Anticoagulants, _Antiplatelet_drugs,_Thrombolytics.pptx

Anticoagulants,_Antiplatelet_drugs,Thrombolytics

1. Anticoagulants Antiplatelet drugs Thrombolytics Presented by Mina Nady Max Vascular Surgeon Specialist - MRCS

2. Overview Hemostasis. Assessment of Coagulation System. Classifications of Drugs used to treat Clotting disorders. Examples of Anticoagulants. Examples of Antiplatelet drugs. Examples of Thrombolytics.

3. Hemostasis Definition: a mechanism that leads to cessation of bleeding from a blood vessel. ( hemo = blood ; stasis = standing ) Steps of mechanism: Vasoconstriction (VC). Platelet plug formation (1ry hemostasis). Fibrin plug formation (2ry hemostasis). Fibrinolysis. Regeneration.

4. Platelet plug formation (1ry Hemostasis): Endothelial injury. Exposure of sub-endothelial matrix proteins (e.g. collagen). Release of von Willebrand factor ( vWf ) & tissue thromboplastin. Platelet adhesion. to the sub-endothelial matrix (directly or indirectly via vWf ). Platelet activation. Shape change to  increase surface area. Degranulation: release of platelet agonists as ADP & TXA2. Platelet aggregation. Fibrinogen binds to activated fibrinogen receptor ( GPIIb / IIIa ) on platelets that links platelets together. Vasoconstriction (VC): Local reflexes, Thromboxane A2 & Serotonin release.

5. Fibrin plug formation (2ry hemostasis): Intrinsic pathway. Activated by exposure of blood components to Sub-endothelial matrix proteins (e.g. collagen). Extrinsic pathway. Activated by Tissue factors (e.g. tissue thromboplastin, tissue phospholipid). Common pathway. Activated by formation of Prothrombinase complex (factors Xa , Va , Ca & platelet phospholipid).

6. vWF III (Tissue factor pathway inhibitor)

7. Fibrinolysis (Fibrinolytic system) Plasminogen Plasmin Fibrin Fibrin degradation products (FDPs) Tissue plasminogen activator ( tPA ) Urokinase Plasminogen activator inhibitor 1 & 2 (PAI) Alpha 2-antiplasmin Alpha 2-macroglobulin Factor XIa , XIIa , Kallikrein Thrombin Thrombin activatable fibrinolysis inhibitor Protein C

8. Clotting factors

9. Assessment of Coagulation System Assessment What to test? Lab tests 1ry hemostasis Platelets Platelets counts PFA-100 Bleeding time 2ry hemostasis Coagulation factors PT, aPTT, INR Fibrinolytic system TPA FDPs, D-dimer

10. Test What to test? Normal range Platelets counts Platelets counts 150,000 to 450,000 /  microliter of blood PFA-100 (Platelet Function Analyzer-100) Platelet function, vWF level, Platelet number & Hematocrit <180 seconds Bleeding time Platelets counts, function & Vascular integrity ( time of small puncture wound to stop bleeding) 1-8 minutes PT (Prothrombin Time) Extrinsic & Common pathways (factors I, II, V, VII & X). (time that plasma takes to clot after addition of tissue factor) 11 to 13.5 seconds aPTT (activated Partial Thromboplastin Time) Intrinsic & Common pathways (all factors except factor VII) (time that plasma takes to clot after addition of Reagent) 30 to 40 seconds INR (International Normalized Ratio) Extrinsic & Common pathways (factors I, II, V, VII & X). (PT of the patient / PT of normal range mean) 0.8 to 1.1 FDPs (Fibrin Degradation Products) fragments of protein that released from fibrinogen & fibrin by action of plasmin < 10 mg/L D-dimer The most notable subtype of fibrin degradation products < .5 mg/L

11. D-dimer Units Adult First trimester Second trimester Third trimester mg/L or µg/mL < 0.5 0.05 - 0.95 0.32 - 1.29 0.13 -1.7 µg/L or ng/mL < 500 50 - 950 320 - 1290 130 - 1700 nmol /L < 2.7 0.3 - 5.2 1.8 - 7.1 0.7 - 9.3 Reference ranges

12. Classifications of Drugs used to treat Clotting disorders Anticoagulants : A medication used to prevent the formation of blood thrombus and to maintain blood vessels opened. Antiplatelet drugs : A medication that interferes with the normal function of blood platelets. Thrombolytics : A medication used to dissolve thrombus in blood vessels to improve blood flow.

