Thrombotic Therapy

Drugs to prevent patients with thrombotic diseases fall into 3 categories:

  • Prevention of initiation or extension of venous thrombosis
    • Heparin
    • Oral anticoagulant (Coumarins)
  • Anti-platelet drugs
    • Aspirin
    • Prostaglandins
    • Antihistamine
  • Thrombolytic agents
    • Streptokinase
    • Urokinase

Heparin

  • Causes clumping of platelets - not good for platelet counts
  • Commercial source is either porcine intestinal mucosa or bovine lung
  • A negatively charged mucopolysaccharide composed of numerous compounds
  • Occur naturally but is not sufficient to overcome thrombosis: associated with the vascular endothelial cell wall - antithrombogenic; associated with basophil granules
  • Works well in conjunction with anti-thrombin III making it more effective (against XIa, Xa, IXa, XIIa and thrombin (but not VIIa - therefore PT not sensitive to effects of heparin)
  • All activated coagulation factors (CFs) are serine proteases
  • Not absorbed via intestinal mucosa so must be injected intravenously or subcutaneously - not orally.
  • Given intermittently (every 6 hours) or continuously
  • Half life (t1/2) of 1-1.5 hours, then cleared by liver
  • Treats thromboembolic disorders, deep venous thrombosis, pulmonary embolism, DIC and is used as an anticoagulant for blood sampling in laboratory tests
  • Monitored via aPTT (very sensitive to effects) and TCT, but no test is available to measure levels in vivo
  • People undergoing orthopaedic surgery (bone restructuring) are very prone to thrombotic development due to Stasis and the release of thromboplastin. Prophylactic use of heparin is suggested for these cases
  • Clinical asymptomatic thrombocytopaenia develops with heparin treatment. (can drop to less than 20x109/L leading to cranial haemorrhage and death).
  • Antibody develops to heparin (especially bovine) that will be attached to platelets (as heparin attaches to platelets). These platelets are then removed by the spleen leading to HI/AT (Heaprin Induced/Associated Thrombocytopaenia. Not a common occurrence (less than 6% of those treated). Can change to porcine heparin
  • A therapeutic range is usually determined by treatment starting from a broad value of 1.5-2.5x pretreatment baseline aPTT level.
  • Some patients may have a DIC with their conditions - the clinician must determine the exact reason for bleeding (DIC or heparin)
    • TCT and aPTT prolonged for both
    • Reptilase Time-use snake venom added to plasma which directly converts fibrinogen to fibrin
        Insensitive to heparin thus an increased time would indicate DIC
  • Effects can be neutralised by giving protamine sulphate (very positvely charged)

Glutamic acid + CO2 + Vitamin K = gamma Carboxyglutamic Acid

    Depressing Vitamin K synthesis stops glutamate carboxylation which, when occurring, binds calcium in proteins such as II, VII, IX, C and protein C & S, resulting in their activation. Therefore we have these proteins circulating in non-functional forms preventing thrombin generation

Half Life of Coagulation Factors

  • VIII approx 6hrs
  • IX 28-40hrs
  • X 40-50hrs
  • II 48-60hrs

Oral Anticoagulants

  • Belonging to Coumarin anticoagulant group
  • Won't see any effect of anticoagulant therapy until half life of the circulating coagulation factors already present has expired
  • PT monitors Warfarin therapy (X, VII, V, II, I)
  • Monitored 2 or 3 times a week, then every 3 or 4 weeks
  • Overuse will lead to bleeding
  • Vitamin K will neutralise the effects of Warfarin within 24hr (already have inactive precursors present)
  • NEVER given to pregnant women as vitamin K is essential for bone formation

Thrombolytic Agents

  • Something which activates plasminogen ie fibrinolytic agents
  • Streptokinase - acts on plasminogen to promote plasmin formation etc
      Beware of antibodies to this Streptococcus and determine a patients titre first. Usually only given as a single shot
  • Tissue Plasminogen Activator - produced through recombinant methods
  • Urokinase - purified from urine, expensive

Anti-Platelet Agents

    • Given for arterial thrombi (which are usually formed by platelets)
    • Aspirin acts to inhibit cyclooxygenase (c-o) for the lifetime of the platelet and also inhibits c-o in endothelial cells. Therefore at low dosages, inhibits thromboxane production more than prostacyclin and is described as antithrombotic
    • Thromboxane A2 - vasoconstrictor, platelet aggregator and antagonist to prostacyclin
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