Direct thrombin inhibitor

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Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin (factor IIa). Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin (and derivatives) and warfarin in various clinical scenarios.

Contents

Types

There are three types of DTIs, dependent on their interaction with the thrombin molecule. Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site. [1] The third class of inhibitors, which are gaining importance recently, is the allosteric inhibitors.

Bivalent

Hirudin and derivatives were originally discovered in Hirudo medicinalis :

Univalent

Univalent DTIs include:

Allosteric inhibitors

Thrombin demonstrates a high level of allosteric regulation. [2] Allosterism in thrombin is regulated by the exosites 1 and 2 and the sodium binding site. A recent patent review has shown that the general consensus among researchers is that allosteric inhibitors may provide a more regulatable anticoagulant. [3] Some of the allosteric inhibitors discovered include DNA aptamers, [3] benzofuran dimers, [4] benzofuran trimers, [5] as well as polymeric lignins. [6] A new sulfated β-O4 lignin (SbO4L) has been discovered which has shown a dual mechanism of action for anti-thrombosis. This SbO4L shows allosteric inhibition of thrombin for fibrinogen, while providing a competitive inhibition of thrombin interaction with platelet glycoprotein Ibα (GPIbα), thereby preventing thrombin mediated platelet aggregation. [7] However, despite the growing interest and the advances in allosterism, no allosteric thrombin inhibitor has yet reached the stage of clinical trials.

Uses

Bivalent DTIs enjoy limited use in circumstances where heparin would be indicated such as the acute coronary syndrome ("unstable angina"), but cannot be used. As they are administered by injection (intravenous, intramuscular or subcutaneous), they are less suitable for long-term treatment. [1]

Argatroban (as well as the hirudins) is used for heparin-induced thrombocytopenia, a relatively infrequent yet serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous thrombosis risk) but not with the causative agent, heparin. [1]

Ximelagatran showed good efficacy compared with warfarin in several trials in prevention and treatment of deep vein thrombosis and as thromboprophylaxis in atrial fibrillation. [1] Development was stopped by manufacturer AstraZeneca, however, because of reports of liver enzyme derangements and liver failure. [8]

Dabigatran is an oral direct thrombin inhibitor. Dabigatran (Pradaxa) was found to be noninferior to Warfarin in prevention of ischemic stroke, as well as intracranial hemorrhage risk and overall mortality for non-valvular atrial fibrillation according to the RE-LY trial. [9]

Monitoring

There is no therapeutic drug monitoring widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). The ecarin clotting time, although not in general clinical use, would be the most appropriate monitoring test. [1]

See also

Related Research Articles

Anticoagulant Class of drugs

Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart-lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

Heparin Anticoagulant

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatment of heart attacks and unstable angina. It is given by injection into a vein or under the skin. Other uses include inside test tubes and kidney dialysis machines.

Ximelagatran

Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity during trials, and discontinue its distribution in countries where the drug had been approved.

Heparin-induced thrombocytopenia Low platelet count due to heparin, associated with a risk of thrombosis

Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia, due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis because platelets release microparticles that activate thrombin, thereby leading to thrombosis. When thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal antibodies that activate platelets. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.

Factor X Mammalian protein found in Homo sapiens

Factor X, also known by the eponym Stuart–Prower factor, is an enzyme of the coagulation cascade. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.

Hirudin

Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches that has a blood anticoagulant property. This is fundamental for the leeches’ habit of feeding on blood, since it keeps a host's blood flowing after the worm's initial puncture of the skin.

Argatroban

Argatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. In 2000, argatroban was licensed by the Food and Drug Administration (FDA) for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). In 2002, it was approved for use during percutaneous coronary interventions in patients who have HIT or are at risk for developing it. In 2012, it was approved by the MHRA in the UK for anticoagulation in patients with heparin-induced thrombocytopenia Type II (HIT) who require parenteral antithrombotic therapy.

Fondaparinux

Fondaparinux is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.