13. Anticoagulants

14. Site of action of Anticoagulants

15. Unfractionated Heparin (UFH) Trade names Heparin , Cal-Heparin Dosage Forms : 5000 IU Rout of administration : IV or SC Mechanism of action Inhibition of factors II, X, IX, XI, XII Therapeutic dose Loading : 80 IU/kg Maintenance : 18 IU/kg/hours Prophylactic dose 5000 IU/8-12 hours Half life 30-90 minutes (dose dependent) Holding Time 4-6 hours Monitoring aPTT / 4 hours (effective if 1.5 to 2 times) Antidote Protamine sulfate ( 1-1.5mg/100 IU of heparin in previous 4 hours) , FFP Side effects & Overdose Bleeding, HIT ( Type 1 : direct effect after 1-4 days & Type 2: immune-mediated after 5-10 days) , Osteoporosis , transient Alopecia, Skin necrosis, Hyperkalemia ( hypo- aldosteronism ) Safety in renal patient safe Safety with pregnancy : safe Safety with lactation : safe Safety in children Therapeutic : (<1Year) Loading : 75 IU/kg Maintenance : 28 IU/kg/hours Therapeutic : (>1Year) Loading : 75 IU/kg Maintenance : 20 IU/kg/hours Prophylactic: 100-150 IU/kg once

16. Low Molecular Weight Heparin (LMWH) Mechanism of action: Inhibition of factors X & II LMWH Average MW Anti- Xa / Anti- IIa activity ratio Bemiparin 3600 8.0 Nadroparin 4300 3.3 Reviparin 4400 4.2 Enoxaparin 4500 3.9 Parnaparin 5000 2.3 Certoparin 5400 2.4 Dalteparin 5000 2.5 Tinzaparin 6500 1.6

17. Enoxaparin (LMWH) Trade names Clexane , Lovenox , Neoparin Dosage Forms : multiple (prefilled syringe) Rout of administration : SC Mechanism of action Inhibition of factors X, II (3.9 : 1) Therapeutic dose 1mg/kg/12hours or 1.5mg/kg/day Prophylactic dose 20-40mg/day Half life 4-6 hours Holding Time 12 hours Monitoring anti-factor Xa assay (usually not required) Antidote FFP, Protamine sulfate ( 1mg/1mg of Enoxaparin in previous 8 hours) Side effects & Overdose Hemorrhage, Hematomas (Epidural or spinal) , Fever, Local site reactions, Ecchymosis, Thrombocytopenia, Nausea , Hyperkalemia, Elevations of ALT & AST Safety in renal patient Half dose was recommended ; Not safe if creatinine clearance level <30 ml/minute Safety with pregnancy : safe Safety with lactation : safe Safety in children Therapeutic : (<2months) 1.5mg/kg/12 hours (≥2 months) 1mg/kg/12 hours Prophylactic: (<2months) 0.75mg/kg/12 hours (≥2 months) 0.5mg/kg/12 hours

18. Dosage Forms of Enoxaparin prefilled syringe 20mg/0.2mL 30mg/0.3mL 40mg/0.4mL 60mg/0.6mL 80mg/0.8mL 100mg/mL 120mg/0.8mL 150mg/mL

19. Dalteparin (LMWH) Trade names Fragmin Dosage Forms : multiple (prefilled syringe) Rout of administration : SC Mechanism of action Inhibition of factors X, II (2.5 : 1) Therapeutic dose 150-200 IU/kg/day (maximum 18,000 IU/day) or 100 IU/kg/12hours Prophylactic dose 75 IU/kg /day Half life 2-5 hours Holding Time 12 hours Monitoring anti-factor Xa assay (usually not required) Antidote FFP, Protamine sulfate ( 1mg/100IU of Dalteparin in previous 8 hours) Side effects & Overdose Not indicated for acute treatment of VTE or Platelets < 50,000/mm³ Injection site hematoma or pain, Thrombocytopenia, Hemorrhage, Hematuria, Hematomas (Epidural or spinal) , Hyperkalemia Elevations of ALT & AST Safety in renal patient Half dose was recommended ; Not safe if creatinine clearance level <30 ml/minute Safety with pregnancy : safe Safety with lactation : safe Safety in children Therapeutic : (1-2 months) 150 IU/kg/12 hours (≥2 months) 100 IU/kg/12 hours Prophylactic: (1-2 months) 75 IU/kg/12 hours (≥2 months) 50 IU/kg/12 hours

