Pharmacology: Anticoagulants and reversal agents

See our page on haemostasis to understand anticoagulants and where they work on the haemostasis pathway.

Antiplatelets are covered in a separate article.

Classification of anticoagulants

Reversing anticoagulation:

Drugs that block the extrinsic pathway:

Warfarin fast facts:

  • Oral synthetic coumarin derivative inhibiting the synthesis of vitamin K dependent clotting factors 2,7,9 and 10 in the liver, as well as protein C and S
  • In more detail: warfarin prevents oxidised vitamin K from becoming reduced again after gamma carboxylation of glutamic acid residues to activate these clotting factors.
  • Circulating factors are not affected – only the newly synthesised factors are, so full effect takes 72h
  • Monitor by PT and INR (different ranges based on indication)
  • Used for prophylaxis against emboli from AF, rheumatic valve disease, prosthetic valve, DVT and treatment of DVT and PE.
  • Side effects: bleeding, teratogenicity in 1st trimester, 3rd trimester crosses the placenta and can cause haemorrhage. Drug interactions.
  • Effect increased by more free drug after competition for plasma binding sites (NSAIDs) and inhibition of metabolism (cimetidine, alcohol, allopurinol, ciprofloxacin, metronidazole, TCAs)
  • Effect decreased by increased breakdown in combination with CYP450 inducers (eg barbiturates, rifampicin, carbamazepine)
  • 100% absorption from gut, highly protein bound (>95%). Hepatic metabolism and excreted in urine.
  • For quick reversal: Prothrombin complex concentrate (FFP not advised) as this contains a lot of appropriate clotting factors
  • For slower reversal: Hold drug, give vitamin K (takes 8-12 hours or more to start working and more for factor levels to return to normal)
  • Magic number before you can perform a block: INR<1.5

Prothrombin complex concentrate (beriplex/octaplex)

  • Virally inactivated plasma derived coagulation factor concentrate – remove antithrombin and factor XI from plasma
  • Mostly have 3 (2,9, 10) or 4 factors (2, 7, 9, 10) concentrates with clotting factor concentration 25x higher than normal plasma
  • Most of the preparations contain heparin to prevent activation
  • Comes in powder with a solvent which has to be attached to the mix2vial system to be reconstituted .

Advantages over fresh frozen plasma (FFP) –

  • More effective at correcting INR
  • Reduced clinical progression of intracerebral bleeding
  • Smaller volumes of PCC needed to reverse anticoagulation. FFP is often administered at doses of 15ml/kg, but PCC only requires 1-2ml/kg to achieve almost 100% warfarin reversal.
  • PCC quicker to prepare than FFP
  • Stored at room temperature as a powder and does not require warming
  • Viral inactivation so safer than FFP (even for prions)
  • No TRALI risk as antibodies removed during manufacturing process, while FFP has a risk of it

Adverse effects of PCC: Allergic reactions, HIT if heparin in preparations, thromboembolic complications

Drugs that block the intrinsic pathway (and common pathway)

Unfractionated heparin fast facts

  • Anionic, mucopolysaccharide organic acid with sulphate residues. Variable molecular weight 5000-25000 Da. Occurs naturally in liver and mast cell granules.
  • Not absorbed orally.
  • Highly negative charge, low lipid solubility and does not cross BBB or placenta. Highly bound in plasma to antithrombin III, albumin, proteases and fibrinogen
  • Uses: Continuous IV infusion to treat DVT/PE/angina/critical peripheral arterial occlusion, subcutaneous prophylaxis against DVT, priming extracorporeal circuits.
  • Dose for cardiopulmonary bypass = 300 units/kg = approx 21000 units for a 70kg person
  • Mechanism: 1000x increase in rate of formation of anti-thrombin III + thrombin complex. At low concentrations, factor Xa inhibited, and as concentrations rise, factors IXa, XIa and XIIa are progressively inhibited. Platelet aggregation inhibited at high concentrations, plasma triglyceride levels lowered due to release of lipoprotein lipase from tissues and reduction in plasma turbidity.
  • Side effects: Bleeding, thrombocytopaenia (Heparin induced thrombocytopaenia HIT see below)
  • HIT: 2 types, type 1 non immune based, rarely has clinical significance. Type 2 severe immune-mediated thrombocytopaenia within 4-14 days of starting IV/SC heparin. Heparin complexes with platelet factor 4, bound by IgG causing platelet aggregation and thrombosis. Half of these patients develop serious thrombosis after platelet count starts to fall and mortality is very high from pulmonary embolus and arterial thrombosis. Treat by stopping heparin, using alternative eg. argatroban and supportive management.
  • Hypotension after rapid IV administration, osteoporosis and alopecia, hyperkalaemia from inhibition of aldosterone secretion.
  • Metabolised by hepatic heparinase and products excreted in urine
  • Monitor factor Xa levels or APTT/ACT during use
  • Reversed by protamine
Low molecular weight heparins

