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Anticoagulant antiplatelet thrombolytic by Dr. William K Lim
- 2. Antiplatelet, Anticoagulant & Thrombolytic Drugs Drugs for 1. Arterial thrombi - antiplatelet drugs 2. Venous thrombi – anticoagulant drugs 3. Existing clot – thrombolytic/fibrinolytic drugs
- 3. 1. arterial thrombi Arterial thrombi: • occur in areas of rapid blood flow e.g. arteries • composed mainly of platelets • result: the clot occludes an artery e.g. coronary or cerebral arteries
- 4. 2. venous thrombi Venous thrombi: • occur in areas of slower blood flow e.g. due to venous stasis or injury/trauma • composed of fibrin and RBC (less platelet) • result: venous thrombosis - clot obstructs a vein e.g. deep vein thrombosis pulmonary embolism
- 5. 3. Existing clot (occluded artery)
- 6. Introduction Arterial thrombi: • composed mainly of platelets
- 7. Introduction to Platelet Aggregation • Platelets form a monolayer at rupture site by binding von Willebrand factor (vWF) released by endothelium • Platelets adhere to collagen at sub-endothelial layer • Platelets are activated and undergo shape change
- 8. Introduction to Platelet Aggregation • Activated platelets release agonists ADP, TXA2 etc to further activate platelets, and agonist 5HT cause vasoconstriction
- 9. Introduction to Platelet Aggregation • GP IIb/IIIa receptors bind (mainly) to fibrinogen •Activated platelets express glycoprotein GP IIb/IIIa receptors
- 10. Introduction to Thrombus Formation • Thrombin (IIa) is produced- activates & aggregates platelets, convert fibrinogen to fibrin & activates Factor XIII to cross-link fibrin to stabilise thrombus.
- 11. Introduction to Thrombus Formation • The stable thrombus traps RBC, macrophages etc • The clot may occlude an artery or form emboli
- 12. Introduction to Thrombus Formation • Design a drug to to prevent arterial thrombi (strokes, MI) - what mechanism do you suggest the drug to have?
- 13. Antiplatelet Drugs: Aspirin (Non Steroidal Anti Inflammatory Drug, NSAID)
- 14. NSAIDs: Mechanism Inflammation Stimulus Cell membranes -phospholipid phospholipase Arachidonic Acid cyclooxygenase (COX-1, COX-2) lipooxygenase leukotrienes prostaglandin, thromboxane, prostacyclin phagocyte activation, etc inflammation alter vascular permeability, secretion inflammation platelet aggregation
- 15. NSAIDs: Mechanism Stimulus Cell membranes -phospholipid phospholipase Arachidonic Acid Cyclooxygenase (COX-1, COX-2) lipooxygenase leukotrienes prostaglandin, thromboxane, prostacyclin phagocyte activation, etc inflammation alter vascular permeability secretion inflammation platelet aggregation
- 16. NSAIDs: Mechanism Stimulus Cell membranes -phospholipid phospholipase Arachidonic Acid Cyclooxygenase (COX-1, COX-2) lipooxygenase leukotrienes prostaglandin, thromboxane, prostacyclin phagocyte activation, etc inflammation alter vascular permeability secretion inflammation platelet aggregation
- 17. Antiplatelet Drugs (NSAID) : Aspirin
- 18. Antiplatelet Drugs (NSAID) : Aspirin Mechanism: • Inhibits mainly COX-1 cyclooxygenase in platelets
- 19. Antiplatelet Drugs (NSAID) : Aspirin Mechanism: • Inhibits mainly COX-1 in platelets - prevents formation of thromboxane A2 (TXA2) in platelets • Since platelets cannot synthesise new proteins, aspirin inhibits COX-1 activity for the lifespan of the platelet (~10 days).
- 20. Antiplatelet Drugs (NSAID) : Aspirin Mechanism: • Prevents platelet releasing TXA2. (Does not prevent platelet aggregation promoted by thrombin, etc. -partial inhibitor of platelet activation) Indications • Secondary prevention of MI, stroke & TIA (in patients who had one episode) • Prevent early graft closure after coronary bypass surgery
- 21. Antiplatelet Drugs (NSAID) : Aspirin Adverse Effect • GI side effects e.g. dyspepsia, nausea (take after food or use enteric coated tablets) • GI bleeding - COX-1 is also the main COX isoform in gastric mucosa - a source of cytoprotective prostaglandin
- 22. Antiplatelet Drugs: Thienopyridines e.g. Ticlopidine
- 23. Antiplatelet Drugs: Thienopyridines e.g. Ticlopidine Mechanism: Irreversibly inhibit the binding of ADP to its receptor on platelets (reduce activation of GP IIb/IIIa receptor)
- 24. Antiplatelet Drugs: Thienopyridines e.g. Ticlopidine Mechanism: Irreversibly inhibit the binding of ADP to its receptor on platelets (reduce activation of GP IIb/IIIa receptor) Use • superior in prevention of vascular events, without increase in bleeding episodes. • Can be used when aspirin is contraindicated/failed.
- 25. Antiplatelet Drugs: Thienopyridines e.g. Ticlopidine Adverse Effect Can cause neutropenia (in first 3 months): - do complete blood count before starting
- 26. Antiplatelet Drugs: Thienopyridines e.g. Clopidogrel
- 27. Antiplatelet Drugs: Thienopyridines e.g. Clopidogrel • Similar to ticlopidine – irreversible inhibitor of a subtype of ADP receptor • lower risk of neutropenia • Slightly better than aspirin in reducing MI, stroke, vascular death, with less GI bleeding.
- 28. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. tirofiban (i.v.)
- 29. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. tirofiban (i.v.) Mechanism • antagonist of the GPIIb/IIIa receptor in platelets - prevents binding of fibrinogen to the receptor, reducing platelet aggregation
- 30. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. tirofiban (i.v.) Use • prevention of death (by MI) in patients with acute coronary syndrome (unstable coronary artery disease - from unstable angina to myocardial infarction) Adverse effect • Most common: increased bleeding
- 31. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists
- 32. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. abciximab (i.v.)
- 33. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. abciximab (i.v.) Mechanism • Antagonist of the GPIIb/IIIa receptor in platelets
- 34. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. abciximab (i.v.) Mechanism • Antagonist of the GPIIb/IIIa receptor in platelets Use 1.To prevent acute cardiac ischaemic complications in patients with unstable angina waiting for angioplasty 2.To reduce complications (M.I./death) during angioplasty
- 35. Antiplatelet Drugs: Glycoprotein IIb/IIIa Receptor Antagonists e.g. abciximab (i.v.) Adverse Effect • Bleeding (especially GI) • Acute severe thrombocytopenia in 0.5% of patients - do platelet counts.
- 37. Introduction: venous thrombi • occur in areas of slower blood flow e.g. due to venous stasis or injury/trauma. • composed of fibrin and trapped RBC (some platelets attach to fibrin)
- 38. Introduction: Economy Class Syndrome “economy class syndrome” : minimal leg movement on long haul flights
- 39. What is the purpose of flight socks? Compression stockings
- 40. Introduction: Deep Vein Thrombosis • Signs/Symptoms: pain, tenderness, swelling, discolouration • Complication: pulmonary embolism
- 41. Anticoagulant Drugs • Anticoagulation = the process of slowing down normal blood clotting to prevent the formation of blood clots. • Anticoagulant = a drug/chemical that slows down or prevents formation of blood clot. Aims of anticoagulant drug therapy: 1. prevent the formation of new blood clots 2. stop existing clots from growing, without causing bleeding complications
- 43. Other Indications for Anticoagulants As prophylaxis against embolisation due to: - Thrombosis arising from major orthopaedic surgery or general surgery in high risk patients (e.g. history of DVT) - Prosthetic heart valve - Heart valve disease - Atrial fibrillation (risk of ischaemic stroke)
- 44. Introduction: Other Indications for Anticoagulation Therapy Prophylaxis against embolisation in: - Thrombosis arising from major orthopaedic surgery or general surgery in high risk patients (e.g. history of DVT) - Prosthetic heart valve - Mitral valve disease - Atrial fibrillation (risk of ischaemic stroke) Prevent occlusion of extra-corporeal devices: intravascular cannulas, haemodialysis machine
- 45. Important parenteral and oral anticoagulants
- 46. Important parenteral and oral anticoagulants • Parenteral : heparin • Oral: warfarin dabigatran
- 47. Heparin
- 48. Heparin • Source • Mechanism • Administration/Onset • Adverse effect/overdose • Monitoring * Standard heparin vs low molecular weight heparins
- 49. Heparin • Natural Source: complex mucopolysaccharide found in secretory granules of mast cells.
- 50. Heparin • Natural Source: complex mucopolysaccharide found in secretory granules of mast cells. • Commercial source: - extracted from porcine GI mucosa/bovine lung - mixture of mucopolysaccharides of 3-30 kDa
- 51. Heparin • Mechanism: prevents further growth of thrombus by binding and activating antithrombin III (“heparin cofactor”). Antithrombin III is synthesised in the liver and circulate in the plasma.
