold increased risk of thrombosis Homozygous FVL = 0.02% of Europeans = 80 fold increased risk of thrombosis Protein C deficiency - 0.2 – 0.3% popn Autosomal dominant but with variable penetrance Levels fall following a large thrombosis Vitamin K dependent à Levels lowered by warfarin (risk of warfarin-induced skin necrosis) Accounts for ~3% of patients with VTE Heterozygotes = 10 – 15 times increased risk of thrombosis Homozygotes can present with neonatal purpura fulminans = life threatening Protein S deficiency Autosomal dominant Vitamin K dependent à warfarin sensitive BUT Risk of warfarin-induced skin necrosis ~3% of patients with VTE Probable mild risk factor for VTE Homozygotes can present with neonatal purpura fulminans • Outline the clinical features of immune thrombocytopaenia, its investigation and treatment. Idiopathic Thrombocytopenia is due to immune destruction of platelets In children – acute but usually self limiting (often following a viral infection or immunization In adults – usually in women & assoc with other autoummune disorders (SLE, thyroid), CLL, solid tumours and after viral infections. Autoantibodies are usually to membrane glycoproteins such as GP IIb/IIIa Features – major haemorrhage is rare and only seen in severe cases. Easy bruising, purpura, epistaxis and menorrhagia are common Investigation – FBC (low plts), marrow (normal / increased megakaryocytes) Treatment Haem 17 of 22 Children – usually not required. If severe à short course of high dose prednisolone. IvIG for very serious bleeding or urgent surgery Adults – none required if plts > 30 x 109/l. First line – oral corticosteroids. IvIgG if rapid rise in no required (e.g. before surgery) Second line - splenectomy • Outline the causes, clinical features of disseminated intravascular coagulation including the laboratory tests used in diagnosis. DIC – Widespread intravascular deposition of fibrin & microclots form in the circulation à clotting factors and platelets consumed faster than production à bleeding problems Causes of dic Infections Gr -ve and meningococcal septicaemia Clostridium perfringens septicaemia Severe falciparum malaria Malignancy Widespread mucin secreting adenocarcinoma Acute leukaemia Obstetric complications Amniotic fluid embolism Premature separation of the placenta Eclampsia Retained placenta Hypersensitivity reactions Incompatible blood transfusion Anaphylaxis Widespread tissue damage E.g. following trauma, Severe burns Miscellaneous Liver failure Snake and invertebrate venoms Hypothermia Heat stroke Acute hypoxia Vascular malformations Management Treat the underlying cause If the patient is bleeding give blood product support: FFP Platelets Cryoprecipitate if fibrinogen <1 Haem 18 of 22 Transfusion • Describe the ABO and Rhesus blood groups and outline their significance in blood transfusion. ABO system is based on CHO antigens on the RBC surface Group A has A antigens and AntiB antibodies Group B has B antigens and AntiA antibodies Group AB has A and B antigens and NO antibodies Group O has no antigens and AntiA and AntiB antibodies = Universal recipient = Universal donor Rhesus factors also factor Factors e, C , D, e and E Rhesus +ve = Rhesus D (85% of population) • Describe the principles of cross matching blood. The blood given must NOT have any antigens for which the recipient has antibodies Group & Save Assess the ABO and Rh groups, and screens the blood for other common antigens Cross Match (approx 1 hr) Checks for agglutination à ABO and Rh typed blood that has been checked for agglutination with intended donor sample Type specific Checks ABO and Rh groups. Then supplies blood with no other antigens • List the blood products available for transfusion and outline the rationale for using fresh frozen plasma, cryoprecipitate and platelets. Packed Red Cells ABO and Rh matched 1 unit à raise Hb by 1 g/dl Should be given within 6 hrs Platelets Must be ABO and Rh matched as contains some donor antibody in plasma High risk for bacterial contamination 1 dose à raise plts by 30-40 x 10l/l Give over 30 minutes Fresh Frozen Plasma (FFP) Must be ABO compatible as donor antibody present Used to replace absent clotting factors (DIC, liver failure, massive RBC transfusion) 20-30 minutes to defrost, then give over 30 minutes Dose = 15ml/kg Cryoprecipitate Must be ABO compatible as donor antibody present Rich in vWF & factor VIII 15-20 minutes to defrost then give over 5 minutes Human Albumin solution Not require ABO matching Used to expand plasma Give over 1-2 hours • Discuss the possible reactions and their management Haemolytic transfusion reaction Haem 19 of 22 ABO mismatch Sx – agitation, flushing, abdo/flank pain, feeling of doom, fever, hypotension, bleeding, haemoglobinuria Rx STOP TRANSFUSION & recheck details. Remove cannula & send