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302: Scientific Bases of Medicine > Haematology > Flashcards

Haematology Flashcards

1
Q

What is JAK-STAT signalling

A

Janus kinase/signal transducers and activators of transcription

  • mediates cellular responses to cytokines i.e IL-6 and growth factors EGF
  • mutations in JAK2 in various cells can cause various presentations of AML
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2
Q

What does the JAK2 mutation lead to in Red cell precursors?

A
  • Polycythaemia Rubra vera,
  • in 30% of cases, this leads to Primary myelofibrosis
  • 5% of cases this s indicative of AML
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3
Q

What does the JAK2 mutation lead to in Megakarycocytes?

A
  • Essential thrombocythaemia
  • in 10-20% of cases associated with Primary myelofibrosis
  • also a mutation in reactive fibrosis
  • in 10% of primary myelofibrosis indicative of AML
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4
Q

What is chronic myeloid leukaemia and what is its genetic origin?

A
  • when there are too many white cells
  • mutation in chromosome 22 - Philadelphia chromosome
  • translocation between chromosome 9 and 22 t(9;22) by FISH analysis
  • BCR-ABL(tyrosine kinase) detection by PCR
    • fusion of these two genes causes CML
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5
Q

How does the genetic mutation for CML work?

A
  • mutation in Chromosome 22 generates a chimeric oncogene in which BCR and c-ABL genes are fused
  • BCR/ABL has elevated tyrosine kinase activity
  • Tyrosine kinase is responsible for maintaining proliferation, inhibiting differentiation and conferring resistance to cell death
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6
Q

What treatment can best be used against CML and what is its action?

A
  • Imatinib (1st gen) (Gleevec)
    • a tyrosine kinase inhibitor
      • a kinase is an enzyme that promotes cell growth,
    • imatinib binds to its active site, antagonist to GRB-2, SHC etc.
  • Dasatinib (2nd gen tyrosine kinase inhibitor)
    • the counts are normalised after 3 weeks
    • remains on treatment with 3monthly BCR-ABL monitoring by quantitative PCR
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7
Q

What is leukaemia?

A
  • it is an uncontrolled proliferation of primitive cells in the bone marrow
  • it can cause, bleeding, anaemia and infections
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8
Q

What are the clinical features of leukaemia

A
  • Anaemia
  • Infections
  • DIC
  • Ulcers
  • Infiltration
  • Bruising
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9
Q

How is leukaemia diagnosed?

A
  • Bone marrow biopsy
  • cytogenetics
  • morphology of blood samples
  • Immunophenotyping
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10
Q

How is AML treated?

A
  • Chemotherapy
  • Supportive therapy: antibiotics, antifungals, transfusions of blood and platelets. Indwelling Hickman line
  • Stem cell transplantation: autograft, Allograft, sibling or matched donor
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11
Q

What is Neutropenic Sepsis?

A
  • a complication of neutropenia (low neutrophil counts
  • temp. > 38 degrees
  • symptoms and signs of sepsis
  • absolute neutrophil count of 0.5x 109
  • gram -ve bacteria are most dangerous e.g Pseudomonas
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12
Q

Go through the 1st 2nd and 3rd line treatment for neutropenic sepsis.

A
  1. Tazocin (Piperacillin/Tazobactam) +/- Gentamicin
  2. Switch to Meropenem +/- Teicoplanin (for Gram +ve)
  3. add anti-fungal e.g Ambisome (amphotericin)
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13
Q

What is Pneumocystis pneumonia?

A
  • lung infection, acquired by those who are immunosuppressed
  • caused by yeast-like fungus Pneumocystis jirovecii
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14
Q

What is graft-vs-host disease?

A
  • an immune condition that occurs after transplant procedures, immune cells of donor attacks host’s recipient cells
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15
Q

What is the standard constitution of full blood cells ?

A
  • 1/3 of the cell needs to be white to be normal
  • largely a uniform size between them all
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16
Q

What causes a high WBC count? Leukocytosis

A
  • infection
  • post op, or traumatic event
  • leukaemia
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17
Q

What causes a low WBC count? Leukopenia

A
  • Chemotherapy: neutropenia —> sepsis
  • Drugs
  • Severe infection
  • Immune disorders
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18
Q

What are neutrophils?

A
  • common phagocytic cells
  • increase with bacterial infection
  • most common
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19
Q

How do Lymphocytes appear/present in infections ?

A
  • increase during viral infection
  • can appear reactive or atypical
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20
Q

How do children’s WBC count differ from and adults?

A
  • children have a reversed differential - higher lymphocytes than neutrophils: immune system is still developing up to around age 10
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21
Q

What is the Erythrocyte Sedimentation Rate ?

A
  • how long does it take for the RBC take to sediment - an increase in acute phase proteins causes faster sedimentation - non-specific
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22
Q

How do Babies blood counts present differently?

A
  • Higher Hb
  • Higher WBC and Hct/PCV
  • Higher WBC
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23
Q

How do children’s blood count present differently?

A
  • lower Hb - reversed differential
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24
Q

How does ethnicity affect the blood count results?

A

Africans/ Afro caribbeans - lower neutrophil - slightly lower platelet counts

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25
Q

What are some causes of Normocytic Anaemias?

A
  • Blood loss
  • Chronic diseases - cytokines decrease effect of EPO on red cells
  • Renal failure, decreased EPO production
  • other acute reasons ( usually in 20’s)
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26
Q

What are some causes of Microcytic Anaemia?

A
  • Iron deficiency - Thalassaemia
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27
Q

What are some causes non-megaloblastic Macrocytic anaemias?

A
  • Large RBC with no DNA involvement
  • Alcohol
  • Liver Disease
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28
Q

What are some causes of megaloblastic macrocytic anaemia?

A
  • Large RBC with DNA affected
  • B12 & Folate deficiency
  • Chemotherapy
  • AZT ( HIV treatment)
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29
Q

What are the clinical symptoms of B12 and folate deficiency?

A
  • weight loss
  • fatigue
  • Glossitis (swollen tongue)
  • jaundice
  • dementia
  • paraesthesia
  • neuropathy
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30
Q

Define Poikilocytosis.

A

variation in RBC shape

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31
Q

Define Anisocytosis.

A

Variation in RBC size

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32
Q

Define Dimorphic RBC.

A
  • responding anaemia or post-transfusion, where there is a variety of different RBCs
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33
Q

What is Thrombocytopenia and what are its two presenting forms?

A

Low platelets due to

> Decreased production

  • Congenital (rare)
  • Acquired: BM damage due to drugs, Alchohol, Blood malignancy

> Increased destruction

  • Congenital ( from maternal antibodies)
  • Aquired: ITP (idiopathic), Infections, drug-induced
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34
Q

Describe the morphology and occurrence of left-shifted immature neutrophils.

A
  • during infections, Myeloproliferative disorders (MPD), Leukemias
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35
Q

Describe the morphology and occurrence of Toxic granulation

A
  • Acute infection
  • dark granulated cytoplasm
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36
Q

Describe the morphology and occurrence of Mylocytes v. Immature

A
  • Severe Infections
  • Leukemias
  • BM
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37
Q

Describe the morphology of hypersegmented (right-shifted) neutrophils

A
  • Megaloblastic conditions
  • B12 & Folic acid deficiency
  • multilobular in appearance
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38
Q

What is Lymphocytosis and when would it present?

A
  • higher than normal lymphocyte levels in an FBC or in a blood film

Presents in

  • Viral infections: measles, chickenpox, IM
  • Some bacterial infections
  • Stress-related: Post MI
  • Vigorous exercise
  • smoking
  • LPD’s i.e CLL (chronic lymphatic leukaemia)
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39
Q

What is Lymphocytopenia and when does it present?

A
  • Lower than normal lymphocyte levels in an FBC or a blood film

Presents

  • Acute stress: surgery/ trauma
  • Acute/ Chronic Renal Failure
  • Carcinoma
  • AIDS/HIV
  • Cytotoxic therapy
  • Some inherited: SCID (severe combined immunodeficiency )
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40
Q

What is neutrophilia and when does it present?