- 52. Heparin • Mechanism: prevents further growth of thrombus by binding and activating antithrombin III (“heparin cofactor”). Antithrombin III is synthesised in the liver and circulate in the plasma. Heparin antithrombin III ACTIVATE
- 53. Heparin • Mechanism: prevents further growth of thrombus by binding and activating antithrombin III (“heparin cofactor”). Antithrombin III is synthesised in the liver and circulate in the plasma. Heparin antithrombin III activated factors XII, XI, X, IX & IIa (thrombin) ACTIVATE BIND & INACTIVATE
- 54. Heparin Administration/Onset • Not absorbed through the GI mucosa • Administer parenterally: - continuous or intermittent i.v. : immediate onset - subcutaneous: 1-2 hours to onset of action
- 55. Heparin Adverse effect • Most important: bleeding (2-5%)
- 56. Heparin Adverse effect (1) Most important: bleeding (2-5%) Usual sites: GIT (melaena) urinary tract (haematuria) oropharynx (epistaxis) soft tissue (haematoma, ecchymosis)
- 57. Heparin Adverse effect (1)Most important: bleeding (2-5%) (2)Thrombocytopenia (platelets < 100,000/µl) - monitor platelet levels
- 58. Heparin Adverse effect (1)Most important: bleeding (2-5%) (2)Thrombocytopenia (platelets < 100,000/µl) - monitor platelet levels Use in pregnancy: Safe in pregnancy (do not cross placenta) Stop 24 hours before delivery (avoid bleeding)
- 59. Heparin Reversal of bleeding complications due to overdosing: • give protamine sulphate to bind and inactivate heparin. • Massive blood loss: give blood transfusion
- 60. Heparin Monitoring Monitoring required because individuals vary in metabolism, protein binding - dosing need to be individualised – based on aPTT (activated partial thromboplastin time) (measures activity of intrinsic system and common pathway)
- 61. Heparin Monitoring Monitoring required because individuals vary in metabolism, protein binding - dosing need to be individualised – based on aPTT (activated partial thromboplastin time) (measures activity of intrinsic system and common pathway) e.g. Therapeutic range - aPTT of 1.5-2.5 times higher than baseline - Perform test before the next dose.
- 62. Low Molecular Weight Heparin (LMWH)
- 63. Low Molecular Weight Heparin (LMWH) • Introduced ~ 20 years ago • Note: “unfractionated/standard heparin” = mixture of polysaccharide units of different chain lengths. with molecular weight 3 - 30 kDa (mean 15 kDa). • LMWH: shorter and more uniform chain length, molecular weight 2 – 8 kDa (mean~ 5 kDa)
- 64. Low Molecular Weight Heparin (LMWH) • Introduced ~ 20 years ago • Note: “unfractionated/standard heparin” = mixture of polysaccharide units of different chain lengths with molecular weight 3 - 30 kDa (mean 15 kDa). • LMWH: shorter and more uniform chain length, mean molecular weight 2 – 8 kDa (mean~ 5 kDa) • Source of LMWH: chemical depolymerisation or physical separation of unfractionated heparin
- 65. Low Molecular Weight Heparin (LMWH) Mechanism: Activate antithrombin III (like unfractionated heparin) but does not inhibit thrombin (IIa). (it is thought that inhibition of IIa causes bleeding episodes)
- 66. Low Molecular Weight Heparin (LMWH) Mechanism: standard heprin Heparin
- 67. Low Molecular Weight Heparin (LMWH) Mechanism: standard and LMW heparin Heparin LMWH
- 68. Low Molecular Weight Heparin (LMWH) • safety and effectiveness equal to heparin, but with lower mortality thought to cause less bleeding and thrombocytopenia. e.g. enoxaparin • similar in use, adverse effects, use in pregnancy, method of reversal as standard heparin
- 69. Low Molecular Weight Heparin - differences • Standard heparin has high binding to plasma and vascular wall proteins (reduced bioavailability for anticoagulant effect) which varies in individuals - require aPTT monitoring to decide dose.
- 70. Low Molecular Weight Heparin - differences Standard heparin has high binding to plasma and vascular wall proteins - LMWH: less protein binding, majority available for anticoagulant effect, more predictable effect in all patients- allows fixed dose/body weight dosing, no routine monitoring to decide dose • Easier to dose
- 71. Low Molecular Weight Heparin - differences - LMWH: less protein binding, majority available for anticoagulant effect, more predictable effect in all patients- allows fixed dose/body weight dosing, no routine monitoring. • aPTT is unchanged by LMWH (due to lack of effect on thrombin). - Effectiveness can be measured using plasma anti- Xa activity (U/mL).
- 72. Low Molecular Weight Heparin - differences • Longer half life (s.c. unfractionated heparin is given 2-3 times daily, but LMWH is given 1-2 times daily)
- 73. Low Molecular Weight Heparin Compared with standard heparin, LMWH is: • As safe and effective • Easier to dose – by fixed dose or body weight • suitable for outpatients to use at home: - long half life (one or twice daily s.c. injection) - no routine blood test necessary
- 74. Important parenteral and oral anticoagulants Parenteral : heparin Oral: warfarin dabigatran
- 75. Warfarin • Mechanism • Administration/Onset • Monitoring • Adverse effect/overdose • Patient advice
- 76. Warfarin Mechanism Prevents synthesis of coagulation factors (VII, IX, X and II) that need vitamin K for its formation (by preventing vitamin K from recycling to its active form). Used since the 1950’s. Feb 2004
- 78. Warfarin Administration Once daily dosing. Onset Prevent synthesis of coagulation factors: 12-24 hrs Antithrombotic effect: 2-7 days
- 79. Warfarin Onset Prevent synthesis of coagulation factors: 12-24 hrs Antithrombotic effect: 2-7 days 1.Why does it take longer for antithrombotic effect?
- 80. Warfarin Onset Prevent synthesis of coagulation factors: 12-24 hrs Antithrombotic effect: 2-7 days (delay due to continued activity of existing coagulation factors in blood which takes time to degrade)
- 81. Warfarin Onset Prevent synthesis of coagulation factors: 12-24 hrs Antithrombotic effect: 2-7 days 1. Why does it take longer for antithrombotic effect? 2. Suggest how to change over patient from heparin to warfarin (when stop heparin, when start warfarin)?
- 82. Warfarin Switching from heparin to warfarin:
- 83. Warfarin Switching from heparin to warfarin: 1. Do aPTT and start on heparin (immediate antithrombotic effect). 2. Adjust heparin dose based on aPTT. 3. Start warfarin and give together with heparin for 4-5 days.
- 84. Warfarin Switching from heparin to warfarin: 1. Do aPTT and start on heparin (immediate antithrombotic effect). 2. Adjust heparin dose based on aPTT. 3. Start warfarin and give together with heparin for 4-5 days. 4. Adjust warfarin dose based on blood clotting test 5. When clotting test result is within therapeutic range, stop heparin.
- 85. Warfarin Monitoring 1. PT (prothrombin time): - PT results are expressed in seconds, PT ratios (patient PT/normal PT), etc
- 86. Warfarin Monitoring Disadvantage of reporting PT: - Thromboplastin from different sources have different sensitivities - Different coagulation analysers give different PT values even with same thromboplastin Result: PT results from different laboratories differ
- 87. Warfarin Monitoring 2. International Normalised Ratio (INR) = (patient PT /Normal PT) ISI • - each manufacturer assign an International Sensitivity Index (ISI) value for their thromboplastin • ISI value indicates relative sensitivity of the thromboplastin compared to an international reference thromboplastin
- 88. Example of therapeutic ranges for Warfarin Therapy Indication INR Prevention of venous thrombosis 2.0 – 3.0 Treatment of venous thrombosis 2.0 – 3.0 Treatment of pulmonary embolism 2.0 – 3.0 Prevention of systemic embolism 2.0 – 3.0 Mechanical prosthetic heart valves 2.5 – 3.5 Prevention of recurrent myocardial infarction 2.5 – 3.5
- 89. Warfarin Adverse effect Most important: bleeding (3-27 %)
- 90. Warfarin Adverse effect Most important: bleeding (3-27 %) -If minor: withhold warfarin until INR back in range -If major: stop warfarin, give fresh frozen plasma, or give vitamin k (phytonadione)
- 91. Warfarin Adverse effect Most important: bleeding (3-27 %) -If minor: withhold warfarin until INR back in therapeutic range -If major: stop warfarin, give fresh frozen plasma, or give vitamin K (phytonadione) Rare: skin necrosis, purple toe syndrome
- 92. Warfarin Adverse effect Most important: bleeding (3 - 27%) -If minor: withhold warfarin until INR back in range -If major: stop warfarin, give fresh frozen plasma, or give vitamin K (phytonadione) Rare: skin necrosis, purple toe syndrome Pregnancy: contraindicated in pregnancy - crosses placenta and cause foetal malformation
- 93. Warfarin Advice to the patient - Need for compliance (not to under or over-dose)
- 94. Warfarin Advice to the patient - Need for compliance (not to under or over-dose) - Need for monitoring (INR)
- 95. Warfarin Advice to the patient - Need for compliance (not to under or over-dose) - Need for monitoring (INR) - Check for bleeding - Limit physical activities
- 96. Warfarin Advice to the patient - Need for compliance (not to under or over-dose) - Need for monitoring (INR) - Check for bleeding - Limit physical activities - Inform Dr. of major change in diet: especially vitamin K-containing foods e.g. green leafy vegetables - Potential drug interactions - Avoid pregnancy
- 99. Dabigatran
- 100. Dabigatran Advantage • No need for monitoring (use fixed dose) • Adverse effect: Tolerable so far (e.g. dyspepsia) Disadvantage • Cost • Needs more information from clinical trials (e.g. effect on foetus, suitable indications)
- 102. Introduction: Fibrinolysis/Thrombolysis • Fibrinolytic system: Plasminogen Plasmin bind & digests (bound to fibrin clots fibrin) tissue plasminogen activator (t-PA) Thrombolytic/Fibrinolytic Drugs: enzymes that dissolve clots by accelerating the conversion of plasminogen into active plasmin
- 103. Fibrinolytic/Thrombolytic Therapy Indication • Lyse arterial thrombi in the management of acute MI/stroke to prevent permanent ischaemic damage to the heart/brain • Acute pulmonary embolism • Thrombosed arteriovenous shunts or mechanical valves
- 104. Fibrinolytic/Thrombolytic Therapy Time requirement • Early reperfusion of ischaemic tissues (from onset of symptoms) reduces death rate and infarct size. • Older clots are more compacted - for benefit, fibrinolytic therapy should be given within hours from onset of symptoms.
