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1. ANTITHROMBOTICS Presenter-Dr Chalie(R1) Moderator-Dr Afework H.(Consultant interinist,Hematologist June 2019

2. outlines overview/principle of antithrombotic managemet Specific antithrombotic drugs Heparins(UFH and LMWH) Vit k antagonists( warfarin ) New oral antagonists (NOAS) Rivaroxaban &Dabigatran Fibrinolytics Antiplatelet agents References

3. Hemostasis

4. Thromboembolic disorders are major causes of morbidity & mortality Arterial & Venous thrombosis composed of platelets, fibrin, and trapped red blood cells, but the proportion different arterial thrombi appear white, whereas venous thrombi are red in color

5. Antithrombotic drugs are used for prevention and treatment of thrombosis. Targeting the components of thrombi, these agents include (1) antiplatelet drugs, (2) anticoagulants, and (3) fibrinolytic agents

6. Strategies to attenuate arterial thrombosis focus mainly on antiplatelet agents. Anticoagulants are the mainstay of prevention and treatment of venous thromboembolism Fibrinolytic therapy is used in selected patients with venous thromboembolism . Pharmaco -mechanical therapy also is used to restore blood flow in patients with extensive DVT involving the iliac and/or femoral veins.

7. Anticoagulants

8. ANTICOAGULANTS Parenteral heparin, low-molecular-weight heparin (LMWH), fondaparinux (a synthetic pentasaccharide ), lepirudin , desirudin , bivalirudin , and argatroban Oral warfarin; dabigatran etexilate , an oral thrombin inhibitor; and rivaroxaban and apixaban, oral factor Xa inhibitors

9. Heparin A sulfated polysaccharide, heparin is isolated from mammalian tissues rich in mast cells Mechanism of action: acts by activating antithrombin and accelerating the rate at which antithrombin inhibits clotting enzymes. To inactivate thrombin it additionally forms a ternary complex in which heparin binds to both AT and to a binding site on thrombin This complex forms only on pentasaccharide -containing chains at least 18 saccharide units long - mol wt. 5400 (which is less commonly present in LMW heparins)- resulting in less antithrombin activity

10. Pharmacology Given parentraly Binds to endothelium, plasma protiens,acute phase reactants,pf4 Dose dependant clearance(t1/2) Onset of action-Rapid(IV),SC 20-30min Metabolized by liver & RES Doesn’t cross the placenta

11. Monitoring (aPTT) or anti-factor Xa level. therapeutic heparin levels are achieved with a two- to threefold prolongation of the aPTT With anti factorXa assay, therapeutic heparin levels range from 0.3 to 0.7 units/ mL. Heparin resistance requires doses >35,000/day. Discrepancy b/n FXa assay and aPTT in cases of AT deficiency, high hep -BP, FVIII, fibrinogen

12. Dosing Prophylaxis :5000 units BID or TID. Therapeutic doses : fixed-dose or weight based heparin nomograms are used. ACS : an IV heparin bolus of 5000 units or 70 units/kg, followed by infusion rate of 12–15 units/kg/ hr. VTE :an IV bolus of 5000 units or 80 units/kg, followed by an infusion of 18 units/kg/ hr.

13. Side effects Bleeding-Reversal- Protamine sulfate thrombocytopenia, osteoporosis and elevated levels of transaminases

14. HIT Life threatening complication Type 1- Mild ,transient drop in platelet count typicaly occurs within the 1 st two days Type 2- Serious form but uncommon Immune mediated characterized by the formation of antibodies against Heparine-pf4 complex

15. Typically, HIT (Type II ) occurs 5–10 days after initiation of heparin therapy Can manifest earlier if the patient has received heparin within the past 3 months HIT can be associated with thrombosis, either arterial or venous. Arterial thrombosis can manifest as ischemic stroke or acute MI. Rarely, platelet-rich thrombi in the distal aorta or iliac arteries can cause critical limb ischemi

