Antithrombotics in cardiovascular medicine.pptx

Antithrombotic

1. ANTITHROMBOTICS By Ahmed Galal Fahmy, MD. National Heart Institute

2. Intro. Thrombosis can occur in arteries or veins In arteries, disruption of atherosclerotic plaque triggers platelet aggregation and activation of coagulation and culminates in the formation of platelet-rich thrombi that obstruct blood flow—a process known as atherothrombosis This process is the underlying cause of myocardial infarction (MI), ischemic stroke, and acute limb ischemia

3. Blood flow in veins is slower than that in arteries, so venous thrombi contain fewer platelets and more fibrin than arterial thrombi   Thrombosis in veins leads to DVT and PE, which collectively are known as venous-thromboembolism (VTE) Arterial and venous thrombosis is responsible for 1 in 4 deaths worldwide causing an estimated 18 million deaths each year

4.   Role of platelets and the coagulation system in atherothrombosis

5. MECHANISMS OF THROMBOSIS Hemostasis is the process that maintains the integrity of a closed, low or high pressure circulatory system When pathologic processes overcome the regulatory mechanisms of hemostasis, excessive quantities of thrombin form, initiating thrombosis In this complex process several elements including platelets or high shear stress, have a close relationship in thrombus developing and in the thrombi final structure

6. The vessel wall and its inner lining of endothelium are critical to the maintenance of a patent vasculature Three thrombo -regulators: nitric oxide, prostacyclin, and the ectonucleotidase CD39 has been identified in the endothelium as the first defense against thrombosis After endothelium disruption, collagen and tissue factors are exposed to the flowing blood, starting formation of a thrombus Exposed collagen triggers the accumulation and activation of platelets, whereas exposed tissue factor initiates the generation of thrombin, converting fibrinogen to fibrin and activating platelets

7. Coagulation is initiated when tissue factor is exposed to plasma, binding coagulation factor (F) VII/ VIIa and forming a complex on cellular surfaces that triggers the coagulation cascade When coagulation cascade is activated, tissue factor triggers a second pathway that initiates platelet activation activating and causing them to release adenosine diphosphate, serotonin, and thromboxane A2

8. Current Model Of Coagulation Classically, coagulation has been categorized in terms of: a) extrinsic pathway (initiated by tissue factor/ FVIIa ) b) intrinsic pathway (coagulation occurs when plasma is in contact with negatively charged surfaces–contact phase activation) c) a common pathway, proceeding after the activation of FX Currently , the process of coagulation is a cell surface-based model that included three overlapping phases: Initiation Amplification Propagation

9. In the initiation phase, tissue factor are exposed to the coagulation factors in the lumen of the vessel. Platelets, activated by vascular injury (plaque rupture) are recruited and adhere to the site of injury The tissue factor/ FVIIa complex activates coagulation factors IX to IXa and X to Xa , and trace amounts of thrombin are generated In the amplification phase, this small amount of thrombin acts as signal for further platelet activation and aggregation

10. On the surface of platelets, thrombin activates FV, FVIII and FXI. In the propagation phase, FVIIIa forms a complex with FIXa ( Xase ), and FVa forms a complex with FXa ( prothrombinase ) on the platelet surface, which accelerates the generation of FXa and thrombin, respectively When FXa associates with FVa , it is protected from tissue factor pathway inhibitor and antithrombin In the propagation phase, a burst of thrombin is generated, which is sufficient for the clotting of soluble fibrinogen into a fibrin meshwork

11. Finally, coagulation included a series of enzymatic process; thrombin generation, the last enzyme of coagulation, is the result of an amplifying cascade, with approximately one molecule of FXa generating approximately 1,000 molecules of thrombin Thrombin serves a number of functions in addition to fibrin formation as platelet activation and aggregation, it has proinflammatory actions, amplifies clotting by activating coagulation FXI and the cofactors FV and FVI. In addition thrombin stabilizes clots by activating FXIII and has anti-fibrinolytic actions

12. Although their pathogenesis differs, the formation of arterial and venous thrombi is dependent on activation of the coagulation system and platelets In most cases, arterial thrombosis is triggered by exposure of TF (tissue factor) at sites of atherosclerotic plaque disruption. In contrast, in venous thrombosis, the vein wall is usually intact However , in response to reduced flow, hypoxia, or inflammatory mediators, the endothelial cells lining the vein become activated and express adhesion molecules, which tether TF-expressing leukocytes and microparticles onto their surface