- 105. Fibrinolytic/Thrombolytic Therapy Toxicity • Major toxicity of fibrinolytic drugs is haemorrhage. 2 effects: (1) lysis of fibrin at general sites of vascular injury (rather than at ‘pathological thrombi’) (2) systemic formation of plasmin resulting in a systemic lytic state (destruction of fibrinogen and some coagulation factors) Most serious: intracranial haemorrhage
- 109. Fibrinolytic/Thrombolytic Therapy: e.g. streptokinase (i.v.) • Produced by β-haemolytic streptococci Mechanism • Binds to plasminogen, then activates it to cleave to form plasmin - can also bind circulating plasminogen (not clot selective) - may cause systemic fibrinolysis.
- 110. Fibrinolytic/Thrombolytic Therapy: streptokinase e.g. streptokinase (i.v.) Use Lysis of thrombi in MI -within 12 hours of symptoms (less effective in stroke) Also used in DVT, pulmonary embolism - 30-60 min infusion Adverse Effect Allergic reactions, bleeding and hypotension
- 111. Fibrinolytic/Thrombolytic Therapy: e.g. urokinase (i.v.) Similar to streptokinase but (1) Isolated from cultured human renal cells- minimal allergic effects (2) More expensive
- 112. Fibrinolytic/Thrombolytic Therapy: e.g. Tissue Plasminogen Activator, t-PA (i.v.) (US: alteplase).
- 113. Fibrinolytic/Thrombolytic Therapy: e.g. Tissue Plasminogen Activator, t-PA (i.v.) (US: alteplase). Naturally occuring enzyme (tPA), or produced by recombinant DNA technology (rtPA) Mechanism A protease that cleave plasminogen into plasmin Relatively ‘clot selective’ - has a binding site for fibrin at thrombus (compared to circulating plasminogen)
- 114. Fibrinolytic/Thrombolytic Therapy: e.g. Tissue Plasminogen Activator, t-PA (i.v.) Use: stroke, MI Dosing • Short half life - continue infusion over 2 hours and require co-administration of heparin to avoid re-occlusion. • e.g. licenced for use in ischaemic stroke within 3 hours of stroke onset Cost Expensive, several times that of streptokinase
- 115. Fibrinolytic/Thrombolytic Therapy: newer agents Smaller versions of the molecule t-PA: Tenecteplase: longer half life and increased fibrin specificity. Only one bolus injection required. Found to give less bleeding than t-PA.
- 116. Drug List Antiplatelet Drugs • Aspirin, Ticlopidine, Clopidogrel • (intravenous) Tirofiban, Abciximab Anticoagulant Drugs • Heparin (standard, LMW) • Warfarin • Dabigatran (intravenous) Thrombolytic/Fibrinolytic Drugs • Streptokinase, Urokinase • t-PA, tenecteplase
- 118. Common Clotting Factors Inhibited by Warfarin Factor IIa or thrombin
- 119. Important Differences Between Anticoagulant Drugs Dose form Mech Onset of antithrom -bosis Monitor Therapy Antidote Preg- nancy use Heparin & LMWH: enoxaparin Pa ren -teral Activate Antithrom -bin III Less effect on IIa Imme -diate -aPTT - none Protamine Yes Warfarin Oral Inhibit synthesis of clotting factors 2-7 days INR Vit K No
Editor's Notes
- 2014 50 min with same few section for ques. Say know plat aggregation but not INR. better entry for dabigatran- news clip show intro here in 2011. ask asri if we have apixaban and rivaroxaban. Also is tenecteplase and .,.,.. In formulary? Tenecteplese is in 2011 formulary, renecteplase need to check up.. Why dabigatran affect thrombin (factor 2A) no need do INR? Compared to usual notes, the section in antiplatelet drugs only has drug names. A systematic review of anticoagulation in pregnant women with prosthetic heart valves34 found very limited data on heparin use throughout pregnancy. Women maintained on warfarin vs heparin between pregnancy weeks 6 and 12 had higher rates of congenital anomalies (6.4% with warfarin vs 3.4% with heparin) and total fetal wastage (33.6% vs 26.5%). The warfarin group had fewer maternal thromboembolic complications (3.9% vs 9.2%), however, and a slightly lower rate of maternal death (1.8% vs 4.2%). Most of the women had higher-risk older-generation valves in the mitral position. http://www.ccjm.org/content/76/2/113.full Warfarin There is overwhelming evidence that warfarin offers the best protection against prosthetic valve thrombosis and avoiding this serious complication in the mother is also in the best interests of the unborn child. However, warfarin crosses the placenta and is associated with a high incidence of fetal loss and carries a risk of embryopathy. Warfarin embryopathy is characterised mainly by skeletal abnormalities and primarily occurs if warfarin is administered during the first trimester of pregnancy, particularly between the 6th and 12th week of gestation. The true incidence of warfarin embryopathy is difficult to establish since appropriate pathological assessment of many fetuses that are lost early in pregnancy may not occur. The incidence has been quoted as low as 1.6% of live births however skeletal deformity and nasal hypoplasia have been reported in up to 10% of babies exposed to warfarin. The risk of birth defects secondary to warfarin is greatly reduced if warfarin is used outside the first trimester. Warfarin can also result in fetal and neonatal haemorrhage and maternal administration at the time of delivery significantly increases this risk.2 http://totw.anaesthesiologists.org/wp-content/uploads/2011/02/214-Management-of-pregnant-women-with-mechanical-heart-valves.pdf 2013 50 min with time to wait for answers to questions. But lots of facts eg ask again what antidote for heparin – a blank. still did not inform to put this lect right after blood lecture. Since dabigatran is in MOH list, include it briefly. Next time can ask Asri what other new drug is also in, and when is it used eg is it: ‘When the risk is significant and the INR cannot be maintained within the target range despite close monitoring, dabigatran is the alternative to warfarin, provided the patient is closely monitored, especially for changes in renal function,[8] adverse events (bleeding) and discontinuation’. 2012- almost one hr with 2 breaks for ques. Edited to improve. mice made VWF deficient by means of gene abrogation are protected from ischemic brain injury. Phase I and II trials: novel therapeutic approaches are DNA aptamers, which act like chemical antibodies by binding with high affinity to VWF, and an array of monoclonal antibodies targeting VWF or its receptor GPIbα on platelets. inform block coord if want to position this lect just after blood lect, else it will be out of sync. 2010 first time lect combines all 3 topics to make use of haemostatics lectures – it was AM and my lect in PM, given free slot after in case i run over time. about 1 hour with 2 occasions of small groups think over question for preunderstanding, and I get some to answer. After the quiz over why take 2-7 days for antithrombotic effect, I change the slide too fast cos want to move to heparin changeover- slow it down so they can copy. And the mech of plat aggregation should spell out the different agonists release by platelet so they can think for mech- seems they not able to say it. And they sugg a inhibitor for VWF- available? I have not dealt with how to choose between standard and LMW heparin. 2010 royal children hosp melb: The decision to use LMWH instead of standard heparin or warfarin will depend upon the clinical scenario and individual patient factors such as risk of bleeding or availability of venous access.- internet data so far is trials here and there or personal preferences based on certain facts- so I am not 100% clear what is SGH practice of choosing between the 2- does cost matter? I delete dipyridamole. Anticoagulant, antiplatelet and thrombolytic drugs 1. List the common anticoagulant drugs (standard heparin, low molecular weight heparin, warfarin) and their mechanism of action, mode of administration, major clinical use, important precautions/adverse effects and treatment for overdose. 2. Outline differences (mechanism, pharmacokinetics, monitoring, clinical use) between standard and low molecular weight heparin. 3. Outline the steps for switching a patient from heparin to warfarin. 4. List the common antiplatelet (aspirin, ticlopidine, clopidogrel, tirofiban, abcizimab) and thrombolytic drugs (streptokinase, urokinase, tPA) and their mode of administration, mechanism of action, major clinical use and important precautions/adverse effects. 