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BLEEDING &
ANTICOAGULATION
TREATMENTS AND MEDICATIONS
TREATMENTS FOR BLEEDING
 Anticoagulants (anti-thrombics, fibrino-lytic, and thrombo-lytics) are a class of drugs that work to
prevent the coagulation (clotting) of blood. Such substances occur naturally in leeches and blood-
sucking insects.
 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 equipment.
TREATMENTS FOR BLEEDING
Medications
 Anticoagulants reduce blood clotting which can help prevent deep vein thrombosis, pulmonary
embolism, myocardial infarction and ischemic stroke.
 The new oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have been
shown to be as good or better than the coumarins (vitamin K antagonists) with less serious side effects.
TREATMENTS FOR BLEEDING
Coumarins (vitamin K antagonists):
 These oral anticoagulants are derived from coumarin, which is found in many plants. A prominent
member of this class is warfarin (Coumadin). It takes at least 48 to 72 hours for the anticoagulant effect to
develop. Where an immediate effect is required, heparin must be given concomitantly.
 These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism
(PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves.
COUMARINS
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.
 These oral anticoagulants are used widely as poisons for mammalian pests, especially rodents.
(For details, see rodenticide and warfarin.) Depletion of vitamin K by Coumadin therapy increases
risk of arterial calcification and heart valve calcification, especially if too much vitamin D is present
Available agents
 Warfarin (Coumadin) is the main agent used in the US and UK.
 Acenocoumarol and phenprocoumon are used more commonly outside the US and the UK.
 Atromentin
HEPARIN AND DERIVATIVE
SUBSTANCES
 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. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually
have a green cap.
HEPARIN AND DERIVATIVE
SUBSTANCES
 Low molecular weight heparin
Low molecular weight heparin, a more highly processed product, is useful as it does not require monitoring of the APTT
coagulation parameter (it has more predictable plasma levels) and has fewer side effects.
Synthetic pentasaccharide inhibitors of factor Xa:
 Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharide) in heparin that bind to antithrombin. It is a
smaller molecule than low molecular weight heparin.
 Idraparinux
 Direct factor Xa inhibitors
 Direct thrombin inhibitors
 Antithrombin protein therapeutics
 Other types of anticoagulants
DIRECT FACTOR XA INHIBITORS
 Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike the
heparins and fondaparinux, which work via antithrombin activation).
 Also betrixaban (LY517717) from Portola Pharmaceuticals, darexaban (YM150) from Astellas and more
recent TAK-442 letaxaban (Takeda) and eribaxaban (PD0348292) (Pfizer).
 The development of darexaban was discontinued in September 2011: in a trial for prevention of
recurrences of myocardial infarction in top of dual antiplatelet therapy, the drug did not demonstrate
effectiveness and the risk of bleeding was increased by approximately 300%.
 The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following
negative results from a Phase II study.
DIRECT THROMBIN INHIBITORS
 Another type of anticoagulant is the direct thrombin inhibitor.
 Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin; and
the monovalent drugs argatroban and dabigatran.
 An oral direct thrombin inhibitor, ximelagatran (Exanta) was denied approval by the Food and
Drug Administration (FDA) in September 2004 and was pulled from the market entirely in
February 2006 after reports of severe liver damage and heart attacks.
 In November 2010, dabigatran was approved by the FDA to treat atrial fibrillation.
ANTITHROMBIN PROTEIN
THERAPEUTICS
 The antithrombin protein itself is used as a protein therapeutic that can be purified from human
plasma or produced recombinantly (for example, Atryn, which is produced in the milk of
genetically modified goats.)
 Antithrombin is approved by the FDA as an anticoagulant for the prevention of clots before,
during, or after surgery or birthing in patients with hereditary antithrombin deficiency.
OTHER TYPES OF ANTICOAGULANTS
Many other anticoagulants exist, for use in research and development, diagnostics,
or as drug candidates.
 Batroxobin, a toxin from a snake venom, clots platelet-rich plasma without
affecting platelet functions (lyses fibrinogen).
 Hementin is an anticoagulant protease from the salivary glands of the giant
Amazon leech, Haementeria ghilianii.
Thank you for your time!
End of Seminar

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Bleeding

  • 2. TREATMENTS FOR BLEEDING  Anticoagulants (anti-thrombics, fibrino-lytic, and thrombo-lytics) are a class of drugs that work to prevent the coagulation (clotting) of blood. Such substances occur naturally in leeches and blood- sucking insects.  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 equipment.
