Haematology Flashcards
How do platelets bind to exposed subendothelial cells/matrix and what does this trigger?
- GlpIa to exposed collagen - GlpIb to Von Willebrand factor - Release of ADP and thromboxane A2 trigger platelet aggregation
What factors are involved in platelet aggregation?
GlpIIb/IIIa crosslink platelets via fibrinogen
Which arachidonic acid metabolites affect platelet aggregation?
Thromboxane A2 induces platelet aggregation Prostacyclin PGI2 inhibits platelet agggregation
What actions does thrombin have?
- Cleaves Fibrinogen - Activates Platelets - Activates procofactors (FV and FVIII) - Activates zymogens (FVII, FXI and FXIII)
Describe the initiation phase?
- Injury of vessels wall leads to contact between blood and subendothelial cells - Tissue factor (TF) is exposed and binds to FVIIa or FVII which is subsequently converted to FVIIa - The complex between TF and FVIIa activates FIX and FX - FXa binds to FVa on the cell surface
Describe the amplification phase?
- The FXa/FVa complex converts small amounts of prothrombin into thrombin - The small amount of thrombin generated activates FVIII, FV, FXI and platelets locally. FXIa converts FIX to FIXa - Activated platelets bind FVa, FVIIIa and FIXa
Describe the propagation phase?
- The FVIIIa/FIXa complex activates FX on the surfaces of activated platelets - FXa in association with FVa converts large amounts of prothrombin into thrombin creating a “thrombin burst”. - The “thrombin burst”leads to the formation of a stable fibrin clot.
What factor is activated to degrade fibrin?
Plasminogen is converted by tissue plasminogen activator (tPA) to plasmin which degrades fibrin.
What physiological anticoagulants are there?
- Antithrombin III: main inhibitor of activated coagulation serine proteases. Also inactivates thrombin and activated factors X, IX, XI. ATIII activity is greatly accelerated (2000-fold) by heparin -Heparin co-factor II: complexes with thrombin inactivating it. Activity is amplified 1000-fold by heparin - Protein C + S: upon activation by thrombin in the presence of thrombomodulin, activated protein C inactivates VIIIa and Va, thus reducing the rate of thrombin generation. Protein S is a cofactor - Tissue factor pathway inhibitor: binds to Xa and TF:VIIa complex, inhibiting their proteloytic activity
Which substances mediate vasoconstriction in haemostasis?
- adrenaline - ADP - kinins - thromboaxanes
Which coagulation factors are dependent on vitamin K for their normal function?
II, VII, IX, X, protein C and protein S
How does clopidogrel inhibit platelet aggregation?
Clopidogrel is a specifc, non-competive inhibitor of ADP- induced platelet aggregation, irreversibly inhibiting the binding of ADP to its platelet membrane receptors. Ultimately it inhibits the activation of the GPIIb/IIIa receptor, its binding to fibrinogen and further platelet aggregation.
What are the common causes of thrombocytopenia?
Immune-mediated Idiopathic Drug-induced Connective tissue disease Lymphoproliferative disease Sarcoidosis Non-immune mediated DIC Microangiopathic hemolytic anemia
What is the treatment for ITP?
>50,000 - Nothing 20-50,000 - Not bleeding: None - Bleeding : Steroids + IVIG <20,000 - Not bleeding: Steroids - Bleeding : Steroids, IVIG, Hospitalization
What are the clinical features of haemophilia?
X-linked congenital deficiency - Factor 8 (A) or 9 (B) Bleeding – Haematoma, joint etc. Prolonged aPTT but normal PT. Clotting factor replacement-Life long.
What are the clinical features of von Willebrand Disease?
Inheritance - autosomal dominant Incidence - 1/10,000 Clinical features - mucocutaneous bleeding Classification: Type 1 - Partial quantitative deficiency Type 2 - Qualitative deficiency Type 3 - Total quantitative deficiency
What are the components of Virchow’s triad?
Vessel wall, blood, flow.
What inherited thrombophilia risk factors are there?
- Anticoagulant deficiency (All rare): Protein C (0.3%), Protein S, Antithrombin (<0.2%) - Procoagulant excess (common): Factor VIII (10% of population), Factor II (2%), Fibrinogen - Additional factors: Factor V Leiden (5% caucasians), Lupus anticoagulant, Prothrombin G20210A
What is Lupus anticoagulant?
An immunoglobulin that binds to phospholipids and proteins associated with the cell membrane and increases the risk of thrombosis.
What acquired thrombophilia risk factors are there?
Age, obesity, previous DVT or PE, immobilisation, major surgery, long distance travel, malignancy (esp. pancreatic), pregnancy, COCP, HRT, antiphospholipid syndrome, polycythaemia, thrombocythaemia
What anticoagulant molecules are normally expressed by blood vessel walls?
- Thrombomodulin: Directs thrombin to activate protein C - Endothelial protein C receptor: Presents PC to Thrombomodulin - Tissue factor pathway inhibitor: Inhibits Tissue factor - Prostacyclin (PGI2): Inhibits platelet activation - Nitirc Oxide: Inhibits platelet activation
What is used as DVT prophylaxis?
Chemical: low molecular weight heparin e.g. Tinzaparin, Clexane Mechanical: TED stockings or intermittent compression devices
What is the treatment for a DVT/PE?
Immediate: Low molecular weight heparin until 2 days therapeutic INR Ongoing: warfarin for 3-6 months, started simultaneously In cancer patients continue LMWH not warfarin THrombolysis reserved for life threatening PE or limb threatening DVT
How does heparin work, how is it administered and what long-term side effects are there?
Potentates antithrombin III which inactivates thrombin and factors 9, 10, 11 LMWH: SC OD, no monitoring (anti-Xa assay) except in renal failure and late pregnancy Unfractionated: IV infusion, monitor APTT Side effects: heparin induced thrombocytopenia and osteoporosis (more common with UFH)
What is the treatment for heparin overdose?
Protamine sulphate
How does warfarin work?
Inhibits regeneration of active vitamin K (via reductase enzymes) thus inhibits synthesis of factors 2, 7, 9, 10 and proteins C, S and Z
How does Rivaroxaban work?
It is an orally active direct factor Xa inhibitor
How does Dabigatran work?
Direct anti-thrombin inhibitor
What is factor V Leiden?
A polymorphic mutation which makes Factor V resistant to protein C. Affects 5% of white population
What are the consequences of red cell antibodies (e.g. anti-RhD) in pregnancy?
Only IgG antibodies can cross the placenta. If the maternal antibody level is high, they can destroy foetal red cells causing the foetus to become anaemic and jaundiced = Haemolytic Disease of the Newborn. Rh D = most important cause of severe HDN, also only one with preventative treatment. Other blood groups can cause HDN e.g.: anti-Rh C, anti-K. IgG ABO antibodies can also cause HDN but this is usually not severe.
How is Haemolytic Disease of the Newborn prevented in a RhD negative women carrying an RhD positive foetus?