2010 – this should combine with anticoagulant to give after Henry’s haemostatics/bleeding disorders lectures cos his lecture deal with blood clot and inhibitor of haemostasis including fibrinolysis then he give a lect on bleeding disorders! So I can remove all my physiol of platelet aggreg and fibrinolysis. Strange to mention the platelet and fibrinolysis one year later just to fit into CAD. CAD2 is ok. Later ques was why heart valve lead to clot- is it damage endothelium- no, it is foreign surface. Why clot in av shunt- cos flow velocity may be slower at times.- may need to elaborate these points under thrombolytics. 22 mins only. (anticoagulants 2009 was 40 min). Some editing and improvements. If not need mention physiol of clot can even shorter. Can find out for strepto and uro in MI- how many hours to max before too late to give, and any time restriction for PE, DVT etc? 2009 can consider giving this together with anticoagulant in block 3 because it uses the clotting mech background of Block 3. Else need to remind them a year later. And I did not dwell on clinical aspect of prevention of CVA or stroke so it focus on drug just like warfarin. But it will lenghten the drug list so need to cut out, and also shorten the anticoagulant lect info. Aust prescriber say streptokinase less bleed than tpa but is very old ref, cannot find reason for it, but know it is generally safe, so delete the phrase that it bleed less than tpa. remove the bats story since irrelevant as the drug was bad, so only one drug for tpa. Found more info to see the overall linkages. Little pictures. Remove some clinical detail cos quite a lot of info now. 2008 same 35 min, very light content – only read off surface of these 2 grps of drugs, not much content. Added 07 report that desmoteplase is useless. Can say the other tpa no need to remember. Read up how tpa can give fibrin specificity- notes said some thrombus recog- is not clear- read it up and rephrase. 2007 also about 35 min. more transistions. Added pics with story but only at end when all drugs have been taught. Be clear of t-PA: it is used for both MI (use within 6 hrs….) and stroke (use within 3 hrs…)- actual guideline need to check with SGH. That platelet aggregan diag is not intuitive in one aspect: it does not show the crucial role of thrombin- so need remember that after the fibrinogen bind, then platelet activate circulating prothrombin to thrombin which then convert to fibrin. It is important to state that the thrombolysis process works on recently formed thrombi. Older thrombi have an extensive fibrin polymerization that makes thrombi more resistant to thrombolysis. Hence, the importance of time for thrombolytic therapy Check mech for clopidrogel and terminology for 2b3a. Is abxicimab given oral for those wait for angio, or is it iv drug? Make it clearer that abciximais is also iv. Remember to say antiplatelet drug suited for prevent arterial thrombi cos arterial thrombi are mainly made of platelet. 2006 Spoken flat and fast cos there was few anecdote, only one on give rtpa fast don’t delay fill name etc. else can put more pics and explanations 35 min.
- 2012- inform block coord if want to position this lect just after blood lect, else it will be out of sync. 2010 first time lect combines all 3 topics to make use of haemostatics lectures – it was AM and my lect in PM, given free slot after in case i run over time. about 1 hour with 2 occasions of small groups think over question for preunderstanding, and I get some to answer. After the quiz over why take 2-7 days for antithrombotic effect, I change the slide too fast cos want to move to heparin changeover- slow it down so they can copy. And the mech of plat aggregation should spell out the different agonists release by platelet so they can think for mech- seems they not able to say it. And they sugg a inhibitor for VWF- available? I have not dealt with how to choose between standard and LMW heparin. 2010 royal children hosp melb: The decision to use LMWH instead of standard heparin or warfarin will depend upon the clinical scenario and individual patient factors such as risk of bleeding or availability of venous access.- internet data so far is trials here and there or personal preferences based on certain facts- so I am not 100% clear what is SGH practice of choosing between the 2- does cost matter? I delete dipyridamole. Anticoagulant, antiplatelet and thrombolytic drugs 1. List the common anticoagulant drugs (standard heparin, low molecular weight heparin, warfarin) and their mechanism of action, mode of administration, major clinical use, important precautions/adverse effects and treatment for overdose. 2. Outline differences (mechanism, pharmacokinetics, monitoring, clinical use) between standard and low molecular weight heparin. 3. Outline the steps for switching a patient from heparin to warfarin. 4. List the common antiplatelet (aspirin, ticlopidine, clopidogrel, tirofiban, abcizimab) and thrombolytic drugs (streptokinase, urokinase, tPA) and their mode of administration, mechanism of action, major clinical use and important precautions/adverse effects. 2010 – this should combine with anticoagulant to give after Henry’s haemostatics/bleeding disorders lectures cos his lecture deal with blood clot and inhibitor of haemostasis including fibrinolysis then he give a lect on bleeding disorders! So I can remove all my physiol of platelet aggreg and fibrinolysis. Strange to mention the platelet and fibrinolysis one year later just to fit into CAD. CAD2 is ok. Later ques was why heart valve lead to clot- is it damage endothelium- no, it is foreign surface. Why clot in av shunt- cos flow velocity may be slower at times.- may need to elaborate these points under thrombolytics. 22 mins only. (anticoagulants 2009 was 40 min). Some editing and improvements. If not need mention physiol of clot can even shorter. Can find out for strepto and uro in MI- how many hours to max before too late to give, and any time restriction for PE, DVT etc? 2009 can consider giving this together with anticoagulant in block 3 because it uses the clotting mech background of Block 3. Else need to remind them a year later. And I did not dwell on clinical aspect of prevention of CVA or stroke so it focus on drug just like warfarin. But it will lenghten the drug list so need to cut out, and also shorten the anticoagulant lect info. Aust prescriber say streptokinase less bleed than tpa but is very old ref, cannot find reason for it, but know it is generally safe, so delete the phrase that it bleed less than tpa. remove the bats story since irrelevant as the drug was bad, so only one drug for tpa. Found more info to see the overall linkages. Little pictures. Remove some clinical detail cos quite a lot of info now. 2008 same 35 min, very light content – only read off surface of these 2 grps of drugs, not much content. Added 07 report that desmoteplase is useless. Can say the other tpa no need to remember. Read up how tpa can give fibrin specificity- notes said some thrombus recog- is not clear- read it up and rephrase. 2007 also about 35 min. more transistions. Added pics with story but only at end when all drugs have been taught. Be clear of t-PA: it is used for both MI (use within 6 hrs….) and stroke (use within 3 hrs…)- actual guideline need to check with SGH. That platelet aggregan diag is not intuitive in one aspect: it does not show the crucial role of thrombin- so need remember that after the fibrinogen bind, then platelet activate circulating prothrombin to thrombin which then convert to fibrin. It is important to state that the thrombolysis process works on recently formed thrombi. Older thrombi have an extensive fibrin polymerization that makes thrombi more resistant to thrombolysis. Hence, the importance of time for thrombolytic therapy Check mech for clopidrogel and terminology for 2b3a. Is abxicimab given oral for those wait for angio, or is it iv drug? Make it clearer that abciximais is also iv. Remember to say antiplatelet drug suited for prevent arterial thrombi cos arterial thrombi are mainly made of platelet. 2006 Spoken flat and fast cos there was few anecdote, only one on give rtpa fast don’t delay fill name etc. else can put more pics and explanations 35 min.