  • 3. TREATMENTS FOR BLEEDING Medications  Anticoagulants reduce blood clotting which can help prevent deep vein thrombosis, pulmonary embolism, myocardial infarction and ischemic stroke.  The new oral anticoagulants (NOACs) including dabigatran, rivaroxaban, and apixaban have been shown to be as good or better than the coumarins (vitamin K antagonists) with less serious side effects.
  • 4. TREATMENTS FOR BLEEDING Coumarins (vitamin K antagonists):  These oral anticoagulants are derived from coumarin, which is found in many plants. A prominent member of this class is warfarin (Coumadin). It takes at least 48 to 72 hours for the anticoagulant effect to develop. Where an immediate effect is required, heparin must be given concomitantly.  These anticoagulants are used to treat patients with deep-vein thrombosis (DVT), pulmonary embolism (PE) and to prevent emboli in patients with atrial fibrillation (AF), and mechanical prosthetic heart valves.
  • 5. COUMARINS 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.  These oral anticoagulants are used widely as poisons for mammalian pests, especially rodents. (For details, see rodenticide and warfarin.) Depletion of vitamin K by Coumadin therapy increases risk of arterial calcification and heart valve calcification, especially if too much vitamin D is present Available agents  Warfarin (Coumadin) is the main agent used in the US and UK.  Acenocoumarol and phenprocoumon are used more commonly outside the US and the UK.  Atromentin
  • 6. HEPARIN AND DERIVATIVE SUBSTANCES  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. In venipuncture, Vacutainer brand blood collecting tubes containing heparin usually have a green cap.
  • 7. HEPARIN AND DERIVATIVE SUBSTANCES  Low molecular weight heparin Low molecular weight heparin, a more highly processed product, is useful as it does not require monitoring of the APTT coagulation parameter (it has more predictable plasma levels) and has fewer side effects. Synthetic pentasaccharide inhibitors of factor Xa:  Fondaparinux is a synthetic sugar composed of the five sugars (pentasaccharide) in heparin that bind to antithrombin. It is a smaller molecule than low molecular weight heparin.  Idraparinux  Direct factor Xa inhibitors  Direct thrombin inhibitors  Antithrombin protein therapeutics  Other types of anticoagulants
  • 8. DIRECT FACTOR XA INHIBITORS  Drugs such as rivaroxaban, apixaban and edoxaban work by inhibiting factor Xa directly (unlike the heparins and fondaparinux, which work via antithrombin activation).  Also betrixaban (LY517717) from Portola Pharmaceuticals, darexaban (YM150) from Astellas and more recent TAK-442 letaxaban (Takeda) and eribaxaban (PD0348292) (Pfizer).  The development of darexaban was discontinued in September 2011: in a trial for prevention of recurrences of myocardial infarction in top of dual antiplatelet therapy, the drug did not demonstrate effectiveness and the risk of bleeding was increased by approximately 300%.  The development of letaxaban was discontinued for acute coronary syndrome in May 2011 following negative results from a Phase II study.
  • 9. DIRECT THROMBIN INHIBITORS  Another type of anticoagulant is the direct thrombin inhibitor.  Current members of this class include the bivalent drugs hirudin, lepirudin, and bivalirudin; and the monovalent drugs argatroban and dabigatran.  An oral direct thrombin inhibitor, ximelagatran (Exanta) was denied approval by the Food and Drug Administration (FDA) in September 2004 and was pulled from the market entirely in February 2006 after reports of severe liver damage and heart attacks.  In November 2010, dabigatran was approved by the FDA to treat atrial fibrillation.
  • 10. ANTITHROMBIN PROTEIN THERAPEUTICS  The antithrombin protein itself is used as a protein therapeutic that can be purified from human plasma or produced recombinantly (for example, Atryn, which is produced in the milk of genetically modified goats.)  Antithrombin is approved by the FDA as an anticoagulant for the prevention of clots before, during, or after surgery or birthing in patients with hereditary antithrombin deficiency.
  • 11. OTHER TYPES OF ANTICOAGULANTS Many other anticoagulants exist, for use in research and development, diagnostics, or as drug candidates.  Batroxobin, a toxin from a snake venom, clots platelet-rich plasma without affecting platelet functions (lyses fibrinogen).  Hementin is an anticoagulant protease from the salivary glands of the giant Amazon leech, Haementeria ghilianii.
  • 12. Thank you for your time! End of Seminar