Direct Thrombin Inhibitor

Aka: Direct Thrombin Inhibitor, Antithrombin, Hirudin, Lepirudin, Refludan, Bivalirudin, Angiomax, Desirudin, Ipravask, Argatroban, Acova

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II. Indications

  1. Thrombus prophylaxis, treatment or Unstable Angina and
  2. Heparin-Induced Thrombocytopenia

III. Dosing: Hirudins (bivalent peptide derivatives from Salivary Gland of medicinal leaches)

  1. Lepirudan (Refludan)
    1. See other references for dosing
  2. Bivalirudin (Angiomax)
    1. Used in Unstable Angina if Heparin contraindicated
    2. Coadminister with Aspirin
    3. Initial: 0.75 mg/kg IV bolus
    4. Later: 1.75 mg/kg/hour for 4 hours
    5. Maintenance: 0.2 mg/kg/hour for up to 20 hours
  3. Desirudin (Ipravask)
    1. DVT Prophylaxis: 15 mg SQ q12 hours after hip surgery

IV. Dosing: Non-Hirudans (Univalent agents)

  1. Dabigatran (Pradaxa)
    1. See Dabigatran
  2. Ximelagatran (Exanta, Exarta)
    1. No longer available in United States due to hepatotoxicity
  3. Argatroban (Acova)
    1. Initial: 2 mcg/kg/minute
    2. Maintenance: Adjusted per PTT

V. Pharmacokinetics

  1. Clearance
    1. Renal clearance for Hirudins
    2. Hepatic clearance for L-Arginine derivatives

VI. Precautions

  1. Serious Allergic Reactions may occur to Hirudins
  2. No antidote for bleeding except for Dabigatran (all recommendations per expert opinion)
    1. Dabigatran (Pradaxa) has a specific antidote (Praxbind)
    2. Stop offending agent (most have short half-life such as 12-14 hours for Dabigatran)
    3. Bleeding unlikely due to Direct Thrombin Inhibitor if aPTT <37 seconds and Thrombin Time <25 seconds
    4. Consider Activated Charcoal if presenting within 2 hours of suspected Overdose ingestion
    5. Dialysis is unlikely to be beneficial
      1. Logistics of placing large bore filtered catheters in actively bleeding, coagulopathic patients
    6. Life threatening bleeding - reversal agents
      1. See Emergent Reversal of Anticoagulation

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Ontology: Antithrombins (C0003440)

Definition (MSH) Endogenous factors and drugs that directly inhibit the action of THROMBIN, usually by blocking its enzymatic activity. They are distinguished from INDIRECT THROMBIN INHIBITORS, such as HEPARIN, which act by enhancing the inhibitory effects of antithrombins.
Definition (CSP) endogenous family of proteins belonging to the serpin superfamily that neutralizes the action of thrombin; includes fibrin and antithrombin III.
Concepts Pharmacologic Substance (T121) , Biologically Active Substance (T123) , Amino Acid, Peptide, or Protein (T116)
MSH D000991
SnomedCT 259742007, 414010005
LNC LP175677-6
English Antithrombins, Thrombin Inhibitors, Direct, Direct Antithrombins, Direct Thrombin Inhibitors, Antithrombins, Direct, antithrombin, antithrombins, Antithrombin Proteins, Antithrombin Proteins [Chemical/Ingredient], Direct thrombin inhibitors, Antithrombin, Antithrombin (substance), DTI - direct thrombin inhibitor, Direct thrombin inhibitor (substance), Direct thrombin inhibitor
French Antithrombines, Antithrombiniques directs, Inhibiteurs directs de la thrombine, Anti-thrombines, Antithrombines directes, Antithrombiniques, Anti-thrombiniques
German Direkte Thrombin-Inhibitoren, Direkte Antithrombine, Antithrombine, Direkte Thrombininhibitoren
Czech antithrombiny, přímé inhibitory thrombinu
Italian Antitrombine
Spanish Antitrombinas Directas, Antitrombinas, antitrombina (sustancia), antitrombina, inhibidor directo de trombina (sustancia), inhibidor directo de trombina
Russian ANTITROMBINY, АНТИТРОМБИНЫ
Portuguese Antitrombinas, Antitrombinas Diretas
Polish Antytrombiny
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: argatroban (C0048470)