- Regardless of whether a blood clot forms in a vein, an artery or the heart, the coagulation cascade generates fibrin, which comprises the main structural scaffolding of the thrombus. However, arterial and venous thrombi contain different proportions of fibrin and platelets. Venous thrombi are rich in fibrin and trapped red blood cells and are therefore referred to as “red clots”. In contrast, arterial thrombi have a higher concentration of platelets and a lower concentration of red blood cells and are referred to as “white clots”.235 Currently, venous thrombosis generally is prevented with medications that interrupt the clotting cascade, while the prevention of arterial thrombi rests more heavily on the use of drugs that block platelet activation.235 However, because thrombin is a potent activator of platelets, and because arterial clots contain fibrin, anticoagulant drugs also have a proven role in the prevention and treatment of arterial thrombosis
- Regardless of whether a blood clot forms in a vein, an artery or the heart, the coagulation cascade generates fibrin, which comprises the main structural scaffolding of the thrombus. However, arterial and venous thrombi contain different proportions of fibrin and platelets. Venous thrombi are rich in fibrin and trapped red blood cells and are therefore referred to as “red clots”. In contrast, arterial thrombi have a higher concentration of platelets and a lower concentration of red blood cells and are referred to as “white clots”.235 Currently, venous thrombosis generally is prevented with medications that interrupt the clotting cascade, while the prevention of arterial thrombi rests more heavily on the use of drugs that block platelet activation.235 However, because thrombin is a potent activator of platelets, and because arterial clots contain fibrin, anticoagulant drugs also have a proven role in the prevention and treatment of arterial thrombosis
- Pulmonary artery carry deoxg blood (prevents dilution of coagulation factors),
- Pulmonary artery carry deoxg blood
- Monolayer to allow healing and stop exposure of endothelium
- Each platelet express up to 100000 GP 2b 3a receptors, and also release signaling molec into bloodstream. Activated platelet expose the receptor, final common pathway to platelet agg. Bind fibrinogen, vW factor, vitronectin etc
- Each platelet express up to 100000 GP 2b 3a receptors, and also release signaling molec into bloodstream. Activated platelet expose the receptor, final common pathway to platelet agg. Bind fibrinogen, vW factor, vitronectin etc. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor.
- Fibrinogen (factor I) is a a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. thrombin, which is responsible for converting fibrinogen into fibrin. Fibrin is then cross linked by factor XIII to form a clot. FXIIIa stabilizes fibrin further by incorporation of the fibrinolysis inhibitors alpha-2-antiplasmin and TAFI (thrombin activatable fibrinolysis inhibitor. As platelet aggregate, thrombin (factor IIa) is produced- one of the most powerful activator of platelets. Thrombin is one of the factors in the common pathway, activable by both intrinsic (release of tissue factors into blood) and extrinsic (exposure of subendothelial memb activates factor VII etc) pathways. thrombin also promotes platelet activation, via activation of protease-activated receptors on the platelet. Factor 13a crosslinks fibrin monomers Overall: Thrombin also activates factor XI, factor V and factor VIII. This positive feedback accelerates the production of thrombin. Factor XIII is also activated by thrombin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot.
- Thrombolus stroke- the brain artery occlude. Embolic stroke- half is arrhtymia cause clot that travel up
- 2014 Expert opinion: The therapeutic approaches aiming to block the collagen-vWF-platelet axis have potentially beneficial effects for prevention and treatment of cardiovascular disease. However, the evidence directly associating vWF blockage with beneficial clinical outcomes is limited and needs further research. Optimal treatment regimes need to be established in relation of specific clinical circumstances and conditions.Read More: http://informahealthcare.com/doi/abs/10.1517/14728222.2013.840585 As platelet aggregate, thrombin (factor IIa) is produced- one of the most powerful activator of platelets. Thrombin is one of the factors in the common pathway, activable by both intrinsic (release of tissue factors into blood) and extrinsic (exposure of subendothelial memb activates factor VII etc) pathways. thrombin also promotes platelet activation, via activation of protease-activated receptors on the platelet. Factor 13a crosslinks fibrin monomers Overall: Thrombin also activates factor XI, factor V and factor VIII. This positive feedback accelerates the production of thrombin. Factor XIII is also activated by thrombin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot.
- Stimulus (pro-inflammatory cytokines) provoke inflammatory reaction causes phospholipid in membrane to be broken into AA PG act like local hormones, where they act for short periods in the area they are released, to initiate processes like inflammation, renin release, platelet aggregation. They also sensitise nociceptors
- to inhibit platelet COX. COX 2 inhibitor supposed to inhibit inflamm mediator but not affect GI Prostacyclin inhibition seems outweigh by TXA2 inhibition Only affect one activator, TXA2, so a weak antiplatelet agent. Lifespan of platelet- effect stay 5-7 days after stop aspirin. Reverse by platelet infusion. Do not affect platelet adhesion. Only need 160mg to inhibit platelet COX.
- There are two isoforms of COX in animals: COX-1, which carries out normal, physiological production of prostaglandins, and COX-2, which is induced by cytokines, mitogens and endotoxins in inflammatory cells, and which is responsible for the production of prostaglandins in inflammation. Regular NSAIDS (generally COX-1 and COX-2 Inhibitors) work by inhibiting the production of prostaglandins (PGs) Over the counter drugs such as Ibuprofen and Naproxen work to inhibit COX-1 and COX-2. Aspirin works more on COX-1 endothelial cells lining the microvasculature in the body express COX-2 Prostacyclin (PGI2) chiefly prevents formation of the platelet plug involved in primary hemostasis (a part of blood clot formation). It does this by inhibiting platelet activation[4]. It is also an effective vasodilator. Prostacyclin&apos;s interactions in contrast to thromboxane(TXA2) Thromboxane A2 (TXA2) is a thromboxane. It is produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. by selectively inhibiting COX-2, prostaglandins (specifically PGI2; prostacyclin) are downregulated Thus, the protective anti-coagulative effect of PGI2 is decreased, increasing the risk of thrombus and associated heart attacks and other circulatory problems Poor biological response to aspirin and/or clopidogrel is also frequent in clinical settings such as diabetes, obesity and acute coronary syndromes. COX 2 inhibitor supposed to inhibit inflamm mediator but not affect GI Prostacyclin inhibition seems outweigh by TXA2 inhibition Only affect one activator, TXA2, so a weak antiplatelet agent. Lifespan of platelet- effect stay 5-7 days after stop aspirin. Reverse by platelet infusion. Do not affect platelet adhesion. Only need 160mg to inhibit platelet COX.
- COX 2 inhibitor supposed to inhibit inflamm mediator but not affect GI Prostacyclin inhibition seems outweigh by TXA2 inhibition Only affect one activator, TXA2, so a weak antiplatelet agent. Lifespan of platelet- effect stay 5-7 days after stop aspirin. Reverse by platelet infusion. Do not affect platelet adhesion. Only need 160mg to inhibit platelet COX.
- COX 2 inhibitor supposed to inhibit inflamm mediator but not affect GI Prostacyclin inhibition seems outweigh by TXA2 inhibition Only affect one activator, TXA2, so a weak antiplatelet agent. Lifespan of platelet- effect stay 5-7 days after stop aspirin. Reverse by platelet infusion. Do not affect platelet adhesion. Only need 160mg to inhibit platelet COX. COX-1 enzyme is relatively ubiquitous in the body and is the only isoform present in platelets, where it converts arachidonic acid to TxA2.[8] COX-1 is also the main COX isoform in gastric mucosa, where it is the predominant source of cytoprotective PG. The expression of COX-2 is increased during inflammation and cellular transformation.[10,11] Strong COX-2 expression is seen in the synovial tissues of patients with rheumatoid arthritis (RA); the level of COX activity in nonarthritic synovial tissues is low. In summary, despite some apparent overlap between expression patterns and functions of the 2 isoforms, COX-1 is mainly expressed constitutively and is involved in homeostasis, whereas COX-2 is mainly induced during pathophysiologic processes. Aspirin, which inhibits COX irreversibly by covalent modification (acetylation).[15] This unique mode of action underlies the cardioprotective clinical efficacy of low-dose aspirin, as the inactivated enzyme cannot be replaced in anucleate platelets. Platelet lifespan is 10 days.
- Aspirin GI effect, 40% in 300mg. GI bleed in 5%. CI in gout (down urinary excretion of uric acid) Primary prevention = in well patients. Result Show risk of bleeding. Ok if has coronary risk and no HT Wiki nsaid: The main ADRs (adverse drug reactions) associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal tract (GIT). NSAIDs cause a dual insult on the GIT: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 reduces the levels of protective prostaglandins. Common gastrointestinal ADRs include:[4] Nausea/Vomiting Dyspepsia Gastric ulceration/bleeding[9]. Diarrhea Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. Indomethacin, ketoprofen and piroxicam appear to have the highest prevalence of gastric ADRs, while ibuprofen (lower doses) and diclofenac appear to have lower rates.[4] Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration.[4] Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a proton pump inhibitor, e.g. omeprazole; or the prostaglandin analogue misoprostol. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhoea). While these techniques may be effective, they prove to be expensive for maintenance therapy.
