Haematology

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Author:
grignoter
ID:
162467
Filename:
Haematology
Updated:
2013-03-10 14:51:04
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haematology pathology medicine
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Haematology
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  1. Hb H thalassaemia
    = 3 defective alpha Hb genes → 4

    Causes abnormal oxygen dissociation curve
  2. Hb Barts thalassaemia
    = 4 defective alpha genes → 4

    High affinity for oxygen means it is not released in tissues. Fatal in utero
  3. Disseminated Intravascular Coagulation - mechanisms
    1. Activation of Tissue Factor  extrinsic pathway  small clots (purpuric rash)

    • 2. Clotting depletes coagulation factors platelets and fibrinogen  bleeding
    • ...may also have depletion of fibrinolytics.

    3. fibrin deposits and clots  occlusion  organ failure
  4. Causes of DIC
  5. sepsis, major tissue damage, inflammation
  6. Iron Overload
    ?Haemosiderosis?
    • 1 unit of blood provides ~ 200mg Fe

    • Deposition:
    • - cirrhosis of the liver
    • - heart failure
    • - hypoendocrinism = pancreas, pituitary, adrenals and parathyroids 

    • Management:
    • MED: desferrioxamine SC, deferiprone PO, deferasirox PO
    • SX: stem cell transplant
  7. Stem Cell Transplant
    for Thalassaemia
    • 90% survival
    • 84% cure

    • Should be done before 17yo, ideally before 5yo
    • > 17yo gives 70% survival

    • + no transfusions or chelation required
    • - may still cause iron overload, infertility.

    Less successful if not well chelated or liver enlarged or fibrosed.
  8. Folate
    Found in fresh leafy vegetables, decreased by cooking

    • RDI 300ug
    • RDI pregnancy 600ug

    Supplement 0.4mg per day for conception and first 12 weeks of pregnancy
  9. Folate and B12 Metabolism
  10. Folate Deficiency
    • Causes:
    • - increased demand = pregnancy, adolescence, haemolysis, Ca, eczema
    • - poor intake = poverty, ignorance, malnutrition, malabsorption, ED
    • - ?folate blocking drugs? chemotherapy +/- immunosuppression

    • Signs and Symptoms:
    • - anaemia = macrocytic, megaloblastic
    • - jaundice
    • - glossitis
    • - angular cheilosis
    • - weight loss
    • - change in bowel habits
    • - sterility

    • Outcome:
    • - decreased homocysteine metabolism (therefore high homocysteine)  atherosclerosis and vascular disease
    • - defects in the foetal neural tube  spina bifida or anencephaly
  11. RDI of B12
    2 - 3ug
  12. Causes of B12 Deficiency
    1. Poor absorption - pernicious anaemia, loss of stomach (intrisic factor) or terminal ieum (absorption) due to resection, IBD, coeliac disease

    2. Poor intake - stores last approx 3 years

    3. Infections - abnormal flora, tropical sprue, fish tapeworm
  13. Symptoms of Vitamin B 12 Deficiency
    symptoms: macrocytic megaloblastic anaemia, jaundice, glossitis, angular cheilosis, weight loss, change in bowel habits, sterility, bilateral peripheral neuropathy, optic atrophy, dementia, parasthesiae, weakness, loss of proprioception, visual impairment, psychiatric changes, Babinski's sign, subacute combined degeneration of the cord
  14. Pernicious Anaemia
    • autoantibodies against Intrinsic Factor or parietal cells of stomach
    • peaks age 60, commoner with family history
    • male sufferers have increased mortality
    • all sufferers have increased risk gastric cancer even after treatment
    • treated with IM or SC B12
  15. Anti-Parietal Cell Antibodies
    • present in 90% people with pernicious anaemia
    • present in 16% women over 60 regardless of whether they have PA
    • more common in relatives of people with PA
  16. Ham's Test
    Place red blood cells in mild acid. Increased fragility = positive test = paroxysmal nocturnal haemoglobinuria or congenital dyserythropoetic anaemia
  17. Paroxysmal Nocturnal Haemoglobinuria (PNH)
    Marchiafava-Micheli syndrome
    • 1. complement-mediated intravascular haemolysis (anaemia symptoms)
    • 2. red appearance of haemoglobinuria
    • 3. thrombosis (DVT, Budd-Chiari) 

    Other symptoms: free haemoglobin binds NO preventing smooth muscle relaxation: oesophageal spasm, erectile dysfunction, abdominal pain

    • Pathophysiology:
    • * acquired cell membrane defect
    • * deficiency in phosphatidylinositol glycan A (PIGA) means can't make glycosylphosphatidylinositol which anchors proteins on cell membranes
    • * without protective proteins, complement causes haemolysis (and damages platelets causing thrombosis?)