A
  • higher than normal neutrophil levels in an FBC or blood film

Presents

  • Acute/ chronic bacterial infections
  • a few viral, fungal and artistic infections
  • Tissue damage
  • Inflammation (UC, RA?)
  • Malignant dx
  • MPD and leukaemias
  • Cytokines (Granulocyte-Colony Stimulating Factor)
  • Drugs: Corticosteroids, lithium
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41
Q

What is neutropenia and when does it present?

A
  • lower than normal neutrophil levels in an FBC or blood film

Presents

  • Bacterial infection and some viral, fungal parasitic infections
  • Anti-cancer drugs
  • Irradiation
  • BM replacement with Ca
  • Aplastic anaemia
  • Autoimmune neutropenia: associated with dx
  • Inherited (rare): Chediak Higashi syndrome (child hood)
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42
Q

What are the five Broad Causes of Anaemia

A
  • Bleeding- main one - Deficiency, iron, B12, folic acid - Haemolytic - Bone Marrow Dysfunction/ infiltration - poor O2 utilisation/loading
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43
Q

What is the Hb normal range for children?

A

110-160 g/L

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44
Q

What is the Hb normal range for Women?

A

115-165 g/L

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45
Q

What is the Hb normal range for pregnant women?

A

110-160 g/L

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46
Q

What is the Hb normal range for men?

A

130-180 g/L

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47
Q

What are four Clinical signs of Anaemia ?

A
  • Pallor, pale conjunctiva - Tachypnoea - Tachycardia - Koilonychia
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48
Q

What are the four diagnostic tests for Iron?

A
  • Serum Ferritin - Serum Iron - Serum Transferrin - % Transferrin Saturation
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49
Q

How many haemoglobin genes are there?

A
  • 4 alpha haemoglobin genes - 2 beta haemoglobin genes
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50
Q

Symptoms of Anaemia

A
  • shortness of breath - headaches - tiredness - palpitations - pale conjunctiva - tachypnoea
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51
Q

Where are RBCs made ?

A
  • sternum - vertebrae - pelvis - femur
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52
Q

Requirements of Iron per day

A

1-2mg/day

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53
Q

Requirements of Vitamin B12

A

1-3mcg

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54
Q

Requirements of Folic Acid per day

A

100 mcg/day - 4 times that amount in women

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55
Q

What are the four main diagnostic Iron tests

A
  • Serum Ferritin - Serum Iron, labile - Serum Transferrin - % Transferrin saturation
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56
Q

What is the function of transferrin?

A
  • carrier molecule of iron - increases if iron is deficient - similar to total iron binding capacity
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57
Q

What is the use of function of ferritin

A
  • storage form of iron
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58
Q

What are the main causes of iron deficiency in the uk

A
  • bleeding via menstruation, occult GI malignancy - GI peptic ulcer - increased requirements
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59
Q

Function of EPO

A

Erythropoietin - production of new RBC - levels are often higher when patient is anaemic

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60
Q

What do Microcytic RBC indicate about the type of anaemia ?

A
  • Iron deficiency - Inherited disorders of haemoglobin
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61
Q

What do Macrocytic RBC indicate about the type of anaemia ?

A
  • B12 or folate deficient- production of nucleotides - myelodysplasia
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62
Q

What do Normocytic RBC indicate about the type of anaemia ?

A
  • aneamia of a chronic disease - acute haemorrhage Renal failure
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63
Q

What are reticulocytes, and how are they useful in blood analysis ?

A
  • new RBC, still have their RNA within them- flow cytometry - indicates the rate of RBC production by the marrow -
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64
Q

What is a reticulocyte?

A

it is an erythrocyte (RBC) precursor, still contains mRNA

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65
Q

What is the diameter of a red cell?

A

7-8 microns

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66
Q

What would be seen under a blood film of megaloblastic bone marrow?

A
  • chromatin is out of phase with DNA replication - very large megaloblasts
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67
Q

What blood results would suggest acquired microcytic anaemia?

A
  • low ferritin - low Fe - high transferrin - low transferrin saturation
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68
Q

What blood results would suggest inherited microcytic anaemia?

A
  • normal ferritin - abnormal Hb electrophoresis/HPLC
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69
Q

What are some causes of B12 autoimmune pernicious anaemia?

A
  • being vegan
  • gastric surgery
  • Crohn’s disease
  • lack of intrinsic factor –> leading to inadequate absorption
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70
Q

What are some causes of folate deficiency?

A
  • lack of folate in the diet - malabsorption (coeliac) - excess utilisation
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71
Q

What biochemical and pathology markers would indicate anaemia of a chronic disease?

A
  • normocytic cells - normal/ raised ferritin, normal/low transferrin - raised hepcidin and inflammatory proteins
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72
Q

What are causes of anaemia of chronic disease?

A
  • Iron trapped inside macrophages - cancer - inflammation - rheumatoid arthritis - renal failure
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73
Q

What would indicate normocytic anaemia due to renal failure?

A
  • lack of erythropoietin (low serum EPO ) - red cell horomone produced by kidney
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74
Q

How could normocytic anemia due to renal failure be treated?

A
  • with weekly sc injections of recombinant EPO
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75
Q

Describe inherited RBC membrane problems? - treatment

A
  • spherical red cells, not biconcave - e.g hereditary spherocytosis, hereditary elliptocytosis - a splenectomy can help
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76
Q

How is haemoglobin analysed?

A
  • Hb electrophoresis
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77
Q

What would be seen in a blood tests to indicate beta-thalassaemia?

A
  • microcytic hypochromic blood film - low MCV
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78
Q

Give examples of acquired immune red cell problems?

A
  • Autoimmune: warm IgG vs. cold IgM
  • Alloimmune: red cell transfusion reaction
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79
Q

Give examples of acquired non-immune (red cell fragments) red cell problems?

A
  • mechanical heart valves can destroy RBC
  • DIC, very sick patients: spesis metastatic cancer
  • MAHA: microangiopathic haemolytic anaemia
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80
Q

How can haemolysis be diagnosed?

A
  • high bilirubin levels
  • patients are jaundiced, may need to check nails and mucous membranes
  • blood film to check for spherocytes
  • high LDH levels
  • high reticulocyte count
  • low haptoglobins
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81
Q

What is haemophilia C

A
  • It is a bleeding condition due to a factor XI deficiency (the Intrinsic pathway)
  • it is commonly found in Jewish populations
  • and is Autosomal recessive
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82
Q

What is deep vein thrombosis?

A
  • when there is a clot in the deep vein of your legs,
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83
Q

What are the compounds secreted by thrombocytes when they are activated, and what do each of them cause?

A
  • ADP: activate platelets further
  • Serotonin: vasoconstriction
  • Thromboxane A2 (TxA2): vasoconstriction and aggregation
  • Calcium and presence of phospholipids: allows coagulation reactions
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84
Q

What are the compounds that initiate the internal and external coagulation cascades?

A
  • Extrinsic (tissue factor) pathway: involves tissue factor
  • Intrinsic (contact activation) pathway: thrombin, factor XIIa, a nucleation site, glass in a laboratory
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85
Q

What are the enzymes directly responsible for transforming fibrinogen to a clot

A
  • Prothrombin –> Thrombin: converts fibrinogen into fibrin
  • Factor XIIIa, cross-links it into a clot
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86
Q

What are the enzymes that are only part of the intrinsic (contact activation) coagulation pathway?

A
  • factor XI
  • factotor XII
  • factor IXa
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87
Q

What is the role of vitamin K in haemostasis?

A
  • necessary for the production of Ca-dependent proteases in the liver - i.e factor II, VII, IX, X (extrinsic tissue factor pathway)
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88
Q

What physiological state might lead a patient to develop a vitamin K deficiency?

A
  • lack of bile salts, if exogenous lipids were not being properly digested
  • Warfarin toxicity: prevents recycling of vitK
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89
Q

What is the aetiology of haemophilia A

A
  • a mutation in the factor VIII gene
  • X-linked recessive disease
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90
Q

What is the aetiology of haemophilia B?

A
  • X-linked recessive - a mutation in the factor IX gene
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91
Q

GIve an overview of how the body responds to an injury in a blood vessel

A
  • formation of a haemostatic plug physically protects and coats the surface of the injury initially: platelet adhesion, activation and aggregation - coagulation - vasoconstriction: decreases local blood flow
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92
Q

Explain the role of platelets in haemostasis?