- Thienopyridines are a class of ADP receptor/P2Y12 (purinergic GPCR) subtype of ADP receptor) inhibitors used for their anti-platelet activity. These drugs include: Prasugrel (Effient),[1] Ticlopidine (Ticlid), Clopidogrel (Plavix). Effect persist for 7-10 day lifespan of platelet Structure is similar
- 2010 Among new adenosine diphosphate receptor antagonists, prasugrel is already registered, and ticagrelor and cangrelor are being developed. New mechanisms being explored are blockade of thrombin-induced platelet aggregation (vorapaxar [SCH 530398]), and inhibition of collagen and ristocetin-mediated platelet functions (DZ-697b). The specific subtype of ADP receptor that clopidogrel irreversibly inhibits is P2Y12 and is important in platelet aggregation and the cross-linking of platelets by fibrin.[1] The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the &quot;final common pathway&quot; for platelet aggregation, and is important in the cross-linking of platelets by fibrin. Effect persist for 7-10 day lifespan of platelet Structure is similar
- Effect persist for 7-10 day lifespan of platelet Structure is similar
- Effect persist for 7-10 day lifespan of platelet Structure is similar
- ? What is the unique indications for this here? Same mech as ticlopidine? Analog of ticlid and also bind ADP receptor irrev
- a death caused by vascular pathologic conditions The specific subtype of ADP receptor that clopidogrel irreversibly inhibits is P2Y12 subtype of ADP receptor and is important in platelet aggregation and the cross-linking of platelets by fibrin.[1] The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. Activation of this receptor complex is the &quot;final common pathway&quot; for platelet aggregation, and is important in the cross-linking of platelets by fibrin. Same mech as ticlopidine? Analog of ticlid and also bind ADP receptor irrev ADP interacts with a family of ADP receptors found on platelets (P2Y1, P2Y12 and P2X1), leading to further platelet activation.[1] The anti-platelet drug Plavix (clopidogrel) inhibits the P2Y12 receptor.
- Avail in SGH Reverse by stop infusion Other eg: eptifibatide
- synthetic, non-peptide inhibitor acting at glycoprotein (GP) IIb/IIIa receptors in human platelets It is sold in parenteral dosage forms intended and readily constituted for IV administration containing 5 mg or 12.5 mg, respectively. Tirofiban has a rapid onset and short duration of action after proper IV administration. Coagulation parameters turn to normal 4 to 8 hours after the drug is withdrawn. It is a modified version of an anticoagulant found in the venom of the saw-scaled viper Avail in SGH Reverse by stop infusion Other eg: eptifibatide
- The acute coronary syndromes encompass a spectrum of unstable coronary artery disease from unstable angina to transmural myocardial infarction. All have a common aetiology in the formation of thrombus on an inflamed and complicated atheromatous plaque. Reverse by stop infusion Other eg: eptifibatide
- Used with heparin. Effect reversed when stop
- ABCIXIMAB (ab SIX i mab) Reverse by platelet transfusion SGH: brought in by special request
- due to its strong affinity for its receptor on the platelets, it may occupy some receptors for weeks. In practice, platelet aggregation gradually returns to normal about 96 to 120 hours after discontinuation of the drug made from the Fab fragments of an immunoglobulin that targets the glycoprotein IIb/IIIa receptor on the platelet membrane Reverse by platelet transfusion SGH: brought in by special request
- Angioplasty is the technique of mechanically widening a narrowed or obstructed blood vessel made from the Fab fragments of an immunoglobulin that targets the glycoprotein IIb/IIIa receptor on the platelet membrane Reverse by platelet transfusion SGH: brought in by special request percutaneous invasive coronary interventions
- ?? Allergic response Up to 24 hr Thrombocytopenia need platelet infusion Given iv bolus with/out short term infusions. - more frequent during re-administration, possibly due to antibody formation after first dose. Prevent by using once only.
- Compression stocking- max pressure at ankle to force blood into deep veins and then lower pressure to prevent back flow and movement
- Red blood cells and fibrin are the main components of venous thrombi,[2] and the thrombi appear to attach to the blood vessel wall endothelium, normally a non-thrombogenic surface, with fibrin.[15] Platelets in venous thrombi attach to downstream fibrin, while in arterial thrombi, they compose the core.[15] As a whole, platelets constitute less of venous thrombi when compared to arterial ones. Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque Pulmonary artery carry deoxg blood (prevents dilution of coagulation factors),
- called DVT
- Compression stocking- max pressure at ankle to force blood into deep veins and then lower pressure to prevent back flow and movement
- Deep vein thrombosis (DVT) = a thrombus forming in the deep veins of the vasculature, most often in the deep veins of the lower leg and thigh. PE: a thrombus/foreign substance arising from the systemic circulation that lodges in the pulmonary artery (or one of its branches), causing partial/complete obstruction of pulmonary blood flow. sudden dyspnoea, cough, tachycardia, chest pain, anxiety 95% of pulmonary emboli originate from deep-venous system of lower extremities ~ 10% of PE result in death What can we do? not all have symptoms. due to interfere with circulation in the area. Block vein so cut off blood supply to that part of lower leg. Else form embolus to form PE. Deep vein = vein that accompany an artery…..
- thrombolytic dissolve existing clot, we cover in CVS, here is anticoagulant to slow down formation of new clot, but cannot remove clot already formed.
- Anticoagulation therapy has a long history. It started with leeches and passed through heparin, warfarin and low molecular weight heparin (LMWH). The development of the novel oral anticoagulants (NOACs) has marked the beginning of a new era in the treatment of VTE. Dabigatran, Rivaroxaban and Apixaban has been approved for different indications of anticoagulation Leech often used today in plastic and reconstructive surgery, because a natural anticoagulant they secrete fights blood clots and restores proper blood flow to inflamed parts of the body. Thousands of patients owe the successful reattachment of body parts to miraculous technological advances in plastic and reconstructive surgery. But some of these operations might have failed if leeches had not been reintroduced into the operating room. The appendages reattached include fingers, hands, toes, legs, ears, noses and nipples following breast reconstructive surgery.
- Implanted mechanical heart valve: emboli developing on the valve AF: 15% of strokes are due to emboli Post stroke also: if due to AF or no risk of bleed Valve disease if hx of stroke or AF Cannula- tube for insertion into vessel The mitral valve is positioned in the heart’s left side, between the left upper chamber (left atrium) and the left lower chamber (left ventricle). Mitral stenosis is a mechanical obstruction or &quot;tightness&quot; of the valve. It is caused by the inability of the valve leaflets to open fully. Over time, the heart weakens as it struggles to get blood through a small valve opening.- blood clot possible. The great majority of cases of mitral stenosis are related to the build up of scar tissue on the valves due to rheumatic heart disease.
- Implanted mechanical heart valve: emboli developing on the valve AF: 15% of strokes are due to emboli Post stroke also: if due to AF or no risk of bleed Valve disease if hx of stroke or AF Cannula- tube for insertion into vessel
- These if released are ingested by macrophages (can’t detect in plasma so it do not give anticoagulant effect). (heparan sulfate is on endothelial cell surface and cause bleed if massive cell lysis) To use an anticoagulant, heparin is extracted from….
- blood anti-coagulation is achieved mostly by endothelial cell-derived heparan sulfate proteoglycans.[3] Heparin is usually stored within the secretory granules of mast cells and released only into the vasculature at sites of tissue injury. It has been proposed that, rather than anticoagulation, the main purpose of heparin is in a defensive mechanism at sites of tissue injury against invading bacteria and other foreign materials.[4] In addition, it is preserved across a number of widely different species, including some invertebrates which lack a similar blood coagulation system. These if released are ingested by macrophages (can’t detect in plasma so it do not give anticoagulant effect). (heparan sulfate is on endothelial cell surface and cause bleed if massive cell lysis). Pharmaceutical grade heparin is derived from mucosal tissues of slaughtered meat animals such as porcine (pig) intestine or bovine (cow) lung
- Previously called heparin cofactor. Antithrombin III (a serine protease inhibitor)synthesise in liver and circulate in plasma, form a 1:1 complex with coagulation factors, (serine protease) of intrinsic and common pathways and inactivate it. Heparin also help ATIII bind thrombin. It open up a site in ATIII for thrombin. To do this, need the the heparin to have more than 3-4 kDa.
- Previously called heparin cofactor. Antithrombin III (a serine protease inhibitor)synthesise in liver and circulate in plasma, form a 1:1 complex with coagulation factors, (serine protease) of intrinsic and common pathways and inactivate it. Heparin also help ATIII bind thrombin. It open up a site in ATIII for thrombin. To do this, need the the heparin to have more than 3-4 kDa.
- Previously called heparin cofactor. Antithrombin III (a serine protease inhibitor)synthesise in liver and circulate in plasma, form a 1:1 complex with coagulation factors, (serine protease) of intrinsic and common pathways and inactivate it. Heparin also help ATIII bind thrombin. It open up a site in ATIII for thrombin. To do this, need the the heparin to have more than 3-4 kDa. Thrombin need be bound by both ATIII and heparin for the thrombin to be inactivated. The other factors just bind to ATIII only.
- Fast onset because factors are inactivated
- Blood in stool Clotted blood in organ, space , tissue Up with dose and duration 5-14 days after therapy. Can lead to arterial thrombosis (platelet-fibrin clot)(?)
- Blood in stool Clotted blood in organ, space , tissue Up with dose and duration 5-14 days after therapy. Can lead to arterial thrombosis (platelet-fibrin clot)(?)
- a normal platelet count ranges from 150,000 and 450,000 per mm3 Blood in stool Clotted blood in organ, space , tissue Up with dose and duration 5-14 days after therapy. Can lead to arterial thrombosis (platelet-fibrin clot)(?) Heparin induce a platelet activating IgG…….