Giving her IM anti-D Ig at times when she is at risk of a feto-maternal haemorrhage; - routine antenatal prophylaxis at 28 and 34 weeks has been shown to significantly reduce the sensitisation, due to ‘silent’ bleeds in the 3rd trimester - during pregnancy if sensitising event occurs: abortion, miscarriage requiring medical/surgical evacuation, abdo trauma, external cephalic version, amniocentesis, stillbirth - at delivery if the baby is RhD positive Anti-D Ig only works if the mother is not already sensitised
What is a Kleihauer test?
A blood test used to measure the amount of foetal haemoglobin transferred from a foetus to a mother’s bloodstream. It is usually performed on Rhesus-negative mothers to determine the required dose of Rho(D) immune globulin to inhibit formation of Rh antibodies in the mother and prevent Rh disease in future Rh-positive children.
What are the two main causes of an immediate severe blood transfusion reaction?
1) Wrong (ABO incompatible) blood 2) Bacterial infection of the blood
What immediate adverse reactions to a blood transfusion can occur?
Immune: - ‘Wrong blood’ ABO incompatibility - Febrile non-haemolytic - Allergic / anaphylaxis - Transfusion related acute lung injury Non-immune: - Bacterial infection - Transfusion associated cardiac overload
What delayed adverse reactions to a blood transfusion can occur?
Immune: - Delayed haemolytic transfusion reaction - Port-transfusion purpura - Transplant -associated GVHD Non-Immune: - Viral infections + other - Iron overload
What causes febrile non-haemolytic transfusion reactions?
White cell antibodies in the patient which react with white cells in the donor’s blood, causing fever and rigors. This is less common since leucodepletion of all donor blood.
What causes transfusion related acute lung injury?
Very rare. Occurs if the donor’s plasma contains potent white cell antibodies incompatible with the recipient’s white cells. Transfusion may cause a severe reaction characterised by chills, fever, a dry cough and breathlessness with cardiac failure. TACO more likely
What causes a delayed haemolytic transfusion reaction?
Many occur in patients who have antibodies (other than ABO), if specially selected blood is not given. Usually manifested by fever days to weeks after a transfusion, accompanied by a falling haemoglobin, and jaundice or haemoglobinuria.
What translation forms the RUNX1-RUNX1T1 fusion protein and what disease is it associated with?
t(8;21) = one of the most frequent karyotypic abnormalities in acute myeloid leukaemia (esp M2 subtype)
What is the two-hit model of AML pathogenesis?
That two different classes of mutation are needed; - Class I mutations confer proliferative and/or survival advantage, but do not affect differentiation e.g. tyrosine kinase mutations - Class II mutations serve primarily to impair haematopoietic differentiation and subsequent apoptosis
What are the common presenting features of chronic myeloid leukaemia?
• M:F 1.4:1 • 40-60 years • Weight loss, lethargy, night sweats • Splenomegaly (often massive) • Features of anaemia • Bruising/bleeding • Gout 100% BCR:ABL fusion gene >95% of cases show Philadelphia chromosome
What are the phases of CML?
Chronic phase 20% blasts
What is the most sensitive method of assessing residual or relapsed CML?
Molecular RT-PCR followed by cytogenetic analysis then haematological response.
What is the first line treatment for CML?
Imatinib - BCR-ABL kinase inhibitor - first line therapy for CML in the chronic phase. If blast crisis (or resistant to all TK inhibitors) - consider allogeneic stem cell transplant
What tyrosine kinase inhibitors are available for CML treatment?
Imatinib - first line Dasatanib Nilotinib
What disease is associated with t(15;17)?
Acute promyelocytic leukaemia
Which chromosomes are commonly duplicated or deleted in AML?
Duplicated: 8 and/or 21 Loss or deletion: 5/5q and/or 7/7q
What risk factors are there for AML?
Unknown aetiology Familial or constitutional predisposition Irradiation Anticancer drugs Cigarette smoking Benzene exposure Down’s syndrome
What are the clinical features of AML?
- Bone marrow failure: Anaemia, Neutropenia, Thrombocytopenia - Local infiltration: Splenomegaly Hepatomegaly Gum infiltration (if monocytic) Lymphadenopathy (only occasionally) Skin, CNS or other sites
How is AML often diagnosed?
Peripheral blood film - circulating blasts - Auer rods
What are the principles of treatment for AML?
- Supportive care to correct the effects of inadequate bone marrow function (red cells, platelets, antibiotics) - Combination chemotherapy - Possibly targeted molecular therapy (strongly indicated for acute promyelocytic leukaemia) - Possibly immunotherapy - Possibly haemopoietic stem cell transplantation
What are the clinical features of ALL?
- Peak incidence in childhood - Bone marrow failure: Anaemia, Neutropenia, Thrombocytopenia - Local infiltration: Lymphadenopathy (± thymic enlargement) Splenomegaly Hepatomegaly Testes, CNS, kidneys or other sites Bone (causing pain)
What cytogenetic factors are good / bad prognostic indicators for ALL?
Hyperdiploidy - good prognosis Hypodiploidy - poor prognosis Philadelphia chromosome - poor prognosis
Which is more common, T- or B-lineage ALL?
B-lineage = 85% T-lineage = 15%
What are the general principles of treatment for ALL?
Specific therapy: - systemic chemotherapy (girls 2 yrs, boys 3 yrs) - CNS directed therapy Supportive care: - blood products - antibiotics - general medical care
What is the cause of an iron deficiency anaemia and what lab findings would there be?
Bleeding until proven otherwise - GI tract - Urinary tract Laboratory findings: - Reduced ferritin and transferrin saturation - Raised TIBC
What are the cancer-associated anaemias?
- Iron deficiency - Anaemia of inflammation - Leucoerythroblastic anaemia - Acquired haemolytic anaemia > Immune mediated > Fragmentation (microangiopathic) mediated Cancer may cause polycythaemia e.g. renal cell cancer
What is the pathogenesis of anaemia of inflammation and what would the laboratory findings be?
- Adequate iron stores but these are not released to the developing erythroid precursors - Iron is sequestered and retained in macrophages > Normo- or microcytic anaemia > Normal or high ferritin > Normal or low iron and TIBC
How and why is iron sequestered in macrophages in anaemia of inflammation?
Hepcidin binds iron as a defence mechanism against bacterial infection
What are the features of leucoerythroblastic anaemia?
- normocytic normochromic anaemia with numerous poikilocytes - normoblasts (nucleated red cells) - low-grade reticulocytosis (2-5%) - circulating immature white cells, generally myelocytes and promyelocytes - thrombocytopaenia is more common than thrombocythaemia
What are the causes of a leucoerythroblastic anaemia?
Bone marrow infiltration - Cancer: haemopoietic, non-haemopoietic - Severe infection: miliary TB, severe fungal infection - Myelofibrosis
What are the common lab features of haemolysis?
- anaemia (though may be compensated) - reticulocytosis - raised Bilirubin (unconjugated) - raised LDH - reduced haptoglobins
What test is used to distinguish between types of acquired haemolytic anaemia?
