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Understanding Pharm: Overview of anticoagulants

3 main mechanisms for anticoagulants

  • Increased effectiveness of antithrombin
  • Directly inhibiting factors 2 and 10
  • Vitamin K antagonists
File:Coagulation full.svg - Wikimedia Commons

Increased effectiveness of antithrombin

Antithrombin is an endogenous substance that mainly inhibits thrombin (factor 2) , 10, 9, 11. Antithrombin has a heparin binding site – when heparin binds to this site, it increases the effectiveness of antithrombin.

In this category we find unfractionated heparin and low molecular weight heparin. We also have fondaparinux which is a synthetic form of heparin.

Unfractionated heparin (otherwise known as just heparin) inactivates factors 10, 2, 9, 11 and 12. Because of its quick onset and offset you may most commonly see it being used perioperatively in hospitals. However, because of its short half life, it is typically given as a continuous infusion but can also be given subcutaneously. UFH is monitored using the aPTT and anti-Xa assay. For urgent reversal of heparin, protamine sulfate is the antidote.

Low molecular weight heparin inactivates factors 2 and 10. In comparison to UFH, it has better bioavailability, and because its effects are more predictable (better correlation between dose and response), it is typically not monitored in the lab and if monitoring is required you can use the anti-Xa assay but not the aPTT. Because of its longer duration of action compared to UFH, it is more suitable for outpatient use than UFH. For urgent reversal of LMWH, there is no good antidote.

LMWH includes

  • Enoxaparin
  • Tinzaparin
  • Nadroparin
  • Dalteparin

UFH has a higher incidence of HIT but also has a reversal agent (protamine sulfate) compared to LMWH which has a 30x lower incidence of HIT and no reversal agent or antidote!

Fondaparinux is a synthetic anticoagulant that also combines with antithrombin like UFH and LMWH, except that it only inhibits factor 10, and not factor 2 like LMWH. However, similar to LMWH it is monitored with the anti-Xa assay and not the aPTT. For urgent reversal of fondaprinux there is no good antidote.

Direct inhibitors of FIIa and FXa (DOACs)

These inhibitors are much more straightforward. They simply directly inhibit the activity of 2 of the common pathway factors (Canadian denominations of currency: 10, 5, 2, 1).

Dabigatran is a factor 2 (thrombin) inhibitor. It is mainly renally cleared and can be used in severe hepatic dysfunction, but cannot be used in patients with a GFR < 30 mL/min. Dabigatran in cases of VTE thromboprophylaxis requires LMWH during the first 5 days of its use.

Rivaroxaban, Apixaban and Edoxaban are all factor 10 inhibitors. Rivaroxaban is intermediately cleared by the kidneys (66 % renal) and apixaban is minimally cleared by the kidneys (25 % renal) and can be used in patients with a GFR > 15 mL/min, but cannot be used in patients with severe hepatic dysfunction.

With direct factor 10 inhibitors you are BANNING factor X!

Dabigatran is a factor 2 inhibitor and is mainly renally cleared.

Rivaroxaban and apixaban are factor 10 inhibitors and are cleared by the liver and kidneys and cannot be used in severe hepatic dysfunction.

Dabigatran and apixaban are BID dosing.

Rivaroxoaban is once daily dosing.

No antidotes for DOACs. No need to monitor INR and aPTT.

Vitamin K antagonists (VKA)

There are certain clotting factors that require vitamin K for their synthesis in the liver as vitamin K acts as a co-factor in an essential enzymatic step of their production. VKA antagonists essential decrease the amount of active vitamin K that is available in the body which decreases the production of vitamin K dependent coagulation factors. These factors include factors 10, 9, 7 and 2 (1972 – Canada and Russia hockey game). (Quick side tip to remember what antithrombin acts on it’s just 1972 but with the 7 and 11 switched, so it’s factors 10, 9, 11 and 2 affected think 7/11)

Warfarin initially also inhibits the production of protien C and S. Like antithrombin, protein C and S are endogenous antithrombotic substances. Warfarin initially increases the production of protein C and S which actually increases the risk of bleeding for the first few days they are on it. This is why we bridge warfarin with heparin.

Warfarin must be monitored with routine INR measurements. The therapeutic range of INR for warfarin generally falls between 2-3 (INR normally should be 0.9 – 1.2), however for certain conditions like having a mechanical heart valve, a higher INR may be required (2.5 – 3.5).

Scenarios in which warfarin may be preferred over newer agents include

  • CKD (as it is not renally cleared)
  • Inexpensive
  • Heart valve replacement patients
  • Anti phospholipid syndrome
  • Easily reversible (simply provide vitamin K, or frozen prothrombin complex concentrate – blood product which contains factors 10, 9, 7 and 2, protein C and protein S)

When should we avoid warfarin?

  • Pregnancy (crosses the placenta)
  • Acute situations since it initially decreases levels of the body’s endogenous anticoagulants, protein C and S
  • Cirrhosis
  • Cancer venous thromboembolism