Lesson 23: Coagulation and Aggregation (3° Medicine) - 2024/25

Lesson 23 Coagulation and Aggregation 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Coagulation BLOOD HAEMOSTASIS is a physiologic mechanism that avoid blood loss from damaged vessels and it is essential to survi...

Lesson 23 Coagulation and Aggregation 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Coagulation BLOOD HAEMOSTASIS is a physiologic mechanism that avoid blood loss from damaged vessels and it is essential to survival. If there is a wound, the main phenomena happening are: Vasoconstriction Platelet adhesion and activation: platelet aggregation and mediators secreted (Von Willebrand) Blood coagulation (fibrin formation)  Coagulation THROMBOSIS: Pathological condition resulting from inappropriate activation of haemostatic mechanisms Pathological formation of a ‘haemostatic’ plug within the vasculature in the absence of bleeding ✓ Arterial thrombosis is usually associated with atherosclerosis, and the thrombus has a large platelet component (white coagule) Usually associated with aterosclerosis Can interrupt blood flow, causing ischaemia or infarction ✓ Venous thrombosis is usually associated with stasis of blood with small platelet component and a large component of fibrin (red coagule)—anticoagulant teraphy Thrombus can break away from its attachment and float through the circulation. Main events of the coagulation cascade In homeostasis there is balance between the coagulation and anticoagulation mechanisms Two types of predispositions: THROMBUS HAEMORRAGHIA DEVELOPMENT HAEMOSTASIA HAEMOSTASIA drugs used: COAGULATION PLATELET STIMULANTS ANTIAGREGANTS PLATELET ANTICOAGULANTS STIMULATIONS THROMBOLYTICS INHIBITORS FIBRINOLYSIS PLATELET ADHESION AND ACTIVATION  Platelet adhesion and activation Platelets maintain the integrity of the circulation When platelets are activate appear processes that are essential for haemostasis but may be inappropriately triggered if the artery wall is diseased (atherosclerosis), resulting in THROMBOSIS Antiplatelet agents are used to PREVENT arterial thrombogenesis: Do not dissolve the clot or the thrombus once formed Aggregation entails fibrinogen binding to and bridging between GPIIb/IIIa receptors on adjacent platelets. Activated platelets constitute a focus for fibrin formation. COX1 produces thromboxane 2 ADP in platelet: estimula agregacion and prostacicline extraplatelet ADP: inhibe agregacion aspirina(in low dose) inhibits thromboxane 2(antiagregan effect COX1  Platelet adhesion and activation ANTIPLATELET DRUGS 1. ASPIRIN 2. DIPYRIDAMOLE 3. ADENOSIN RECEPTOR ANTAGONISTS 4. GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONISTS 5. OTHERS  Platelet adhesion and activation ANTIPLATELET DRUGS (interference with arachidonic acid) ASPIRIN (acetylsalicylic acid) Irreversible platelet COX1 inhibition Inhibition of TXA2 formation COX2-mediated increase in PGI2 formation (antiaggregatory action) Long-lasting antiplatelet aggregation action Platelet half-life=approx.10 days (drug half-life) LOW DOSIS OF ASPIRINE INHIBITS ONLY TXA2, has no effect in PGI2 8  Platelet adhesion and activation ANTIPLATELET DRUGS ASPIRIN (acetylsalicylic acid) Low-dose aspirin in chronic use profoundly (>95%) inhibits platelet TXA2 synthesis. For acute indications (thrombotic stroke in evolution, acute myocardial infarction):A single dose of approximately 300 mg in order to achieve rapid substantial (>95%) inhibition of platelet thromboxane synthesis. Followed by regular daily doses of 75 mg. Thromboprophylaxis is reserved for people at high cardiovascular risk ADRs: peptic ulcer, Bleeding Allergy to salicylates Reye's syndrome Asthma 100mg more antiplatelet effect tan anti-inflammatory 38  Platelet adhesion and activation ANTIAGREGATION DRUGS DIPYRIDAMOLE Mechanism of action: Dipyridamole inhibits platelet aggregation by various mechanism: Inhibition of PDE (phosphodiesterase): decreased degradation of AMPc in AMP ( intraplatelet AMP reduce the platelet aggregation) Increased adenosine (extraplatelet) Increases synthesis of PGI2 The beneficial effects of aspirin and dipyridamole are additive Not increased risk of bleeding.  Interference with GP IIb/IIIa complex function The final step in platelet aggregation is the expression of platelet GPIIb/IIIa receptors. A fibrinogen molecule acts as a link between two platelets by binding to GPIIb/IIIa: if the receptor is occupied by another substrate, platelet aggregation does not occur. These drugs compete with fibrinogen and other ligands for occupancy of the platelet GPIIb/IIIa receptor.  Platelet adhesion and activation ADENOSINE (P2Y12) RECEPTOR ANTAGONISTS CLOPIDOGREL PRASUGREL TICAGRELOR Mechanism of action Clopidogrel is well absorbed orally, it is a prodrug Urgent situations is given orally as a loading dose of 300 mg followed by maintenance dosing of 75 mg once daily. INTERACTION! Not to combine with proton pump inhibitors (omeprazole) and cimetidine ( the are both metabolised by CYP2C19)  Platelet adhesion and activation ADENOSINE (P2Y12) RECEPTOR ANTAGONISTS CLINICAL USE CLOPIDOGREL Combined with low-dose aspirin in patients with unstable coronary artery disease, usually for up to 1 year. Instead of aspirin: in patients with symptomatic atheromatous disease. Usually reserved for patients who are intolerant of aspirin (asthma and peptic ulcer) Pretreatment with clopidogrel and aspirin followed by longer-term therapy is also effective in patients with ischaemic heart disease undergoing percutaneous coronary interventions. PRASUGREL Dose adjustment. Indicated in older and underweight patients. TICAGRELOR A loading dose followed by twice daily maintenance.  Platelet adhesion and activation GLYCOPROTEIN IIB/IIIA RECEPTOR ANTAGONISTS ABCIXIMAB Murin-humanized monoclonal antibody For use in high-risk patients undergoing coronary angioplasty, as an adjunct to heparin and aspirin Single administration TIROFIBAN Given IV as an adjunct to aspirin and a heparin preparation, they reduce early events in acute coronary syndrome tirofiban  Platelet adhesion and activation OTHER ANTIPLATELET DRUGS EPOPROSTENOL (PGI2) (IV) Agonist at prostanoid IP receptors Vasodilatation as well as inhibiting platelet aggregation Indications To prevent thrombosis During haemodialysis Especially in patients in whom heparin is contraindicated. Severe pulmonary hypertension Circulatory shock associated with meningococcal septicaemia. ADRs: Flushing, headache and hypotension. 44