pharmacology 5

bleeding

anticoagulants

heparins
- unfractionated
  - anionic mucopolysaccharide glycosaminoglycan
  - 5 - 25 kDa
  - 4 actions (PLAV)
    - inhibits platelet aggregation
    - release of lipoprotein lipase
      - decreased plasma turbidity
      - lowers plasma triglyceride levels
    - Forms ionic bond with anti-thrombin III which enhances formation of anti-thrombin III-thrombin (factor II) complex 1000x, which inhibits:
      - IX
      - X
        
        at low doses
      - XI
      - XII
    - increased vascular permeability
  - dose
    - prophylaxis: 5000 units BD
    - treatment: 300 units/kg
    - T1/2: 60 minutes
  - PK
    - hepatic heparinise then urine
  - monitored by APTT
  - SE’s ‘HHOAA’
    - HIT
      - 5-14 days after therapy
      - complex between heparin, PF4 and IgG
    - hypotension
    - osteoporosis
    - alopecia
    - aldosterone inhibition
      - HYPERKALAEMIA
  - SC or IV: wait 4 hours before neuroaxial block, then can give 1 hour after, wait 4 hours before removing catheter
  - partially reversed by protamine
    - basic protein
    - binds to and antagonises heparin
    - potent vasodilator and myocardial depressant
    - 1mg antagonises 100 IU of heparin
- LMWH
  - 2 - 8 kDa
  - more effective Xa inhibition
  - advantages
    - more predictable
    - longer T1/2
    - less risk of HIT
    - less effect on vWF and platelets
  - monitoring not normally necessary but would need to be Xa assay
  - wait 12 hours before neuroaxial block, then can give 2 hours later. Wait 24 hours if Tx dose
    
    Luca talk: wait 4 hours! Also double all times if CrCl < 30, wait 8 hours if traumatic or multiple attempts
  - partially reversed by protamine
anti-platelets
- aspirin
  - irreversible COX inhibitor
    - reduced TXA2
  - no contraindication to neuroaxial block
- clopidogrel
  - ADP inhibitor
  - stop 7 days before neuroaxial block
- dipyridamole
  - inhibits adenosine and platelet phosphodiesterase (PDE5 selective), causing increased CAMP and increased PGI2 activity
- abciximab
  - glycoprotein IIb/IIIa inhibitor
  - monoclonal antibody
oral anticoagulants
- warfarin
  - vitamin K epoxide reductase inhibitor
  - inhibits
    - II
    - VII
    - IX
      - metabolised by CYP 2 CCCC 9 (like 2, 7, 9 ,10)
    - X
    - proteins C & S
  - SE’s
    - haemorrhage
    - teratogenicity
    - drug interactions
      - highly protein bound drugs potentiate effect
        
        NSAIDs
        
        amiodarone
        
        OHG's
        
        diuretics
      - CYP450
  - PK
    - racemic (S- 2.5 more potent)
    - met. multiple CYP’s
  - monitored by PT and INR
  - INR < 1.5 before neuroaxial block
fibrinolytics
- streptokinase, urokinase, alteplase
- facilitate conversion of plasminogen to plasmin

Bleeding contd…

arrest of bleeding

normal blood volume = 70mL/kg
products
- whole blood
- PRBC’s
- platelets
  - endogenous plts T1/2 = 4 days
  - cleaved from megakaryocytes
- FFP
  - has all factors but insufficient quantities
- PCC
  - II, VII, XI, X, protein C and protein S
  - better: less volume, less risk of viral transmission, anaphylaxis and transfusion reactions, no thawing, not group specific
  - expensive
- recombinant factor VIIa
  - used in intractable PPH
  - high risk of arterial thrombosis
- cryoprecipitate
  - aim fibrinogen >1g/L
  - also rich in factor VIII, XIII and vWF
- anti-fibrinolytics
  - TXA
reactions
- early
  - haemolytic reaction
  - non-haemolytic febrile reaction
  - TRALI
    - Immune
      - 60%
      - Leukocyte antibodies
    - Non-immune
      - 40%
      - Reactive lipid products from donor
    - Common pathway: neutrophil granulocyte cells migrate to lungs and release free radicals and proteolytic enzymes
  - allergic reaction to proteins
  - reaction to bacterial contamination
  - circulatory overload
  - air embolism
  - citrate toxicity
- late
  - tranfusion related GVHD
    - in immunocompromised
    - maculopapular rash, abdo pain, diarrhoea

measurement

bleeding time
- time to form platelet plug
- not normally increased by warfarin or heparin!
- 2-5 minutes
clotting time
- time to form thrombin
- whole blood clotting time
  - 9 - 12 minutes
- activated clotting time
  - celite added to speed up process
  - 100-140 seconds
- PT
  - tissue factor (e.g. brain extract)
- PTT
  - kaolin
- TT
  - tests conversion of fibrinogen to fibrin
- RT
  - reptilase time
  - snake venom added which should convert fibrinogen to fibrin
- TEG
  - blood moved around a tube and resistance measured
- ROTEM
  - tube moved in blood