what are the 3 key physiological events that occur with the onset of bleeding?
- 1. vasoconstriction
- 2. platelet aggregartion to form PRIMARY HAEMOSTATIC PLUG
- 3. activation of clotting cascade to form a fibrin plug (SECONDARY HAEMOSTATIC PLUG)
where are platelets formed?
- megakaryocytes in bone marrow
- platelets: anucleate, but cytoplasm has electron dense granules, lysosomes, mitochondria
what is the half life of platelets in blood?
where are clotting factors made?
what converts fibrinogen to fibrin?
what prevents over-clotting of the blood by degrading fibrin?
why do women in pregnancy have a physiological anaemia?
due to increased circulating plasma volume
if pregnant women have Hb<10.5g/l what should they be given?
is B12 deficiency common in pregnancy?
no vary rare. due to excess alcohol
what are the histological findings of pernicious anaemia?
atrophy of gastric mucosa so failure of IF and gastric acid production (achlorhydria) and so B12 malab
what is the schilling's test?
what 2 types of anaemia are associated with coeliac disease?
- iron deficiency anaemia
- megaloblastic anaemia: folate, B12 deficiency
what type of cells are characteristic for megaloblastic anaemia?
what is aplastic anaemia?
- pancytopenia in the absence of reticulocytes
- bone marrow failure: hypocellular
what types of anaemia do chronic alcoholics tend to have?
- megaloblastic anaemia: due to the toxic effect of alcohol on erythropoiesis or dietary folate deficiency
- macrocytic anaemia
what is a megaloblast?
RBC in which nuclear maturation is delayed compared with the cytoplasm so you get hypersegmented neutrophils (immature)
give 3 causes of megaloblastic anaemia
- B12 (cobalamin) deficiency
- folate deficiency
give 4 causes of non megaloblastic microcytic anaemia
- alcohol excess
- haemolytic anaemia: get reticulocytosis
- pregnancy: increased demand from foetus
what is the underlying mechanism for megaloblastic anaemia?
defective DNA synthesis so get hypersegmented neutrophils, leucopenia, thrombocytopenia, MCV > 110
what are the clinical features of B12 deficiency anaemia?
- glossitis: beefy red sore tongue
- lemon tinge to skin - pallor (anaemia), jaundice (haemolysis)
- angular stomatitis
- paraesthesia, peripheral neuropathy
- depressed, irritable, psychosis
- subacute combined degeneration of the spinal cord (not seen in folate deficiency): peripheral neuropathy, optic atrophy (vision changes), dementia, both symmetrical DC loss (LMN signs) and symmetrical corticospinal tract loss (UMN signs) so get classic triad of extensor plantar reflex (UMN) (positive babinski), absent knee jerk (LMN), absent ankle jerk (LMN)
why do patients with untreated B12 deficiency anaemia tend to fall at night?
subacute combined degeneration of the spinal cord - get ataxia due to JOINT POSITION and vibration sense affected and optic atrophy (reduced vision)
Why are pain and temperature sensation still in tact?
spinothalamic tracts are not affected
what is the MCV and MCHC like in anaemia of chronic disease?
normocytic normochromic anaemia
in chronic diseases such as RA, what kind of anaemias can you get?
- take NSAID - gastritis and chronic blood loss - microcytic hypochromic anaemia (IDA)
- normocytic normochromic anaemia (ACD)
what test is done to detect AIHA?
Direct antiglobulin test (Coombs' test): detects autoAb on surface of red cells
what are features of a blood film in haemolytic anaemia?
- normocytic normochromic anaemia
what would be found in the blood of haemolytic anaemia?
what is the difference between warm and cold AIHA?
- temperature at which Ab attaches better to the RBC
- cold: lower than 37
what causes warm AIHA? which Ab mediates it?
- bind at body temp 37 degrees
- autoimmune diseases: eg SLE
- lymphoproliferative disease: e.g. CLL, lymphoma
What causes cold AIHA? which Ab?
- IgM mediated
- bind at lower temp <4degrees, activating cell surface complement
- following infection e.g. mycoplasma pneumonia, EBV
what is the treatment of warm AIHA?
steroids or immunosuppressants (think autoimm disease and lymphoprolif)
what is the treatment of cold AIHA?
- keep warm
- chlorambucil may help
what are the hereditary causes of haemolytic anaemia?
- RBC enzyme defect: glucose-6phosphate dehydrogenase deficiency. asymp but susceptible to oxidative crisis due to reduced glutathione prod precip by drugs, fauvism; pyruvate kinase deficiency
- membrane defect: hereditary spherocytosis - less deformable spherical RBC so trapped in spleen - extravasc haemolysis
- Hb defect: sickle cell, thalassaemia
what are the consequences of parvovirus B19 infection?
