Hemostatic Agents & Clot Formation

• Hemostatic agents affect clot formation.

Requirements

• Review the Hemostatic Agents presentation.
• Read textbook Chapter 10 (pages 173-177) and answer chapter questions 7 and 8.
• Review the Ornge Drug Monograph for acetylsalicylic acid (ASA), clopidogrel (Plavix), and heparin.
• Review the ALS PCS medical directive for cardiac ischemia for PCP, ACP.
• Watch videos covering blood clots, coagulation cascade, and anticoagulants & antiplatelet drugs.

Objectives

• Recall the process of clot formation.
• Recall the clotting cascade.
• Discuss intrinsic vs. extrinsic mechanisms.
• List classifications and examples of hemostatic drugs.
• Discuss the indications, mechanisms of action, adverse effects, and reversal agents for platelet inhibitors, anticoagulants, and thrombolytic agents.
• Platelet inhibitors include ASA, adenosine diphosphate receptor antagonists, and glycoprotein IIb/IIIa inhibitors.
• Anticoagulants include heparin, coumadin, and direct oral anticoagulants (DOACs).
• Discuss the pharmacology of acetylsalicylic acid (ASA) and its role in managing cardiac ischemia.

Drugs expected to know

• ALS PCS: acetylsalicylic acid (ASA), and tranexamic acid (TXA)
• Emergency care: eptifibatide, heparin, enoxaparin, alteplase, tenecteplase, and Vitamin K.
• Home meds: clopidogrel, apixaban, rivaroxaban, dabigatran, and coumadin (warfarin).

Hemostasis Physiology Review

• Hemostasis is the process of clot formation.

Clot formation

• Vasoconstriction occurs when damaged endothelium stops producing NO, which is a vasodilator and an inhibitor of platelet aggregation.
• Platelet binding: Collagen exposure from damaged endothelium allows platelets to adhere by binding to von Willebrand factors, secreted by both platelets and endothelium.
• Platelet aggregation: Bound and activated platelets release ADP, serotonin, thromboxane A2, and other substances that cause platelets to aggregate.
• Formation of fibrin: Fibrin binds the platelets together and traps blood cells to form a clot.
• Fibrin is formed from its precursor, fibrinogen, via the enzyme thrombin.
• Thrombin is formed via the clotting cascade.
• Thrombin formation stimulates clotting factors XI, VII, and V, creating a positive feedback loop.

Clotting cascade

• Intrinsic pathway components are contained in the blood.
• Extrinsic pathway components for initiation are contained outside the blood.
• The two pathways converge and form a common pathway prior to thrombin formation.
• During platelet plug formation, plasminogen becomes plasmin due to plasminogen activating factors in tissue.
• Plasmin interferes with clot propagation and dissolves the fibrin network as the wound heals.
• The body inactivates stray clotting factors with antithrombin III, protein C, and tissue factor pathway inhibitor to keep hemostasis under control.
• Physiologic removal of clots (1-3 weeks) is achieved with plasmin, which digests fibrin.

Hemostatic Drugs

• Thrombosis is pathological clot formation, known as a thrombus.
• Arterial occlusion can lead to MI, CVA, or peripheral ischemia.
• Venous occlusion can lead to DVT and PE. Arterial thrombi mainly consist of platelets, while venous thrombi mainly consist of fibrin.

Anticoagulants

• Inhibit clotting factors and prevent clot formation.

Antiplatelet drugs

• Inhibit platelet aggregation and prevent platelet plugs.

Thrombolytic drugs

• Lyse, or break down, existing clots.

Platelet inhibitors

• Platelet inhibitors include Abciximab, Aspirin, Cangrelor, Cilostazol, Clopidogrel, Dipyridamole, Eptifibatide, Prasugrel, Ticagrelor, Ticlopidine, and Tirofiban.

Acetylsalicylic acid (ASA)

• Mechanism of action: irreversibly inhibits the formation of thromboxane A2 via acetylation of platelet cyclooxygenase, thus inhibiting platelet aggregation.
• It irreversibly inhibits cyclooxygenase-1 and -2 enzymes, via acetylation, which results in the decreased formation of prostaglandin precursors.
• It has antipyretic, analgesic, and anti-inflammatory features.