Direct Antiglobulin (DAT or Coombs test) Distinguishes between immune (+) or non-imune (-)
What are the causes of a non-immune acquired haemolytic anaemia?
Infection (malaria) Micro-angiopathic Paroxysmal nocturnal haemoglobinuria
What features are there on a blood film with microangiopathic haemolytic anaemia?
Red cell fragments Thrombocytopenia Schistocytes
What are the causes of a microangiopathic haemolytic anaemia?
Mechanical RBC destruction by fibrin mesh in vessels - haemolytic uraemic syndrome - thrombotic thrombocytopenic purpura - DIC (adenocarcinomas - low grade DIC) - pre-eclampsia
What is paroxysmal nocturnal haemoglobinuria?
Marchiafava-Micheli syndrome: a rare, acquired loss of protective surface GPI markers on RBCs leading to complement-induced intravascular haemolytic anaemia, red urine and thrombosis.
What are the causes of a neutrophilia?
- infection - corticosteroids - underlying neoplasia - tissue inflammation (e.g.colitis, pancreatitis) - myeloproliferative/ leukaemic disorders
Which infections characteristically do not produce a neutrophilia?
- brucella - typhoid - many viral infections
What are the causes of a reactive eosinophilia?
- parasitic infestation - allergic diseases e.g. asthma, rheumatoid, polyarteritis, pulmonary eosinophilia. - Underlying Neoplasms, esp. Hodgkin’s, T-cell NHL (reactive eosinophilia) - Drugs (reaction erythema mutiforme)
What are the causes of a monocytosis?
Rare but seen in certain chronic infections and primary haematological disorders: - TB, brucella, typhoid - Viral; CMV, varicella zoster - sarcoidosis - chronic myelomonocytic leukaemia (MDS)
An ESR >100 mm/hr is suggestive of what?
- Myeloma - Systemic autoimmune disease - Active TB
What is plasma cell myeloma?
A neoplastic proliferation of bone marrow plasma cells associated with a monoclonal protein in serum and/or urine = 1% of all cancers, average survival 3-5 years
What are the clinical features of myeloma?
- asymptomatic - Calcium high - Renal failure (plus amyloidosis and nephrotic syndrome) - Anaemia (and pancytopenia) - Bone pain, lytic lesions and fractures - hyperviscosity syndrome
What staging system is used for plasma cell myeloma?
Durie-Salmon, I-III Also International Staging System (ISS) based on beta-2-microglobulin
When is the ESR normal in a patient with myeloma?
When the myeloma produces only free light chains and no serum paraprotein or is non-secretory (3%)
What are the general aspects of treatment for myeloma?
• Hypercalcaemia: rehydration, intravenous infusion of a bisphosphonate, e.g. pamidronate. • Renal failure: correct dehydration, treat hypercalcaemia, dialysis if required • Anaemia: usually improves when the disease responds. Blood transfusions may be needed • Bone disease: local radiotherapy for pain, long-term bisphosphonate. • Infection: treat promptly and vigorously, influenza vaccine annually.
What are the specific treatment options for myeloma?
• Chemotherapy often combined with steroids. e.g. CTD (cyclophosphamide, thalidomide and dexamethasone), melphalan and prednisolone. • Bortezomib is used as second-line therapy and lenalidomide is used as third-line therapy. • Radiotherapy for local areas of disease, e.g. for pain or cord compression • High-dose therapy with stem cell support in younger patients (autologous or allogeneic)
What are myelodysplastic syndromes?
A heterogenous group of progressive disorders featuring ineffective proliferation and differentiation of abnormally maturing myeloid stem cells characterised by: - peripheral cytopenia - qualitative abnormalities of cell maturation - risk of AML transformation Typically seen in elderly, symptoms develop over weeks & months
What is Pelger-Huet anomaly?
Hyposegmented neutrophil - bilobed nucleus Pseudo-Pelger-Huet anomaly can be seen in MDS
What abnormal blood and bone marrow morphological features can be seen in MDS?
- Hypercellular bone marrow (normal < 5% blasts) - Defective cells > WBCs: Pseudo-Pelger-Huet anomaly and dysganulopoieses of neutrophils, myelokathexis > Dyserythropoiesis of RBCs e.g. ring sideroblasts > Dysplastic megakaryocytes e.g. micro-megakaryocytes
What is myelokathexis?
Retention of neutrophils in the bone marrow - often have hypersegmented nuclei
What stain is used to show ringed sideroblasts?
Prussian blue stain
How is prognosis worked out in MDS?
International prognostic scoring system, depends on BM blast %, karyotype, degree of cytopenia. Mortality ‘rule’: 1/3 die from infection, 1/3 bleeding and 1/3 acute leukaemia
What is the general treatment for MDS?
Supportive care: - Blood product support - Antimicrobial therapy - Growth factors (Epo, G-CSF) Biological Modifiers: - Immunosuppressive therapy - Azacytidine - Lenalidomide Chemotherapy: similar to AML Allogenic SCT
What are the blood and bone marrow features of refractory anaemia? (RA)
Blood: anaemia, no blasts BM: erythroid dysplasia with <5% blasts
What are the blood and bone marrow features of refractory anaemia with ringed sideroblasts? (RA +RS)
Blood: anaemia, no blasts BM: erythroid dysplasia with >15% ringed sideroblasts
What are the blood and bone marrow features of refractory cytopenia with multi-lineage dysplasia? (RCMD)
Blood: Bicytopenia or pancytopenia BM: Dysplasia in >10% cells in 2 or more cell lines
What are the blood and bone marrow features of refractory cytopenia with multi-lineage dysplasia and ringed sideroblasts? (RCMD +RS)
Blood: Bicytopenia or pancytopenia BM: Dysplasia in >10% cells in 2 or more cell lines and >15% ringed sideroblasts
What are the blood and bone marrow features of refractory anaemia with excess blasts-1? (RAEB I)
Blood: Cytopenias, <5% blasts, no Auer rods BM: Dysplasias, 5-9% blasts
What are the blood and bone marrow features of refractory anaemia with excess blasts-2? (RAEB II)
Blood: Cytopenias or 5-19% blasts or Auer rods BM: Dysplasias, 10-19% blasts or Auer rods
What are the blood and bone marrow features of MDS with 5q deletion?
Blood: Anaemia, normal or increased platelets BM: Megakaryocytes with hypolobulated nuclei and <5% blasts
What are the blood and bone marrow features of Myelodysplasia Syndrome Unclassified?