16. Diagnosis ELISA-to detect antibodies against He-pf4 Serotonin release assay

17. LMWH Prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization MOA - similar to UFH but shorter chain limits their capacity to bind and inactivate thrombin bind less avidly to endothelial cells, macrophages, and heparin-binding plasma proteins- dose independent clearance and longer half life (~ 4hrs) Cleared almost exclusively by the kidneys, and the drug can accumulate in patients with renal insufficiency

18. Advantages of LMWH Better bioavailability and longer half life after subcutaneous injection Dose-independent clearance Predictable anticoagulant response Lower risk of heparin-induced thrombocytopenia Lower risk of osteoporosis

19. UFH vs LMWH

20. Monitoring Usually do not require monitoring If necessary, anti factor Xa levels monitored Therapeutic levels -- 0.5 to 1.2 units/ mL Prophylactic levels --- 0.2-0.50units/ml Indications Renal insufficiency Obesity Pregnancy Mechanical heart valves Infants/ childre

21. Side effects Bleeding Risk of major bleeding is lower than UFH Increased in patients with risk factors Protamine sulfate can be used antidote but incompletely neutralizes the anticoagulant activity Pts at high risk of bleeding may be safely treated with UFH Thrombocytopenia LMWH bind less avidly to platelets and PF4 Fivefold lower risk of HIT- Cannot be used to treat HIT

22. Osteoporosis : risk is very low , so is the better choice for extended treatment

23. ORAL ANTICOAGULANTS For many years, vitamin K antagonists such as warfarin were the only available oral anticoagulants. This situation changed with the introduction of the direct oral anticoagulants, which include dabigatran , rivaroxaban, apixaban, and edoxaban

24. Warfarin initially introduced in 1948 as a pesticide against rats and mice, and is still used for this purpose approved for use as a medication in 1954 Mechanism of action inhibition of the vitamin K -dependent gamma- carboxylation of factors II, VII, IX, and X The onset of action of warfarin is delayed until the newly synthesized clotting factors with reduced activity gradually replace their fully active counterparts

25. The antithrombotic effect of warfarin depends on a reduction in the functional levels of factor X and prothrombin These clotting factors have half-lives of 24 and 72 h, respectively. patients with established require concomitant treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux, for at least 5 days

26. Warfarin is rapidly and almost completely absorbed from the gastrointestinal tract. Levels of warfarin in the blood peak about 90 min after drug administration. Racemic warfarin has a plasma half-life of 36–42 h, and more than 97% of circulating warfarin is bound to albumin. Only the small fraction of unbound warfarin is biologically active

27. Factors that influence effect of warfarin Genetic Polymorphisms in CYPC29 and VKORC1 Diet Drugs Disease states

28. Warfarin interaction

29. Monitoring Using PT (prothrombin time) The test is performed by adding thromboplastin, a reagent to citrated plasma and determining the time to clot formation. INR - developed to circumvent many of the problems associated with the prothrombin time. INR = INR of pt * ISI Mean INR (ISI), the international sensitivity index which is an index of the sensitivity of the thromboplastin used Most current thromboplastins have ISI values that range from 1.0 to 1.4.

30. For most indications, warfarin is administered in doses that produce a target INR of 2.0–3.0. An exception is patients with mechanical heart valves, target INR of 2.5–3.5 is recommended. Vitamin K antagonists have a narrow therapeutic window

31. Dosing usually started at a dose of 5–10 mg Lower doses in some groups of patients Dose titration Requires frequent monitoring

32. Side effects Bleeding Most serious & common related primarily to patient characteristics, the degree of the anticoagulation, and the duration of therapy Bleeding may occur even when INR is in the therapeutic range

33. Risk factors for bleeding Increased age ,Female sex Diabetes mellitus , Hypertension ( ie , systolic >180 or diastolic >100 mmHg) Presence of malignancy Acute or chronic alcoholism, liver disease ,Severe chronic kidney disease; elevated creatinine Anemia Poor drug compliance or clinic attendance Prior stroke or intracerebral hemorrhage Presence of bleeding lesions ( eg , gastrointestinal blood loss, peptic ulcer disease) Bleeding disorder (coagulation defects, thrombocytopenia) Concomitant use of Drugs Instability of INR control and INR >3.0 , Pre-treatment INR >1.2 Previous severe hemorrhage during treatment with warfarin with an INR in the therapeutic range