- aplastic anaemia due to BM stops working
- rheumatoid arthritis
- adults: gets better on own.
- children: slapped cheek syndrome - bright red rash over cheeks
what is the blood film and symptoms like in G6PD deficiency attack?
- oxidative crises - so oxidised denatured Hb - form Heinz bodies
- bite cell and blister cell: after removal of Heinz body by spleen.
what cells are present in Hodgkin's lymphoma?
Reed-Sternberg cells: have mirror image nuclei (2nuclei)
what are the 2 peaks of incidence of hodgkins lymphoma?
how does lymphoma present?
enlarged PAINLESS non tender rubbery LN - cervical or axillary or inguinal (the superficial ones)
in Hodgkins lymphoma, what can induce LN pain?
what can mediastinal LN involvement in HL cause?
- mass effect: bronchial or SVC obstruction
- direct extension: causing pleural effusion
why do you get lymphadenopathy in lymphomas?
malignant proliferation of lymphocytes which accumulate in LN
what are the investigations needed for HL?
- blood: FBC, film (RSC), LDH (raised as inc cell turnover), Ca, urate, LFT, high ESR, low Hb worse pro
- tissue diagnosis: LN excision biopsy
what is the Rx for HL?
- chemo, radio or both (SE both: AML, NHL, infertility)
- chemo: ABVD
- stem cell transplantation
- radio SE: solid tumours (lung, breast, thyroid) near radiation field, IHD, hypothyroid, lung fibrosis
- chemo SE: alopecia, BM suppression, nausea, infection
what are the emergency presentations of HL?
- SVC obstruction: inc JVP, fullness in head, dyspnoea, blackouts, facial oedema
what is the most common type of HL?
which type of HL is associated with EBV?
mixed cellularity - admixture of lymph, histio, eosino, plasma
which type of HL is assoc. with HIV?
lymphocyte deplete. bad prognosis
what is the differential diagnosis of lymphadenopathy?
- infection: CMV, EBV, HIV, TB
- infiltration: RA, SLE, sarcoid
what is NHL?
- all lymphomas WITHOUT Reed-Sternberg cells
- most derived B-lymphocute
what are the causes of NHL?
- congenital immunodeficiency
- acquired immunodeficiency: HIV, EBV, drugs, H.pylori (in MALT), toxins in environ, HTLV-1
Give examples of low, high and very high grade B cell NHL:
- low: (indolent, incurable, widely disseminated at presentation) eg follicular lymphoma, CLL, mantle cell lymphoma inc MALT assoc. with chronic H.pylori infection, if eradicate H.pylori lymphoma remission
- high: more aggressive but long term cure possible e.g. diffuse large B cell lymphoma
- v.high: Burkitts lymphoma, lymphoblastic lymphoma
Give a cutaneous T cell lymphoma
what do you have to do before you strait Rx of folicular lymphoma?
repeat biopsy in case histological transformation to DLBCL
what is the treatment of FL?
- stage I: involved field radio, may cure
- R-CHOP or R-CVP chemo for others
what is the translocation in FL?
- t(14:18) gene Bcl-2/IgH
- Bcl is anti apoptotic gene
What type of lymphoma is the commonest?
- DLBCL, high grade, aggressive, can be cured
- Rx: RCHOP
What is Burkitt's lymphoma? what is it associated with?
- v high grade, major risk of dissemination to CNS
- one type is endemic in Africa, assoc. with EBV (jaw lymphadenopathy)
- immunodeficiency assoc HIV or post transplant
what is the treatment and prognosis?
- if rapidly and aggressively treated then good prognosis as cells are very active and proliferating therefore susceptible to chemotherapy so in young and fit cure rates are high
- Rx: short course v.intenseive therapy and CNS prophylaxis - intra thecal chemo and ones cross BBB
what is the staging called for lymphoma? describe it
- Ann Arbor staging system
- 1: single node region
- 2: 2 or more node regions, SAME side of diaphragm
- 3: nodes BOTH sides of diaphragm
- 4: EXTRALYMPHATIC involvement eg liver and BM
- suffix A: absence of B symptoms
- suffix B: B symptoms (fever, night sweats, weight loss)
what is myeloma
malignant clonal proliferation of B-lymphocyte derived plasma cells
in myeloma which Igs are the most common paraprotein?
which type of white cell disorder is linked to bone lesions, bone pain?
myeloma due to deposits in vertebrae, ribs, skull
which is the most common paraprotein to be made by neoplastic plasma cells in myeloma?
what does paraproteinaemia mean?
presence of Ig made by a single clone of plasma cells in the blood
what is the paraprotein recognised as on serum electrophoresis?
monoclonal band (M band) on serum electrophoresis
what are the causes of paraproteinaemia?