Acetylsalicylic acid (ASA) Indications

• Prevention and treatment of acute coronary syndromes; specifically, ST-elevation MI, non-ST-elevation MI, unstable angina, acute ischemic stroke, and transient ischemic episodes.
• In pediatrics to address Kawasaki’s disease, rheumatic fever, and pericarditis.

Acetylsalicylic acid (ASA) Contraindications

• Known allergy, active bleeding, history of GI bleeding, and with caution in reactive airway disease.

Acetylsalicylic acid (ASA) Adverse effects

• Dose-related effects are rare at low dosages, including bleeding, GI ulcers, renal dysfunction, and hypersensitivity reactions.

Acetylsalicylic acid (ASA) Reversal agent

• Desmopressin (dDAVP) and Platelets.

Adenosine diphosphate receptor antagonists (-grel-) Mechanism

• Irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface, preventing activation of the GP IIb/IIIa receptor complex, thereby reducing platelet aggregation.
• Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite.
• Platelets are affected for the remainder of their lifespan, around 7-10 days.

Adenosine diphosphate receptor antagonists

• Examples include Clopidogrel and Ticagrelor

Adenosine diphosphate receptor antagonists Indications

• Secondary prevention of myocardial infarction, ischemic stroke, cardiovascular death, and/or refractory ischemia in patients with acute coronary syndromes.
• Secondary prevention of stroke in high-risk atrial fibrillation patients with low bleed risk unable to take oral anticoagulants.

Adenosine diphosphate receptor antagonists Contraindications

• Allergy, active bleeding, and concomitant usage with proton pump inhibitors.

Adenosine diphosphate receptor antagonists Adverse effects

• Bleeding, pruritis, and thrombotic thrombocytopenic purpura.

Adenosine diphosphate receptor antagonists Reversal agent

• Desmopressin (dDAVP) and platelets.

Glycoprotein IIb/IIIa inhibitors Mechanism

• Prevents the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GP IIb/IIIa receptor sites on activated platelets, thus inhibiting platelet aggregation.
• Abciximab, first approved in this class of drugs, is a chimeric monoclonal antibody directed against the IIb/IIIa complex including the vitronectin receptor
• Eptifibatide and tirofiban inhibit ligand binding to the IIb/IIIa receptor by their occupancy of the receptor but do not block the vitronectin receptor.

Glycoprotein IIb/IIIa inhibitors examples

• Eptifibatide, abciximab, and tirofiban

Glycoprotein IIb/IIIa inhibitors indication

• Adjunct to PCI for the prevention of cardiac ischemic complications in patients undergoing PCI and unstable angina not responding to medical therapy when PCI is planned within 24 hours.
• Intended for use with aspirin and heparin.

Glycoprotein IIb/IIIa inhibitors Contraindication

• Allergy, recent GI bleeding, CVA within 2 years, Thrombocytopenia, Intracranial mass AVM, Uncontrolled HTN, Vasculitis.
• Caution advised with co-administration with other drugs affecting hemostasis.

Glycoprotein IIb/IIIa inhibitors Side effects

• Adverse effects include bleeding, pulmonary hemorrhage, thrombocytopenia, and hypersensitivity reactions.

Glycoprotein IIb/IIIa inhibitors reversal agents

• Desmopressin and platelets

Anticoagulants

• Suffixes include -PARIN and -ABAN.

Anticoagulants Examples

• Apixaban , argatroban, betrixaban, bivalirudin, dabigatran, dalteparin, desirudin edoxaban, enoxaparin, fondaparinux, heparin, rivaroxaban, and warfarin.

Heparin, mechanism of action

• Binds to endothelial cell surfaces and a variety of plasma proteins.
• Depends on the endogenous anticoagulant antithrombin for its biologic activity.
• Accelerates these reactions 1000-fold in presence of heparin
• Active heparin molecules tightly bind to antithrombin and cause a conformational change that exposes its active site for more rapid interaction with the proteases.
• Heparin functions as a cofactor for the antithrombin-protease reaction without being consumed.
• Once the antithrombin-protease complex forms, heparin is released intact for renewed binding to more antithrombin.
• Results in the inactivation of thrombin and prevents the conversion of fibrinogen to fibrin.
• UFH inhibits blood coagulation by inhibiting all three factors, especially thrombin and factor Xa.