    • Diagnosis:
    • * intravascular haemolysis: low HB, high LDH, reticulocytosis, high BR, low haptoglobin
    • * direct coomb's negative
    • * Ham's acid haemolysis test
    • * FACS for CD55 and CD59

    • Management:
    • BMT - allogeneic
    • eculizumab reduces transfusion requirement
  18. Activated Partial Thromboplastin Time
    - technique
    Measures: the intrinsic (f12/contact activation) and common pathways

    • Technique:
    • 1. plasma (without platelets) + phospholipid (cephalin) + contact activator (Kaolin, silica or ellagic acid) + calcium
    • 2. Calcium initates clotting. The result is time from calcium addition to clot.

    Normal range: around 27 - 35 seconds (depends on lab)
  19. Causes of Isolated Prolonged APTT
    • more than 20% deficiency of 12, 11, 9 or 8 - Haemophilia
    • contact factor (pre-kallikrein) deficiency
    • acquired clotting factor inhibitors
    •        - auto-Ab - most commonly against f8
    •        - allo-Ab in Haemophilliacs exposed to exogenous f8
    •        - lupus anticoagulant targets phospholipid
  20. Prolonged APTT and PT simultaneously
    • * Vitamin K deficiency (decreased gamma carboxylation of 2,7,9,10)
    •        - liver disease
    •              - malabsorption of fat-soluble vits including K
    •              - decreased synthesis of clotting factors
    • * Acquired dysfibrinogenemia - changes in
    • sialic acid content of fibrinogen
    • * Thrombin inhibitors - hirudin, argatroban, dabigatran
    • * DIC
    • * Dilutional coagulopathy (fluids, blood)
    • * Thrombolysis
    • * Combined clotting factor deficiencies - e.g. 5 and 8
    • * Common pathway deficiencies - 5, prothrombin, fibrinogen
  21. Increased APTT
    with or without marginally Prolonged PT
    • Unfractionated heparin (PT only prolonged in significant over-coagulation)
    • Antiphospholipid Ab (rarely prolongs the PT as PT reagents contain high levels of phospholipid)
    • Acquired clotting factor inhibitors - F5, F8
  22. Coagulation Tests in Patients of Warfarin
    • PT/INR is prolonged
    • APTT may go up with high doses but not if stable
  23. Normal Prothrombin Time
    13 - 15 seconds
  24. Prothrombin Time
    • Measures extrinsic (tissue factor) and common pathways, and Warfarin therapy.
    • (Factors 7, 10, 5, 2 and fibrinogen.)

    • 1. plasma (platelet poor) + Tissue Factor + phospholipid + calcium
    • 2. measure time to clot

    Normal value: approx 13 - 15 seconds
  25. Prolonged PT in association with other coagulation abnormalities
    • Vitamin K problems: deficiency, antagonists (warfarin, phenindione), liver disease, malabsorption
    • High concentrations of unfractionated heparin
    • Direct thrombin inhibitors e.g. Lepirudin, argatroban
    • Deficiency of: f5, f7, f8, fibrinogen
    • Dilutional e.g. massive blood transfusion
  26. Shortened Prothrombin Time
    treatment with rVIIa
  27. Normal Thrombin Time
    13 - 15 seconds
  28. What is Thrombin Time?
    • Thrombin cleaves fibrinogen to fibrin
    • TT measures abnormalities in this conversion.

    • 1. bovine or human thrombin + plasma (platelet poor)
    • 2. measure time to clotting

    Affected by heparin
  29. Decreased Fibrinogen
    • Congenital deficiency or low levels
    • Dysfibrinogenaemia (a dysfunctional fibrinogen)
    • Acquired deficiency
    •       - DIC
    •       - thrombolytics
    •       - liver disease
    •       - malignancy
  30. Prolonged Thrombin Time
    • Unfractionated heparin (NOT LMWH unless over-dosed)
    • Hirudin, Argatroban
    • (NOT Warfarin)
    • Low fibrinogen levels - congenital or acquired (liver disease, malignancy, thrombolytics, DIC)
    • Decreased fibrin polymerisation
    •       - High FDP concentrations
    •       - paraproteins
    • Low albumin
    • Amyloidosis (inhibition of conversion of fibrinogen to fibrin)
    • Exposure to bovine thrombin --> inhibitors
    • Heparin-like anticoagulants rarely occur in malignancy
    • Hyperfibrinogenaemia (mechanism unclear?)
    • Fetal fibrinogen (normal for neonates)
  31. Disorders of Secondary Haemostasis
    bleeding into muscles and joints, may be delayed or relapsing

    • 1. Genetic loss of clotting factors
    •     - haemophilia A (f8) (X-linked)
    •     - haemophilia B (f9)
    •     - factor 11 (bleed after trauma only)

    • 2. Acquired loss of clotting factors
    •     - liver disease
    •     - dilution (RBC transfusion without plasma)
    •     - drugs (Warfarin)

    3. Increased consumption - DIC
  32. Thrombin Time

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