20. Dosage Forms of Dalteparin prefilled syringe 2,500 IU/0.2 mL 5,000 IU/0.2 mL 7,500 IU/0.3 mL 10 , 00 IU/0. 4 mL 12,500 IU/0.5 mL 15,000 IU/0.6 mL 18,000 IU/0.72 mL Body Weight (kg) FRAGMIN Dose (IU) (prefilled syringe) once daily <46 7.500 46 to 56 10.000 57 to 68 12.500 69 to 82 15.000 ≥83 18.000

21. Tinzaparin (LMWH) Trade names Innohep Dosage Forms : multiple (prefilled syringe) Rout of administration : SC Mechanism of action Inhibition of factors X, II (1.6 : 1) Therapeutic dose 175 IU/kg/day Prophylactic dose 50-75 IU/kg /day Half life 2-5 hours Holding Time 12 hours Monitoring anti-factor Xa assay (usually not required) Antidote FFP, Protamine sulfate ( 1mg/100IU of Tinzaparin in previous 8 hours) Side effects & Overdose Hemorrhage, Thrombocytopenia, Elevations of ALT & AST, Injection site hematoma or pain,, Hematuria, Hematomas (Epidural or spinal) , Hyperkalemia. Safety in renal patient Half dose was recommended ; Not safe if creatinine clearance level <20 ml/minute Safety with pregnancy : LMWH of choice Safety with lactation : safe Safety in children Therapeutic : (<10 years) 200-275 IU/kg/day (≥10 years) 175 IU/kg/day Prophylactic: (<10 years) 75 IU/kg/day (≥10 years) 50 IU/kg/day

22. Dosage Forms of Tinzaparin prefilled syringe 3 ,500 IU/0. 35 mL 4 , 5 00 IU/0. 45 mL 10 , 00 IU/0. 5 mL 14 , 00 IU/0. 7 mL 18 , 00 IU/0. 9 mL Age Therapeutic dose 0-2 months 275 IU/kg/day 2-12 months 250 IU/kg/day 1-5 years 240 IU/kg/day 5-10 years 200 IU/kg/day 10-16 years 175 IU/kg/day Adult 175 IU/kg/day

23. Fondaparinux (Tiny Heparin) Trade names Arixtra , Fondaparinux Dosage Forms : multiple (prefilled syringe) Rout of administration : SC Mechanism of action Inhibition of factors X Therapeutic dose 5 mg/day ( <50 kg) - 7.5 mg/day ( 50-100 kg) - 10 mg/day ( >100 kg) for 5-10 days Prophylactic dose 2.5 mg/day for 5-10 days Half life 17-21 hours Holding Time 1-3 days Monitoring anti-factor Xa assay (usually not required) Antidote No specific antidote Side effects & Overdose Hemorrhage, Hematomas (Epidural or spinal) , Anemia, Fever, Nausea, Rash, Thrombocytopenia, Constipation, Diarrhea, Hypotension, Insomnia N.B: It may be used as an alternative to Heparin when it is contraindicated especially with HIT Safety in renal patient Not safe if creatinine clearance level <30 ml/minute Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe <18 years

24. Dosage Forms of Fondaparinux prefilled syringe 2.5mg/0.5mL 5mg/0.4mL 7.5mg/0.6mL 10mg/0.8mL

25. Warfarin Trade names Marevan , Coumadin, Jantoven Dosage Forms : 1, 2, 2.5, 3, 4, 5, 6, 7.5, 10 mg Rout of administration : Oral Mechanism of action Vitamin K epoxide reductase inhibitor ; Inhibit production of factors X, IX, VII, II , Protein C & S Initial dose 10 mg / day for 2 days then Check INR (simultaneously parenteral anticoagulant UFH or LMWH or Fondaparinux given for at least 5 days until INR >2.0 to prevent transient procoagulant states ) Maintenance dose 2-10 mg/day according to INR (2.0-3.0) Half life 40 hours Holding Time 4-5 days Monitoring INR / 4-8 weeks (1-2 weeks if d osage change) Antidote Vitamin K , FFP, Prothrombin complex concentration (PCC) Side effects & Overdose Bleeding, Bruises, Skin necrosis, Severe headache, Stomach pain, Joint pain, Diarrhea, Vomiting, Fever, Elevations of ALT & AST (Half dose was recommended ) Safety in renal patient safe Safety with pregnancy : teratogenic, cause miscarriage Safety with lactation : safe Safety in children Initial : 0.1 – 0.2 mg/kg/day for 2 days then Check INR Maintenance: 0.09 – 0.33 mg/kg/day