Blood: Complex - cytopenias, no blasts, no Auer rods BM: Complex - myeloid or megakaryocytic dysplasia, <5% blasts
Blood: anaemia, no blasts BM: erythroid dysplasia with <5% blasts
refractory anaemia (RA)
Blood: anaemia, no blasts BM: erythroid dysplasia with >15% ringed sideroblasts
refractory anaemia with ringed sideroblasts (RA +RS)
Blood: Bicytopenia or pancytopenia BM: Dysplasia in >10% cells in 2 or more cell lines
refractory cytopenia with multi-lineage dysplasia (RCMD)
Blood: Bicytopenia or pancytopenia BM: Dysplasia in >10% cells in 2 or more cell lines and >15% ringed sideroblasts
refractory cytopenia with multi-lineage dysplasia and ringed sideroblasts (RCMD +RS)
Blood: Cytopenias, <5% blasts, no Auer rods BM: Dysplasias, 5-9% blasts
refractory anaemia with excess blasts-1 (RAEB I)
Blood: Cytopenias or 5-19% blasts or Auer rods BM: Dysplasias, 10-19% blasts or Auer rods
refractory anaemia with excess blasts-2 (RAEB II)
Blood: Anaemia, normal or increased platelets BM: Megakaryocytes with hypolobulated nuclei and <5% blasts
MDS with 5q deletion
Blood: Complex - cytopenias, no blasts, no Auer rods BM: Complex - myeloid or megakaryocytic dysplasia, <5% blasts
Myelodysplasia Syndrome Unclassified
What inherited bone marrow failure syndromes are there?
Fanconi anaemia Dyskeratosis congenita Schwachman-Diamond syndrome Diamond-Blackfan syndrome
What are the acquired causes of aplastic anaemia?
Idiopathic (70%) Marrow infiltration: > Haematological (leukaemia, lymphoma, myelofibrosis) > Non-haematological (Solid tumours) Radiation Drugs Chemicals (benzene) Autoimmune (SLE) Infection (Parvovirus, Viral hepatitis)
What is the general management of aplastic anaemia?
> Supportive - transfusions, antibiotics, iron chelation > Drugs to promote marrow recovery - growth factors, oxymetholone > Immunosuppressants (idiopathic AA ~70%) > Stem cell transplant
What is aplastic anaemia and how is it classified?
Aplastic anaemia is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin. It is classified as non-severe, severe, or very severe on the basis of the degree of peripheral-blood pancytopenia
What is Fanconi anaemia?
Commonest form of inherited (AR or X) aplastic anaemia. Multiple genes responsible: normally contribute to genomic stability. Blood counts and marrow cellularity often normal until 5-10 yrs then pancytopenia develops, 10% progress to AML. Skeletal abnormalities (thumbs), renal malformations, microcephaly, hypogonadism, short stature, skin pigmentation.
What is dyskeratosis congenita?
X-linked disorder characterised by marrow failure, cancer predisposition and somatic abnormalities. Classic triad: skin pigmentation, nail dystrophy, oral leukoplakia
What is Schwachman-Diamond syndrome?
A rare AR congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction (neutropenia +/- others), skeletal abnormalities, and short stature.
What is Diamond-Blackfan Syndrome?
A congenital hypoplastic anaemia that usually presents in infancy with pure red-cell aplasia, normal WCC and platelets. Often other congenital anomalies.
What are the blood count changes in pregnancy?
Mild anaemia: RCM 120-130%, plasma volume 150% = net dilution Macrocytosis: MCV rises 5-10 fl Neutrophilia Thrombocytopenia: increased platelet size
What supplements are recommended during pregnancy?
Iron: 3x increase in requirements, need extra 800mg, RDA 30mg. No routine supplementation in UK Folate: additional 200mcg/day required WHO recommends 60mg Fe +400mcg folic acid daily during pregnancy
What possible effects are there of iron deficiency during pregnancy?
Preterm delivery Low birth weight, Possibly placental abruption, Increased peripartum blood loss,
What happens to the platelet count during pregnancy?
Decrease ~10% - can drop into thrombocytopenic range. Combination of haemodilution and increased platelet activation and clearance.
What are the causes of thrombocytopenia in pregnancy?
- Physiological - Pre-eclampsia - Immune thrombocytopenia (ITP) - Microangiopathic syndromes - All other causes: bone marrow failure, leukaemia, hypersplenism, DIC etc.
What is the relationship between pre-eclampsia and thrombocytopenia?
50% get thrombocytopenia: proportionate to severity. Probably due to increased activation and consumption. Usually remits following delivery.
What are the treatment options for immune thrombocytopenia in pregnancy?
When symptomatic or count <20 IV immunoglobulin Steroids etc. (Anti-D where Rh D +ve) Baby may be affected for up to 5 days post delivery (IVIG if low)
What are the main coagulation changes in pregnancy?
Increase in vWF (x3-5), fibrinogen (x2) and factors 7, 8, 10 50% decrease in protein S Also increase in plasminogen activator inhibitors 1+2 Net effect = procoagulant state
When are pregnant women at risk of thromboembolism?
From the very beginning of pregnancy until well into postpartum period
What factors increase the risk of thrombosis in pregnancy?
Bed rest Obesity Pre-eclampsia Operative delivery Previous thrombosis/thrombophilia Age Parity Multiple pregnancy IVF: ovarian hyperstimulation
How should pregnant women with VTE risk factors be managed?
- Prophylactic heparin +TED stockings > Either throughout pregnancy > Or in peri-post- partum period > Highest risk get adjusted dose LMWH heparin - Mobilise early - Maintain hydration
How should pregnant women with a VTE be managed?
- LMWH as for non-pregnant - Do not convert to warfarin (teratogenic) - After 1st trimester monitor anti Xa - Stop for labour or planned delivery, esp. for epidural
What is the definition of post partum haemorrhage and what are the major factors?
>500 ml blood loss - uterine atony - trauma haematological factors minor except - dilutional coagulopathy after resuscitation - DIC in abruption, amniotic fluid embolism etc
What conditions can precipitate decompensation to DIC in pregnancy?
Amniotic fluid embolism Abruptio placentae Retained dead fetus Pre-eclampsia (severe) Sepsis
What possible consequences of haemolytic anaemia are there?
Anaemia(+/-) - Erythroid hyperplasia with increased rate of RBC production and circulating reticulocytes - Increased folate demand - Susceptibility to effect of parvovirus B19 - Increased risk of gallstones, iron overload, osteoporosis
What are the main inherited causes of haemolytic anaemia?
- Membrane defects: hereditary spherocytosis, hereditary elliptocytosis - Enzyme defects: G6PD deficiency, pyruvate kinase deficiency - Haemoglobinopathies: sickle cell disease, thalassaemias
What is hereditary spherocytosis?
75% AD cause of extravascular haemolysis Spectrin or ankyrin deficiency Suseptible to parvovirus B19 and gallstones Diagnosed by blood film and osmotic fragility test Treat with splenectomy and folic acid
What is hereditary elliptocytosis?
AD spectrin mutations Broad range in severity
What does G6PD do?
Glucose-6-phosphate dehydrogenase catalyses first step in pentose phosphate pathway - generates NADPH required to maintain intracellular glutathione (GSH)
Where is G6PD deficiency prevalent?
In areas of malarial endemicity i.e.. African, Mediterranean and Middle Eastern populations
What are the clinical features of G6PD deficiency?
X-linked RBC enzyme deficiency Neonatal jaundice Acute haemolytic attacks with bite cells, Heinz bodies, dark urine Attacks precipitated by oxidants Chronic haemolytic anaemia (rare)
What agents may provoke haemolysis in G6PD deficiency?