A
  • aggregate at the site of injury, over fibrinogen, forming a haemostatic plug - contribute to vasoconstriction by releasing vasoconstrictor compounds, serotonin TxA2 - secrete/provide compounds that encourage coagulation, including the phospholipids
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93
Q

List 4 differentiated cell types that develop from the lymphoid precursor cells

A
  • B cells
  • T helper cells
  • NK cells
  • Plasma cells
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94
Q

List 4 differentiated cell types that develop from the myeloid precursor cells

A
  • eosinophils - monocytes/macrophages - neutrophils - RBC
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95
Q

Explain platelet activation

A
  • change dramatically in response from ADP or exposed collagen
  • more spindly shape
  • metabolism goes up
  • exocytose many granules
  • their membranes gain proteins (GP2b/3a)
  • many reactions of the clotting cascade can only take place on the membrane of an activated platelet
  • platelet aggregation can only occur on the surface of already activated platelets
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96
Q

What prevents blood from clotting spontaneously and inappropriately?

A
  • Fibrinolysis.
  • Anticoagulation factors.
  • Maintaining platelets in the inactivated state.
  • Keeping coagulation initiation signals sequestered (eg Factor III/Tissue factor behind the endothelium).
  • Rapid blood flow
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97
Q

What is Factor X and Xa? What are its roles?

A
  • Factor Xa is an activated enzyme. It catalyses the conversion of prothrombin (factor II) to thrombin. Its activity is substantially increased when it combines with active factor five.
  • Factor X is the inactive form of Factor Xa
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98
Q

What is Xase?

A
  • converts Factor X to Xa
  • Intrinsic Xase is Factor IX + factor VIII,
  • Extrinsic Xase is Factor VII + tissue factor
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99
Q

What are three types of bleeding disorders?

A
  • Vascular disorders
  • Platelet disorders: thrombocytopenia, defective function
  • defective coagulation: inherited v acquired
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100
Q

where does the blood go

What are the different patterns of bleeding?

A

Vascular and platelet bleed cause:

  • bleeding into mucous membranes and skin

Coagulation disorders cause:

  • bleeding into joints and soft tissue
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101
Q

Give examples of Inherited and acquired vascular bleeding

A

Inherited:

  • Hereditary haemorrhagic telangiectasia (Oslo-Weber-Render syndrome), abnormal blood vessel formation, autosomal dominant
  • Ehlers-Danlos syndrome: affects connective tissue

Acquired:

  • Scurvy
  • Steriods: corticosteroids in GI bleeding
  • Senile
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102
Q

What is the normal platelet count range?

A
  • 150-400 x 109/L
  • below 150 is thrmobocytopenia
  • symptoms are seen when plts are <10
103
Q

What are some symptoms of thrombocytopenia?

A
  • Epistaxis
  • GI bleeds
  • menorrhagia
  • bruising
104
Q

What are some causes of thrombocytopenia?

A

failure to produce

  • selective megakaryocyte depression: drug toxixity or viral infection
  • General bone marrow failure

Increased consumption

  • immune and autoimmune
  • idiopathic
  • assoiciated ith systemic lupus erythematosus, CLL or lymphoma
  • infections: Helicobacter pylori, HIV, malaria drug induced = heparin
105
Q

What is ITP and what is its treatment?

A

Immune thrombocytopenia

  • treat with corticosteroids
  • intravenous immunoglobulins: rapid rise in platelet count
  • sometimes a splenectomy
106
Q

Explain Haemophilia A an B

A

Haemophilia A

  • sex linked chromosome
  • defect is in the absence of or low factor VII
  • largely caused by missense or frameshift mutaions or deletion in the factor VII gene

Haemophilia B

  • Christmas disease, incidence is 1/5 of Haem. A
  • Factor IX deficiency
107
Q

Haeme. A and B are the same

What are the clinical features of haemophilia

A
  • spontaneous bleeding into joints (haemarthrosis) and muscle
  • unexpected post-operative bleeding
  • chronic debilitating joint diseases
  • family history in the majority of cases
108
Q

Clinical diagnosis of haemophilia

A

Prolonged Activated Partial Thromboplastin Yome (APTT)

  • Factor VII, IX, XI, XII assay in the intrinsic pathway

Normal Prothrombin Time (PT)

  • testing factor II, V, VII, X in the intrinsic pathway
  • Low factor VII or IX levels: the lower the % the more severe
109
Q

What treatment is given for haemophilia?

A
  • Infusions of recombnant VIII or factor IX to 50-100% normal
  • if patients factor VIII is raised to 30-50% spontaneous bleeding should be controlled
  • 1-Diamino-8-D-arginine vasopressin (DDAVP); alternative for increasing plasma factor VIII level in milder hameophiliacs
110
Q

also what is VWF?

What is Von Willebrand disease?

A
  • reduced level or abnormal function of von Willebrand factor (VWF)
  • caused by a variety of missense mutations. autosomal dominant disease

VWF

  • produced in endothelial cells and megakaryocytes
  • large multimeric protein that carries factor VIII in the blood, prevents its premature destruction
  • promotes platelet adhesion
111
Q

What is the presentation of von Willebrand disease?

A
  • women are more badly to be affected than men at a given VWF level
  • mucous membrane bleeding: epistaxes, menhorrhagia
  • excessive blood loss from superficial cuts and abrasions
  • operative ad post-truamatic haemorrhage
112
Q

What are the lab tests for vWD?

A
  • prolonged APTT
  • normal PT
  • low vWF level/ function
  • low factor VIII level
  • prolonged bleeding time
  • defective platlet function
113
Q

What is the treatment for vWD?

A
  • antifibrinolytic agent: tranexamic acid for mild bleeding
  • DDAVP infusion for type 1 vWD: releases VWF from endothelial cells 30 minutes after infusion
  • high-purity VWF for patients with very low VWF levels
114
Q

What are Acquired disorders of coagulation?

A
  • Vitamin K deficiency
  • Liver disease
  • Disseminated intravascular coagulation
115
Q

How does Liver disease affect coagulation?

A
  • Biliary obstruction → impaired absorbiton of vitamin K. therefore decreased synthesis of clotting proteins
  • Decreased thrombopoeitin production from the liver contributes to thrombocytopenia
  • Impaired platlet function and fibrinolysis
116
Q

Explain Disseminated Intravscular Coagulation

A

This is the widespread intravascular deposition of fibrin with consumption of coagulation factors and platlets

  • occurs as a consquence of many disorders that release procoagulent material into the circulation or cause widespread endothelial damage or platelet agggregation
  • causes both bleeding and thrombosis to occur
117
Q

Disseminated intravascular Disease

What is the lab presentation of meningococcal DIC

A
  • Prolonged PT, APTT, TT
  • Low fibrinogen
  • low platelts
  • Raised D-dimers or FDPs
118
Q

What anticoagulent drugs are there?

A
  • Heparin: used to treat- MIs, PE, DVTs
  • Warfarin: used to treat- PEs, DVTs, AF, prothetic valves

Direct (novel) Oral anti-coagulants

  • Direct thrombin inhibitors: dabigatran, argatroban
  • Factor xa inhibitars: rivaroxaban, apixaban
119
Q

Explain Vitamin K deficency and its role in coagulation disorders

A
  • required for gamma-carboxylation of factors II, VII, IX, X
  • Inhibited by warfarin: interferes with the action of vitamin K epoxide reductase leading to functional vitamin K deficiency

Deficiency can be due to:

  • Malabsorption of vitamin K, or inadequete in the diet, or inhibited by drugs like warfarin
  • Biliary obstruction (jaundice)
  • Haemorrhagic disease of the newborn ( give 1mg at birth )
120
Q

What are characterised as deep veins?

A
  • Iliac Vein
  • Femoral Vein
  • Popilteal vein
  • Tibial Vein
121
Q

What would make a DVT more likely?

A
  • more risk if a lot is above the knee as there is more risk of embolism
  • occur in the deep veins where blood flow is slower
122
Q

Virchows Triad

What are risk factors for a DVT?