- a normal platelet count ranges from 150,000 and 450,000 per mm3 Blood in stool Clotted blood in organ, space , tissue Up with dose and duration 5-14 days after therapy. Can lead to arterial thrombosis (platelet-fibrin clot)(?) Heparin induce a platelet activating IgG…….
- Blood in stool Clotted blood in organ, space , tissue Up with dose and duration 5-14 days after therapy. Can lead to arterial thrombosis (platelet-fibrin clot)(?) Heparin induce a platelet activating IgG…….
- Need monitor cos each have variable saturable metab and amount/types of plasma/vascular proteins that will bind up heparin Patient examine for bleed at catheter site, ecchymosis, haematoma. Avoid im. No fetal malformation. Avoid postpartum bleed. APTT 50-80secs. Therapeutic: usu 1.5 – 2.5 times the normal
- Need monitor cos each have variable saturable metab and amount/types of plasma/vascular proteins that will bind up heparin Patient examine for bleed at catheter site, ecchymosis, haematoma. Avoid im. No fetal malformation. Avoid postpartum bleed. APTT 50-80secs. Therapeutic: usu 1.5 – 2.5 times the normal
- Heparin used for 50 yrs
- Heparin used for 50 yrs Sgh get enox in 2002. The first LMW heparin, enoxaparin, has been approved for preventing blood clots following hip replacement surge ry. average molecular weight of these LMW heparins typically ranges from 2,000 to 8,000 Da
- Heparin used for 50 yrs
- Shorter chain so cannot bind thrombin. Therapeutic anti-Xa level for treatment dose therapy is 0.5-1 units/mL. The target anti Xa level for prophylactic dose therapy is 0.2-0.4 units/mL. Sample 4 hrs after sc or 10 min after iv. However, it does not correlate directly with therapeutic efficacy (but used as a guide) Heparin high interpatient variability- dose guided by APTT. Efficacy tend to be equal to heparin
- Unfract heparin is long enough to bind thrombin and antithrombin so bring both together. For the other factors, the 5 saccharide units is enough. LMWH is not long enough to bind thrombin. Shorter chain so cannot bind thrombin. Therapeutic anti-Xa level for treatment dose therapy is 0.5-1 units/mL. The target anti Xa level for prophylactic dose therapy is 0.2-0.4 units/mL. Sample 4 hrs after sc or 10 min after iv. However, it does not correlate directly with therapeutic efficacy (but used as a guide) Heparin high interpatient variability- dose guided by APTT. Efficacy tend to be equal to heparin
- Unfract heparin is long enough to bind thrombin and antithrombin so bring both together. For the other factors, the 5 saccharide units is enough. LMWH is not long enough to bind thrombin. Activate Factor 10 no problem even if heparin is short. Shorter chain so cannot bind thrombin. To do this, need the the heparin to have more than 3-4 kDa. Thrombin need be bound by both ATIII and heparin for the thrombin to be inactivated. The other factors just bind to ATIII only. Therapeutic anti-Xa level for treatment dose therapy is 0.5-1 units/mL. The target anti Xa level for prophylactic dose therapy is 0.2-0.4 units/mL. Sample 4 hrs after sc or 10 min after iv. However, it does not correlate directly with therapeutic efficacy (but used as a guide) Heparin high interpatient variability- dose guided by APTT. Efficacy tend to be equal to heparin
- Shorter chain so cannot bind thrombin. Therapeutic anti-Xa level for treatment dose therapy is 0.5-1 units/mL. The target anti Xa level for prophylactic dose therapy is 0.2-0.4 units/mL. Sample 4 hrs after sc or 10 min after iv. However, it does not correlate directly with therapeutic efficacy (but used as a guide) Heparin high interpatient variability- dose guided by APTT. Efficacy tend to be equal to heparin
- 90% bioavailable after sc. More reproducible results when given as per kg. Less heparin resistance. More prot binding during inflammation Also: heparin elimination is dose dependent, saturable first phase that depend on reticuloendothelial system. LMWH is non saturable first order, by renal clearance.
- Enoxaparin is administered by s.c. injection only and is not to be injected by any other route or added to i.v. solutions.
- Enoxaparin is administered by s.c. injection only and is not to be injected by any other route or added to i.v. solutions.
- a naturally occurring inhibitor of coagulation, anti-Xa But protamine less effect in reversal
- But cost more. But easier to use and discharge earlier
- WARF= Wisconsin Alumni Research Foundation Synthetic drug developed by this res institute in wisconsin. Feb 2004 identify gene code for vit k epoxide reductase. Warfarin block this protein so reduced vit k cannot be regenerated. Warfarin and related 4-hydroxycoumarin-containing molecules decrease blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly prothrombin and factor VII. Despite being labeled a vitamin K antagonist,[2] warfarin does not antagonize the action of vitamin K, but rather antagonizes vitamin K recycling, depleting active vitamin K The clotting factors need carboxylation of glutamic acid residues to bind phospholipids to the clotting factors. The carboxylation process is related to the oxidation of vitamin K, which produces vitamin K epoxide. Vitamin K epoxide is then reprocessed to the condensed form of the vitamin by an enzyme called vitamin K epoxide reductase (VKOR). Warfarin prohibits the actions of VKOR, reducing the available stores of vitamin K and the production of clotting (coagulation) factors. The body’s store of previously created factors decreases over the course of several days and the effects of warfarin become apparent. Coagulation factors are still produced by the body, but their function is impaired as a consequence of undercarboxylation. The factors are collectively known as proteins induced by vitamin K absence (or antagonism), or PIVKAs.
- Why take 2-7 days? If so long, when should start warfarin? (pat start with heparin for quick onset, when to start warfarin?)
- Mean half life 40 hrs. Why take 2-7 days? If so long, when should start warfarin? (pat start with heparin for quick onset, when to start warfarin?)
- Mean half life 40 hrs. Why take 2-7 days? If so long, when should start warfarin? (pat start with heparin for quick onset, when to start warfarin?)
- Why take 2-7 days? If so long, when should start warfarin? (pat start with heparin for quick onset, when to start warfarin?)
- Mean half life 40 hrs. Why take 2-7 days? If so long, when should start warfarin? (pat start with heparin for quick onset, when to start warfarin?)
- For hospitalised patients start on heparin who will need anticoagulation after discharge.
- For hospitalised patients start on heparin who will need anticoagulation after discharge.
- For hospitalised patients start on heparin who will need anticoagulation after discharge.
- The mean normal PT is determined in each laboratory by averaging the PT values from at least 20 healthy individuals. Different thromboplastin has different sensitivity.
- Different thromboplastin has different sensitivity.
- Each manufacturer assigns an ISI value (International Sensitivity Index) for any tissue factor they manufacture. The ISI value indicates how a particular batch of tissue factor compares to an international reference tissue factor. The ISI is usually between 1.0 and 2.0 The INR is the ratio of a patient&apos;s prothrombin time to a normal (control) sample, raised to the power of the ISI value for the analytical system used. Different thromboplastin has different sensitivity. If a thromboplastin has the same sensitivity as the reference thromboplastin, then its ISI is 1.0. A higher ISI value indicates that a thromboplastin is less sensitive than the reference thromboplastin.
- From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. To speed up syn of clotting factors..Heparin not go breast milk, warfarin also not cross but need more studies.
- From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. To speed up syn of clotting factors..Heparin not go breast milk, warfarin also not cross but need more studies.
- From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. To speed up syn of clotting factors..Heparin not go breast milk, warfarin also not cross but need more studies.
- Different thromboplastin has different sensitivity. From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. Heparin not go breast milk, warfarin also not cross but need more studies.
- Different thromboplastin has different sensitivity. From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. Heparin not go breast milk, warfarin also not cross but need more studies. Limit contact sports
- Different thromboplastin has different sensitivity. From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. Heparin not go breast milk, warfarin also not cross but need more studies. Limit contact sports
- Different thromboplastin has different sensitivity. From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. Heparin not go breast milk, warfarin also not cross but need more studies. Limit contact sports
- Different thromboplastin has different sensitivity. From structures eg intracranial, or massive internal (eg GIT, intra peritoneal)3-27% risk factor: &gt; 65, past GI bleed, excessive dose, liver disease etc Vit k: iv, sc , oral. Heparin not go breast milk, warfarin also not cross but need more studies. Limit contact sports
- Withdrawn due to high ALT- liver failure. Ximelagatran in 2003: first new oral anticoagulant since warfarin (withdrawn in 2006)
- RE-LY® (Randomised Evaluation of Long term anticoagulant therapy) was a global, phase III, randomised trial of 18,113 patients enrolled in over 900 centres in 44 countries, investigating whether dabigatran etexilate is as effective as well controlled warfarin for stroke prevention. Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
- Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
- T pa released from endothelial cells when there is stasis due to vascular occlusion etc, and cleared by inhibitors. Plasminogen and plasmin both bind fibrin. Plasminogen is inactive. Tpa also bind fibrin to convert plasminogen.
