Lesson 23- Coagulation and Aggregation (pt.2) PDF

Lesson 23 Coagulation and Aggregation 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Pharmacology of hemostasis Platelet aggregation: Deficit: Hemorragias Platelet Concentrate Excess: Vascular thrombosis An...

Lesson 23 Coagulation and Aggregation 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Pharmacology of hemostasis Platelet aggregation: Deficit: Hemorragias Platelet Concentrate Excess: Vascular thrombosis Antiplatelet agents Coagulation: Deficit: Bleeding Procoagulants Excess: vascular thrombosis anticoagulants Fibrinolysis: Deficit: vascular thrombosis Fibrinolytics Excess: bleeding antifibrinolytics DRUGS THAT ACT ON THE COAGULATION CASCADE https://youtu.be/cy3a__OOa2M?si=ppuRTFiTr1rr55JM  DRUGS THAT ACT ON THE COAGULATION CASCADE ANTICOAGULANTS HEPARIN DIRECT THROMBIN INHIBITORS O R WARFARIN/ACENOCUMAROL A L  DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN Heparin is not a single substance but a family of sulfated glycosaminoglycans Doses are specified in units of activity. Types of Heparins: - LMWHs: heparin fragments ENOXAPARIN DALTEPARIN -FONDAPARINUX: a synthetic pentasaccharid that inhibits factor Xa Longer acting usually preferred - UNFRACTIONATED HEPARINS (UFH) Reserved for special situations such as patients with renal failure in whom LMWHs are contraindicated. DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN Mechanism of action It interferes with the blood clotting process by binding to ANTITHROMBIN III (accelerating its action by 1000 times) and enhances its inhibitory effects on factor IIa (Thrombin) and Factor Xa inhibition of coagulation General anticoagulant effect (inactivation of thrombin and Xa factor) UFH> LMWH> Fondaparinux Selective anticoagulant effect (inactivation Xa factor) Fondaparinux> LMWH> UFH LMWHs selectively accelerates interaction of ATIII with factor Xa DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN Administered IV (acts inmediately) or subcutaneously (acts 60 min. delayed) Half-life is approximately 40–90 min Dose of heparin is adjusted In urgent situations: to start with a bolus IV dose, followed by a constant-rate infusion. LMWH vs UNFRACTIONATED Given SC Longer elimination half-life LMWH More predictable and dosing less frequent (once or twice a day). Monitoring is not required routinely. Eliminated mainly by renal excretion. DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN Low-molecular-weight heparins (LMWHs) are at least as safe and effective as unfractionated heparin (UFH) and offer greater convenience, as patients can learn to self-administer injections at home without the need for frequent blood monitoring or dose adjustments  DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN ADRs: Haemorrhage Treated by stopping therapy PROTAMINE SULFATE (IV) can reverse the effect of heparin The dose is estimated from the dose of heparin. (1mg of protamine per 100 UI of heparin) Osteoporosis after long-term (6 months or more) Hypersensitivity Hypoaldosteronism: Heparin reduces the sensitivity and number of angiotensin II receptors in the zona glomerulosa of kidneys, decreasing aldosterone synthesis. Aldosterone is essential for regulating sodium retention and potassium excretion, so its suppression can lead to hyperkalemia (elevated potassium levels) and other electrolyte imbalances  DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN ADRs: Type II-Heparin-induced thrombocytopenia (HIT) It is a serious immune-mediated complication triggered by heparin. The immune system produces antibodies against complexes formed with unfractionated heparin between heparin and platelet factor 4 (PF4), a protein released by activated platelets. These antibodies activate platelets and other cells, promoting thrombin generation, which leads to excessive clotting (thrombosis). Despite low platelet counts (thrombocytopenia), patients can develop life- threatening clots, such as deep vein thrombosis or pulmonary embolism *LMWH is less likely to cause HIT because of its reduced interaction with PF4, leading to fewer immune responses and a lower incidence of thrombocytopenia and thrombosis. DRUGS THAT ACT ON THE COAGULATION CASCADE 1.ANTICOAGULANTS HEPARIN Indications Prevention and treatment of: Pulmonar embolism Profound venous thrombus Myocardium infarct Coronary ischaemia Contraindications Alcoholism Surgery Haemophylia *Safe in Pregnancy and lactation History of thrombocytopenia comparation = warfarin = teratogenic  DRUGS THAT ACT ON THE COAGULATION CASCADE 1. ANTICOAGULANTS DIRECT THROMBIN INHIBITORS AND Xa INHIBITORS (parenteral administration) HIRUDIN, LEPIRUDIN (recombinant hirudin) Used for thromboembolic disease in patients with type II HIT The dose being adjusted depending on the APTT, and can cause bleeding or hypersensitivity reactions BIVALIRUDIN COX 1 inhibitor block recept of ADP on platelet Used in combination with ASPIRIN AND CLOPIDOGREL in patients undergoing