A
  • Hypercoagulable state: pregnancy, contraceptive pills,
  • Circulatory stasis: long periods of sitting/ inactivity
  • Epithelial injury: IV drug abuse, cancer, post operative
123
Q

What are the clinical presentations for DVTs, and possible differential diagnosis?

A
  • asymptomatic
  • unilateral calf swelling/heat/pain/redness/hardness

Differential

  • cellulitis
  • Baker’s cyst
  • muscular pain

Risk factors should be considered

124
Q

How is a DVT diagnosed?

A
  • a doppler ultrasound
  • shows a lack of blood flow in the leg
  • use a Wells score
  • use of a D-dimer test: indicates activation of the clotting cascade

raised score indicates a DVT has a high predictive negative value

125
Q

What is the initial treatment of a DVT?

A
  • Therapeutic anti-coagulation using sub-cut LMW heparin: tinzaparin or enoxaparin
  • Dosing is according to the patient’s weight, no monitoring required
  • if the patient has a renal impairment (creatinine clearances less than 30ml/min) anticoagulant with i.v. unfractionated heparin is used instead. This require monitoring
126
Q

What is the subsequent treatment for a patient with DVT?

A
  • oral warfarin for 3-5 days
  • stop LMW heparin when INR (International Normalised Ratio, based on the prothrombin time) > 2.0 for 2 days
  • if it’s there 1st DVT (femoral or iliac)- 6 months course of warfarin
  • if it’s there 2nd DVT/PE: lifelong warfarin
  • INR should be maintained between 2.0-3.0
127
Q

What are the classical symptoms of a Pulmonary embolism?

A
  • Pleuritic pain
  • acute dyspnoea
  • haemoptysis (coughing up of blood)
  • could cause syncope or death

On examination

  • tachycardic
  • tachypnoiec
  • hypotensive
128
Q

saddle embolism, pre and post embolysis

What investigations can be done to confirm a Pulmonary embolism?

A

CTPA scan

  • CT Pulmonary angiogram
129
Q

What is and what can be seen in a V/Q scan when investigating a PE?

A

a V/Q scan, uses a radioisotope to get images of the lung

  • under perfusion, even though ventilation is very good: V/Q mismatch
  • underlying lung disease

intermediate scans (rarely done)

130
Q

What can be seen on an ECG investigating a PE?

A
  • Sinus tachycardia: an increase in pulse rate
  • Atrial Fibrillation
  • Right Heart strain: right bundle branch block, struggle to get blood through the right lung
  • Classic: SI, QII, TIII pattern on the ECG (rare)
131
Q

What does a CXR when investigating a PE show?

A
  • usually normal
  • may see a small effusion
  • possibly linear atelectasis (shadowing)
132
Q

What are the outcomes for a PE?

A
  • 5% mortality with treatment: even with treatment
  • 4% develop pulmonary hypertension: clots in the pulmonary circulation
  • Cause of death in 10-30% of in-patient post mortems
  • Up to 60% have micro-emboli at post mortem
  • A leading cause of ‘preventable’ death in the western world (25,000 deaths/yr in England)
133
Q

What is the signs and treatment for a massive PE?

A
  • signs of shock, hypotension and acute SOB
  • Mx: thrombolysis and iv heparin
  • this presents with a 2-6% serious risk of bleeding
134
Q

What is the standard treatment for a PE?

A
  • LMW heparin injections – e.g. Tinzaparin
  • Warfarin (target INR 2.5) for 6 months
  • Consider underlying causes: possibly stop taking the pill
  • LMW heparin is better if underlying cancer
  • Inferior Vena Cava filters
  • Consider a DOAC (NOAC) as an alternative
  • Dabigatran p.o (direct thrombin inhibitor)
  • Rivaroxaban p.o (direct Xa inhibitor)
135
Q

What is a thrombophilia screen?

A
  • occasionally in younger patients with VTE (Venous thromboembolism)
  • Inherited risk factors
  • factor V Leiden
  • Prothrombin gene variant

- Anti-thrombin deficiency, rare

- Protein C deficiency, rare

- Protein S deficiency, rare

natural anticoagulant, more prone to clotting if you are deficient in these

  • Acquired risk: anti-phospholipid syndrome
  • increased risk of miscarriage
  • the phospholipid is required as part of the formation of prothrombinase
136
Q

What is the treatment for AML?

A
  • Chemotherapy – kills rapidly dividing cells:
  • Combination regimes
  • Myelo-ablative cycles of treatment
  • Supportive therapy:
  • Antibiotics, antifungals
  • Transfusions of blood and platelets
  • Allogeneic stem cell transplantation:
  • Allograft (full or reduced intensity)
  • Sibling (1-in-4 chance of being a match)
  • Matched unrelated donor (Anthony Nolan)
137
Q

What is the prognosis for Acute Myeloid Leukemia based on certain mutations?

A
  • Good: mutation in APML t(15;17)
  • Intermediate: DNMT3A, NPM1
  • Poor: p53, FLT3, monosomy 7

age is the biggest risk factor for a worse prognosis, diagnosis at >60 y/o is a worse prognosis

138
Q

What is the prognosis for Acute myeloid Leukemia based on certain mutations?

A
  • Good: mutation in APML t(15;17)
  • Intermediate: DNMT3A, NPM1
  • Poor: p53, FLT3, monosomy 7
139
Q

What is the presentation of Multiple Myeloma?

A
  • CRABBI
  • Calcium
    • Hypercalcaemia occurs as a result of increased osteoclast activity within the bones
    • This leads to constipation, nausea, anorexia and confusion
  • Renal
    • Monoclonal production of immunoglobulins results in light chain deposition within the renal tubules
    • This causes renal damage which presents as dehydration and increasing thirst
    • Other causes of renal impairment in myeloma include amyloidosis, nephrocalcinosis, nephrolithiasis
  • Anaemia
    • Bone marrow crowding suppresses erythropoiesis leading to anaemia
    • This causes fatigue and pallor
  • Bleeding
    • bone marrow crowding also results in thrombocytopenia which puts patients at increased risk of bleeding and bruising
  • Bones
    • Bone marrow infiltration by plasma cells and cytokine-mediated osteoclast overactivity creates lytic bone lesions
    • This may present as pain (especially in the back) and increases the risk of fragility fractures
  • Infection
    • a reduction in the production of normal immunoglobulins results in increased susceptibility to infection
140
Q

What is the management of neutropenic sepsis?

A
  • 1st line – Tazocin (Piperacillin/Tazobactam) +/- Gentamicin
  • 2nd line – Switch to Meropenem +/- Teicoplanin (for Gram +ve)
  • 3rd line – Add anti-fungal e.g. Ambisome (Amphotericin)

Resuscitate with IV fluids if hypotensive and may require inotropic support in ITU

141
Q

What is Graft-vs-host disease and how does it present?

A
  • Caused by donor/host mismatches in major and minor HLA loci
  • Results in acute GVH (<100 days) and chronic GVH (>100 days) post-transplant
  • Prevented by using:
  • T-cell depletion of infused donor cells (graft)
  • Immunosuppression of recipient (ciclosporin)
  • Clinical manifestations:
  • Skin rash, sometimes severe
  • Diarrhoea, can be bloody
  • Deranged liver function, can lead to liver failure
  • Graft-vs-leukaemia effect is how the stem cell transplant cures leukaemia
  • Donor lymphocyte infusions (DLI) post-Tx can treat relapse by augmenting GVL effect
142
Q

What is the most common mutation in Acute Myeloid Leukemia?

A
  • NPM1 = Nucleophosmin 1
  • FLT3 = Tyrosine kinase gene
  • DNMT3A = DNA methylation gene
    • initiating mutation in AML
143
Q

What are the clinical features of Acute Myeloid Leukemia?

A
  • Anaemia
  • Infections
  • Disseminated Intravascular coagulation (DIC)
  • Ulcers
  • Inflitration
  • Bruising
144
Q

What is Myeloma?

A

Infiltration of malignant plasma cell in the bone marrow causing symptoms of ‘bone marrow failure’ → tiredness, infections, bruising

  • Plasmacytomas erode the bones causing ‘lytic lesions’ in bones (holes or less dense areas in imaging)
  • Plasma cells produce monoclonal immunoglobulin (IgG or IgA)
  • An M-band is detected as paraprotein serum protein electrophoresis
  • producing an abnormal light chain ratio in Kappa and Lambda
145
Q

What investigations are done for Mulitple Myeloma?