- arteriovenous shunt 1. the diversion of blood from an artery directly to a vein. 2. a U-shaped plastic tube inserted between an artery and a vein; usually to allow repeated access to the arterial system for hemodialysis. The most common method of providing permanent access to the bloodstream for hemodialysis is an arteriovenous (AV) fistula. An AV fistula is created surgically by connecting an artery to a vein, usually in the forearm. An AV fistula requires planning more than other kinds of access because it takes two to six months to develop. During this time, the stronger blood flow from the artery causes the vein to become larger. This allows the fistula to take repeated needle insertions, and for blood to flow quickly to the dialyzer. The valve is made of a high-tech material with an extremely smooth surface; however the material does not resemble the natural surface of the endothelial cells which line the heart and the blood vessels. The body does not recognize the artificial heart valve as a wound but as a &quot;foreign surface&quot;. The blood proteins which bind to the artificial heart valve become altered in such a way that they trigger coagulation Thrombosis of dialysis grafts and fistulae represents a frequent complication4. Predisposing factors are an underlying stenosis or aneurysmatic vein causing flow turbulences5,6, as well as arterial hypotension, low cardiac output, compromised arterial inflow, and clotting disorders7. available percutaneous treatment regimens for thrombosed dialysis grafts and fistulae include mechanical thrombectomy, pharmacomechanical thrombolysis, and percutaneous infusion pharmacologic thrombolysis. As natural heart valves are lined with an endothelium continuous with the endothelium lining the heart chambers they are not normally thrombogenic. This is important as should thrombi form on the heart valve leaflets and become seeded with bacteria, so called &quot;bacterial vegetations&quot; will form. Such vegetations are difficult for the body to deal with as the normal physiological defense mechanisms are not present within the valve leaflets because they are avascular and largely composed of connective tissue Lyse coronary artery thrombi to improve ventricular function and lower risk of CHF. ?acute thromboembolism. Myocardial ischaemia- MI, ST segment elevation, left bundle branch block.
- Pharmacological thrombolysis is only effective in the limited therapeutic window of 3 to 4.5 hours after the onset of symptoms of cerebral ischemia (the sooner the treatment, the higher the efficacy), and the risk of intracerebral bleeding looms large. Moreover, antiplatelet and anticoagulant drugs are of more limited efficacy in the acute phase of ischemic stroke than in acute coronary syndromes, but at the same time they carry a high risk of bleeding in the central nervous system. Older clots have more fibrin cross-linking and are more compacted; therefore, older clots are more difficult to dissolve. Strepto and uro also has time requirement? Need to speed paramedic team to patient, or to speed up admission of patient: symptom to needle, and door to needle time. Pref 30 min. For MI, give within 24 hrs of onset of symptom.
- Contraindications Active bleeding or known bleeding disorder Unstable angina (no benefit, may cause MI) - Unnecessary in deep vein thrombosis or uncomplicated pulmonary embolism – frequency of haemorrhage is higher than in MI patients.
- tPA binds to fibrin on the surface of the clot Activates fibrin-bound plasminogen Plasmin is cleaved from the plasminogen associated with the fibrin Fibrin molecules are broken apart by the plasmin and the clot dissolves circulating plasminogen becomes more prone to convert to plasmin, thus increasing the likelihood of degrading plasma proteins other than fibrin. Specifically, depletion of fibrinogen and factors V and VIII may occur. As levels of plasmin in circulating plasma increase, available supplies of a2-antiplasmin (endogenous neutralizer of plasmin) are depleted and the risk of a systemic fibrinolytic state increases. In theory, alteplase should be effective only at the surface of fibrin clot. In practice, however, a systemic lytic state is seen, with moderate amounts of circulating fibrin degradation products and a substantial systemic bleeding risk. lysis of normal hemostatic plugs. The bleeding is often noted at a catheterization site, although gastrointestinal and cerebral hemorrhages may occur. Therefore, patients who have experienced trauma injury or who have a history of cerebral hemorrhagic stroke are not usually administered thrombolytics. Need to speed paramedic team to patient, or to speed up admission of patient: symptom to needle, and door to needle time.
- circulating plasminogen becomes more prone to convert to plasmin, thus increasing the likelihood of degrading plasma proteins other than fibrin. Specifically, depletion of fibrinogen and factors V and VIII may occur. As levels of plasmin in circulating plasma increase, available supplies of a2-antiplasmin (endogenous neutralizer of plasmin) are depleted and the risk of a systemic fibrinolytic state increases. In theory, alteplase should be effective only at the surface of fibrin clot. In practice, however, a systemic lytic state is seen, with moderate amounts of circulating fibrin degradation products and a substantial systemic bleeding risk. Plasmin is an important enzyme(EC 3.4.21.7) present in blood that degrades many blood plasmaproteins, most notably, fibrinclot lysis of normal hemostatic plugs. The bleeding is often noted at a catheterization site, although gastrointestinal and cerebral hemorrhages may occur. Therefore, patients who have experienced trauma injury or who have a history of cerebral hemorrhagic stroke are not usually administered thrombolytics. Need to speed paramedic team to patient, or to speed up admission of patient: symptom to needle, and door to needle time.
- &gt; 65 yr old. Only list some impt CI.
- Bind to plasminogen, will change conformation of it to become active, then plasminogen self cleave to become plasmin. May increase level of protein C. Resistance if recent strep infection- lots of antibodies. Preferred in high risk group eg female elderly hypertensive. Avoid use if used before, to prevent allergy. Not sure why is not clot selective, may give systemic fibrinolysis or lytic state, yet may have less bleeding- can give to hi risk group, lesser intracranial bleeding. Cleave peptide bond
- Because the cost of t-PA is nearly 10-fold more than that of streptokinase, streptokinase continues to be the available fibrinolytic agent for millions who sustain AMIs in developing countries. For the patient with ischemic symptoms characteristic of AMI of &lt;12 hours&apos; duration and with electrocardiographic findings of ST-segment elevation or left bundle-branch block of unknown duration, administration of any fibrinolytic agent (streptokinase, anistreplase, alteplase, reteplase, or tenecteplase) is strongly advocated (Grade 1A). For patients with symptom duration of &lt;6 hours, the administration of alteplase, rather than streptokinase, is recommended. For patients with an acute posterior AMI of &lt;12 hours&apos; duration, any fibrinolytic agent is indicated (Grade 2C). While both streptokinase and rt-PA have been shown to benefit patients with acute MI, only alteplase (rt-PA) has been shown to benefit selected patients with acute ischemic stroke. Bind to plasminogen, will change conformation of it to become active, then plasminogen self cleave to become plasmin. May increase level of protein C. Resistance if recent strep infection- lots of antibodies. Preferred in high risk group eg female elderly hypertensive. Avoid use if used before, to prevent allergy. Not sure why is not clot selective, may give systemic fibrinolysis or lytic state, yet may have less bleeding- can give to hi risk group, lesser intracranial bleeding.
- Bind to plasminogen, cleave it to plasmin (like tpa). May increase level of protein C. Resistance if recent strep infection- lots of antibodies. Preferred in high risk group eg female elderly hypertensive. Avoid use if used before, to prevent allergy. US: 3x more expensive than streptokinase Urokinase less used in US It has limited clinical use because, like SK, it produces considerable fibrinogenolysis; however, it is used for pulmonary embolism. One benefit over SK is that UK is non-antigenic; however, this is offset by a much greater cost.
- Clot selective. Not effective to convert plasminogen in circulation. Bind fibrin (with greater affinity than streptokinase/urokinase) For stroke also MI
- tPA catalyzes the conversion of plasminogen into plasmin. It does so by cleaving the single-chain plasminogen into two chains. These two chains are linked by a disulfide bond and the resulting molecule is called plasmin. As of today, alteplase is the only thrombolytic drug approved for acute ischemic stroke. Reteplase (r-PA, Retavase) is a second-generation recombinant tissue-type plasminogen activator that seems to work more quickly and to have a lower bleeding risk than the first-generation agent alteplase. Clot selective. Not effective to convert plasminogen in circulation. Bind fibrin (with greater affinity than streptokinase/urokinase) For stroke also MI
- While both streptokinase and rt-PA have been shown to benefit patients with acute MI, only alteplase (rt-PA) has been shown to benefit selected patients with acute ischemic stroke. Clot selective. Not effective to convert plasminogen in circulation. Iv heparin for 48 hrs. licenced in US for stroke- use in 3 hrs.
- Reteplase (r-PA, Retavase) is a second-generation recombinant tissue-type plasminogen activator that seems to work more quickly and to have a lower bleeding risk than the first-generation agent alteplase. . Reteplase: longer half life, only need 2 bolus injections, 30 min apart. For overview, not examined.
- 3 column Say antidote mean agent that counteract a poison Know when its needed, how to change over from parenteral to oral