- Anti-malarials: Primaquine - Antibiotics: Sulphonamides, Ciprofloxacin, Nitrofurantoin - Other drugs: Dapsone, Vitamin k, Aspirin - Fava beans - Mothballs
For which haemolytic anaemias is there substantial benefit from splenectomy?
PK deficiency and some other enzymopathies Hereditary spherocytosis Severe elliptocytosis/pyropoikilocytosis Thalassaemia syndromes Immune haemolytic anaemia
What are the indications/criteria for splenectomy as a treatment for haemolytic anaemia?
Transfusion dependence Growth delay Physical limitation Hb < 8g/dl Hypersplenism Age not < 3 yrs but before 10 yrs to maximise prepubertal growth
What is pyruvate kinase deficiency?
Majority autosomal recessive Severe neonatal jaundice, splenomegaly, haemolytic anaemia Most do not require treatment but may include transfusion or splenectomy
What is the incidence of lymphoma?
1 new case per 5000 each year Non-Hodgkin’s Lymphomas 80% Hodgkin Lymphoma 20%
What risk factors are there for lymphoma?
- Majority of case no identifiable risk factors - Constant antigenic stimulation - Infection(viral infection of cells) - Immunosupression (HIV and immunosuppresants)
What three inherent characteristics of the immune system make it susceptible to malignant change?
Rapid cell proliferation in immune response > Proliferating cells risk DNA replication error Dependent on apoptosis (90% of normal cells die!) > Apoptosis is “switched off” in germinal centre DNA molecules are cut and rejoined plus undergo deliberate point mutations > Potential for rejoining errors and new point mutations
What is the epidemiology of Hodgkin’s Lymphoma?
M>F 20-29 peak, second smaller peak >60 EBV-associated
What is the classical clinical presentation of Hodgkin’s Lymphoma?
- Asymmetrical painless lymphadenopathy =/- obstructive/mass effect symptoms +/- Constitutional (B) symptoms; fever, night sweats, weight loss, pruritis - Rarely alcohol induced pain - Pel-Ebstein fever: cyclical 1-2wk in minority - reed-sternberg cell
What subtypes of Hodgkin’s Lymphoma are there?
Nodular sclerosing 80% Mixed cellularity 17% Lymphocyte rich (rare) Lymphocyte depleted (rare, poor prog) Nodular Lymphocyte predominant 5% (not classical HL)
How is Hodgkin’s Lymphoma staged?
I - one group of nodes (includes spleen) II - >1 group of nodes same side of the diaphragm III - nodes above and below the diaphragm IV - extra nodal spread (liver, BM) Plus A if no constitutional symptoms, B if there are any Same staging system used for NHL too.
What is the commonest chemotherapy regime used to treat Hodgkin’s Lymphoma?
ABVD: Adriamycin, Bleomycin, Vinblastine, Dacarbazine (DITC) - given at 4-weekly intervals - preserves fertility - can cause pulmonary fibrosis and cardiomyopathy later
What is non-Hodgkin’s lymphoma?
All lymphomas other than Hodgkin’s, ~ 40 different subtypes Can be classified as; - mature or immature - high or low grade - B or T cell lineage
What are the clinical features of non-Hodgkin’s lymphoma?
Presentation varies significantly from subtype to subtype Similarities: painless lymphadenopathy, often involving multiple sites, constitutional symptoms, no pain after alcohol Staging as per Hodgkin’s
Examples of indolent, low grade non-Hodgkin’s lymphomas?
- Follicular lymphoma - Small lymphocytic/CLL - Mucosa associated (MALT)
Examples of aggressive, high grade non-Hodgkin’s lymphomas?
Aggressive - Diffuse Large B cell - Mantle cell Very aggressive - Burkitt Lymphoma - T or B cell Lymphoblastic leukaemia/lymphoma
What is the commonest subtype of non-Hodgkin’s lymphoma and what is a standard treatment regime?
Diffuse large B cell lymphoma 30-40% of all NHL 6-8 cycles of R-CHOP - Rituximab - Cyclophosphamide - Adriamycin (Hydroxydaunomycin) - Vincristine (Oncovin) - Prednisolone
How is prognosis calculated for diffuse large B cell lymphoma?
International Prognostic Index, a point for each of; - Age > 60y - serum LDH > normal - performance status 2-4 - stage III or IV - more than one extranodal site
What is the commonest indolent non-Hodgkin’s lymphoma and what is it associated with?
Follicular lymphoma ~35% of NHL Associated with t(14;18) which results in over-expression of bcl2 an anti-apoptosis protein Incurable, median survival 12-15 years
What is a MALT lymphoma?
A Marginal zone NHL involving extranodal lymphoid tissue due to chronic antigen stimulation; - Sjogrens syndrome ; parotid lymphoma - H.Pylori ; Gastric MALT lymphoma Can be pathogen dependent so antibiotics cure
What sections can the lymphoreticular system be classified into?
- Generative: Bone marrow and thymus - Reactive: Lymph nodes and spleen - Acquired: Extranodal lymphoid tissue
What is the definition of a lymphoma?
Neoplastic proliferation of lymphoid cells forming discrete tissue masses. Arise in and involve lymphoid tissues (including acquired lymphoid tissue).
What immunohistochemistry and translocations identify a folicular lymphoma?
- CD10, bcl-6 (GC) and bcl-2 - 14;18 translocation involving bcl-2 gene
What immunohistochemical profile does small lymphocytic lymphoma/CLL have?
CD5, CD23 +
What immunohistochemical profile and translocations does mantle cell lymphoma have?
- CD5, cyclin D1 over expression - 11;14 translocation
What are the features and associations of Burkitt’s lymphoma?
- Jaw or abdominal mass children/young adults - EBV associated - “starry-sky” appearance on histology - CD10, bcl6 (GC) - C-myc translocation (8:14, 2:8, 8;22)
Which has a better prognosis, germinal center or post-germinal center diffuse large B cell lymphoma?
Germinal center phenotype
What type of lymphoma is associated with HTLV-1?
Human T-lymphotropic virus type I causes adult T cell leukaemia and lymphoma
What translocation and protein expression is associated with anaplastic large cell lymphoma?
2;5 translocation Alk-1 protein expression CD30 +, T cell or null phenotype
What is the histological picture of Hodgkin’s lymphoma?
Sclerosis, mixed cell population in which scattered Reed-Sternberg and Hodgkin cells with eosinophils
What is chronic lymphocytic leukaemia and how does it normally present?
Progressive accumulation of malignant mature B lymphocytes in the blood, bone marrow and lymphoid tissues. Commonest leukaemia in western world. 70-80% incidental diagnosis, majority over 60. Bone marrow failure, recurrent sinopulomary infection (hypogamaglobulinaemia) and auto-immune phenomena (AIHA, ITP)
What peripheral blood and bone marrow findings are there in chronic lymphocytic leukaemia?