13. Antithrombotic drugs

14. Anticoagulants Slow down clotting, thereby reducing fibrin formation and preventing clots from forming and growing There are two classes of antithrombotic drugs:  Antiplatelet Prevent platelets from clumping and also prevent clots from forming and growing . Fibrinolytic drugs: Stimulate lysis of an already-formed clot following a thromboembolic event

15. Major Classes and Therapeutic Indication Drugs Therapeutic Indication Anticoagulant drugs Warfarin Unfractionated Heparin Low molecular weight Heparins (LMWHs) Fondaparinux (Heparin Pentasaccharide ) Direct Thrombin inhibitors Factor Xa inhibitors Coronary artery disease (acute myocardial infarction) Coronary artery bypass surgery, coronary angioplasty/stenting Atrial fibrillation (AF) Valvular heart disease (natural & artificial valves) Deep Venous Thrombosis (DVT)  Antiplatelet drugs Aspirin P2Y12 blockers: Clopidogrel , Cangrelor , Prasugrel , Ticagrelor Glycoprotein IIb / IIIa inhibitors Coronary artery disease (stable angina or acute myocardial infarction) Coronary artery bypass surgery Coronary angioplasty/stenting Stroke & transient ischemic attack  Fibrinolytic drugs: Streptokinase, Urokinase , tissue plasminogen activator and its derivatives Acute STEMI & pulmonary embolism

16. Mechanism of Antiplatelets and anticoagulants

17. Parenteral Indirect Anticoagulants

18. Unfractionated Heparin Heparin is a sulfated polysaccharide with a molecular weight range of 3000 to 30 000 Da (mean, 15 000 Da) It produces its major anticoagulant effect by inactivating thrombin and factor Xa through an AT-dependent mechanism By inactivating thrombin, heparin not only prevents fibrin formation but also inhibits thrombin-induced activation of platelets and of factors V and VIII Because the anticoagulant response to heparin varies among patients with thromboembolic disorders, it is standard practice to adjust the dose of heparin and monitor its effect by measurement of the activated thromboplastin time (APTT) or, when very high doses are used, by the activated clotting time (ACT)

19. Clinical Uses of Heparin Coronary Artery Disease: The totality of evidence supports the view that IV heparin reduces death and MI in patients with ACS. Specifically, IV heparin is effective when combined with aspirin In patients undergoing PCI, it is standard practice to give heparin, commencing with either an IV bolus of 10 000 U followed by repeated smaller bolus injections as required or a weight-adjusted dose regimen of 100 to 175 U/kg followed by 10 to 15 U/kg per hour. The dose is adjusted to maintain the ACT at >300 to 350 seconds Treatment of Venous Thromboembolism: Patients with acute venous thromboembolism (VTE) should receive initial treatment with heparin or LMWH. A loading dose of 5000 U heparin should be given, followed by a continuous infusion of at least 30 000 U every 24 hours

20. Low-Molecular-Weight Heparins Selectively inhibit factor Xa with little effect on IIa Act only by inducing conformational change in AT III. Hence LMW heparins have smaller effect on aPTT and whole blood clotting time than UFH They have lesser antiplatelet action—less interference with hemostasis Lower incidence of hemorrhagic complications compared to UFH Elimination - primarily by renal excretion

21. Oral Anticoagulants

22. Vit K Antagonists (Warfarin) Warfarin inhibits the synthesis of coagulation factors whose formation is dependent on vitamin K, factors II, VII, IX, and X. Warfarin inhibits the enzyme vitamin K epoxide reductase blocks recycling of the oxidized form of vitamin K (epoxide form) to its reduced form (which acts as a cofactor in the carboxylation of coagulation factors ) prevents the biosynthesis of factors II, VII, IX, and X. Warfarin has no effect on the already-synthesized factors plasma levels of vitamin K-dependent factors must decline before the anticoagulant effect of becomes apparent, typically requiring several days (3 to 5d )

23. Warfarin is well absorbed from the gut given orally Extensively metabolized in liver before being excreted in the urine Unlike heparin, warfarin crosses the placenta and can cause fetal hemorrhage so CI in pregnancy Warfarin has a delayed onset of action. A period of several days is also required for coagulation factor levels to return to normal after warfarin has been The dosage of Warfarin is monitored using the prothrombin time (PT ) INR

24. Direct thrombin inhibitors (Dabigatran) Administered orally A prodrug that is activated in the gut, blood, and liver Primarily eliminated by renal excretion Renal impairment prolongs the t1/2 of the drug so doses should be reduced in renal dysfunction Mechanism of action : Dabigatran is a potent, competitive, reversible inhibitor of thrombin so blocks conversion of fibrinogen to fibrin in the final step of blood coagulation. Unlike heparin, Dabigatran inhibits both fibrin-bound and unbound (free) thrombin

