Direct thrombin inhibitors (DTIs) are a class of

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

that act as

anticoagulant 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 the ...

s (delaying

blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

) by directly inhibiting the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...

(factor IIa). Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace

heparin 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 treatm ...

(and derivatives) and

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent strok ...

in various clinical scenarios.

Types

There are three types of DTIs, dependent on their interaction with the thrombin molecule. ''Bivalent'' DTIs (

hirudin Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as '' Hirudo medicinalis'') that has a blood anticoagulant property. This is fundamental for the leeches’ habit of feeding on blood, since it keeps ...

and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site. The third class of inhibitors, which are gaining importance recently, is the allosteric inhibitors.

Bivalent

Hirudin and derivatives were originally discovered in ''

Hirudo medicinalis ''Hirudo medicinalis'', the European medicinal leech, is one of several species of leeches used as "medicinal leeches". Other species of ''Hirudo'' sometimes also used as medicinal leeches include '' H. orientalis'', ''H. troctina'', and '' H. ...

'': *

Hirudin Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as '' Hirudo medicinalis'') that has a blood anticoagulant property. This is fundamental for the leeches’ habit of feeding on blood, since it keeps ...

Bivalirudin Bivalirudin (Bivalitroban), sold under the brand names Angiomax and Angiox and manufactured by The Medicines Company, is a direct thrombin inhibitor (DTI). Chemically, it is a synthetic congener of the naturally occurring drug hirudin, found in ...

(transient inhibition - is cleaved by thrombin) *

Lepirudin Lepirudin is an anticoagulant that functions as a direct thrombin inhibitor. Brand name: Refludan, Generic: Lepirudin rDNA for injection. Lepirudin is a recombinant hirudin derived from yeast cells. Lepirudin is almost identical to hirudin extr ...

* Desirudin

Univalent

Univalent DTIs include: *

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 thrombocyto ...

* Inogatran *

Melagatran Ximelagatran (Exanta or Exarta, H 376/95) 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 therap ...

(and its prodrug

ximelagatran Ximelagatran (Exanta or Exarta, H 376/95) 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 therap ...

) *

Dabigatran 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 kn ...

Allosteric inhibitors

Thrombin demonstrates a high level of

allosteric regulation In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

. 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. Some of the allosteric inhibitors discovered include DNA aptamers, benzofuran dimers, benzofuran trimers, as well as polymeric lignins. 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. 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

would be indicated such as the

acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome (a set of signs and symptoms) due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally loca ...

("unstable angina"), but cannot be used. As they are administered by injection (

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have l ...

or subcutaneous), they are less suitable for long-term treatment. Argatroban (as well as the hirudins) is used for

heparin-induced thrombocytopenia Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis (the abnormal formation of blood clots ...

, a relatively infrequent yet serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous

thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...

risk) but not with the causative agent, heparin.

Ximelagatran Ximelagatran (Exanta or Exarta, H 376/95) 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 therap ...

showed good efficacy compared with warfarin in several trials in prevention and treatment of

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...

and as thromboprophylaxis in atrial fibrillation. Development was stopped by manufacturer

AstraZeneca AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includin ...

, however, because of reports of

liver enzyme Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin tim ...

derangements and liver failure. 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.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.

Monitoring

There is no

therapeutic drug monitoring Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily ...

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.

References

{{Antithrombotics