Rivaroxaban Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

Danaparoid sodium (Orgaran) is an anticoagulant with an antithrombotic action due to inhibition of thrombin generation (TGI) by two mechanisms: indirect inactivation of Factor Xa via AT and direct inhibition of thrombin activation of Factor IX. It also possesses a minor anti-thrombin activity, mediated equally via AT and Heparin Co-factor II producing a ratio of anti-Xa:IIa activity >22. [Meuleman DG. Haemostasis 1992;22:58-65 and Ofosu FA Haemostasis 1992;22:66-72]

Bivalirudin

Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI).

Heparin cofactor II

Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.

Lepirudin is an anticoagulant that functions as a direct thrombin inhibitor.

Dicoumarol

Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K. It is also used in biochemical experiments as an inhibitor of reductases.

Dabigatran Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. It is taken by mouth.

Ecarin clotting time

Ecarin clotting time (ECT) is a laboratory test used to monitor anticoagulation during treatment with hirudin, an anticoagulant medication which was originally isolated from leech saliva. Ecarin, the primary reagent in this assay, is derived from the venom of the saw-scaled viper, Echis carinatus.

An exosite is a secondary binding site, remote from the active site, on an enzyme or other protein.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

References

  1. 1 2 3 4 5 Di Nisio M, Middeldorp S, Büller H (2005). "Direct thrombin inhibitors". N Engl J Med. 353 (10): 1028–40. doi:10.1056/NEJMra044440. PMID   16148288.
  2. ↑ Lechtenberg, BC; Freund, SM; Huntington, JA (Sep 2012). "An ensemble view of thrombin allostery". Biological Chemistry. 393 (9): 889–98. doi:10.1515/hsz-2012-0178. PMID   22944689. S2CID   3065608.
  3. 1 2 Mehta, AY; Jin, Y; Desai, UR (Jan 2014). "An update on recent patents on thrombin inhibitors (2010 - 2013)". Expert Opinion on Therapeutic Patents. 24 (1): 47–67. doi:10.1517/13543776.2014.845169. PMID   24099091. S2CID   24817396.
  4. ↑ Sidhu, Preetpal Singh; Liang, Aiye; Mehta, Akul Y.; Abdel Aziz, May H.; Zhou, Qibing; Desai, Umesh R. (2011). "Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin". Journal of Medicinal Chemistry. 54 (15): 5522–5531. doi:10.1021/jm2005767. ISSN   0022-2623. PMC   3150610 . PMID   21714536.
  5. ↑ Sidhu, Preetpal Singh; Abdel Aziz, May H.; Sarkar, Aurijit; Mehta, Akul Y.; Zhou, Qibing; Desai, Umesh R. (2013). "Designing Allosteric Regulators of Thrombin. Exosite 2 Features Multiple Subsites That Can Be Targeted by Sulfated Small Molecules for Inducing Inhibition". Journal of Medicinal Chemistry. 56 (12): 5059–5070. doi:10.1021/jm400369q. ISSN   0022-2623. PMC   3717983 . PMID   23718540.
  6. ↑ Henry, BL; Monien, BH; Bock, PE; Desai, UR (Nov 2, 2007). "A novel allosteric pathway of thrombin inhibition: Exosite II mediated potent inhibition of thrombin by chemo-enzymatic, sulfated dehydropolymers of 4-hydroxycinnamic acids". The Journal of Biological Chemistry. 282 (44): 31891–9. doi: 10.1074/jbc.M704257200 . PMC   2643123 . PMID   17804413.
  7. ↑ Mehta, AY; Thakkar, JN; Mohammed, BM; Martin, EJ; Brophy, DF; Kishimoto, T; Desai, UR (Apr 10, 2014). "Targeting the GPIbα binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects". Journal of Medicinal Chemistry. 57 (7): 3030–9. doi:10.1021/jm4020026. PMC   4203406 . PMID   24635452.
  8. ↑ "AstraZeneca Decides to Withdraw Exanta" (Press release). AstraZeneca. 2006-02-14. Retrieved 2006-05-08.
  9. ↑ R. Hinojar, J. J. Jimenez-Natcher, C. Fernandez-Golfin and J. L. Zamorano, "New Oral Anticoagulants: a practical guide for physicians," European Heart Journal - Cardiovascular Pharmacotherapy, vol. 1, no. 2, pp. 134-145, 2015.
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