Haemostasis (part 2: secondary haemostasis)

Describe primary and secondary homeostasis
1. Primary homeostasis
  1. Characterised by injured blood vessel constriction/spasm (different response (vasodilation) in uninjured vessels) - followed by thrombocytic plug
  2. Depends on the platelet and blood vessel wall
    1. Platelets aggregate at the site of injury to reduce and arrest the bleeding
2. Secondary homeostasis
  1. When the clotting cascade is activated (by tissue factor from the surface of endothelial cells and platelet secretions)
    1. Coagulation and coagulation factors
      1. Platelets, vascular and clotting factors
      2. Extrinsic pathway
      3. Intrinsic pathway
      4. Reversed by fibrinolysis
Clotting cascade
1. Intrinsic pathway (stimulated by exposed collagen)
  1. XII (Hageman factor)
    1. XIIa
      1. +
        Kallikrien
        Prekallikrien
      2. +
        High molecular weight kininogen (HMWK)
      3. +
        XI
        XIa
        +
        IX
        IXa
        IXa + VIIIa (+ (Ca(2+) + phospholipids) = tenase complex
        +
        Xa
        Xa + Va (+ Ca(2+) + phospholipids) = prothrombinase complex
        Va
        +
        Thrombin (IIa)
        V
        +
        Prothrombin (II)
        Thrombin (IIa)
        +
        Fibrinogen (I)
        Fibrin monomer (Ia)
        +
        Fibrin clot
        +
        Digested fibrin products
        Fibrinolysis
        Plasmin
        +
        Plasminogen
        Urokinase
        tPA
        +
        XIII
        XIIIa
        COMMON PATHWAY
        X
        VIIa (+ tissue factor)
        +
        VII
        Tissue factor
        Tissue injury
        Extrinsic Pathway (stimulated by endothelial damage -> tissue factor release)
        VIIIa
        +
        VIII
        Thrombin (IIa)
        vWF
        Thrombin (IIa)
  2. +
  3. +
  4. Recruits a complex of; prekallikrien, XII and HMWK
Coagulation factors
1. Generated in the liver (except VIII - at least the vWF-interacting portion)
  1. VII produced in multiple organs
2. Three types
  1. The fibrinogen family
    1. Fibrinogen
    2. V
    3. VIII
    4. XIII
  2. The prothrombin family
    1. II
    2. VII
    3. IX
    4. X
    5. Protein C
      1. Binds with thrombomodulin on endothelial cells
        This complex becomes activated by portein S
        Activated complex inhibits Va and VIIa
    6. Protein S
  3. The contact family
    1. VII (Hageman factor)
Monitoring haemostasis
1. Bleeding time (Duke's method)
  1. Patient skin is cleaned with alcohol wipe
    1. Prick made with a lancet
      1. Filter paper applied to the area every 30 seconds
        BT = no. of blood spots (until blleding stopped) divided by 2
        This gives the BT in mins (normal is 3-6 mins)
        Measures time for primary haemostasis
        Not very reliable
        Varies greatly between patients
        In cold it is shortened (due to capillary constriction)
        In warmth = opposite
        Prolonged by
        Lack of platelets (thrombocytopaenia)
        Platelet disorders (heparin, aspirin)
        Severe anaemia
        vWD
        Collagen vascular disease
2. Clotting time - capillary tube method
  1. Prep and prick the patient
    1. Fill a capillary tube up with blood
      1. Every 30 secs blot the capillary tube on filter paper and drag back slightly
        Fibrin formation is identified when a fibrinous clot is dragged from the capillary tube
        Seen as a fibrin thread
        Normal clotting time = 5-8 mins
        It is increased in haemophilia
        Not relying on primary haemostasis alone (outside of the body)
3. Coagulation tests
  1. Measuring the intrinsic system
    1. Activated partial thromboplastin time (aPTT)
      1. Performed at 37degressC
        Plasma collected (9:1 ratio of trisodium citrate anticoagulate and blood)
        Add kaolin/elgaic acid (source of phospholipids) and Ca(2+) - activate the intrinsic pathway
        Measure the time for a clot to form
        Normal = 22-35secs
        Prolonged aPTT
        Heparin/direct thrombin inhibitors
        Factor deficiencies (intrinsic factors; XII, XI, IX, VIII)
        Common pathway factor deficiencies (X, V, II, I)
        Luopus anticoagulant
        Specific inhibitors (VIII or IX)
        Possible warfarin, liver dysfunction DIC?
  2. Measuring the extrinsic system
    1. Prothrombin time (PT)
      1. Performed by adding thromboplastin and Ca(2+) to plasma
        Thromboplastin mimicks tissue factor (activates VII - i.e. the extrinsic system)
        Can be human or rabbit
        Measure the time for clot formation
        Can be performed automatically or manually
        Normal PT time = 11-15 secs
        Prolonged PT time
        Factor deficiency
        VII (extrinsic pathway)
        or, II, V and X (common pathway)
        Warfarin
        High dose heparin
        Liver dysfunction
        Vitamin K deficiency
        VII requires vitamin K for activity