26. Factor Half life X 48-72 hours IX 24 hours VII 4-6 hours II 60 hours Protein C 8 hours Protein S 30 hours

27. Algorithms for monitoring warfarin use : dose adjustment and bleeding control

28. Dabigatran (Direct Thrombin F II inhibitor) Trade names Pradaxa Dosage Forms : 75, 110, 150 mg Rout of administration : oral Mechanism of action DTI : Direct Thrombin (Factor II) inhibitor Therapeutic dose 150 mg/12hours Prophylactic dose 150 mg/12hours Half life 12-14 hours Holding Time 2-5 days (according to creatinine clearance level) Monitoring Ecarin clotting time, TT, aPTT (usually not required) Antidote Idarucizumab ( Praxbind ) : 5 mg (2 separate doses each 2.5mg given no more than 15 min apart) Side effects & Overdose Dyspepsia, Gastritis, Bleeding , Bruises N.B : preferred start Dabigatran 5-10 days after parenteral anticoagulant or in patients with recurrent DVT and PE who have been previously treated by other anticoagulant. Safety in renal patient Not safe if creatinine clearance level <30 ml/minute Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe <18 years

29. Lepirudin (Recombinant Hirudin ) (Direct Thrombin F II inhibitor) Trade names Thrombexx Dosage Forms : 15 mg amp & 1120 IU gel, cream Rout of administration : IV, SC, Gel, Cream Mechanism of action DTI : Direct Thrombin (Factor II) inhibitor ( inhibits only the activated thrombin) Therapeutic dose (IV) Initial: 0.4 mg/kg (maximum 44mg) slowly over 15 to 20 seconds. Maintenance 0.15 mg/kg/hour (maximum 16.5mg/hour)  for 2 to 10 days . Prophylactic dose (SC) 15 mg / 12 hours Half life 80 hours Holding Time ???? Monitoring aPTT (effective if 1.5 to 2.5 times) tested 4 hours after Initial dose then daily Antidote No specific (Desmopressin IV, Hemodialysis) Side effects & Overdose It is used as an alternative to Heparin when it is contraindicated especially with HIT Bleeding, Anaphylaxis, Anti- lepirudin antibodies formation (40%) Safety in renal patient Adjustment dose needed if CrCl < 60ml/minute Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe <18 years

30. Treatment of HIT Stop all heparin: (both UFH & LMWH), including flushes. Alternative anticoagulant: Lepirudin : cleared by the kidney. Argatroban: cleared by the liver. Fondaparinux

31. Rivaroxaban (Direct Factor X inhibitor) Trade names Xarelto , Rivarospire , Vaxato Dosage Forms : 2.5, 10, 15, 20 mg Rout of administration : oral Mechanism of action Direct Factor X inhibitor Therapeutic dose Loading : 15 mg /12hours for 21 days Maintenance : 20 mg/day (with food) Prophylactic dose 10 mg/day Half life 9-13 hours Holding Time 1-2 days Monitoring anti-factor Xa assay , PT (usually not required) Antidote Andexxa (modified form of the human Factor Xa molecule) Side effects & Overdose Bleeding, Hematoma, Back pain, Abdominal pain, Dizziness, Pruritus, Insomnia, Anxiety, Blister, Fatigue, Muscle spasm, Depression Safety in renal patient Not safe if creatinine clearance level <30 ml/minute (if needed give 15mg/day) Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe <18 years

32. Apixaban (Direct Factor X inhibitor) Trade names Eliquis , Elimbosis , Iksaront Dosage Forms : 2.5, 5 mg Rout of administration : oral Mechanism of action Direct Factor X inhibitor Therapeutic dose Loading : 10 mg /12hours for 7 days Maintenance : 5 mg /12hours Prophylactic dose 2.5 mg /12hours Half life 8-15 hours Holding Time 1-2 days Monitoring anti-factor Xa assay , PT (usually not required) Antidote Andexxa ( modified form of the human Factor Xa molecule) Side effects & Overdose Bleeding, Hematoma, headache, Dizziness, Insomnia, Anxiety, Fatigue, chest pain, Swelling of the face or tongue, Trouble breathing, Wheezing Safety in renal patient Not safe if creatinine clearance level <15 ml/minute Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe <18 years

