Anticoagulant

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Resident
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Guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some chemical compounds are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis equipment. They also have military applications, whereby their introduction into the wounds of enemy soldiers will make their treatment significantly more difficult.

As medications

Anticoagulants are given to people to stop thrombosis (blood clotting inappropriately in the blood vessels). This is useful in primary and secondary prevention of deep vein thrombosis, pulmonary embolism, myocardial infarctions and strokes.

Vitamin K antagonists

The oral anticoagulants are a class of pharmaceuticals that act by antagonizing the effects of vitamin K.

Examples include:

It is important to note that they take at least 48 to 72 hours for the anticoagulant effect to develop fully. In cases when any immediate effect is required, heparin must be given concomitantly. Generally, these anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation (AF), and mechanical prosthetic heart valves.

Adverse effects

Patients aged 80 years or more may be especially susceptible to bleeding complications with a rate of 13 bleeds per 100 person-years.[1]

These oral anticoagulants are used widely as poisons for mammalian pests, especially rodents. (For details, see rodenticide and warfarin.)

Available agents

The most important oral anticoagulants are:

Heparin and derivative substances

Main article: Heparin

Heparin is a biological substance, usually made from pig intestines. It works by activating antithrombin III, which blocks thrombin from clotting blood. Heparin can be used in vivo (by injection), and also in vitro to prevent blood or plasma clotting in or on medical devices. Vacutainer brand test tubes containing heparin are usually colored green.

Low molecular weight heparin

Low molecular weight heparin is a more highly processed product that is useful as it does not require monitoring of the APTT coagulation parameter (it has more predictable plasma levels) and has fewer side effects.

Ultra low molecular weight heparin

Ultra low molecular weight heparin

Direct Acting Oral Anticoagulants

The direct acting oral anticoagulants act in various locations of the coagulation cascade.

  • The role of direct acting oral anticoagulants for the treatment of pulmonary embolism has been reviewed by the Cochrane Collaboration.[2]
  • Recommendations for safe usage have been made by Thrombosis Canada.[3]
  • "An elevated PT for anti-Xa inhibitors and an elevated aPTT for dabigatran suggest clinically relevant drug effect at the time of testing" but "Up to 50% of people taking a direct Xa inhibitor with clinically relevant anticoagulation effect can have a normal PT"[4].
  • These agents can probably be reversed with prothrombin complex concentrate according to case series of patients[5]

Factor Xa Inhibitors

Direct factor Xa Inhibitors

Factor Xa Inhibitors, "xabans" include:

Factor Xa inhibitors can be reversed by andexanet.[6][7]

Pentasaccharides

Pentasaccharides are synthetic sugar composed of the five sugars (pentasaccharide) in heparin that bind to antithrombin III and so are indirect inhibitors of factor Xa. They are smaller molecules than low molecular weight heparin. Pentasaccharides may help prevent venous thromboembolism[8] and heparin-induced thrombocytopenia[9].

Examples include:

Direct thrombin inhibitors

Main article: direct thrombin inhibitor

Direct thrombin inhibitors include:[10]

An oral direct thrombin inhibitor, ximelagatran (Exanta®) was denied approval by the Food and Drug Administration (FDA) in September 2004 [2] and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks. [3]

Idarucizumabcan reverse dabigatran.

Reversal of DOACS

A consensus statement[11] and clinical practice guidelines are available to guide reversal decisions[12].

Prothrombin complex concentrate (PCC) can reverse DOACs but can be prothrombotic.

Antifibrinolytics such as tranexamic acid and epsilon-aminocaproic acid can reverse DOACs.

Ciraparantag (aripazine) can reverse many anticoagulants including Factor Xa Inhibitors (edoxaban[13]) and heparins.

Reversal of Factor Xa Inhibitors

Andexanet Alfa can reverse Factor Xa Inhibitors[6][14][7].

Ciraparantag (aripazine) can reverse (edoxaban[13]).

Reversal of Direct thrombin inhibitors (DTIs)

Idarucizumab is a monoclonal antibody that specifically reverses dabigatran[15][16].

Anticoagulants outside the body

Laboratory instruments, test tubes, blood transfusion bags, and medical and surgical equipment will get clogged up and become nonoperational if blood is allowed to clot. Chemicals can be added to stop blood clotting. Apart from heparin, most of these chemicals work by binding calcium ions, preventing the coagulation proteins from using them.