Definition (NCI) A synthetic derivative of L-arginine with antithrombotic activity. Argatroban is a univalent and direct inhibitor of fibrin-bound thrombin. This agent reversibly binds to the thrombin active site thereby preventing the thrombin-dependent reactions, which include conversion of fibrinogen to fibrin; the activation of factors V, VIII and XI; the activation of protein C; and platelet aggregation. Argatroban is highly selective for thrombin and is able to inhibit the action of both free and clot-associated thrombin. As a result, stabilization of blood clots and coagulation is inhibited.
Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH C031942
SnomedCT 116508003, 398738008
LNC LP94569-8, MTHU032477
English 2-Piperidinecarboxylic acid, 1-(5-((aminoiminomethyl)amino)-1-oxo-2-(((1,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl)amino)pentyl)-4-methyl-, 4-methyl-1-(N(2)-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl)-2-piperidinecarboxylic acid, MMTQAP, MPQA, 1-[5-guanidino-2-[(3-methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonylamino]pentanoyl]-4-methyl-piperidine-2-carboxylic acid, ARGATROBAN, Argatroban (medication), argatroban [Chemical/Ingredient], Argatroban, Argatroban (product), Argatroban (substance), Argipidine, argatroban
Spanish argatrobano (sustancia), argatroban, argatroban (producto), argatrobán (producto), argatroban (sustancia), argatrobán, argatrobano
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: bivalirudin (C0168273)

Definition (NCI) A 20 amino acid long synthetic peptide with thrombin-specific anticoagulant properties. Bivalirudin reversibly binds thrombin, free as well as clot bound, at the catalytic site and the anion-binding exosite, thereby preventing the formation and activation of fibrin, factor XIIIa, and other coagulation factors. This drug is primarily used during coronary angioplasty procedures, in combination with aspirin, in patients with unstable angina.
Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
MSH C074619
SnomedCT 400610005, 129498009
LNC LP171388-4
English Phe-Pro-Arg-Pro-(Gly)4 desulfato-Tyr63'-hirugen, Phe-Pro-Arg-Pro-(Gly)4-desulfohirudin-(53-64), L-Leucine, D-phenylalanyl-L-prolyl-L-arginyl-L-prolylglycylglycylglycylglycyl-L-asparaginylglycyl-L-alpha-aspartyl-L-phenylalanyl-L-alpha-glutamyl-L-alpha-glutamyl-L-isoleucyl-L-prolyl-L-alpha-glutamyl-L-alpha-glutamyl-L-tyrosyl-, Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu, bivalirudin, bivalirudin (medication), BIVALIRUDIN, bivalirudin [Chemical/Ingredient], Bivalirudin (product), Bivalirudin (substance), Bivalirudin
Spanish bivalirrudina, bivalirudina (producto), bivalirudina, bivalirrudina (sustancia), bivalirudina (sustancia)
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: desirudin (C0378366)