        (So does XI - but not part of the extrinsic pathway)
        Disseminated intravascular coagulation (DIC)
        Lupus anticoagulant
        Considerations
        Underfilling with blood can alter the anticoagulant:blood ratio of 9:1
        Polycythaemia alters the anticoagulant:blood ratio of 9:1
        Errors in the optical end point analysis by...
        Lipaemia
        Haemolysis
        Hyperbilirubinaemia
        Hyperproteinaemia
        Internationational normalised ratio (INR) - accounts for differences between different nationalalities
        Can be tested using a portable electronic system
        Calculation of the INR = (patients PT in secs / mean normal PT i secs)^international sensitivity index
        Thromboplastin reagents vary in sensitivity between labs - the INR allows for standardisation by introducing an international sensitivity index (IS)
        For the purpose of standardising the monitoring of warfarin therapy
  3. Measuring the common pathway alone
    1. Thrombin time (TT)
      1. Performed by adding thrombin (IIa) to patients plasma
        Measures the conversion of fibrinogen to fibrin
        Normal = <20 secs
        Shortened TT in dysfibrinogenemia
        Prolonged TT in
        DIC, liver disease, hypofibrinogenemia, heparin, lupus
4. Measuring fibrinogen levels
  1. Detects deficiencies of fibrinogen or the ability to convert to fibrin
  2. Normal = 200-400mg/dL
    1. May do titers to assist in evaluation
    2. Levels decreased in
      1. DIC (consumption of clotting factors)
      2. Liver disease (decreased synthesis)
      3. Massive transfusion (dilutional coagulopathy)
      4. Hypo-, dys- and afibrinogenemia
    3. Increased in
      1. Age
      2. Females; pregnancy, oral contraceptive and menopause
      3. Acute phase reaction
      4. Disseminated malignancy
5. Activated clotting time (ACT)
  1. Measures clot formation in intrinsic and common pathways
    1. Freshly obtained blood added to a tube containing negatively charged particles
      1. Negative charge initiates intrinsic pathway
      2. Type of charged particle affects the normal length of ACT
        e.g. Kaolin (90-150secs); glass (110-190secs)
        Prolonged in
        Heparin, hypothermia, platelet dysfunction, haemodilution, cardioplegic solutions, hypofibrinogenemia, factor 9intrinsic and common) deficiencies
      3. Used in cardiopulmonary bypass; haemodialysis; vascular and general surgery
Bleeding disorders
1. Haemophilia A
  1. X-linked (affects mostly males)
  2. Severity associated with the level that factor VIII is affected
  3. Bleeding - joints, gut, trauma, intracerebral haemorrhage at birth
  4. Treated with recombinant factor VIII
  5. Lab results
    1. Long aPTT
    2. Reduced fVIII activity
2. Anticoaglants
  1. Why?
    1. Prevent thrombus formation -> embolus
      1. e.g. DVT and pulmonary embolism
  2. Over-anticoagulation
    1. Reversal urgent!
      1. Heparin overdose
        Give: protamine sulphate
        Inhibits thrombin formation
      2. Warfarin overdose
        Give: vitamin K
        Inhibits vitamin K activating enzymes (vitamin K-epoxide reductase)
        Certain clotting factors arent activated (II, VII, IX, X)
    2. Unstoppable bleeds (prolonged clotting times etc.)
  3. Duration of anticoagulant therapy is important
    1. First DVT/PE (previous risk factors) = 3 month therapy
    2. First DVT/PE (idiopathic = spontaneous) = 6-12 months
    3. >2 episodes = indefinite therapy
  4. Targetting Xa
    1. Why?
      1. Pivotal upstream location - at the start of the common pathway
      2. Primary site of cascade amplification
      3. Rate-limiting component in the production of thrombin
    2. Inhibtion of Xa
      1. One molecule of Xa inhibited prevents ~138 molecules of fibrin being generated
    3. Function of Xa - only to promote coagulation (compared to thrombin)
    4. Indirect Xa inhibitors
      1. Mediated through the binding to and activation of antithrombin(III) - e.g. heparin-like molecules
    5. Direct Xa inhibitors
      1. Bind directly to Xa (without the need for antithrombin(III)
      2. Currently undergoing clinical trials
      3. Inhibit Xa bound to activated platelets
        i.e. trapped within a forming thrombus at the prothrombinase (Xa+Va+Ca(2+) + phospholipids)
        Possible advantage over heparin and indirect Xa inhibitors
        Appears to inhibit thrombus formation, but allow sufficient thrombin formation - mainting the ability to form a haemostatic plug elsewhere
        Lower bleeding risk
  5. Inhibitors of thrombin
    1. Heparin (indirectly through antithrombin(III)
    2. Direct = Bivalirudin
      1. Binds directly to exosite 1 or active site
      2. Does not bind platelet factor 4
      3. Few other interactions
      4. Wide therapeutic window
      5. Expensive

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Haemostasis (part 2: secondary haemostasis)

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