- multiple myeloma
- waldenstroms macroglubulinaemia
- primary amyloidosis (AL amyloid)
- MGUS: monoclonal gammopathy of uncertain significance: can develop myeloma or lymphoma in future
what is waldenstroms macroglubulinaemia? and what symptoms do you get?
- lymphoplasmacytoid lymphoma making monoclonal IgM.
- get hyperviscosity with CNS and ocular symptoms.
what are the signs of waldenstroms macroglubilinaemoa?
- lymphadenopathy, splenomegaly
- inc ESR
- IgM paraprotein on serum electrophoresis
what can be detected in the urine of myeloma pts?
Bence-Jones proteins which are excreted by the kidney into the urine - light chains (either kappa or lambda type) from the paraprotein
which race and age are more likely to get myeloma?
- over 70s=peak age
- afrocaribbean:caucasian 2:1
name 6 symptoms of myeloma and explain them
- osteolytic bone lesions: backache, fractures, vertebral collapse due to increased osteoclast activation from signalling by myeloma cells
- symptoms of hypercalcaemia: due to osteoclast activity
- pancytopenia symptoms: due to BM infiltration of proliferating plasma cells causing anaemia, bleeding, infection
- recurrent bacterial infection: immunoparesis, low neutrophils
- impaired renal function: light chain deposition
- systemic AL amyloidosis in 15% only
describe the blood test results of a patient with myeloma
- FBC: normocytic, normochromic anaemia
- persistently high ESR, PV
- increased urea and creatinine (as renal impairment)
- increased calcium
- alk phase normal (unless healing fracture)
what is the screen test for myeloma?
serum and urine electophoresis
what is a prognostic test for myeloma?
what are the Xray signs of myeloma?
- punched out lesions e.g. pepper pot skull
- vertebral collapse
what would the blood film of a patient with myeline look like?
what is the diagnostic criteria for myeloma?
- serum or urine electrophoresis: monoclonal protein band
- BM biopsy: increased plasma cells
- end organ damage from myeloma: hypercalcaemia, renal impairment, anaemia, bone lesions
what is the supportive treatment of myeloma?
- bone pain: analgesics (avoid NSAID..as risk kidney impairment)
- to reduce fracture rate: bisphosphonates eg zolendromate, pamindronate
- to help focal disease: local radiotherapy
- vertebral collapse: vertobroplasty, kyphoplasty
- anaemia: blood transfusions and EPO
- renal failure: rehydrate at least 3l/day avoid light chain nephropathy, dialysis if ARF
- infections: treat rapidly with broad spec antibiotics until culture, may need regular ivIg infusion if recurrent infection
how can you treat the myeloma itself?
- old ppl: melphalan/cyclophosphamide with prednisolone
- young/fit ppl: VAD (vincristine, adriamycin, dexamethasone); SCT, allogeneic transplantation can be curative but high mortality (30%)
- Thalidomide in relapsed disease
what is used to test prognosis of myeloma?
what is the common cause of death in myeloma patients?
what are the complications of myeloma? and how to manage?
- hypercalcaemia: rehydrate with iv saline, iv bisphosphonates
- spinal cord compression: urgent MRI, dexamethasone, local radiotherapy
- hyperviscosity: causes reduced cognition, vision probs, bleeding. plasmapheresis to remove light chains
- ARF: rehydrate, urgent dialysis
what is amyloidosis?
- extracellular deposits of protein
- in abnormal fibrillar form
- resistant to degradation
where is the amyloid protein deposited?
- kidney: glomerular lesions: proteinuria and nephrotic syndrome
- heart: restrictive cardiomyopathy, arrhythmia, angina
- Nerves: peripheral and autonomic neuropathy, carpal tunnel syndrome
- Gut: macroglossia, malab, perf, haemorrhage, obstruct, hepatomeg
- Vascular: purpura, esp periorbital
what is a characteristic feature of amyloidosis that you can see on a patient
what is the philadelphia chromosome and which leukaemia is it associated with?
- chronic myeloid leukaemia
- reciprocal translocation between chr 9 and 22
- fusion of Bcr gene and abl proto-oncogene
- tyrosine kinase activity
what is CML?
- uncontrolled clonal proliferation of myeloid cells
- myeloproliferative disorder
peak age and sex of CML?
age: 40-60yrs, rare in childhood. male more
what are the symptoms of CML?