percutaneous coronary artery surgery. IV bolus followed by an infusion during and up to 4 h after the procedure. It can cause bleeding and hypersensitivity reactions. * APTT: activated partial tromboplastin time is a blood test that measures the time it takes for blood to clot, specifically assessing the intrinsic and common coagulation pathways. It is used to evaluate the function of certain clotting factors (factors XII, XI, IX, VIII, X, V, II, and fibrinogen) in these pathways. Oral Anticoagulants DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS https://youtu.be/OnzF0oJkYe0?si=hRVuZoJlnT89JECd DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS Vitamin K is needed for: The formation of clotting factors II, VII, IX and X Activation of factor X  DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS Mechanism of action: VITAMIN K antagonist They prevent the physiological regeneration of the active form of vitamin K (Vit. K reduced), necessary for the formation of coagulation factors II, VII, IX and X protein C and S. They only act in vivo Inhibit VKOCR1 (vitamin K epoxide reductase) IMPORTANT: The most important oral anticoagulant drug. Frequent blood tests to individualise dose Low margin of safety DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS The peak pharmacological effect occurs about 48 h later. The effect starts after approximately 12–16 h and lasts 4–5 days. Is teratogenic It appears in milk during lactation. DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS The effect is monitored by measuring prothrombin time (PT), which is expressed as an international normalised ratio (INR). Therapeutic use of warfarin REQUIRES A CAREFUL BALANCE between giving too little and giving too much. Therapy is complicated :numerous medical and environmental conditions modify sensitivity to warfarin, including interactions with other drugs DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS FACTORS THAT LESSEN THE EFFECT OF WARFARIN/ACENOCUMAROL Physiological state/disease Pregnancy Hypothyroidism (reduced degradation of coagulation factors) Several drugs The dose of warfarin must be reduced when the interacting drug is discontinued, to avoid haemorrhage. INTERACTION WITH: VITAMIN K DRUGS THAT INDUCE HEPATIC P450 ENZYMES DRUGS THAT REDUCE ABSORPTION (COLESTYRAMINE) HIGH AMOUNTS OF VIT K!!!!  DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS FACTORS THAT POTENTIATE WARFARIN/ACENOCUMAROL pharmacodynamic Liver disease warfarin bind strongly plasma p so if use of other drugs binding plasma p = displaced warfarin = increase warfarin in plasma = increase effect Drugs that inhibit hepatic metabolism CIPROFLOXACIN, METRONIDAZOLE, AMIODARONE AND MANY ANTIFUNGAL AZOLES. Drugs that inhibit platelet function ASPIRIN: This combination can be used safely with careful monitoring NSAIDs ANTIBIOTICS: Including MOXALACTAM AND CARBENICILLIN, inhibit platelet function. Drugs that displace warfarin from binding sites on plasma albumin CHLORAL HYDRATE, NSAIDs Drugs that decrease the availability of vitamin K BROAD-SPECTRUM ANTIBIOTICS AND SOME SULFONAMIDES Vitamin K is naturally produced by bacteria in the intestinal flora. The use of antibiotics reduces the bacterial population, which in turn reduces the production of vitamin K (enhances the anticoagulant effect). DRUGS THAT ACT ON THE COAGULATION CASCADE 2. ORAL ANTICOAGULANTS ACENOCOUMAROL, WARFARIN ANTI-VITAMIN K AGENTS ADRs: Haemorrhage ✓ Treated with holding warfarin (for minor problems) ✓ Life-threatening bleeding: Administration of Vitamin K, Fresh plasma ✓ Concentrates of coagulation factor Hepatotoxicity Teratogenic Necrosis of soft tissues Due to inhibition of protein C (anticoagulant factor). https://youtu.be/74oq1p_tziE?si=kEN2dIxsC_HNE6tY  DRUGS THAT ACT ON THE COAGULATION CASCADE 3. DIRECT ORAL ANTICOAGULANTS (DOAC) DABIGATRAN Mechanism of action Reversible direct inhibitor of thrombin (acts at the very last step of the coagulation pathway) Prevention of venous thromboembolism following hip or knee replacement Administered 1–4 hours after surgery and then once daily for up to a month Prevention of stroke and systemic embolism in atrial fibrillation Twice daily indefinitely ADRs: Nausea and vomiting Constipation Insomnia Peripheric oedema  DRUGS THAT ACT ON THE COAGULATION CASCADE 3. DIRECT ORAL ANTICOAGULANTS (DOAC) RIVAROXABAN, APIXABAN, EDOXABAN Mechanism of action Direct inhibitor of factor Xa Due to its unspecificity, increased PATHWAY risk of hemorrhage!! Damaged surface ADRs: EXTRINSIC PATHWAY Trauma Nausea Tachycardia Anaemia Thrombocytopenia Increase transaminases Hepatoxicity- Rivaroxaban  DRUGS THAT ACT ON THE COAGULATION CASCADE 3. DIRECT ORAL ANTICOAGULANTS (DOAC) How to reverse the effect of DOACs? IDARUCIZUMAB Humanised mAb that binds dabigatran and its metabolites, blocking its effect Licensed for emergency procedures or severe bleeding caused by dabigatran ANDEXANET ALPHA It is a modified human factor Xa which binds rivaroxaban and apixaban reducing their anticoagulant effect. Warfarin: acts on VITAMIN K CLINICAL USES OF ANTICOAGULANTS HEPARIN (often as low-molecular-weight heparin) is used acutely. WARFARIN OR A DIRECT THROMBIN OR XA INHIBITOR are used for more prolonged therapy. ANTICOAGULANTS ARE USED TO PREVENT: Deep vein thrombosis Extension of established deep vein thrombosis Pulmonary embolism Thrombosis and embolisation in patients with atrial fibrillation Thrombosis on prosthetic heart valves Clotting in extracorporeal circulations (e.g. during haemodialysis) Progression of myocardial damage in patients with unstable angina and during treatment of ST-elevation myocardial infarction. 