33. Dose adjustment of Anticoagulation with Renal Impairment Drug Mild (Cr Cl, 60-89ml/min) Moderate (Cr Cl, 30-59ml/min) Sever (Cr Cl, 15-29ml/min) Dialysis (Cr Cl, < 15ml/min) UFH No adjustment No adjustment No adjustment 70% of dose Enoxaparin No adjustment No adjustment Half dose Half dose Dalteparin No adjustment No adjustment Contraindicated Contraindicated Tinzaparin No adjustment No adjustment No adjustment * Contraindicated Fondaparinux No adjustment 40% of dose Contraindicated Contraindicated Warfarin No adjustment No adjustment 75% of dose 75% of dose Dabigatran No adjustment No adjustment Half dose Contraindicated Lepirudin No adjustment 30-50% of dose 15% of dose Contraindicated Rivaroxaban No adjustment No adjustment Contraindicated ** Contraindicated Apixaban No adjustment No adjustment No adjustment Contraindicated *** * Tinzaparin not used if Cr Cl < 20ml/min. ** If needed, give 15 mg/day as a therapeutic dose. *** If patient on RHD, Apixaban may be given with no adjustment of its dose.

34. Dose adjustment of Anticoagulation with Hepatic Impairment Drug Child-Pugh A Child-Pugh B Child-Pugh C UFH No adjustment No adjustment No adjustment Enoxaparin No adjustment No adjustment Use with caution Dalteparin No adjustment No adjustment Use with caution Tinzaparin No adjustment No adjustment Use with caution Fondaparinux No adjustment No adjustment Use with caution Warfarin No adjustment No adjustment No adjustment Dabigatran No adjustment Use with caution Contraindicated Lepirudin No adjustment No adjustment Use with caution Rivaroxaban No adjustment Contraindicated Contraindicated Apixaban No adjustment Use with caution Contraindicated Use with caution: Observe closely for signs of bleeding and Monitor liver functions .

35. Safety of Anticoagulation with specific cases Drug Pregnancy Lactation Pediatrics Geriatrics UFH Category B Safe Safe Use with caution Enoxaparin Category B Safe Safe Use with caution Dalteparin Category B Safe Safe > 1 month Use with caution Tinzaparin Category B Safe Safe Use with caution Fondaparinux Category B Not safe Not safe Use with caution Warfarin Category D Safe Safe Use with caution Dabigatran Category C Not safe Not safe Not safe > 75 years Lepirudin Category B Not safe Not safe Use with caution Rivaroxaban Category C Not safe Not safe Half dose > 80 years Apixaban Category B Not safe Not safe Half dose > 80 years Use with caution: Observe closely for signs of bleeding and may need to decrease the dose . Tinzaparin not used in patients >70 years of age with renal impairment.

36. Antiplatelet drugs

37. Site of action of Antiplatelet drugs

38. Site of action of Antiplatelet drugs

39. Classifications of Antiplatelet drugs

40. Aspirin (Acetylsalicylic acid) Trade names multiple Dosage Forms: 75, 81, 150, 162, 162.5, 300, 325, 500, 600, 650 mg Rout of administration : oral & rectal Mechanism of action Irreversibly inhibits COX-1 & COX-2 (in high dose) Dose Anti-platelet dose: 75 mg/day Analgesic dose: 325-600 mg/4-6 hours Anti-inflammatory dose: 1.2 g/4-6 hours Half life 3.5 - 4.5 hours Holding Time According to Cardiac and Bleeding Risk : Low & Intermediate risk: Maintain aspirin High risk : Stop aspirin five days before surgery & r estart within 24 hours after surgery. Monitoring Bleeding time, PFA-100 (Platelet Function Analyzer-100) (usually not required) Antidote No specific (Sodium bicarbonate, Activated charcoal. Severe cases may need Hemodialysis) Side effects & Overdose ASPIRIN : A sthma, S alicylate intolerance (allergy), P eptic ulcer disease, I ntestinal & gastric bleeding, R eye's syndrome, I diosyncrasy (odd habit), N oise (tinnitus) Safety in renal patient avoiding if CrCl < 10 mL/minute Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe < 18 years unless indicated ( e.g Juvenile Rheumatoid Arthritis)

41. Clopidogrel Trade names Plavix, Clopex Dosage Forms : 75, 300 mg Rout of administration : oral Mechanism of action Irreversibly blocks the ADP receptor (P2Y12) on platelets (reducing platelets aggregation) Loading d ose 300 – 600 mg Maintenance dose 75 mg / day Half life 6 hours Holding Time According to Cardiac and Bleeding Risk : Low & Intermediate risk: Maintain Clopidogrel High risk : Stop Clopidogrel five days before surgery & r estart within 24 hours after surgery. Monitoring Aggregometry , vasodilator-stimulated phosphoprotein VASP phosphorylation (test platelet response to ADP) (usually not required) Antidote No specific ( platelet transfusions ) Side effects & Overdose Bleeding, Upper respiratory tract infection, Chest pain, Headache, Flulike syndrome, Arthralgia, Pain, Dizziness, Diarrhea, Rash, Rhinitis, Depression, Urinary tract infection. Safety in renal patient safe Safety with pregnancy : safe Safety with lactation : safe Safety in children Not safe < 18 years