- chronic and insiduous
- B: wt loss, tired, fever, sweats
- gout: purine breakdown
- bleeding: plt dysfunction
- abdo discomfort: splenomegaly
signs of CML?
what is FBC of CML?
high WBC: whole spectrum of myeloid cells - neutro, myelocytes, baso, eosin, may see lots of granulocytic cells at different stages of differentiation, low/N Hb
what is the BM like in CML?
what is the treatment of CML?
- chemo: imatinib (Glivec) tyrosine kinase inhibitor but may cause myelosupp
- hydroxycarbamide if imatinib ineffective
- stem cell transplantation: allogeneic HLA matched - only cure
what is CLL?
monoclonal proliferation of non-functional MATURE Blymphocytes
age and sex of CLL?
m:f 2:1; elderly 65yo
what are the symptoms of CLL?
none, infection, anaemia, B symp
what are the signs of CLL?
- enlarged, rubbery, non-tender nodes
what is FBC of CLL?
- increased lymphocytes
- marrow infiltration so low Hb, low neutro, low platelets
what cell do you see on blood film of CLL?
smear cell: fragile cell so damaged in preparation
complications of CLL?
- autoimmune haemolysis
- infection as hypogammaglobulinaemia (low IgG) - bacterial, viral esp herpes zoster
- marrow failure: pancytopenia
what is the most common haematological malignancy?
what is the treatment of CLL?
- asymp: monitor
- chemo: chlorambucil reduce lymphos, improve BM, reduce node size
- steroids: Autoimmune haemolysis
- radio: relief of lymphadenopathy, splenomeg
- supportive: transfusions, ivIg if recurrent infections
why do you get spherocytes on the blood film of CLL?
- autoimmune haemolytic anaemia in CLL too
- warm IgG
give 4 examples of myeloproliferative disorders:
- RBC: polycythaemia rubra vera - hyperviscosity so get headache, tinnitus, dizziness.
- WBC: CML
- platelet: essential thrombocythaemia. abnormal plt so may cause bleeding, thrombosis, chest pain, light headed
- fibroblasts: myelofibrosis - B symptoms, hepatosplenomeg, blood film: leucoerythroblastic cells (nucleated RBC), teardrop RBC
what is the treatment of each myeloproliferative disorder?
- polycythaemia rubra vera: venesection, hydroxycarbamide if high risk e.g. over 60/previous thrombosis, aspirin 75mg PO
- essential thrombocythaemia: low dose aspirin 75mg PO, hydroxycarbamide if over 60/previous thrombosis
- myelofibrosis: marrow support, allogeneic SCT curative but high mortality
what is the most common childhood cancer?
ALL (rare in adults)
what is ALL?
- uncontrolled proliferation of immature T or B lymph blast cells with BM failure, tissue infiltration
- CNS involvement common
signs and symptoms of ALL?
- marrow failure: low Hb, infection, bleeding
- infiltration: hepato, spleno megaly, lymphadenopathy, orchidomegaly
- CNS involvement: CN palsy, meningism
what are the features of blood film and BM in ALL?
blasts, need to know blast count on FBC
what investigations need to be done in suspected ALL?
- blood film & BM: blasts
- CXR, CT: mediastinal and abdo lymphadenopathy
- LP: CNS involvement
what is the treatment of ALL?
- supportive: blood transfusions, platelet transfusions, iv fluids, allopurinol (prevent tumour lysis), Hickman line
- infection: immediate iv Abx. neutropenic regimen, prophylactic drugs
- chemo: for remission induction, CNS prophylaxis (intrathecal methotrexate)
- marrow transplant
what is ALL?
- neoplastic proliferation of blast cells from marrow MYELOID elements
- very rapidly progressive, death in 2 months if untreated!
what is age of AML?
- age: old.
- long term complication of chemo e.g. for lymphoma!
- assoc. with myelodysplasia
what are the symptoms of AML?
- marrow failure: anaemia, infection, bleeding
- infiltration: hepato, spleno megaly, GUM HYPERTROPHY, skin, NB CNS involvement rare
how can you diagnose AML?
- FBC: WCC high but can be low/normal!
- BM biopsy: blast cells
- microscopy: Auer rods
how can you manage a patient with AML who is waiting for chemo?
- put in a side room as LOW neutrophils so risk of infection
- blood and platelet transfusion
- iv fluids
- allopurinol: prevent tumour lysis
- blood culture and iv antibiotics
what is the most common leukaemia assoc. with DIC? how do you reduce risk of DIC in these pt?
- use all trans retinoic acid with chemo
which leukaemia is massive splenomegaly assoc. with?