34. Pregnancy Warfarin crosses the placenta and can cause fetal abnormalities or bleeding. The fetal abnormalities include a characteristic embryopathy, which consists of nasal hypoplasia and stippled epiphyses

35. New oral antcoagulants Factor Xa inhibitors Rivaroxaban Apixaban Edoxaban Factor IIa inhibitors Dabigatran

36. Have rapid onset $ offset of action Can be give once or twice daily Produce predictable anticoagulation No need of freguent monitoring

37. Rivaroxaban A direct factor Xa inhibitor and can inhibit both free and thrombus-associated factor Xa . renal excretion, and bioaccumulation may occur in patients with renal insufficiency Peak anticoagulantf effect within 4hrs Effective in a number of clinical settings

38. Rivaroxaban is effective in a number of clinical settings. In the EINSTEIN-PE39 and EINSTEIN-DVT38 randomized clinical trials treatment with rivaroxaban (15 mg BID for 3 weeks followed by 20 mg once daily) was noninferior to standard anticoagulation (LMWH followed by warfarin) in preventing recurrent thrombosis in patients with acute VTE.

39. In a large randomized trial of patients with nonvalvular atrial fibrillation , rivaroxaban was noninferior to warfarin for prevention of stroke or systemic embolism. Prophylactic rivaroxaban (10 mg once daily) significantly reduced rates of postoperative VTE compared to the LMWH Lovenox (40 mg once daily) following hip arthroplasty (1.1 percent vs, 3.7 percent, p<0.001)84 and knee arthroplasty (9.6 percentvs. 18.9 percent), and in hospitalized acutely medically ill patients was noninferior to Lovenox for standard 10-day thromboprohylaxis

40. In a pooled analysis of the EINSTEIN studies, major bleeding was less common in patients receiving rivaroxaban compared to standard anticoagulation (1.0 percent vs. 1.7 percent, p = 0.002), and this includes a significant reduction in intracranial bleeding

41. Dabigatran In the RE-LY trial , patients with nonvalvular atrial fibrillatio n and a risk of stroke were randomized to dabigatran etexilate (110 mg BID or 150 mg BID) or dose-adjusted warfarin. In this noninferiorit y trial, rates of stroke or systemic embolism were 1.69 percent per year with warfarin, 1.53 percent per year with dabigatran etexilate 110 mg (relative risk [RR] 0.91, p<0.001 for noninferiority ) and 1.11 percent per year with dabigatran etexilate 150 mg (RR 0.66, p<0.001 for superiority). The rates of major bleeding in the RE-LY trial were similar between higher dose dabigatran and warfarin, but significantly lower for low-dose dabigatran compared to warfarin. The rate of intracranial bleeding was lower for both doses of dabigatran compared to warfarin

42. The RE-COVER trial was a randomized double-blind noninferiority trial comparing dabigatran etexilate (150 mg BID) to dose-adjusted warfarin in patients with acute VTE who received initial parenteral anticoagulation for a median of 9 days. The rates of recurrentVTE were similar (2.4 vs. 2.1 percent, P<0.001 for non inferiority). In a meta-analysis of three large randomized trials, dabigatran was as effective as LMWH for prevention of VTE and VTE-related mortality after hip and knee replacement, and had a similar bleeding risk. Dabigatran does not appear to be safe or effective in prevention of thromboembolic complications following heart valve replacement. The RE-ALIGN study randomized patients to dabigatran or warfarin following valve replacement and was terminated early because of excess thrombotic and bleeding complications in dabigatran -treated patients.