A
  • Bloods will show anaemia (FBC) and thrombocytopenia (FBC); raised urea and creatinine (U&E) and raised calcium
  • Peripheral blood film: rouleaux formation
  • Serum or urine protein electrophoresis: raised concentrations of monoclonal IgA/IgG proteins will be present in the serum. In the urine, they are known as Bence Jones proteins
  • Bone marrow aspiration and trephine biopsy: confirms the diagnosis if the number of plasma cells is significantly raised
  • Whole-body MRI (or CT if MRI is not suitable) is used to survey the skeleton for bone lesions
146
Q

What is the Chemotherapy treatment for Myeloma

A
  • Velcade,
  • Cyclophosphamide,
  • Dexamethasone

Thalidomide = immunomodulatory drug (but beware teratogenicity)

Bortezomib = proteasome inhibitor (or Velcade, blocks the cell’s garbage can)

Daratumumab = monoclonal antibody that targets CD38 on plasma cells

147
Q

What are haematological emergencies in Myeloma and how are they managed?

A
  • Hypercalcaemia
    • Consider myeloma
    • Give iv Pamidronate (bisphosphonate)
    • Give iv fliuds +/- dexamethasone
  • Cord compression
    • Consider if neurology (weak legs or cauda equina symptoms)
      • Request urgent MRI imaging
    • Surgical decompression or emergency radiotherapy
    • Dexamethasone 8mg bd
  • Acute renal failure caused by light chains blocking the neprons
    • Hydration with IV fluids
  • Anaemia
    • Blood transfusion (caution of increased viscosity of blood)
148
Q

What are agglutinins?

A
  • they are naturally occurring complete pentameric IgM antibodies
  • able to fix complement and cause haemolysis
149
Q

What can occur if a transfusion is ABO incompatible? Why is it incompatible?

A

causes intraventricular haemolysis

  • shock, hypotension, tachycardia
  • renal failure, loin pain, haemoglobin
  • disseminated intravascular coagulation
  • death Antibodies for the red cell antigen occur naturally due to cross-reactivity with gut bacterial antigens
150
Q

What is forward (cell) grouping?

A

A two-part test

  • testing for A/B antigens
  • testing the serum or plasma for ABO antibodies
151
Q

What is reverse grouping (serum confirmation) ?

A
  • testing to see what antibodies are in a persons blood
  • the serum is tested with either antigen A B or O
152
Q

What is entailed in compatibility testing?

A
  • donor red blood cells suspended with recipient serum
  • incubated between room temp and 37 degrees
  • observed to ensure no agglutination takes place
153
Q

Give examples of some other blood groups

A
154
Q

What are atypical antibodies?

A
  • These occur due to sensitisation with foreign red cell antigens, from either previous transfusion or by pregnancy
  • can cause blood transfusion reactions to take place if the patient transfused with incompatible blood in the future
155
Q

anti-globulin test

What is the Coombs test/

A
  • uses anti-immunoglobulin antibodies to agglutinate red cells
  • Two types, Direct and Indirect, DAT/IAT
156
Q

Direct anti-immunoglobulin

What does a DAT test show

A

Uses blood sample from the patient

  • tells us if the red cells are coated with antibody
  • positive after a transfusion reaction and in HDN
  • positive in autoimmune haemolytic anaemia
157
Q

indirect anti-immunoglobulin

What does a IAT test show?

A

Uses recipients serum, then donor blood is added

  • a lab test for blood group antigens
  • indicates if a patient is psoitive for Rhesus and other blood groups
158
Q

Explain the Rhesus system

A
  • Rh positive peopl cannot devekip antibodies
  • 15% of people ar Rh negative
  • Rh -ve people can devlope antibodies if they are transfused with Rh +ve blood or are pregnant with a rh +ve baby
  • this is rhesus sensitisation and the antibody generated is IgG type
159
Q

What is haemnolytic disease of the newborn?

A
  • When a Rh(D) -ve mother is pregnant with an Rh positive fetus,
  • greatest cause is anti-D
  • she may produce antibodies (IgG) that can cross the placenta and harm the baby
  • this can lead to neonatal haemolytic anaemia, fetal/ neotal jaundice and kernicterus (brian damage)
160
Q

Prevention od haemolytic disease of the newborn

A
  • ABO and Rh blood group check at 12 weeks
  • Rh-ve women (15%) receive anti-D antibody i.m injection at 28 and 34 weeks to prevent sensitisation
  • baby tested at birth, if Rh +ve mother recieves further anti-D until Leihauer test (foetal cells) become negative
  • if already sensiised, foetus requires monitoring via trans-cranial dopplers
  • may require intra-uterin transfusion if there are signs of anaemia
161
Q

What is in a bag of blood

A
  • RBC
  • Buffy coat: whit cells, platelets
  • Plasma: albumin, gamma globulins, coagulation factors
  • wate, electrolytes, additives
162
Q

How is blood selected and sorted, into its Blood compenets

A
163
Q

Blood Bag Labelling

A
164
Q

What is Aphereis?

A
  • technique where whole blood is extracted and centrifuged into its celuular compenents and plasma
  • in leucapheresis, the white cells are removed
  • process can be used to pefrom a red cell exchange in those with sickle cell aneamia
  • used to isolate lymphocytes for donation; treatment of relapse following stem cell transplan
  • used to isolate haemopoeitic stem cells for donation
165
Q

When do you give a blood transfusion?

A
  • Severe acute blood loss: RTA, GI blood loss, Obsttric blood loss
  • Elective surgery associated with significant blood loss
  • Medical transfusion: cnacer, chemo, renal failure
166
Q

What type of blood transfusions are there?

A
  • Blood components: red cells, platlets, Fresh frozen plasma, cryoprecipitate (fibrinogen)
  • Plasma derivatives: pooled products, immunoglobulin, coagulation factors, albumin
  • Autologous blood ( blood to yourself)
167
Q

What are some hazards of blood transfusion?

A
  • Major ABO incompatibilities
  • Anaphylaxis and sever allergic reaction
  • Minor allergic reaction
  • Late transfusion reactions
  • Fluid overload
  • Iron overload
168
Q

What are some transfusion transmitted infections?

A

Bacterial

  • Syphilis
  • pyogenic infections
  • contamination infectins (pseudomonas)

Viral

  • Hep B, C
  • HIV
  • HTLV, CMV
  • Emerging- West Nile Virus
  • Malaria
  • vCJD (brain disease)
169
Q

What are the components of the immune system?

A
170
Q

What WBCs are known as auxiliary cells?

A
  • Basophil
  • Mast cells
  • Platelets

They act as inflammatory mediators

171
Q

What WBC type are granulocytes?

A
  • Neutrophils
  • Eosinophils
  • Basophils
172
Q

What are Mast cells?

A
  • not found in blood only in the tissue
  • releases substances that affect vascular permeability
  • prominent in mucosal and epithelial tissue
  • Express FceRI (binds IgE)
  • release granules containing histamine and other active agents
173
Q

What is the breakdown of Blood counts in adults?

A
  • neutrophils 50-70% - lymphocytes 20-40% - monocytes 3-10% - Eosinophil 1-3% Basophil <1%
174
Q

What is the role of NK cells?

A
  • act as part of the adaptive immune system
  • 5% of lymphocytes
  • non-specific antigens
175
Q

What are Basophils and what do they do?

A
  • cells that are lobed nuclei and heavily granulated cytoplasm
  • express FceRI
  • circulate in the blood
  • recruited to sites of allergic reaction or ectoparasites
  • Non-phagocytic cell
  • can bind to allergen-specific IgE
176
Q

What are Eosinophils and what do they do?

A
  • bilobed nuclei with a granulated cytoplasm: granules contain peroxidases (toxin)
  • motile phagocytic cells: migrate from the blood into tissues
  • play a role in defence against the parasitic organism: in the GI respiratory and genito-urinary tracts
  • Express FceRI when activated
177
Q

Describe the physiology and biology of Neutrophils

A
  • polymorphonuclear cells
  • multilobed nucleus
  • found in the blood: makeup 60% of circulating leukocytes
  • short lifespan: 8hr- 4days
  • release myeloperoxidase and ROS
178
Q

What is ROS and what does it do?