34  Pharmacology of hemostasis Platelet aggregation: Déficit: Hemorragias Platelet Concentrate Excess: Vascular thrombosis Antiplatelet agents Coagulation: Deficit: hemorragias Procoagulants Excess: vascular thrombosis anticoagulants Fibrinolysis: Deficit: vascular thrombosis Fibrinolytics Excess: hemorrhagia antifibrinolytics DRUGS THAT ACT ON THE FIBRINOLYSIS  FIBRINOLYSIS (thrombolysis) Fibrinolysis is the degradation of the fibrin networks formed in the blood clotting process, preventing thrombus formation.  FIBRINOLYSIS (thrombolysis) The fibrinolytic cascade is triggered simultaneously with the coagulation cascade. This ensures that clots do not persist longer than necessary. Plasmin, a key enzyme in fibrinolysis, is generated within the clot (coagulum). It plays a crucial role by digesting fibrin, which is the structural framework of a clot. Plasmin is a trypsin-like protease that not only breaks down fibrin but also degrades fibrinogen (a precursor of fibrin) and clotting factors like II, V, and VIII, along with other proteins involved in coagulation.  FIBRINOLYSIS (thrombolysis) 1. FIBRINOLYTIC DRUGS (non-specific) all IV not orally STREPTOKINASE Mechanism of action: It is a plasminogen activating protein Binds to circulating plasminogen and makes it more sensitive to endogenous plasminogen activators Plasmin formation more quickly and in greater quantity Infused IV, it reduces mortality in acute myocardial infarction Beneficial effect is additive with aspirin Its action is blocked by antibodies, which appear 4 days or more after the initial dose. Its use should not be repeated after this time has elapsed (wait minimum 6 months) ADRs: hemorrhage, allergy, fever or hypotension, so the patient should be monitored during and after the infusion.  FIBRINOLYSIS (thrombolysis) 1. FIBRINOLYTIC DRUGS (specific) ALTEPLASE and DUTEPLASE (intravenous infusions) Tissue plasminogen activator Fibrinolysis is only activated if fibrin is present More active on plasminogen-bound fibrin (‘’clot selective’’) and not at systemic level Can be used in patients likely to have antibodies to streptokinase. Standard of care for patients with ischemic stroke RETEPLASE (bolus administration) In myocardial infarction  FIBRINOLYSIS (thrombolysis) 1. FIBRINOLYTIC DRUGS ADRs: BLEEDING Including gastrointestinal haemorrhage and haemorrhagic stroke --->Treated with: TRANEXAMIC ACID, FRESH PLASMA, COAGULATION FACTORS Contraindications: Internal bleeding Haemorrhagic cerebrovascular disease Bleeding diaseses Pregnancy Uncontrolled hypertension Invasive procedures in which haemostasis is important recent trauma  FIBRINOLYSIS (thrombolysis) CLINICAL USES OF FIBRINOLYTIC DRUGS Acute MYOCARDIAL INFARCTION: Main use. Within 12 h of onset (the earlier the better!). Other uses include: – Acute thrombotic stroke within 3 h of onset –Clearing thrombosed shunts and cannulae – Acute arterial thromboembolism – Life-threatening deep vein thrombosis and pulmonary embolism  2. ANTIFIBRINOLYTIC DRUGS Inhibit fibrinoliysis TRANEXAMIC ACID Inhibits plasminogen activation and prevents fibrinolysis. It can be given orally or IV. Used to revert: Stop bleeding! Haemorrhage following surgery In menorrhagia Life-threatening bleeding following thrombolytic drug administration. It is also used in patients with the rare disorder of hereditary angiooedema. Monitoring the safety of antifibrinolytics: Risk of thrombus formation Muscle fatigue Monitor chest pain or dyspnea (pulmonary thrombosis)  The importance of Vitamin K the vitamin of coagulation Lack of vit. K causes hypoprothrombinemic hemorrhage: due to insufficient diet, parenteral nutrition, multiple antibiotic therapy Liposoluble, it requires bile salts for absorption. When there is colelithiasis, the secretion of bile is decreased and this decreases the absorption of Vitamin K Oral or parenteral administration (i.m. or i.v.) It acts in the liver for the synthesis of factors II, VII, IX, X Delayed effect 12h  Vitamin K CLINICAL USES OF VITAMIN K Treatment and/or prevention of bleeding: – From excessive oral anticoagulation – In babies: to prevent haemorrhagic disease of the newborn. For vitamin K deficiencies in adults: – Sprue, coeliac disease, steatorrhoea – Lack of bile (e.g. with obstructive jaundice).