  • EDTA is denoted by mauve or purple caps on Vacutainer brand test tubes. This chemical strongly and irreversibly binds calcium. It is in a powdered form.
  • Citrate is usually in blue Vacutainer tube. It is in liquid form in the tube and is used for coagulation tests, as well as in blood transfusion bags. It gets rid of the calcium, but not as strongly as EDTA. Correct proportion of this anticoagulant to blood is crucial because of the dilution. It can be in the form of sodium citrate or ACD.
  • Oxalate has a similar mechanism to citrate. It is the anticoagulant used in fluoride (grey top) tubes.

For the meaning of more colors, see Vacutainer#including coagulants.

References

  1. ↑ Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S (2007). "Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation". Circulation. 115 (21): 2689–96. doi:10.1161/CIRCULATIONAHA.106.653048. PMID 17515465.
  2. ↑ Robertson L, Kesteven P, McCaslin JE (2015). "Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism". Cochrane Database Syst Rev. 12: CD010957. doi:10.1002/14651858.CD010957.pub2. PMID 26636644.
  3. ↑ Gladstone DJ, Geerts WH, Douketis J, Ivers N, Healey JS, Leblanc K (2015). "How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society". Ann Intern Med. 163 (5): 382–5. doi:10.7326/M15-0143. PMID 26121536.
  4. ↑ Sholzberg M, Xu Y. Coagulation Test Interpretation in a Patient Taking Direct Oral Anticoagulant Therapy. JAMA. Published online September 14, 2018. doi:10.1001/jama.2018.13998
  5. ↑ Levy JH, Douketis J, Steiner T, Goldstein JN, Milling TJ (2018). "Prothrombin Complex Concentrates for Perioperative Vitamin K Antagonist and Non-vitamin K Anticoagulant Reversal". Anesthesiology. doi:10.1097/ALN.0000000000002399. PMID 30157037.
  6. ↑ 6.0 6.1 Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH; et al. (2019). "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors". N Engl J Med. 380 (14): 1326–1335. doi:10.1056/NEJMoa1814051. PMID 30730782.
  7. ↑ 7.0 7.1 Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL; et al. (2015). "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity". N Engl J Med. doi:10.1056/NEJMoa1510991. PMID 26559317.
  8. ↑ Dong K, Song Y, Li X, Ding J, Gao Z, Lu D; et al. (2016). "Pentasaccharides for the prevention of venous thromboembolism". Cochrane Database Syst Rev. 10: CD005134. doi:10.1002/14651858.CD005134.pub3. PMID 27797404.
  9. ↑ Aljabri A, Huckleberry Y, Karnes J, Gharaibeh M, Kutbi HI, Raz Y; et al. (2016). "Cost-effectiveness of anticoagulants for the management of suspected heparin-induced thrombocytopenia in the US". Blood. doi:10.1182/blood-2016-07-728030. PMID 27793877.
  10. ↑ Di Nisio M, Middeldorp S, Büller HR (2005). "Direct thrombin inhibitors". N. Engl. J. Med. 353 (10): 1028–40. doi:10.1056/NEJMra044440. PMID 16148288.
  11. ↑ Cuker A, Burnett A, Triller D, Crowther M, Ansell J, Van Cott EM; et al. (2019). "Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum". Am J Hematol. 94 (6): 697–709. doi:10.1002/ajh.25475. PMID 30916798. Comment in JWatch
  12. ↑ Milling TJ, Pollack CV (2020). "A review of guidelines on anticoagulation reversal across different clinical scenarios - Is there a general consensus?". Am J Emerg Med. 38 (9): 1890–1903. doi:10.1016/j.ajem.2020.05.086. PMC 9245126 Check |pmc= value (help). PMID 32750627 Check |pmid= value (help).
  13. ↑ 13.0 13.1 Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso MA, Brown K; et al. (2017). "Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban". Thromb Haemost. 117 (2): 238–245. doi:10.1160/TH16-03-0224. PMC 6260118. PMID 27853809.
  14. ↑ Milling TJ, Middeldorp S, Xu L, Koch B, Demchuk A, Eikelboom JW; et al. (2023). "Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors". Circulation. 147 (13): 1026–1038. doi:10.1161/CIRCULATIONAHA.121.057844. PMID 36802876 Check |pmid= value (help).
  15. ↑ Pollack CV, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA; et al. (2017). "Idarucizumab for Dabigatran Reversal - Full Cohort Analysis". N Engl J Med. 377 (5): 431–441. doi:10.1056/NEJMoa1707278. PMID 28693366.
  16. ↑ Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA; et al. (2015). "Idarucizumab for Dabigatran Reversal". N Engl J Med. 373 (6): 511–20. doi:10.1056/NEJMoa1502000. PMID 26095746.

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