- Lymphocytosis between 5 and 300 x 10^9/L - Smear cells - Normocytic normochromic anaemia - Thrombocytopenia Bone marrow: lymphocytic replacement of normal marrow elements
What does immunophenotyping usually reveal in chronic lymphocytic leukaemia?
CD5 CD19 CD20 CD23 CD79a Surface IgM
What staging systems are used for CLL?
Rai staging (0-IV) or Binet staging (A-C)
What chromosomal abnormalities detected via FISH are prognostic for CLL?
Deletion of 13q - good prognosis, better than normal Trisomy 12 - good Deletion of 11q (ATM) - poor Deletion of 17p (TP53) - very poor
What carries a better prognostic value, mutated or unmutated IgH gene in CLL?
Unmutated worse prognosis
What is Richter’s syndrome?
Aka Richter’s transformation, is a complication of CLL and hairy cell leukaemia in which the leukaemia changes into a fast-growing diffuse large B cell lymphoma or Hodgkin’s lymphoma. Happens to 5-10% of CLL patients. Treat with CHOP-R
What are the indications for treatment of CLL?
- Progressive lymphocytosis >50% increase over 2 months or lymphocyte doubling time <6 months - Progressive marrow failure - Massive or progressive lymphadenopathy/splenomegaly - Systemic (B) symptoms - Autoimmune cytopenias (treat with steroids or Rituximab)
What antibodies are sometimes used as therapies for CLL and when?
Alemtuzemab/Campath: anti-CD52 > 1st line: 17p deleted patients > 2nd line: relapsed refractory patients > Toxicity - T-cell immunosuppression, CMV reactivation, fevers Rituximab: anti-CD20 > part of FCR standard 1st line
What oral chemotherapy drug is used in CLL?
Chlorambucil
What is FCR combination chemotherapy?
Fludarabine, cyclophosphamide and rituximab. Used to treat CLL
What are the causes of polycythaemia in the foetus or neonate?
- Twin-to-twin transfusion - Intrauterine hypoxia - Placental insufficiency
What are some unique causes of anaemia in the foetus or neonate?
- Twin-to-twin transfusion - Fetal-to-maternal transfusion - Parvovirus infection (virus not cleared by immature immune system) - Haemorrhage from the cord or placenta
When does the first mutation that leads to acute lymphobastic leukaemia usually occur?
in utero. Pre-leukaemic cells carrying this mutation can even spread from one twin to another
What type of leukaemia solely affects children with Down’s syndrome?
Transient myeloproliferative disease aka transient abnormal myelopoiesis (TAM) Affects 3–10% of infants, not typically serious, often resolves without treatment. 20–30% risk of developing acute lymphoblastic leukemia
Why is sickle cell anaemia not clinically apparent at birth?
Clinical features manifest as gamma chain production and haemoglobin F synthesis decrease and betaS and haemoglobin S production increase.
Why/how does sickle cell anaemia in the infant and child differ from the same disease in the adult?
> The distribution of red bone marrow (susceptible to infarction) differs - the hand/foot syndrome > The infant still has a functioning spleen - splenic sequestration can occur > The infant has an immature immune system and has not developed immunity to pneumococcus or parvovirus > The infant and child is growing rapidly and has a greater need for folic acid
What is splenic sequestration?
> Acute pooling of a large percentage of circulating red cells in the spleen, causes the spleen to enlarge and the Hb to fall acutely and death can occur. > Doesn’t happen in older children and adults because recurrent infarction has left the spleen small and fibrotic
Why is infection with parvovirus B19 more serious in children with sickle cell disease than in a normal child?
Parvovirus infection nearly completely prevents red blood cell production for 2-3 days. In normal individuals, this is of little consequence, but the shortened red cell life of sickle-cell patients results in an abrupt, life-threatening anaemia that may require transfusion.
Why does folic acid matter more in a child with sickle cell disease than in a normal child or an adult?
- Hyperplastic erythropoiesis requires folic acid - Growth spurts require folic acid - Red cell life span is shorter so anaemia can rapidly worsen
How do we manage sickle cell anaemia and other forms of sickle cell disease in the infant and child?
Accurate diagnosis Educate parents Vaccinate Prescribe folic acid and penicillin
Siblings with sickle cell anaemia present simultaneously with severe anaemia and a low reticulocyte count—likely diagnosis?
Parvovirus B19 infection
What is beta thalassaemia?
A condition resulting from reduced synthesis of beta globin chain and therefore haemoglobin A. It often becomes apparent in the first 3-6 months of life. Beta thalassaemia homozygosity causes a severe anaemia that, in the absence of blood transfusion, is fatal in the first few years if life.
What are the clinical effects of poorly treated thalassaemia major?
Anaemia > heart failure, growth retardation Erythropoietic drive > bone expansion, hepatomegaly, splenomegaly Iron overload > heart failure, gonadal failure
How do we manage an infant/child with beta thalassaemia major?
- Accurate diagnosis and family counselling - Blood transfusion - Once iron overload starts to occur, chelation therapy (desferioxamine, deferiprone) - Consideration of the child as an individual and as part of a family
What specific questions can be asked in the history of a child with suspected inherited defect of coagulation?
- Was there umbilical cord bleeding or bleeding when a heel-prick was done for Guthrie spot? - Was there haematoma formation after vitamin K injection of vaccinations? - Was there bleeding after circumcision?
A 1-year-old boy presents with joint bleeding, Hb, WBC and platelet count are normal, aPTT is prolonged, PT is normal, bleeding time normal—most likely diagnosis?
Haemophilia A (more common than B)
What is the treatment for autoimmune thrombocytopenia purpura?
- Observation (often remits spontaneously) - Corticosteroids - High dose intravenous immunoglobulin - Intravenous anti Rh D (if Rh-positive)
What cell marker is specific for haematopoetic stem cells?
CD34
What complications can occur after a stem cell transplant?
- Graft failure - Infections - Graft-versus-host disease (GVHD): allografting only - Relapse
What different phases of immune defects are there following an allogenic bone marrow transplant?
Aplastic phase (0-3 wks) GVHD phase (3 wks - 6 mths) Late phase (6 mths - yrs)
What pathogens is a patient particularly susceptible to in the aplastic phase following a bone marrow transplant?
Bacteria gram +/- Candida HSV RSV Influenza
What pathogens is a patient particularly susceptible to in the GVHD phase following a bone marrow transplant?
CMV VZV HHV-6 Aspergillus (10-15% deaths) Candida Adenovirus
What pathogens is a patient particularly susceptible to in the late phase following a bone marrow transplant?
Pneumococci H. influenzae VZV RSV
What are some of the treatment options for GVHD?
Corticosteroids Cyclosporin A FK506 Mycophenylate mofetil Monoclonal antibodies Photopheresis Total lymphoid irradiation
What treatments are used to prevent GVHD?
Methotrexate Corticosteroids Cyclosporin A CsA plus MTX FK506 T-cell depletion
What drugs are frequently used as a conditioning regimen prior to stem cell transplantation and what are the common side effects?