43. Monitoring of DOAS Only needed in some conditions assessment of adherence, detection of accumulation or overdose, identification of bleeding mechanisms, and determination of activity prior to surgery or intervention. PT for F Xa inhibitors aPTT for thrombin inhibitors

44. Side effects Bleeding-especially GI bleeding Dyspepsia Pregnancy-contraindicated

45. MANAGEMENT OF BLEEDING Minor bleeding-hold few doses Other antithrombotics should be held Resuscitation with fluid & blood products as needed Bleeding site should be identified Reversal in life threatening bleeding Idarucizumab –Dabigatran Andexanet alf a-Rivaroxaban

46. Fibrinolytics Drugs administered systemically or via catheter to degrade thrombi Systemic delivery used in acute MI, acute ischemic stroke, and most cases of massive PE Catheter directed fibrinolysis Peripheral arterial thrombi and thrombi in the proximal deep veins of the leg

47. Mechanism of action

48. Streptokinase Obtained from - hemolytic streptococci Binds with circulating plasminogen to form complex that activates plasminogen to plasmin Non fibrin specific t ½ = 30 -80 min Antigenic , Pyrogenic Destroyed by circulating antistreptococcal Antibodies Hypotension & arrhythmia can occur

49. Alteplase r ecombinant t issue P lasminogen A ctivator( rt -PA ) Selectively activates plasminogen bound to fibrin Non antigenic ,not destroyed by antibodies Rapid acting, more potent Superior in dissolving old clots Short half life 4-8 min Nausea, mild hypotension, fever may occur More Expensive,more effective

50. Urokinase Enzyme isolated from human urine, now prepared from cultured human kidney cells Direct plasminogen activator t ½ of 10 to 15 min Non antigenic, Non allergenic Fever can occur but hypotension rare Indicated in patients in whom streptokinase has been for an earlier episode urokinase is often employed for catheter-directed lysis of thrombi in the deep veins or the peripheral arteries

51. Contraindication to thrombolytic Intracranial hemorrage , Head injury/major surgery in past 3 month Intracranial tumors /aneurysm Active bleeding/bleeding disorders Peptic ulcer Severe hypertension

52. Antifibrinolytic drugs Drugs which block the conversion of plasminogen to plasmin Eg. Epsilon amino- caproic acid(EACA) Tranexamic acid Antidote for fibrinolytic drugs In cardio-pulmonary bypass surgery Tonsillectomy,prostatic surgery,tooth extraction Menorrhagia,recurrent epistaxis,peptic ulcer

53. ANTIPLATELETS The commonly used antiplatelets include Aspirin, ADP receptor inhibitors thienopyridines (clopidogrel and prasugrel) and ticagrelor, Dipyridamole, Gp IIb/ IIIa antagonists

54. ASPIRINE Irreversibly acetylates and inactivate COX thus blocking production of thromboxane A2 Has dose dependant action on COX enzymes

55. Aspirin is widely used for secondary prevention of cardiovascular events in patients with coronary artery, cerebrovascular, or peripheral vascular disease. Compared with placebo, aspirin produces a 25% reduction in the risk of cardiovascular death, MI, or stroke. Aspirin is also used for primary prevention in patients whose estimated annual risk of MI is >1%, a point where its benefits are likely to outweigh harms

56. Dosage Aspirin is usually administered at doses of 75–325 mg once daily Due to side effects 75–100 mg are recommended for most indications Side effects GI – dyspepsia, erosive gastritis,…ulcers Bleeding Allergic

57. ADP RECEPTOR ANTAGONISTS Target the P2Y 12 – ADP receptors Include Thienopyridines (Clopidogrel ,Prasugrel) Ticagrelor Cangrelor

58. Clinical Use Stroke prevention Acute coronary syndromes PAD, CAD Side effects Bleeding Rarely- thrombocytopenia, neutropenia, TTP

59. GP IIb/ IIIa antagonists

60. Indications Abciximab and eptifibatide are used in patients undergoing percutaneous coronary interventions, particularly those who have not been pretreated with an ADP receptor antagonist. Tirofiban is used in high-risk patients with unstable angina. Eptifibatide also can be used for this indication

61. Dipyridamo Phosphodiesterase inhibitor blocks the breakdown of cyclic adenosine monophosphate (AMP). Increased levels of cyclic AMP reduce intracellular calcium and inhibit platelet activation. Clinical use- mainly adjunctive therapy for prophylaxis of thromboembolism with cardiac valve replacement Side effects- include headache, dizziness, hypotension

62. REFERENCES Harrison principles of internal medicine 20th edition Hematology basic principles & practice -6th edition Williams hematology-9th edition Uptodate 2018