Direct thrombin inhibitor
Encyclopedia
Direct thrombin inhibitors (DTIs) are a class of medication
that act as anticoagulant
s (delaying blood clotting
) by directly inhibiting the enzyme
thrombin
. 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.
and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.
would be indicated but cannot be used, such as the acute coronary syndrome
("unstable angina"). As they are administered by injection (intravenous, intramuscular or subcutaneous), they are less suitable for long-term treatment.
Argatroban (as well as the hirudins) are used for heparin-induced thrombocytopenia
, a rare but serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous thrombosis
risk) but not with the putative agent, heparin.
Ximelagatran
showed good efficacy compared with warfarin in several trials in prevention and treatment of deep vein thrombosis
and as thromboprophylaxis in atrial fibrillation
. Development was stopped by manufacturer AstraZeneca
, however, because of reports of liver enzyme derangements and liver failure
. Dabigatran is under development for similar indications. Recent studies have indicated Dabigatran is slightly more effective for stroke thromboprophylaxis in the setting of atrial fibrillation than coumadin.
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.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that act as anticoagulant
Anticoagulant
An anticoagulant is a substance that prevents coagulation of blood. A group of pharmaceuticals called anticoagulants can be used in vivo as a medication for thrombotic disorders. Some anticoagulants are used in medical equipment, such as test tubes, blood transfusion bags, and renal dialysis...
s (delaying blood clotting
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
) by directly inhibiting the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
thrombin
Thrombin
Thrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
. Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin
Heparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
(and derivatives) and warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
in various clinical scenarios.
Types
There are two types of DTIs, dependent on their interaction with the thrombin molecule. Bivalent DTIs (hirudinHirudin
Hirudin is a naturally occurring peptide in the salivary glands of medicinal leeches that has a blood anticoagulant property...
and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.
Bivalent
Hirudin and derivatives were originally discovered in Hirudo medicinalis:- HirudinHirudinHirudin is a naturally occurring peptide in the salivary glands of medicinal leeches that has a blood anticoagulant property...
- BivalirudinBivalirudinBivalirudin is a specific and reversible direct thrombin inhibitor .1Chemically, it is a synthetic congener of the naturally occurring drug hirudin .Bivalirudin is a DTI that overcomes many limitations seen with indirect thrombin inhibitors, such as heparin...
(transient inhibition - is cleaved by thrombin) - LepirudinLepirudinLepirudin 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. It is almost identical to...
- Desirudin
Univalent
Univalent DTIs include:- ArgatrobanArgatrobanArgatroban is an anticoagulant that is a small molecule direct thrombin inhibitor. In 2000, argatroban was licensed by the Food and Drug Administration for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia...
- Melagatran (and its prodrug ximelagatranXimelagatranXimelagatran 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...
) - DabigatranDabigatranDabigatran is an oral anticoagulant from the class of the direct thrombin inhibitors...
Uses
Bivalent DTIs enjoy limited use in circumstances where heparinHeparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
would be indicated but cannot be used, such as the acute coronary syndrome
Acute coronary syndrome
Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....
("unstable angina"). As they are administered by injection (intravenous, intramuscular or subcutaneous), they are less suitable for long-term treatment.
Argatroban (as well as the hirudins) are used for heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is the development of thrombocytopenia , due to the administration of various forms of heparin, an anticoagulant...
, a rare but serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
risk) but not with the putative agent, heparin.
Ximelagatran
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...
showed good efficacy compared with warfarin in several trials in prevention and treatment of deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
and as thromboprophylaxis in atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
. Development was stopped by manufacturer AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
, however, because of reports of liver enzyme derangements and liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
. Dabigatran is under development for similar indications. Recent studies have indicated Dabigatran is slightly more effective for stroke thromboprophylaxis in the setting of atrial fibrillation than coumadin.
Monitoring
There is no therapeutic drug monitoringTherapeutic drug monitoring
- Background :Therapeutic drug monitoring is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication concentrations in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed...
widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). The ecarin clotting time
Ecarin clotting time
Ecarin clotting time is a laboratory test used to monitor anticoagulation during treatment with hirudin, an anticoagulant medication which was originally isolated from leech saliva...
, although not in general clinical use, would be the most appropriate monitoring test.