- melphalan, busulphan and cyclophosphamide - side effects include alopecia, gastro-intestinal problems of nausea, vomiting, diarrhoea and mucositis, cardiotoxicity, pulmonary fibrosis, haemorrhagic cystitis, liver toxicity known as veno-occlusive disease and gonadal failure.
What therapy is most commonly used as a conditioning regimen prior to allogenic-SCT and what common side effects are there?
- total body irradiation (TBI) - side effects include gastro-intestinal disturbance, pulmonary damage, pancreatitis, parotitis, gonadal failure and veno-occlusive disease
How is acute GCHD defined?
Occurs within 100 days of SCT and usually affects the skin, gastro-intestinal tract and liver Fatal in 10% of recipients of sibling grafts and in 20% of recipients of unrelated volunteer cells
What are the transplant related mortality figures for stem cell transplants?
Risk of death due to the transplant as opposed to the disease: ~5% in auto-SCT, 20-30% in sibling allo-SCT 30-50% in unrelated allo-SCT.
What are the normal ranges for WBC, Hb, MCV, and platelet count in adults?
WBC Hb MCV Platelets
Acanthyocytes
Spiculated RBCs Hyposplenism, liver disease, Abetalipoproteinaemia
Basophilic RBC stippling
Accelerated erythropoiesis or defective Hb synthesis -> small rRNA dots on periphery. Lead poisoning, megaloblastic anaemia, MDS, liver disease, Hbopathy
Burr cells
aka echinocyte (irregularly shaped) uraemia, GI bleed, stomach Ca
Heinz bodies
Inclusions in RBCs G6PD deficiency Also chronic liver disease Associated with Bite cells as liver takes a bite out of RBC to remove Heinz body
Howell-Jolly body
Basophilic nuclear remnants Hyposplenism (or post-splenectomy). Also megaloblastic anaemia, hereditary spherocytosis.
Leucoerythyoblastic anaemia
nucleated RBCs and primitive WBCs in peripheral blood Due to marrow infiltration - myelofibrosis, malignancy
Pelget Huet cells
Hyposegmented PMNs Congenital - lamin B receptor mutation Acquired - MDS - myelogenous leukaemia
Right shift
Hypersegmented PMNs (>5) Megaloblastic anaemia, uraemia, liver disease
Rouleaux
Red cells stack together due to hyperviscosity. Myeloma, paraproteinaemia, chronic inflammation.
Schistocytes
Fragmented RBCs MAHA - DIC, TTP, HUS Pre-eclampsia
Stomatocytes
Rod like RBCs with central pallor. ‘Smiling face’ or ‘Fish mouth’ appearance. Hereditary stomatocytosis High alcohol intake + liver disease
Target cells
aka codocytes Bull’s eye appearance in central pallor. 3H’s - hepatic pathology - hyposplenism - Hbopathies - thalassemia (IDA)
Pencil cells
IDA
Causes of microcytic anaemia
FAST Fe-deficiency ACD Sideroblastic anaemia Thalassemia
Causes of macrocytic anaemia
Megaloblastic: - B12 or folate - cytotoxic anti-folate drugs: phenytoin Non-megaloblastic: - Alcohol excess or liver disease - Reticulocytosis - eg. 2nd to haemolysis - Hypothyroidism - Pregnancy Other haem disorder: - MDS - myeloma - myeloproliferative disorders
Plummer-Vinson syndrome triad
IDA + dysphagia + oesophageal webs
Treatment for sideroblastic anaemia
Remove underlying cause (MDS, chemo, irradiation, alcohol excess, lead excess, anti-TB drugs, myeloproliferative) Pyridoxine (vitamin B6) - promotes RBC production, reducing ineffective erythropoiesis.
Iron, TIBC and Ferritin in: IDA
Iron - Down TIBC - Up Ferritin - Down
Iron, TIBC and Ferritin in: ACD
Iron - Down TIBC - Down Ferritin - Up (acute phase protein)
Iron, TIBC and Ferritin in: Sideroblastic anaemia
Iron - Up TIBC - N Ferritin - Up
Pernicious anaemia serology
Parietal cell autoAb - 90% IF autoAb - 50%
Hereditary spherocytosis inheritance pattern
AutoD 25% recessive or de novo
Hereditary spherocytosis mutations
Vertical cytoskeleton Band 3 - Protein 4.2 - Ankyrin - B spectrin
Hereditary spherocytosis tests
Osmotic fragility - increased lysis in hypotonic solution DAT -ve Spherocytes on blood film
Hereditary elliptocytosis mutations
Horizontal cytoskeleton a-spectrin - B-spectrin - protein 4.1 AutoD (except hereditary pyropoikilocytosis = autoR)
G6PD inheritance
X linked
Management of acute haemolysis
Folate Avoid precipitant Transfusion Immunisation vs BBVs ?cholecystectomy Splenectomy. - prophylaxis vs encapsulated bacteria.
Precipitants of oxidative stress if G6PDD
Drugs - antimalarials (primaquine), antibiotics (sulphonamides) Favism (aflatoxin) Acute stressors Moth balls Acute infection
Pyruvate kinase inheritance
AutoR
Does splenic sequestration occur more in adults or children with sickle cell disease
Children. By adulthood it becomes atrophic.
Diagnosis of Sickle cell disease
Blood film - sickle cells, target cells, boat cells, Howell-Jolly bodies Sickle solubility test Hb electrophoresis Guthrie test at birth
Types of B thalassemia
Absent (B0) or Reduced (B-) B chains, excess a chains B-thalassemia minor - heterozygous B-/B; B0/B B-thalassemia intermedia - B-/B-; B0/B B-thalassemia major - homozygous B0/B0 (infant presentation)
Type of mutation in B thalassemia
point mutation
Type of mutation in a thalassemia
deletion
Types of A thalassemia
Reduced a chain (4 genes), excess B chains a-thalassemia trait - 1/2 deleted: asymptomatic HbH disease - 3 deleted: moderate anaemia + splenomegaly Hydrops fetalis - 4 deleted: lethal
Signs of B thalassemia
Anaemia - severity increases with number of mutations Skull Xray - skull bossing, maxillary hypertrophy, hairs on end skull Hepatosplenomegaly
Donath-Landsteiner antibodies
Paroxysmal cold haemoglobinuria Rare AIHA. Usually affects children in acute setting after an infection. Sudden haemoglobinuria and jaundice after exposure to cold temperatures. Donath-Landsteiner Abs = IgG autoAb vs RBC surface Ags. Increasing intravascular haemolysis at low temperatures.