Heparin

• Indications:
• Prophylaxis and treatment of thromboembolic disorders, ST elevation myocardial infarction and Non-ST elevation acute coronary syndrome and to maintain patency of IV catheter.
• Contraindications:
• Hypersensitivity to heparin or any component of the formulation, sever thrombocytopenia, and uncontrolled active bleeding.
• Adverse effects:
• These include thrombocytopenia, hemorrhage, hyperkalemia, and hypersensitivity reactions.
• Reversal agent:
• Protamine.

Low-Molecular-Weight (LMW) Heparin (-parin) Mechanism of action

• Preferentially inactivates factor Xa, less active on thrombin and prevents the conversion of fibrinogen to fibrin.

Low-Molecular-Weight (LMW) Heparin (-parin) Comparison with UFH

• Just as effective as unfractionated heparin.
• Given subcutaneously allowing home administration.
• LMW not generally measured expect in the setting of renal insufficiency, obesity, and pregnancy. Examples: Fragmin (dalteparin), Lovenox (enoxaparin)

Coumadin Mechanism of action

• Competitively inhibits the vitamin K epoxide reductase complex 1 (VKORC1), an essential enzyme for activating vitamin K.
• Warfarin is used to deplete functional vitamin K which reduces synthesis of active clotting factors.
• Consideration must be given to the hepatic synthesis of coagulation factors II, VII, IX, and X, as well as coagulation regulatory factors protein C and protein S for which vitamin K is an essential cofactor.

Coumadin

• CYP450 isozymes are involved in the metabolism of warfarin.
• More frequent INR monitoring required when starting or stopping other drugs or changing dosages.

Coumadin Indications

• Prevention and treatment of DVT and PE, stroke prevention of atrial fibrillation and defective heart valves, protein C and S deficiency, and antiphospholipid syndrome.
• Prevention of VTE following orthopedic surgery.

Coumadin Contraindications

• Allergy, Active bleeding, and pregnancy, and unsupervised patients with conditions which would result in non compliance.

Coumadin Adverse effects

• Bleeding, Skin lesions, Necrosis, Cholesterol microemboli (purple toe syndrome). and kidney injury.

Coumadin Reversal Agents

• Vitamin K, Octaplex (PCC), FFP and Factor VII.

Direct Oral Anticoagulants (DOACs)

• Xa inhibitors (-xaban) prevent the formation of factor II to factor Ila and able to bind to free and clot bound factor Xa
• The inhibitors do direct effect platelet aggregation induced by collagen, ADP or thrombin and indirectly decrease induced clot formation.
• No pharmacodynamic monitoring is needed. Dabigatran has little effect on prothrombin time.
• Examples are Apixaban, rivaroxaban, dabigatran.

Direct Oral Anticoagulants (DOAC)

• Indications lowering the risk of stroke and embolism from nonvalvular AF.
• DVT prophlaxis, treatment ,and secondary prophlaxis DVT and PE.
• Contraindications history of GI bleeding, mechanical heart valves, and severe mitral stenosis

Direct Oral Anticoagulants adversities

• Dyspepsia, abdominal pain, and abdominal discomfort.
• Reversal agents Idarcizumab and FFP.

Thrombolytic Agents

• Alteplase and Tenecteplase

Alteplase (tPA) and Tenecteplase (TNK) indications

• Managing acute myocardial infarction, acute ischemic stroke and for lysis of acute pulmonary emboli.

Alteplase (tPA) and Tenecteplase (TNK) Mechanism of action

• Binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin. It also produces limited conversion of plasminogen in the absence of fibrin.

Alteplase (tPA) and Tenecteplase (TNK) side effects

• Hypersensitivity less than 1%;anaphylaxis and CV: Cholesterol embolization.

Tranexamic acid (TXA)

• Treats Trauma-associated hemorrhage and management of massive bleeding.
• Forms a reversible complex that displaces plasminogen from fibrin ,it is also inhibits the proteolytic activity of Plasmin.

Tranexamic acid Adverse effects

• Anaphylaxis a throat and hypotension and thrombosis.

Vitamin K

• Treats coagulation disorders which are due to faulty formation of factors.

Vitamin Mechanism

• Via the liver of active prothrombin
• Hypotension, sweating, tachycardia and anaphylaxis.