Enoxaparin, dalteparin, tinzaparin – depolymerised heparin to small molecular weights from 2000-8000 Da given subcutaneously.

Advantages over heparin: single daily dose, longer half life, reduced affinity for von Willebrand factor, less platelet effect and reduced risk of HIT and less need for monitoring. Better at inhibiting factor Xa, less effective at promoting formation inactive antithrombin-thrombin complex.

Disadvantages: Protamine is not fully effective in reversal, dose remaining not known, monitoring difficult as it mainly inhibits factor Xa so APTT not altered

Protamine

Basic protein from fish sperm, positive charge neutralises negatively charged heparin into an inactive complex cleared by the reticuloendothelial system.

Used in formulation of certain insulins and to reverse heparin after cardiopulmonary bypass or interventional procedures.

1mg reverses 100 IU heparin, so for a fully anti coagulated 70kg patient on CPB, 210mg reverses 21000 units heparin. Protamine comes in a 10mg/ml preparation so 21ml of protamine is required.

Side effects:

  • Systemic hypotension from histamine release
  • Pulmonary hypertension due to complement activation and thromboxane release
  • Dyspnoea
  • Bradycardia
  • Flushing after rapid IV administration
  • Anaphylaxis (especially patients receiving insulin and allergic to fish)
  • If given in excess, will cause anticoagulant effects

Direct thrombin inhibitors eg dabigatran – DOAC

  • Used for VTE prophylaxis and AF
  • Competitive direct thrombin inhibitor
  • Prodrug that is rapidly converted by plasma and liver esterases to active dabigatran moiety
  • Dose adjustment in elderly
  • Side effects – bleeding, GI upset
  • Reversed by idarucizumab, which is a specific humanised monoclonal antibody fragment that binds the thrombin-binding site of dabigatran with high affinity, neutralising its anticoagulant effects. IV infusion. Costs £2400 per dose! No dose adjustment required in elderly/renal function/weight.

Factor Xa inhibitors – rivaroxaban, apixaban

  • Used for VTE prophylaxis and treatment and AF
  • Direct Xa inhibitors
  • Interactions with CYP3A4 inducers due to decreased drug levels
  • Risk of haemorrhage, GI upset
  • Monitoring by anti-factor Xa activity assays
  • No antidotes

Drugs that increase fibrin breakdown – streptokinase, alteplase, urokinase

Streptokinase – enzyme produced by group C beta haemolytic streptococci

  • Dissolves clot in arterial and venous vessels (acute MI, peripheral arteries, PE, DVT)
  • Forms a complex with plasminogen and facilitates the conversion of further plasminogen to plasmin. Clot can then by lysed
  • Side effects – massive haemorrhage, reperfusion arrhythmias and hypotension
  • Allergic reactions – very antigenic
  • Given IV as loading dose + infusion

Alteplase – tissue type plasminogen activator = glycoprotein activated only when bound to fibrin, inducing conversion of plasminogen to plasmin. Less fibrinolysis than streptokinase, slightly safer from bleeding point of view

Urokinase – from human male adult urine. Used in lysis of clots in AV shunts and hyphaema (anterior chamber haemorrhage + refractory thrombi)

Drugs that prevent fibrin breakdown – aprotinin and TXA

Aprotinin – proteolytic enzyme inhibitor of trypsin, plasmin and tissue kallikrien. Inhibits activity of streptokinase-plasminogen complex. Preserves platelet function and decreases activation of clotting cascade. Side effects – anaphylaxis, prolongs ACT

Tranexamic acid – synthetic derivative of lysine and available in tablet and IV formulations. Inhibits conversion of plasminogen to plasmin and prevents fibrin breakdown. Used in major trauma (CRASH 2), MOH (WOMAN), elective arthroplasty, cardiac, and multiple other settings to reduce bleeding. Given as a slow IV bolus 0.5-1g.

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