Type of Ig in Warm AIHA
IgG WarminG
Type of Ig in Cold AIHA
IgM I’M cold
Causes of warm AIHA
Idiopathic - mainly Lymphoma CLL SLE methyldopa
Causes of cold agglutinin disease
Primary idiopathic Lymphoma Infections - EBV, mycoplasma
Ham’s test
Paroxysmal nocturnal haemoglobinuria A pig a night with red urine. Test - in vitro acid-induced lysis
TTP pentad of symptoms
1) MAHA 2) Fever 3) Renal impairment 4) Neuro abnormalities 5) Thrombocytopenia
Vascular defects: causes of
Congenital - Osler-Weber-Rendu syndrome (HHT) - CTD: Ehlers-Danlos, pseudoxanthoma elasticum Acquired - senile purpura - scurvy - infection - steroids
Haemophilia A inheritance
X linked recessive fVIII deficiency. (intrinsic pathway - APTT prolonged)
Haemophilia A management
avoid NSAIDs and IM injections Desmopressin - increases vWF release which is fVIII carrier fVIII replacement
Treatment of ITP
>50,000 platelets - none 20-50,000 platelets + bleeding - steroids + IVIg <20,000 + bleeding - steroids + IVIg + admission
Vitamin K deficiency causes
Warfarin Malabsorption/malnutrition Abx therapy - alters gut flora that produces vitamin K Biliary obstruction
Antidote to heparine
Protamine sulphate
Heparin-induced thrombocytopenia
Ab vs. heparin bound to platelets. Assoc. w/ older heparins. Treat w/ fondaparinux.
Treatment of INR 5-8, no bleed.
Withold few doses, reduce maintenance. Restart when INR <5
Treatment of INR 5-8, minor bleed.
Stop warfarin. Slow vitamin K po. Restart when INR<5
Treatment on INR >8
Stop warfarin Vitamin K po/IV If major bleed - PCC, FFP
% Blasts in acute leukaemia
Blasts >20%
Gum hypertrophy differential
Acute leukaemia Drugs - cyclosporin, phenytoin, amlodipine
Auer rods
AML
ALL chemo regimen
Remission induction - High dose agents often given steroids Consolidation - High dose multi drug chemo CNS treatment - intrathecal chemo Maintenance - 2y in girls, 3y in boys (increased risks of testicular recurrence)
PML mutation
t(15;17): PML-RARA (retinoic acid receptor)
PML (M3 AML) treatment
All-trans retinoid acid (or arsenic) - neurotoxicity risk
3 Phases of CML
Chronic Phase - 10% blasts - nearly 80% progress to this phase - manifestations such as splenomegaly Blast Phase - >20% blasts - resembles acute leukaemia
CML treatment
Oral hydroxyurea/interferon - suppresses WCC Imatinib TKi - >95% 5 year survival Dasatinib/nilotinib for resistance (BMT, allogeneic SCT)
Evan’s syndrome
AIHA + ITP assoc. w/ CLL
Richter’s transformation
Progression of CLL to lymphoma (DLBC) Occurs in 3%
Smear cells
CLL
Reed-Sternberg cell
Hodgkin’s lymphoma Owl eyed cells with that is bi/multinucleate.
Ann Arbor staging for lymphomas
Stage 1 - one LN region (can include spleen) Stage 2 - 2 or more LN regions, same side of diaphragm Stage 3 - 2 or more LN regions, opposite sides of diaphragm Stage 4 - extranodal sites (liver, BM) A: No constitutional symptoms B: Constitutional symptoms
Hodgkin’s lymphoma Chemo combination
ABVD Adriamycin Bleomycin Vinblastine Dacarbazine
Pel-Ebstein fever
Hodgkin’s lymphoma cyclical 1-2 week fever. Rarely seen.
Pain in lymph nodes after drinking alcohol.
Hodgkin’s lymphoma
Alemtuzumab
anti-CD52 (aka CamPath) Use in CLL and T cell lymphomas Also approved for use in MS.
3 types of Burkitt’s lymphoma
1) Endemic - EBV-associated - Equatorial Africa. P. falciparum wears down immune system vs EBV. - Jaw involvement 2) Sporadic - EBV-associated - Out of Africa 3) Immunodeficiency - Non-EBV associated - HIV/post-transplant pts.
Starry sky appearance on histology
Burkitt’s lyphoma
Translocation in Burkitt’s
t(8; 14) - c-myc overexpression
Translocation in Mantle cell lymphoma
t(11; 14) deregulation - cyclin D1 deregulation. Aggressive lymphoma
Translocation in Follicular lyphoma
t(14;18)
Chronic Ag stimulants leading to MALT
H.pylori -> gastric MALT Sjogren’s -> parotid lymphoma
Ig in Multiple Myeloma
IgG
5 solid tumours that metastasise to bone
Lytic 1) breast 2) thyroid 3) renal 4) lungs Sclerotic 5) Prostate
Clinical, Plasma cell and Monoprotein for Multiple myeloma
CRAB >10% plasma cells >30g/L monoprotein
Clinical, Plasma cell and Monoprotein for MGUS
no CRAB <30g/L monoclonal paraprotein
Clinical, Plasma cell and Monoprotein for Smouldering myeloma
no CRAB >10% plasma cells >30g/L monoprotein
Ig in Waldenstrom’s
IgM
Lymphoplasmacytoid cell
Waldenstrom’s Macroglobinaemia
Apple green birefringence on congo red stain
Amyloidosis
Fanconi anaemia
AutoR Paediatric: 5-10y Pancytopenia. Skeletal abnormalities (radii + thumbs). Renal malformation. Microopthalmia. Short. Skin pigmentation.
Dyskeratosis congenita
X linked Telomere shortening TRIAD: skin pigmentation + nail dystrophy + oral leukoplakia. Also BM failure
Schwachmann-Diamond syndrome
AutoR PRoPoSe - Pancreastic insufficiency - Recurrent infection - Pancytopenia - Skeletal abnormalities Neutrophilia
Diamond-Blackfan syndrome
Pure RED cell aplasia. Neonatal/infant presentation.
AutoR Paediatric: 5-10y Pancytopenia. Skeletal abnormalities (radii + thumbs). Renal malformation. Microopthalmia. Short. Skin pigmentation.
Fanconi anaemia
X linked Telomere shortening TRIAD: skin pigmentation + nail dystrophy + oral leukoplakia. Also BM failure
Dyskeratosis congenita
AutoR PRoPoSe - Pancreastic insufficiency - Recurrent infection - Pancytopenia - Skeletal abnormalities Neutrophilia
Schwachmann-Diamond syndrome
Mutation in polycythemia rubra vera
JAK2 (V617F) - point mutation. Activation of STAT pathway leading to cellular proliferation.
Aquagenic pruritus + peptic ulcers + gout + erthromelagia
Polycythemia rubra vera Aquagenic pruritus - contact with hot water -> histamine release Histamine -> peptic ulcer Erythromelagia (red, painful extremities) and gout due to hyperviscosity.
Treatment for PRV
Venesection - keep haematocrit <45% Hydroxycarbamide - cytoreductive therapy for maintenance. Aspirin - reduce thrombosis risk
Tear-drop poikilocytes
Myelofibrosis aka dacrocytes
Dry tap BM trephine
myelofibrosis. Fibrotic replacement of BM. High reticulin.
Anagrelide treatment
Used in essential thrombocythemia. Reduces formation of plts from megakarocytes. Used in conjunction with aspirin (anti-thrombotic) and hydroxycarbamide (cytoreductive).
Ig in haemolytic disease of the newborn
IgG. Only it can cross the placenta.