A

Reactant Oxygen Species

  • oxygen-containing molecules that have an extra, highly reactive electron ( O2-)
  • oxygen radicals donate their electrons to other nearby molecules at random and can damage macromolecules in a random way
  • not a specific mechanism and can damage nearby molecules of the host
179
Q

Describe the physiology and biology of Monocytes

A
  • kidney-shaped nucleus
  • there is a reservoir of monocytes in the spleen
  • circulate the bloodstream where they are enlarge
  • migrate into tissue approx. 1 day after release from the bone marrow
180
Q

Describe the physiology and biology of Macrophages

A
  • they are tissue-specific:
  • 5-10x larger than monocytes: contain more organelles as well e.g lysosomes
  • lifespan is months to years
181
Q

What is the primary response of leukocytes in bacterial infection?

A
  • increase in neutrophils
  • increase in monocytes in a chronic infection
182
Q

What is the primary response of leukocytes in viral infection?

A
  • increase in lymphocytes; sometimes an increase in monocytes
183
Q

What is the primary response of leukocytes in parasite infection?

A
  • increase in eosinophils + activation of mast cells
184
Q

What is the primary response of leukocytes in a fungal infection?

A
  • increase in monocytes
185
Q

What is the primary response of leukocytes in allergy?

A
  • increase in basophils
  • activation of mast cells
  • increase of eosinophils in the chronic phase
186
Q

What are the three areas of pathogenesis in Atherosclerosis?

A
  • Dysregulation of lipid metabolism (cholesterol)
  • Endothelial cell dysfunction
  • Inflammation: mediated by monocytes and macrophages
187
Q

What are key indicators of Acute inflammation?

A
  • develops within minutes
  • predominantly mediated by neutrophils
  • resolves once the stimulus is removed
  • lasts for hours or days
188
Q

What are key indicators of Chronic inflammation

A
  • predominantly mediated by mononuclear cells; macrophages,lymphocytes
  • tissue destruction
  • attempts at healing (fibrosis)
189
Q

What is MCP-1?

A
  • Monocyte chemotactic protein-1
  • aka CCL-2
  • this is a chemokine, whose function is to attract leukocytes; in this case monocytes would be attracted
190
Q

What are the two types of contact between the endothelium and circulating cells?

A

Initial Contact

  • P-selectin and E-selectin on endothelium recognized by oligosaccharides on leukocytes

Tighter adhesion

  • intercellular adhesion molecules (ICAMs) on the endothelium recognised by integrins on leukocytes
191
Q

What are the Adhesion molecules on the surface of the endothelium for Transient Initial Contact?

A
  • P- selectin binds to PSGL-1, sialyl-Lewisx
  • E-selectin binds to sialyl-Lewisx​
192
Q

Explain the platelet monocyte interaction

A
  • platelets bound to the endothelium express P-selectin and other endothelial ligands
  • monocytes with complementary proteins, PSGL- 1 and MAC-1 bind to the platelet
  • this activates the monocyte –> inflammation of the monocyte
193
Q

Explain the activation of macrophages by pathogens.

What do the macrophages release when they are activated?

A
  • activated macrophages also release proinflammatory cytokines:
  • IL-1ß, TNF-alpha, IL-6
194
Q

How do phagocytes recognise what to ingest?

A

Through pattern-recognition receptors such as:

  • Macrophage mannose receptor
  • Scavenger receptors
  • Toll-like receptors (TLRs)
195
Q

What is/are the corresponding ligand(s) to scavenger receptors?

A
  • anionic polymers
  • acetylated and oxidised LDL
196
Q

What is/are the corresponding ligand(s) to macrophage mannose receptors?

A
  • conserved carbohydrate structures
197
Q

What is/are the corresponding ligand(s) to Toll-like receptors (TLRs)? (trick)

A
  • there is a range of them
198
Q

What WBCs are known as phagocytes?

A
  • Mononuclear
  • Neutrophil
  • Eosinophil
199
Q

What WBCs are known as lymphocytes?

A
  • B cells
  • T cells
  • Large granular lymphocytes
200
Q

What are cytokines?

A
  • these are proteins or glycoproteins with a low molecular weight
  • that act as messenger molecules in the immune system
  • primarily secreted by WBCs
  • assist in regulating the development of immune effector cells
  • they generally act locally: paracrine signalling
201
Q

Explain the process of recruitment of monocytes at the site of inflammation

A
202
Q

What are the Adhesion molecules on the surface of the endothelium for Tighter binding

A

- ICAM-1 (CD54): binds to LFA-1, Mac1

- ICAM-2 (CD102): binds toMac1

  • VCAM-1 (CD106): binds to VLA-4

LFA-1 – Lymphocyte function-associated antigen 1

VLA-4 – Very Late Antigen-4 (Integrin alpha4beta1)

VCAM-1 – Vascular cell adhesion molecule

203
Q

What does VCAM-1 – Vascular cell adhesion molecule do and where is it expressed?

A
  • it binds monocytes and lymphocytes to activated cell endothelium
  • expressed by endothelium over nascent fatty streaks
  • expressed by microvessels of the mature atheroma
204
Q

Warfarin

A
  • Vitamin K antagonist
  • therefore Prevents γ-carboxylation of factors II, VII, IX, X
  • Prolongs the extrinsic pathway (tested by measuring prothrombin time)
  • Monitored by the international normalised ratio (INR)
  • Target INR usually 2.5 for DVT/PE and AF
  • Target 3.5 for recurrent VTE or metal heart valves
205
Q

Describe the metabolism of warfarin

A
206
Q

Describe the Pharmaco-dynamics of warfarin

A
  • reduces the half-life of Factor VII, IX, X and II
  • Warfarin can take > 3 days to reach therapeutic levels
  • also inhibits the natural anti-coagulants: Protein C and S
  • these have a shorter half-life so become prothrombotic before combing anticoagulant because the natural sources (protein C and S) are initially depleted
207
Q

How should warfarin be prescribed?

A
  • usually loaded with low molecular weight heparin (LMWH) cover
  • typically: 10mg, 5mg
  • a fall in Protein C and S occurs within hours, can result in a temporary procoagulant state
  • hence, LMWH is usually continued until the INR is > 2.0 for 2 consecutive days
208
Q

thrombomodulin is a endothelial cell surface receptor

What are Protein C and S? describe their action.

A
  • they are inhibitors of coagulation factor V and VIII
  • bothe are vitamin K dependent proteins
  • Protein C is activated by a thrombin-Thrombomodulin complex
  • activated protein C is able to destroy factor Va and VIIIa
  • therefore further thrombin cannot be generated: creating a negative feedback loop
  • Protein S promotes the action of protein C
  • activated protein C is inactivated by serpins( serum protease inactivators) e.g antithrombin

​

209
Q

What other drugs/chemicals does warfarin interact with?

A
  • beware of interactions with other drugs due to cytochrome P450 in the liver
  • enzyme inhibitors potentiate warfarin: may want to reduce the dosage
  • carbamazepine, azathioprine, allopurinol
  • erythromycin, ciprofloxacin, metronidazole, fluconazole
  • Enzyme inducers inhibit warfarin: may want to increase the dosage
  • rifampicin, amiodarone, citalopram, phenytoin
  • Interactions with alcohol: may have a high IRN and are at risk of bleeds
210
Q

What are some side effects of warfarin?

A
  • teratogenic: must use LMW heparin in pregnancy
  • significant haemorrhage risk: leads to intracranial bleeds p to 15 a year, increased risk in elderly with a higher INR target
  • minor bleeding: 20% per ann.
  • skin necrosis
  • alopecia: hair loss
211
Q

Explain how warfarin can be reversed

A
  • Give vitamin K 2-10mg iv/po depending on INR level
  • 6-12 hours to take into effect so give other treatments first (octaplex)
  • The patient can become refractory to re-loading with warfarin
  • If life-threatening bleed, give activated prothrombin complex (Octaplex) containing factors II, VII, IX and X (25-50 units per kg), plasma-derived product
  • Fresh frozen plasma (FFP) can also be used
212
Q

Heparin

A
  • Mucopolysaccharide that potentiates anti-thrombin
  • Irreversibly inactivates factors IIa (thrombin) and Xa
  • Administered parenterally

Two formulations of heparin:

  • Unfractionated heparin given by i.v. infusion
  • Low molecular weight heparin given as s.c. injections

Safe in pregnancy

213
Q

first binds to antithrombin

Describe the action of Heparin

A
214
Q

How/ when is unfractionated heparin used?