25. Direct Factor X inhibitors They bind to the active catalytic site of Xa so inhibiting the activity of both free Xa and that bound in the prothrombinase complex

26. Antiplatelets

27. Thrombin receptor blockers (PAR-1 blocker ) Vorapaxa Blocking GP Iib / IIIa glycoproteins Abciximab

28. Low dose Aspirin   Aspirin (high dose ) is a NSAID, has analgesic, antipyretic, and anti-inflammatory effects Aspirin (low dose 75-100 mg/d ) inhibits platelet aggregation, used to prevent/treat arterial thromboembolic disorders Low doses of aspirin selectively & irreversibly inhibit platelet cyclooxygenase-1 (COX1) enzyme so ↓ synthesis of thromboxane A2 (TXA2 ), hence inhibit platelet aggregation Aspirin inhibits platelet aggregation for the life of the platelet

29. ADP receptor blockers They block ADP receptors on platelet (P2Y12 receptors ) so inhibit activation ADP-induced platelet aggregation Clopidogrel and prasugrel are irreversible P2Y12 antagonists that inhibit platelet function for the life of the platelet Ticagrelor are reversible P2Y12 antagonists Clopidogrel and prasugrel are prodrugs metabolized to active drugs by CYP450 enzymes Prasugrel has a more rapid onset of action than Clopidogrel and it produces a higher and more consistent level of platelet inhibition than Clopidogrel Ticagrelor does not require activation has a more rapid onset of action & action wears off more rapidly after discontinuation of Ticagrelor

30. Fibrinolytic drugs

31. Comparison of different fibrinolytics

32. Contraindications Absolute History of haemorrhagic stroke or stroke of unknown origin Ischaemic stroke in previous 6 months Central nervous system neoplasm Major trauma, surgery, or head injury in previous 3 weeks Bleeding diathesis Active bleeding Relative Transient ischaemic attack in previous 6 months Oral anticoagulation Pregnancy or first post-partum week Non-compressible puncture sites Traumatic resuscitation Refractory hypertension (systolic BP >180 mmHg) Advanced liver disease Infective endocarditis Active peptic ulcer

33. Anticoagulants in ER

34. Acute coronary syndrome (ACS)

35. Recommendations for antithrombotic treatment in acute coronary syndrome patients Aspirin 300mg orally initially (dissolved or chewed) followed by 100-150mg/day is recommended for all patients with ACS in the absence of aspirin hypersensitivity A P2Y12 receptor inhibitor is recommended in addition to aspirin, and maintained over 12 months unless there are contraindications or an excessive risk of bleeding: Prasugrel in P2Y12 receptor inhibitor-naı¨ve patients proceeding to PCI (60 mg LD, 10 mg/d as standard dose (IB) Ticagrelor irrespective of the planned treatment strategy (invasive or conservative) (180 mg LD, 90 mg b.i.d .) (IB) Clopidogrel ( 300-600 mg LD, 75 mg daily dose ) (IC)

36. Parenteral anticoagulation is recommended for all patients, in addition to antiplatelet treatment, at the time of diagnosis and, especially , during revascularization procedures according to both ischaemic and bleeding risks UFH (weight-adjusted i.v. bolus during PCI of 70-100 IU/kg, or 50-70 IU/kg in combination with a GP IIb / IIIa inhibitor; activated clotting time target range of 250-350 s, or 200-250 s if a GP IIb / IIIa inhibitor is given) is recommended in patients undergoing PCI Discontinuation of parenteral anticoagulation should be considered immediately after an invasive procedure Crossover of UFH and LMWH is not recommended

37. In Acute pulmonary embolism In patients with high or intermediate clinical probability of PE, anticoagulation should be initiated while awaiting the results of diagnostic tests This is usually done with subcutaneous, weight adjusted LMWH or fondaparinux , or i.v. UFH LMWH and fondaparinux are preferred over UFH for initial anticoagulation in PE, as they carry a lower risk of inducing major bleeding and heparin-induced thrombocytopenia

38. Trials on the treatment of acute VTE demonstrated the non-inferiority of NOACs compared with the combination of LMWH with VKA for the prevention of symptomatic or lethal VTE recurrence, along with significantly reduced rates of major bleeding Apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily Rivaroxaban 15  mg twice daily for 3 weeks, then 20 mg once daily for at least 6  months Dabigatran 150 mg BID; 110 mg BID for patients ≥80 years

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