42. Cilostazol Trade names Pletal , Claudicat Dosage Forms : 50, 100 mg Rout of administration : oral Mechanism of action Phosphodiesterase III inhibitor (-- platelets aggregation & ++ VD) D ose 100 mg / 12 hours (30 minutes before or 2 hours after meals) Discontinue if symptoms not improved after 3 months of therapy Half life 11 hours Holding Time 2 days (usually not required) Monitoring Sings of complication Antidote No specific ( platelet transfusions ) Side effects & Overdose Headache, Diarrhea, P alpitations (++ HR ) , Hypotension, Dizziness, Rhinitis, Pharyngitis N.B : u se with caution in moderate to severe hepatic Impairment Safety in renal patient Safe but must use with caution if CrCl < 25 mL/minute (acute tubule-interstitial nephritis) Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe < 18 years

43. Mechanism of action of Cilostazol

44. Thrombolytics

45. Uses of Thrombolytics Acute myocardial infarction (AMI). Acute ischemic stroke (AIS). Pulmonary embolism (PE). Deep vein thrombosis (DVT). Acute peripheral arterial occlusion. Occlusion of indwelling catheters.

46. Site of action of Thrombolytics

47. Classifications of Thrombolytics Non-fibrin specific Fibrin specific Streptokinase Urokinase Anistreplase Tissue Plasminogen Activator (t-PA) Alteplase ( rt -PA) Reteplase (r-PA) Tenecteplase (TNK- tPA )

48. Streptokinase Trade names Streptase Dosage Forms : 250000, 750000, 1500000 IU Rout of administration : IV Mechanism of action Combines with plasminogen and increases its conversion to active plasmin Catalyzes factors V & VII Loading d ose 250,000 IU/ over 30 min. Maintenance dose 100,000 IU/hour for 24-72 hours Half life 18-23 minuets Holding Time 2 hours Monitoring Sings of complications Antidote Aminocaproic acid ( Amicar ): inhibit activation of plasminogen to plasmin. Side effects & Overdose Nausea, Headache, Dizziness, Hypotension, Mild fever, Bleeding, Rash, Itching, Flushing, Muscle or bone pain, Shivering, Allergic reactions. Safety in renal patient Safe Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Loading: 1000 IU/ over 30 min. Maintenance: 1000 IU/kg/hour

49. Urokinase Trade names Kinlytic , Abbokinase Dosage Forms : 10000, 25000, 100000, 250000, 500000 IU Rout of administration : IV Mechanism of action Directly converts plasminogen to active plasmin ( Human enzyme synthesized by the kidney) Loading d ose 4400 IU/kg over 1 0 min. Maintenance dose 4400 IU/kg/hour for 12 hours Half life 14-20 minuets Holding Time 2 hours Monitoring Sings of complication Antidote Aminocaproic acid ( Amicar ): inhibit activation of plasminogen to plasmin. Side effects & Overdose Bleeding, -- hematocrit, Chest pain, ++ heart rate, Fever, Chills, Nausea, Vomiting, Anaphylaxis reactions. Safety in renal patient Not safe Safety with pregnancy : not safe Safety with lactation : not safe Safety in children Not safe

50. Alteplase ( rt -PA) (recombinant t-PA) Trade names Activase , Cathflo Activase Dosage Forms : 2, 50, 100 mg Rout of administration : IV Mechanism of action Selectively binds to fibrin in a thrombus & converts entrapped plasminogen to plasmin. D ose For Arterial Thrombosis & Embolism Trans catheter intra-arterial infusion : 0.05-0.1 mg/kg/ hr for 1-8 hours or until clot resolution. IV infusion : 0.9 mg/kg (maximum 90mg) ; 10% as initial bolus over 1 min & 90% over 60 min. Half life 4-8 minuets Holding Time 2 hours Monitoring Sings of bleeding, BP, Neurological deficits Antidote Aminocaproic acid ( Amicar ): inhibit activation of plasminogen to plasmin. Side effects & Overdose Bleeding (ICH), Hypotension, Fever, Nausea, Vomiting, dizziness, Anaphylaxis reactions. Safety in renal patient Safe Safety with pregnancy : Safe Safety with lactation : Safe Safety in children Trans catheter intra-arterial infusion: avoided due to small vessel size may increase the chance of local damage to blood vessels and formation of a new thrombus. IV infusion : 0.5 mg/kg/hour for 6 hours.

