Final Antithrombotic Academy PDF

41 THERAPEUTIC CONTROL OF THROMBOTIC DISORDERES ILOs By the end of this lecture, students will be able to 1. Differentiate between agents inducing clot lysis from those preventing thrombus formation or propagation. 2. Classify antiplatelets in correlation to its role in inhibiting thrombus activatio...

41 THERAPEUTIC CONTROL OF THROMBOTIC DISORDERES ILOs By the end of this lecture, students will be able to 1. Differentiate between agents inducing clot lysis from those preventing thrombus formation or propagation. 2. Classify antiplatelets in correlation to its role in inhibiting thrombus activation or aggregation. 3. Deduce anticoagulants blocking relevancy on phases of coagulation to interpret their clinical selection 4. Correlate the role of different thrombolytics in rescue of acute insults in the face of their hazardous effects ANTITHROMBOTICS; are drugs that either: ▪ Limit thrombus formation and progression as Anticoagulants and Antiplatelets ▪ Enhance thrombus lysis as Fibrinolytics (Thrombolytics) I. ANTIPLATELETS: Refer also to lect. Hemostasis 1; Platelets Are drugs inhibiting platelet activation and/or aggregation (figure 1). They are effective against platelet rich arterial thrombi as those inducing ischemic heart disease (AMI), stroke…etc. 1. TXA2 Inhibitors. Are irreversible inhibitors of COX1 during the whole life span of platelets as new synthesis cannot be achieved knowing that the platelet is non nucleated. To block only TXA2 and to spare the antiaggregatory action of PGI2 formed by the endothelium only a small dose of aspirin 75 -325 mg/day is given better as a chewable (for rapid action) or as enteric coated tablet to eliminate gastric injury. 2. ADP Receptor Antagonists: Are antagonist to the purinergic receptor subtype (P2Y12), that is required for platelets activation. The famous prototype clopidogrel is an irreversible antagonist and a pro-dug that need to be activated by hepatic metabolizing enzymes, so needs to be given as a loading dose of 4 tablets initially at time of insult. Patients are continued on combined ADP antagonist and aspirin. This is termed “Dual Antiplatelet Therapy” “DAPT” that must be continued for 6-12 month as secondary prevention after the insults. 3. Glycoprotein IIb/IIIa receptor Inhibitors: Inhibit glycoprotein GP IIb/IIIa receptors, by competing with fibrinogen and von Willebrand factor. It is given by infusion during or post intervention. 4.Protease-Activated-Receptor-1(PAR-1) Antagonists It is a potent oral selective competitive PAR-1 antagonist that blocks thrombin receptor to inhibit platelet activation and aggregation. It is given by infusion during or post intervention till hospital discharge ( up to two days). II. ANTICOAGULANTS: Refer also to lect. Hemostasis 2; Coagulation and Fibrinolysis Are drugs inhibiting coagulation (figure 2) to prevent formation or progression of a thrombus by acting as: 1. Indirect Thrombin Inhibitors: They inhibit coagulation factors (II, X, IX, XI, XII) by variably binding and activating antithrombin III. Unfractionated heparin (UFH) is rapid short acting so useful during intervention procedures. It is given IV in hospital setting as it needs to be repeated monitoring [by partial thromboplastin time (aPTT)]. It does not inhibit fibrin-bound thrombin so re-thrombosis can issue. Immune reaction can develop to heparin that can lead to thrombosis and thrombocytopenia. The LMWH acts more on factor X, is given subcutaneous and has longer duration of action. It does not need monitoring and is less to induce immune reactions. That is way it is favorably given outside the hospital setting. Both drugs are the only anticoagulant approved in pregnancy. 2. Direct Thrombin (DT) Inhibitors: They bind directly to inhibit thrombin, whether present as free or fibrin bound. That is why they are specifically recommended in treatment of thrombosis especially due to immune heparin reactions. The parenteral forms can be used during intervention, while the oral forms are grouped in the New Oral Anti-Coagulants; NOACs that are now indicated in prevention or treatment of many thrombotic disorders. 3. Factor X Inhibitors: They inhibit factor X to suppress thrombin formation. This inhibition could be achieved: - Indirectly through binding to antithrombin III. These are parenterally used during interventions - Directly through binding and these are oral forms grouped in NOACs. It has become clear that NOACs; the non-homogeneous group that include both Oral Direct Thrombin Inhibitors and Factor X Inhibitors have gained wide use in thrombotic disorders specially in the era of COVID 19 thrombotic complications. They are less hazardous than warfarin the only oral anticoagulant that existed for tens of years. 4. Vit K Antagonists: Warfarin inhibits an enzyme that activates vitamin K in the liver that is essential for carboxylation of coagulation factors II, VII, IX, and X, turning them into a functionally active coagulation factor that are released as proteolytic enzyme precursors to the blood. By antagonizing the role of vitamin K, warfarin exerts its anticoagulant effect. Its action takes 4-5 days latency to fully act, which is the time needed to deplete the circulatory pool of functionally activated clotting factors. This means that warfarin can never be initiated in acute insults, but its administration should be started together with heparin which will instantaneously act to cover the 4-5 days latency stated after which it is withdrawn leaving warfarin to exert its anticoagulant action. This could be justified by finding prolongation of prothrombin time (PT) or International Normalized ratio (INR). Because warfarin has a narrow therapeutic index, such investigations must be routinely used to monitor its action. Also, as it has many side effects and drug and food interactions, the newly introduced oral group of NOACs anticoagulant has taken over in treatment and prevention of many thrombotic disorders. All oral anticoagulants are not given in pregnancy. III. THROMBOLYTICS: Refer also to lect. Hemostasis 2; Coagulation and Fibrinolysis Are drugs used to lyse the already formed thrombus. They reside on mimicking the action of the natural fibrinolytic system in the body (figure 3) either: - Specifically [by activating tissue plasmin activator (t-PA) that lyse fibrin within a thrombus] - Non-specifically [by activating urokinase (u-PA) that also acts systemic on circulating plasminogen and other coagulation factors as well]. They are more efficacious on recently formed than older thrombi (that have extensively polymerized fibrin resistant to lysis) making their success cure rates depending on time of administration with a therapeutic window ranging from 6-12 hours post insult. They are divided into: - Fibrin-Specific Thrombolytics; are recombinant-human t-PAs that are more efficacious and safer. They are given as single or double bolus or by infusion depending on duration of action. - Fibrin-Non-Specific Thrombolytics; as streptokinase, is most popular being much cheaper but can induce more hemorrhage and hypotension due to their widespread systemic action. They are antigenic and can induce allergic reactions in patients with recent streptococcal infection; being synthesized from streptococci. With All ANTITHROMBOTIC DRUGS: Adherence to recommended doses should be strict as re-thrombosis (due to lower doses) or bleeding tendencies to overt hemorrhages (by larger doses) may issue. The later can be severe necessitating the need of blood transfusion, fresh plasma extracts along with selective antidotes specific to some of these drugs after the patient is resuscitated and the drug is withdrawn. That is why it is advisable to refrain from giving most of such agents in patients with bleeding disorders or have had recent hemorrhage or undergone surgery….etc. ___________