A
  • Not often used due to inconvenience, unless in renal failure
  • Given i.v. with 5000U bolus and ~1000U/hour infusion
  • Monitored by APTT with a target range of 1.5-2.5 x normal
  • Safe in renal failure
  • Can be partially reversed with protamine sulphate
  • Thrombocytopenia and VTE is a rare complication resulting in heparin-induced thrombocytopenia (HIT)
215
Q

When/ How is Low molecular weight heparin used

A
  • Very convenient due to once daily s.c. injections
  • Prescribed according to patient’s weight
  • Not usually monitored (but can use the anti-Xa assay)
  • Patient must have creatinine clearance of over 30ml/minute

LMW heparin formulations include:

  • Tinzaparin (Innohep) 175U/kg
  • Enoxaparin (Clexane) 1.5mg/kg
  • Dalteparin (Fragmin)

Used for thromboprophylaxis for hospital in-patients:

  • 3,500U or 4,500U Tinzaparin
  • 20 or 40mg Enoxaparin
216
Q

What are Novel oral anticoagulants?

A
  • alternative to warfarin
  • orally available, no monitoring required, has a good safety profile
  • Dabigatran: direct thrombin (IIa) inhibitor
  • Rivaroxaban: direct factor Xa inhibitor
  • trials show that it is as good as warfarin and LMW heparin but the anticoagulation action is irreversible
217
Q

It is a novel anticoagulant drug class

Explain how Dabigatran is used.

A
  • used as a direct inhibitor to factor IIa (thrombin)

Indications (usage)

  • used as a VTE (venous thromboembolism) prophylaxis
  • treatment for DVTs and PEs
  • stroke prevention in atrial fibrillation
  • Dosing is 110mg bd or 150mg bd
  • must be a creatine clearance of > 30ml/min
  • Argatroban: direct thrombin inhibitor given iv: safe in renal failure
218
Q

Explain how Rivaroxaban is used

A
  • is a direct factor Xa inhibitor

Indications:

  • VTE prophylaxis
  • Used for treatment of DVTs and PEs
  • Stroke prevention in atrial fibrillation
  • Dosing is 15mg bd for 3 weeks, then 20mg od
  • or 15mg od if CrCl is 15-50ml/min
  • Apixaban is alternative drug dosed bd (morning and evening), slightly better plasma levels with this drug
219
Q

Describe the action of antiplatelet drugs

A
220
Q

three glycoprotein inhibitors

List five main types of anti-platelet drugs

A
  • Aspirin: cyclo-oxygenase inhibitor
  • Clopidogrel: ADP receptor blocker
  • Dipyridamole: inhibits phosphodiesterase
  • Prostacyclin: stimulates adenylate cyclase

Glycoprotein IIb/IIIa inhibitors: also used in cardiac clot prevention in patients who have had stents inserted

  • Abciximab – monoclonal antibody
  • Eptifibatide – snake venom derivative
  • Tirofiban – blocks platelet aggregation
221
Q

What are fibrinolytic agents?

A
  • Thrombolytic agents are used to lyse fresh thrombi (arterial) by converting plasminogen to plasmin
  • e.g Tissue Plasminogen Activator (tPA, Alteplase) and Streptokinase
  • Administered systemically in acute MI, recent thrombotic stroke, major PE or iliofemoral thrombosis
  • Standardized dosage regimens have to use within 6 hours
  • Beware of contra-indications to thrombolysis
222
Q

What is Sickle-cell Anaemia?

A

Sickle-cell anaemia is an autosomal recessive condition that results for synthesis of an abnormal haemoglobin chain termed HbS.

More common in people of African descent as the heterozygous condition offers some protection against malaria.

Around 10% of UK Afro-Caribbean’s are carriers of HbS (i.e. heterozygous). Such people are only symptomatic if severely hypoxic

Symptoms in homozygotes don’t tend to develop until 4-6 months when the abnormal HbSS molecules take over from fetal haemoglobin

223
Q

What is the pathophysiology of Sickle-cell Anaemia?

A
  • haemoglobin
    • normal haemoglobin: HbAA
    • sickle cell trait: HbAS
    • homozygous sickle cell disease: HbSS. Some patients inherit one HbS and another abnormal haemoglobin (HbC) resulting in a milder form of sickle cell disease (HbSC)
  • polar amino acid glutamate is substituted by non-polar valine in each of the two beta chains (codon 6). This decreases the water solubility of deoxy-Hb
  • in the deoxygenated state the HbS molecules polymerise and cause RBCs to sickle
    • HbAS patients sickle at p02 2.5 - 4 kPa
    • HbSS patients at p02 5 - 6 kPa
  • sickle cells are fragile and haemolyse; they block small blood vessels and cause infarction
224
Q

How is Sickel cell anaemia diagnosed?

A

Haemoglobin electrophoresis

225
Q

What typical features are seen on a blood film of someone with hyposplenism?

A

e.g. post-splenectomy, coeliac disease (occurs in around 30% of coeliac patients)

  • target cells
  • Howell-Jolly bodies
  • Pappenheimer bodies
  • siderotic granules
  • acanthocytes
226
Q

What typical features are seen on a blood film of someone with Iron-deficiency anaemia?

A
  • target cells
  • ‘pencil’ poikilocytes
  • if combined with B12/folate deficiency a ‘dimorphic’ film occurs with mixed microcytic and macrocytic cells
227
Q

What typical features are seen on a blood film of someone with Megaloblastic anaemia?

A
  • hypersegmented neutrophils
228
Q

What is Dessminated intravascular coagulation? and how is Tissue factor relevant

A

the processes of coagulation and fibrinolysis are dysregulated, and the result is widespread clotting with resultant bleeding

One critical mediator of DIC is the release of a transmembrane glycoprotein (tissue factor =TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumour necrosis factor, and endotoxin. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta

229
Q

What are causes of DIC?

A
  • sepsis
  • trauma
  • obstetric complications e.g. aminiotic fluid embolism or hemolysis, elevated liver function tests, and low platelets (HELLP syndrome)
  • malignancy
230
Q

How does DIC present in blood tests and films?

A
  • ↓ platelets
  • ↓ fibrinogen
  • ↑ PT & APTT
  • ↑ fibrinogen degradation products
  • schistocytes due to microangiopathic haemolytic anaemia
231
Q

What is Hodgkin’s lymphoma?

A

Hodgkin’s lymphoma is a malignant proliferation of lymphocytes characterised by the presence of the Reed-Sternberg cell. It has a bimodal age distribution being most common in the third and seventh decades

232
Q

How do patients with Acute Promyelocytic Leukemia clinically present?

A
  • Usually present with profoundly deranged clotting - Disseminated Intravascular coagulation
  • increased risk of intracranial haemorrhage
233
Q

What is Acute Promyelocytic Leukemia?

what are the genetic hallmarks and cytological presentation of APML

A

a subtype of Acute Myeloid Leukemia they characteristically present with, represents 11% of AML cases

  • Hypercellular, abnormal hypergranular promyelocytes +++
    • characteristically have Auer rods
  • Immunophenotyping: CD34, HLA-DR -ve / MPO, CD13, CD33 +ve
  • Rapid interphase FISH analysis: PML-RARA rearrangement t(15;17)
  • PCR: PML-RARA confirmed by real time PCR
234
Q

How does Differentiation syndrome present? and how is it managed?

A
  • raising WCC
  • the rapid differentiation of promyelocytes results in the release of cytokines resulting in target organ damage e.g lungs causing ARDS
  • Dyspnoea, fever, weight gain oedema
  • Txt: by stopping ATRA and dexamethasone
235
Q

How can Acute Promyelocytic Leukemia be treated?

Risks?