blood + giving set back to bloodbank. Check FBC (haemolyisis), Coag (DIC), Bacterial cultures, U&E (free Hb à ATN à ARF), urinalysis (Hb in urine) Catheter & monitor output Re-CrossMatch Bacterial contamination Suspect if cloudy bag / high fever Treat for transfusion reaction + Abx Anaphylaxis Usually only occur if IgA deficient (congenital / haem malignancy) Sx – urticaria, erythema, rash, facial oedema, bronchospasm, hypotension, circulatory collapse Rx STOP TRANSFUSION & disconnect blood from cannula. (after event à recheck details & send blood + giving set back to bloodbank). Remove cannula O2 Adrenalin – 0.5ml of 1:1000 IM IV fluids to maintain circulating volume IV hydrocortisone IV chlorpheniramine Febrile transfusion reaction Rare – due to antiHLA / antigranulocyte Ab in recipient AND WBC in transfusion Rx – slow the transfusion, give paracetamol, hydrocortisone & chlorpheniramine Delayed transfusion reaction When recipient Ab is stimulated 7-10 days post transfusion à anaemia, fever & jaundice Rx - Cross Match and re-transfuse Haem 20 of 22 Miscellaneous haematology • Outline the clinical features of myelofibrosis. Hyperplasia of megakaryocytes (which produce platelet derived growth factor) --> intense marrow fibrosis & myeloid metaplasia (haemopoesis in spleen & liver) --> hepatosplenomegaly Presentation: night sweats, fever weight loss, abdominal discomfort (due to hepatosplenomegaly) OR bone marrow failure (anaemia, infections, bleeding) Ix: FBC --> bone marrow biopsy Rx: marrow support, stem cell transport may --> cure but high mortality Prognosis - 4-5 yrs mean survival • Outline the clinical features of polycythaemia rubra vera. Malignant proliferation of a clone derived from one pluripotentent marrow stem cell. The offspiring cells do not require EPO to avoid apoptosis. --> Excess proliferation of RBC's, WBC's and platelets --> thrombotic complications due to hyperviscosity. Usually affects patients over 60yrs S&S - can be detected on FBC or signs of hyperviscosity. headaches, dizziness, tinnitus, visual disturbance, itch after hot bath. Splenomegaly. Gout due to increased urate from RBC turnover. Thrombosis Ix: FBC (raised RBC, Hb, HCT, PCV, WBC & Plts), B12 raised, Marrow shows increased cellularity, low EPO Rx: aim to keep Hct < 0.45 to reduce risk of thrombosis (by venesection or blocking cell turnover). Give low dose aspirin to reduce clot risk. Prognosis: may remain well for years. thrombosis & haemorrhage are the main complications. 30% --> myelofibrosis, 5% --> acute leukaemia. Monitor FBC every 3 months • Outline the clinical features of essential thrombocythaemia. Clonal proliferation of megakaryocytes --> persistently high platelets (> 1000 x 109 / L) with abnormal function --> bleeding, or arterial and venous throombosis with microvascular occlusions --> headache, atypical chest pain, light headed. Rx: low dose aspirin, supress plt production if > 60 or prev thrombosis • Outline the clinical features of aplastic anaemia and describe the laboratory diagnosis and principles of treatment. Rare stem cell disorder --> pancytopenia & hypoplastic bone marrow. Present with anaemia, infections or bleeding Causes: mostly autoimmune, triggered by drugs or irradiation Ix: bone marrow biopsy Rx: support marrow (see below), consider transplant if young, immunosupression may stop autoimmune process Marrow support - neutrophils last 1-2d, plts last 8 days, RBC last 120d. Red cell transfusion Plts transfusion Neutropenic regime - full barrier nurse, Avoid IM injections, wash perineum post defecation, swab skin with chlorhexidine, 2 hrly mouth washes, TPR with high calories Haem 21 of 22 • Describe the management of the splenectomised patient. Problems post splenectomy Increased platelets (600-1000 x 109 / l) lasts for 2-3 weeks Thromboembolic events may occur Increased risk of infections – esp pneumococcus OPSS – overwhelming post splenectomy sepsis NB: patients should be pre-vaccinated (2-3 weeks) if elective splenectomy Pneumococcus – repeat every 5 yrs Men C Annual flu vaccine HiB Long term penicillin if problems NB: if emergency splenectomy due to trauma then vaccinate 10-14 days after • Explain ESR and factors affecting the reading ESR = Erythrocyte sedimentation rate (RBCs sedimenting through the serum) RBCs have –ve charge & so repel each other à slow sedimentation 2 proteins have +ve charge à cells aggregate à faster sedimentation à higher ESR • Fibrinogen – t1/2 = 3 days. Increases in acute phase response • Immunoglobulin – t1/2 = 28 days If high immunoglobulins level à request plasma electrophoresis Polyclonal = normal in acute phase response and infection Monoclonal = myeloma / lymphoma Low albumin (e.g. liver disease) à serum is less viscous à higher ESR Anaemia = less cells à sediment faster à higher ESR Haem 22 of 22