51. Catheter- Directed Thrombolysis (CDT)

52. Ekosonic Endovascular System (EKOS)

53. Reteplase (r-PA) Trade names Retavase Dosage Forms : 10 IU Rout of administration : IV Mechanism of action Selectively binds to fibrin in a thrombus & converts entrapped plasminogen to plasmin. D ose Trans catheter infusion : 0.1-1.0 IU/ hr for 22–42 hours or until clot resolution. IV infusion : 10 IU bolus (over 2 minutes) and repeated after 30 min. Half life 13-16 minuets Holding Time 2 hours Monitoring Sings of bleeding, BP, Neurological deficits Antidote Aminocaproic acid ( Amicar ): inhibit activation of plasminogen to plasmin. Side effects & Overdose Bleeding (ICH), Hypotension, Fever, Nausea, Vomiting, dizziness, Anaphylaxis reactions. Safety in renal patient Safe Safety with pregnancy : not Safe Safety with lactation : not Safe Safety in children Not Safe

54. Tenecteplase (TNK- tPA ) Trade names Tenecteplase, TNKase Dosage Forms : 50 mg Rout of administration : IV Mechanism of action Selectively binds to fibrin in a thrombus & converts entrapped plasminogen to plasmin. D ose Trans catheter infusion : 5 mg bolus then 0.5 mg/h for 14-43 hours or until clot resolution. IV infusion : 0.5 mg/kg IV bolus over 10 sec once (maximum 50mg). Half life 20-24 minuets Holding Time 2 hours Monitoring Sings of complications Antidote Aminocaproic acid ( Amicar ): inhibit activation of plasminogen to plasmin. Side effects & Overdose Bleeding (minor), Fever, Reperfusion arrhythmias, MI, Cholesterol embolization, Nausea, Vomiting, dizziness, Anaphylaxis reactions. Safety in renal patient Safe Safety with pregnancy : not Safe Safety with lactation : not Safe Safety in children Not safe

55. Anistreplase (APSAC) Trade names Eminase Dosage Forms : 30 IU Rout of administration : IV Mechanism of action Anisoylated plasminogen-streptokinase activator complex ( APSAC ) consists of: Plasminogen and Streptokinase bound noncovalently D ose 30 IU once over 2 to 5 minutes. Half life 70 minuets Holding Time 2 hours Monitoring Sings of complications Antidote Aminocaproic acid ( Amicar ): inhibit activation of plasminogen to plasmin. Side effects & Overdose Bleeding, Cardiac arrhythmias, Fever, Nausea, Vomiting, dizziness, Anaphylaxis reactions, I tching, Flushing, Skin rash, H eadache Safety in renal patient Safe Safety with pregnancy : not Safe Safety with lactation : not Safe Safety in children Not safe

56. Thrombolytic Therapy for Blocked Catheters Alteplase If ≥ 30 kg: Inject 2 mg in 2 mL of saline inside blocked catheter. If < 30 kg: fill 100% of the internal lumen volume of the catheter (but do not exceed 2 mg ). Leave the agent for 30 minutes to 2 hours, then withdraw it. Repeat the same dose if needed. If this is unsuccessful, 2 mg/50 mL may be infused (IV) over 4 hours. Urokinase 5000 IU in each lumen. Leave the agent for 1-4 hours, then withdraw it. Repeat with 10,000 U in each lumen if needed. Streptokinase 250,000 IU in 2 mL of saline in each lumen over 1-2 minutes. Leave the agent for 2 hours, then withdraw it.