A
  • Induction treatment with ATRA - All-trans retinoic acid (Vitamin A)
    • binds to the receptor and induces differentiation of the promyelocytes which allows the cells to progress along normal myeloid differentiation

→ Risk of Differentiation syndrome, occurs in 15% of patients. All the promyelocytes simultaneously differentiate and then enter into circulation and causing infiltration of the tissues e.g the Lungs resulting in ARDS

  • 2nd cycle consolidation treatment with more ATRA or Arsenic trioxide
236
Q

How does Acute Myeloid Leukemia present on blood film?

A
  • Neutropenia
  • Marked thrombocytopenia
  • Primitive myeloid blast cells
  • Auer rods seen
237
Q

How is a Bone marrow biopsy taken and what is done with the sample?

A
  • taken from the iliac crest with patient curld up
  • Look at the bone marrow aspirate, BM trephine (keeps bone marrow intact)
  • Flow cytometry
  • Molecular analysis - mutations in known AML genes:
  • DNMT3A (DNA methyltransferase gene) = poor risk
  • CEBPA (myeloid transcription factor) = good risk
  • GATA2 (myeloid transcription factor) = neutral
  • FLT3 and NPM1
238
Q

What is the treatment for AML?

management as well

A
  • Insertion of PICC line
  • Patient commenced on standard “DA 3+10” chemotherapy regime: (causes pancytopenia)
  • Daunorubicin (anthracycline) – infusions days 1, 3, 5
  • Cytarabine (nucleoside analogue) – bd infusions days 1-10
  • Daily platelet support to maintain above 50 x 109/L
  • Red cell transfusions to maintain above 90g/L
  • Broad-spectrum antibiotics started for neutropenic fever, high CRP:
  • Tazocin
  • Teicoplanin

and also give antifungal treatment

239
Q

What is the prognosis of APML?

A
  • High early mortality due to haemorrhrage
  • Initial management is to prevent bleeding
  • Overall prognosis today is 80-90% survival at 10 years
    • usually presents in young people which helps with prognosis
240
Q

What is the staging for Chronic Lymphocytic Leukemia?

A

Binet Staging: this is classified by the number of lymphoid tissues involved (e,g spleen, lymph nodes of the neck, groin and under arms), and the presence of Anemia and Thrombocytopenia

  • stage A (monitored)
    • fewer than three areas of enlarged lymphoid tissue
    • no anaemia
    • no thrombocytopenia
    • * lymphadenopathy in the neck, axillary, inguinal as well as the splenic involvement, are each considered as “one group,” whether unilateral (one-sided) or bilateral (on both sides)
  • stage B
    • three or more areas of enlarged lymphoid tissue
    • no anaemia
    • no thrombocytopenia
  • stage C
    • patients have anaemia and/or thrombocytopenia regardless of lymphadenopathy
241
Q

What is Chronic Lymphocytic Leukemia?

A

Most common leukaemia. It is slowly progressing that begins in the lymphocytes of bone marrow and extends into the blood.

This causes painless enlarged lymph nodes, pain in upper left side of abdomen, night sweats, weight loss, and fever

242
Q

What is the medication used to manage CLL? Side effects?

A
  • Ibrutinib: Bruton tyrosine kinase inhibitor
    • Haemorrhagic colitis
    • Hypertension
    • Arrhythmias
  • Rituximab: targets B lymphocytes via binding to CD20
  • Venetoclax: Bcl-2 (B-cell lymphoma - 2) inhibitor
    • Tumour lysis: prevented by weekly step-wise escalation of venetoclax daily dose over 5 weeks (when the WCC normalises)
      • twice weekly tumour lysis syndrome blood monitoring with each increment

→ all medications are targeting B cells therefore likely to develop immune paresis (low Ig’s) increasing risk of opportunistic infections

243
Q

What is the progression of CLL?

A

likely to progress to non-Hodgkins Lymphoma

244
Q

What is Tumour lysis syndrome, and how does it present and how is it managed?

A
  • a complication of Venetoclax (Bcl-2 inhibitor)
  • it is a result of mass cell apoptosis caused by the drug, releasing the cell contents causing
  • Hyperkalaemia, hyperphosphataemia, hypocalcemia and raised creating presenting in renal failure
    • can cause arrhythmias due to high potassium
  • Treated with
    • Hydration, IV
    • Rasburicase* to break down urate then *Allopurinol, to prevent urate nephropathy
245
Q

How is CLL diagnosed and how is management guided?

A
  • Type of lymphoproliferative disorder
  • Lymphocyte count > 5x109/L
  • Splenomegaly + lymphadenopathy
  • CLL work-up:
  • Diagnosis by morphology and immunophenotyping
  • Staging by Binet system (A,B,C)
  • Management is determined by p53 mutation or deletion (del17p)
    • these patients have a more targeted therapies required more targeted therapies from the onset
  • IgVH mutation stats can also help to determine prognosis
246
Q

How does the genetics and disease process of CLL guide treatment?

A
  • Treatment is indicated for marrow failure (cytopenias):
  • If p53 wild-type:
  • First line treatment with chemo-immunotherapy regime FCR:
  • Fludarabine, cyclophosphamide, rituximab (anti-CD20 monoclonal Ab)
  • If less fit then for Bendamustine/Rituximab or Chlorambucil/Obinutuzumab treatment
  • If p53 mutated or deleted, or relapsed CLL disease then for targeted therapy:
  • Ibrutinib (oral BTK inhibitor = Bruton’s tyrosine kinase)
  • Venetoclax (oral BCL2 inhibitor = anti-apoptotic protein)
  • Idelalisib (oral PI3K inhibitor = B cell receptor signalling protein)
  • If CLL is complicated by AIHA or ITP, then treat with steroids (prednisolone)
247
Q

How does Venetoclax work?

A
  • Triggers apoptosis of CLL cells )sometimes causing tumour lysis syndrome)
  • Results in eradication of detectable MRD in a proportion of patients
  • Venetoclax approved in 2016 for patients with CLL:
  • with 17p deletion or TP53 mutation or relapse post-first line chemo-immunotherapy
248
Q

What are the morphological features of Myelofibrosis in a blood test and blood film

A
  • Anaemia
  • low platelets
  • High white cells - mainly neutrophils
  • High B12 levels and LDH levels
  • Blood film
    • Leucoerythroblastic blood film (red cells with a nucleus)
      • bone marrow is under stress and is releasing premature red cells and myeloid cells
    • Myelocytes
    • Teardrop red cells
249
Q

What are the morphological features of Primary Myelofibrosis in a Bone Marrow test

A
  • Hypercellular on bone marrow aspirate
  • Excess myeloid cells with left shift
  • Reticulin fibrosis grade 3 on trephine
  • Abnormal megakaryocytes
  • Mild increase in CD34+ve blasts
  • +ve JAK2 V617F mutation
250
Q

What is the management of Primary Myelofibrosis?

A
  • Hydroxycarbamide 500mg daily initially - to lower white cells
    • causes reduction in splenomegaly
  • Allopurinol 300mg daily for gout and urate nephropathy prevention
  • Ruxolitinib (JAK2 inhibitor)
251
Q

What are the symptoms of Primary Myelofibrosis?

A
  • Splenomegaly causing abdominal pain
    • can cause pain radiating to the shoulder due to irritation of the diaphragm C3,4,5
  • Fatigue
  • Nightsweats
  • Itchiness (pruritis)
  • Bone pain
  • Weight loss
252
Q

What does Primary Myelofribosis develop from and develop into

A
  • Essential thrombocytopenia → polycythemia vera
  • both can form Myelofibrosis
  • Myelforbisos → Acute Myeloid Leukaemia
253
Q

How do you diagnose Essential thrombocytopenia

A
  • Confirm diagnosis by JAK2 mutation analysis
  • If -ve, rule out reactive thrombocytosis
  • Raised inflammatory markers?
  • Malignancy, infection, bleeding etc?
  • Bone marrow biopsy – increased megakaryocytes?
  • If age < 60 and plts < 1500 and no hx of VTE then Aspirin only
  • If > 60 or plts > 1500 or previous VTE or other significant risk factors, then add Hydoxycarbamide to maintain platelets in normal range

302: Scientific Bases of Medicine (9 decks)

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