Definition (NCI) A synthetic recombinant form of the naturally occurring hirudin, the anticoagulant substance found in leech. Desirudin is a selective and almost irreversible inhibitor of thrombin, both free and clot-bound, by blocking its active site. This anticoagulant agent has no effect on other components of the hemostatic system. Desirudin is particularly used to prevent deep vein thrombosis in patients undergoing hip and knee replacement surgery.
Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
MSH C060225
SnomedCT 319718008, 407117009
English desulfatohirudin, desulphatohirudin, recombinant HV1 hirudin, desirudin, 63-Desulfohirudin(Hirudo medicinalis isoform HV1), desirudin (medication), DESIRUDIN, desirudine, Desirudin (product), Desirudin, Desirudin (substance), Desirudine, Desulfatohirudin
Spanish desirudina (producto), desirudina, desirudina (sustancia), desirudin
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Refludan (C0661608)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
MSH C083544
English Refludan, lepirudin (Refludan), refludan, Hoechst Brand of Lepirudin, Aventis Behring Brand of Lepirudin, Aventis Brand Lepirudin, Aventis Pharma Brand of Lepirudin, Berlex Brand of Lepirudin, Pharmion Brand of Lepirudin, Refludin, Schering Brand of Lepirudin
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: lepirudin (C0772394)

Definition (NCI_NCI-GLOSS) A drug that inhibits blood clotting. It is being studied in cancer treatment.
Definition (NCI) A yeast cell-derived recombinant polypeptide related to the naturally occurring, leech-derived anticoagulant hirudin. Lepirudin directly binds to and inactivates thrombin, producing dose-dependent increases in the activated partial thromboplastin time (aPTT) and prothrombin time (PT). The mechanism of action of this agent is independent of antithrombin III and is not inhibited by platelet factor 4. Natural hirudin, a family of highly homologous isopolypeptides, is produced in trace amounts by the leech Hirudo medicinalis.
Definition (PDQ) A recombinant hirudin, a polypeptide naturally produced by the leech Hirudo medicinalis, derived from yeast cells and a highly specific inhibitor of thrombin. Lepirudin directly binds to thrombin, thereby inactivating the thrombogenic activity of thrombin. This anticoagulant produces dose-dependent increases in activated partial thromboplastin time (aPTT). Its action is independent of antithrombin III and it is not inhibited by platelet factor 4. Check for "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=43356&idtype=1" active clinical trials or "http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?id=43356&idtype=1&closed=1" closed clinical trials using this agent. ("http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&code=C1839" NCI Thesaurus)
Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
MSH C083544
SnomedCT 108995001, 386955005
LNC LP171615-0
English Recombinant Hirudin, 1-Leu-2-Thr-63-desulfohirudin, lepirudin, lepirudin (medication), lepirudin (rDNA), LEPIRUDIN, lepirudin [Chemical/Ingredient], lepirudin,recombinant, Lepirudin, Lepirudin (product), Lepirudin (substance)
Spanish lepirudina (producto), lepirudina (sustancia), lepirudina
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Acova (C0939245)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C031942
English Acova, SmithKline Beecham brand of argatroban
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Angiomax (C0939677)

Concepts Pharmacologic Substance (T121) , Amino Acid, Peptide, or Protein (T116)
MSH C074619
English Angiomax, The Medicines Company brand of bivalirudin
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Hirudins (C1451270)

Definition (MSH) Single-chain polypeptides of about 65 amino acids (7 kDa) from LEECHES that have a neutral hydrophobic N terminus, an acidic hydrophilic C terminus, and a compact, hydrophobic core region. Recombinant hirudins lack tyr-63 sulfation and are referred to as 'desulfato-hirudins'. They form a stable non-covalent complex with ALPHA-THROMBIN, thereby abolishing its ability to cleave FIBRINOGEN.
Definition (CSP) active principle in the buccal gland secretion (saliva) of leeches; it acts as an antithrombin and as an antithrombotic agent.
Concepts Amino Acid, Peptide, or Protein (T116) , Pharmacologic Substance (T121)
MSH D006629
English hirudin, Hirudins [Chemical/Ingredient], HIRUDIN, Hirudins
Swedish Hirudiner
Czech hirudiny
Finnish Hirudiinit
Russian GIRUDIN, GIRUDINY, ГИРУДИН, ГИРУДИНЫ
Polish Hirudyny
French Hirudines
German Hirudine
Italian Irudine
Portuguese Hirudinas
Spanish Hirudinas
Derived from the NIH UMLS (Unified Medical Language System)

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