57. References LaPelusa , A., & Dave, H. D. (2019). Physiology, hemostasis. https://commons.wikimedia.org/wiki/File:Coagulation_full.svg#metadata https://tmedweb.tulane.edu/pharmwiki/doku.php/all_heme_module_drugs https://en.wikipedia.org/wiki/File:Fibrinolysis.png https://www.ucsfhealth.org/medical-tests/003655 Reference Values During Pregnancy  at perinatology.com. Retrieved October 2014. Ansell, J. E. (2019). Outpatient Oral Anticoagulant Therapy. In Consultative Hemostasis and Thrombosis (pp. 747-777). Content Repository Only!. https://www.rxlist.com/heparin-drug.htm#indications https://reference.medscape.com/drug/calciparine-monoparin-heparin-342169#0 https://www.rxlist.com/fragmin-drug.htm#dosage Gutierrez, J. J. P., & Rocuts , K. R. (2020). Perioperative Anticoagulation Management.  StatPearls [Internet]. Kano, E. K., Borges, J. B., Scomparini , E. B., Curi , A. P., & Ribeiro, E. (2017). Algorithms for monitoring warfarin use: Results from Delphi Method.  Revista da Associação Médica Brasileira , 63(10), 842-855.

58. Aursulesei , V., & Costache , I. I. (2019). Anticoagulation in chronic kidney disease: from guidelines to clinical practice. Clinical cardiology, 42(8), 774-782. Qamar , A., Vaduganathan , M., Greenberger, N. J., & Giugliano , R. P. (2018). Oral anticoagulation in patients with liver disease. Journal of the American College of Cardiology, 71(19), 2162-2175. https://www.uptodate.com/contents/heparin-unfractionated-drug-information https://www.sciencedirect.com/science/article/pii/S073510971635032X http://druginformation.com/rxdrugs/L/Lepirudin%20(rDNA)%20Injection.html https://www.aafp.org/afp/2010/1215/p1484.html Homoncik M, Jilma B, Hergovich N, Stohlawetz P, Panzer S, Speiser W. Monitoring of aspirin (ASA) pharmacodynamics with the platelet function analyzer PFA-100. Thromb Haemost . 2000 Feb;83(2):316-21. PMID: 10739392. Geiger J, Teichmann L, Grossmann R, Aktas B, Steigerwald U, Walter U, Schinzel R. Monitoring of clopidogrel action: comparison of methods. Clin Chem. 2005 Jun;51(6):957-65. doi : 10.1373/clinchem.2004.047050. Epub 2005 Apr 7. PMID: 15817818. Balinski , A. M., & Preuss , C. V. (2019). Cilostazol.

59. Shima , H., Tashiro , M., Yamada, S., Matsuura, M., Okada, K., Doi , T., ... & Kawashima, S. (2018). Cilostazol-induced acute tubulointerstitial nephritis accompanied by IgA nephropathy: a case report. BMC nephrology, 19(1), 1-5. https://www.stemi-care.com/metalyse/thrombolytics https://www.slideshare.net/rahuth/thrombolytics-ppt https://www.rxlist.com/streptase-drug.htm#dosage https://www.rxlist.com/streptase-side-effects-drug-center.htm https://www.rxlist.com/kinlytic-drug.htm#side_effects https://www.drugs.com/pregnancy/urokinase.html#:~:text=Urokinase%20Pregnancy%20Warnings&text=US%20FDA%20pregnancy%20category%20B,controlled%20studies%20in%20pregnant%20women . https://www.medicinenet.com/urokinase-injection/article.htm#which_drugs_or_supplements_interact_with_urokinase-injection https://reference.medscape.com/drug/activase-tpa-alteplase-342287#0 https://www.activase.com/ais/dosing-and-administration/dosing.html https://acp-online.org/wp-content/uploads/2018/02/Micki-Pilbin-EKOS_DVT_Referral_.pdf https://reference.medscape.com/drug/activase-tpa-alteplase-342287#4

60. https://www.uptodate.com/contents/alteplase-drug-information#F132232 Simpson, D., Siddiqui, M. A. A., Scott, L. J., & Hilleman , D. E. (2006). Reteplase . American journal of cardiovascular drugs, 6(4), 265-285. https://reference.medscape.com/drug/retavase-reteplase-342289#0 https://www.rxlist.com/retavase-drug.htm#description https://reference.medscape.com/drug/tnk-tpa-tnkase-tenecteplase-342291#5 https://en.wikipedia.org/wiki/Tenecteplase https://www.rxlist.com/tnkase-drug.htm#medguide https://www.jvir.org/article/S1051-0443(07)60348-0/pdf https://www.researchgate.net/publication/8047727_Initial_Clinical_Results_of_Tenecteplase_TNK_in_Catheter-Directed_Thrombolytic_Therapy https://www.drugs.com/dosage/anistreplase.html https://www.sciencedirect.com/topics/medicine-and-dentistry/anistreplase https://emedicine.medscape.com/article/811234-overview#a1

61. Mina Nady Max Vascular Surgeon Specialist - MRCS