Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII X Prothrombin Thrombin Fibrinogen Fribrin monomer Fibrin polymer XIII Intrinsic PathwayExtrinsic Pathway Factors affected By Heparin Vit. K dependent Factors Affected by Oral Anticoagulants

 Prevent coagulation  Dissolve clots  Prevent bleeding and hemorrhage - Hemostatic  Overcome clotting deficiencies (replacement therapies)

A. Reduce the formation of fibrin clots. 1. INDIRECT THROMBIN INHIBITORS  UFH: Heparin  LMWH: Enoxaparin, dalteparin, tinzaparin  SYNTHETIC: Fondaparinux 2. DIRECT THROMBIN INHIBITORS  Parenteral: Hirudin, lepirudin  Oral: Ximelagatran, dabigatran 3. ORAL ANTICOAGULANT DRUGS  Coumarin anticoagulants  warfarin – dicumarol

B. Lyse thrombi already formed  Streptokinase, Urokinase, Anistreplase  Tissue Plasminogen Activator: Alteplase, Reteplase, Tenecteplase C. Antiplatelet drugs  Aspirin, clopidogrel, ticlopidine  Platelet glycoprotein IIa/IIIb Receptor blockers  Others: dipyridamole, cilostazol

 INR  Ratio of PT of patient  PT of normal person plasma INR = (patient PT/mean normal PT) ISI ISI= International sensitivity Index Relate measured prothrombin time to WHO reference standard thromboplastin ISI = 1

 Life saving drugs  Enhance degradation of clots  Activation of endogenous protease  Plasminogen (inactive form) is converted to Plasmin (active form)  Plasmin breaks down fibrin clots  Recently formed thrombus is easily lysed by these drugs.  Aged thrombi (72 hrs) are usually resistant.

 Exogenously administered drugs  Streptokinase - synthesized by streptococci convert plasminogen to plasmin  Urokinase - human enzyme synthesized by kidney convert plasminogen to plasmin no immune response Plasmin is formed inside a thrombus, is protected from plasma antiplasmins, which allow it lyse the thrombus from within

 Alteplase : Tissue plasminogen activator (tPA) - genetically cloned  no immune reaction  EXPENSIVE  Activate plasminogen bound to fibrin Tenectreplase mutant form of t PA has longer half life Anistreplase (APSAC) Purified human plasminogen and bacterial streptokinase

 Pulmonary embolism with hemodynamic instability  Severe deep venous thrombosis  Ascending thromboplebitis  Acute myocardial infarction (streptokinase loading dose 250,000 units)  Acute ischemic stroke (Recombinant t PA)

 Bleeding:  Fibrinolytic drugs may lyse both normal and pathologic thrombi.  Less effect is seen with t-PA (selectively activates plasminogen that is bound to fibrin) than streptokinase.  Bleeding can be controlled by Aminocaproic acid (inhibits plasminogen activation)  Hypersensitivity reaction: streptokinase  Arrhythmias:  Bradycardia, tachycardia  Free radicals generated after fibrinolysis.

Absolute  Prior intracranial hemorrhage  Known structural cerebral vascular lesion  Known malignant intracranial neoplasm  Ischemic stroke within 3 months  Suspected aortic dissection  Active bleeding or bleeding diathesis

Relative  Uncontrolled hypertension  Major surgery within 3 weeks  Recent internal bleeding  For streptokinase prior allergic reaction  Pregnancy  Active peptic ulcer  Current use of warfarin

 Drugs which inhibit plasminogen activation and dissolution of clot  1- Epsilon amino-caproic acid (EACA)  2- Tranexaemic acid Indications  Overdose of streptokinase  To prevent recurrence of subarachnoid and G.I hemorhage  Abruptio placentae, PPH and menorhagia

 THROMBOXANE A 2 INHIBITORS  Aspirin  ADP RECEPTOR INHIBITORS  Ticlopidine  Clopidogrel  Prasugrel  GLYCOPROTEIN IIB/IIA INHIBITORS  Abciximab  Eptifibatide  PHOSPHODIESTERASE INHIBITORS  Cilostazol

GP Ia GP IIb/IIIa Fibrinogen GP IIb/IIIa Platelet.. … … … … … … … Granules TXA 2 ADP 5-HT Aspirin Clopidogrel Ticlopidine  Abciximab GP Ib Collagen Vascular Endothelium vWF

Mechanism & Pharmacological effects  Aspirin and most other NSAIDs inhibit the synthesis of prostaglandins:  Decrease endothelial synthesis of PGI 2 (prostacyclin)  Decrease thromoboxane A 2 production in platelets by inhibiting cyclooxygenase type I and type 2  Irreversible inhibition of cyclooxygenase and platelet aggregation for the life of the platelet  It may cause bleeding, especially in the GI, and hypoprothrombinemic effect (high doses)

 Dose of aspirin mg  Prophylactic for transient cerebral ischemia  Reduce the incidence of recurrent MI  Decrease mortality in postmyocardial infarction patients

Mechanisms and Pharmacological effects:  Inhibits adenosine diphosphate (ADP)- induced expression of platelet glycoprotein receptors & reduces fibrinogen binding and platelet aggregation.  Can be used in patients who are unresponsive to aspirin to prevent thrombotic stroke.

 Prevent thrombosis in patients undergoing placement of a coronary stent  Ticlopidine Prevention of stroke in patients with a history of transient ischemic attack (TIA) or thrombotic stroke Adverse effects: Nausea, dyspepsia and diarrhea, thrombotic thrombocytopenic purpura

 Unstable angina or non-ST elevation acute myocardial infarction in combination with aspirin  Neutropenia- Less with clopidogrel  Clopidogrel is preferred over ticlopidine

 Chimeric (human-murine) monoclonal antibody  binds to platelet glycoprotein IIb/IIIa receptors and prevents binding by fibrinogen  used solely for the prevention of thrombosis in patients undergoing coronary angioplasty  Parenteral administration

 Inhibits platelets adhesion to damaged blood vessels   dosage  increase in platelets cAMP formation and  platelet Ca ++ which inhibits platelets aggregation  Used in combination with aspirin to prevent cerebrovascular ischemia

 Vitamin K (oral and parenteral forms) K 1 and K 2 newborns, vit k deficiency in patients with poor diet, parenteral nutrition, recent surgery  Plasma factors: factor VII, VIII, IX  Desmopressin acetate (increase the factor VIII activity)  Autoplex (factor VIII)  Cryoprecipitate (plasma protein fraction) Used in DIC

Fibrinolytic Inhibitors  Aminocaproic acid  Tranexamic acid

 Adjunctive therapy in hemophilia  Control bleeding from fibrinolytic therapy  Prophylaxis for bleeding from intracranial aneurysms  Post-surgical GI bleeding  Bladder hemorrhage secondary to radiation & drug-induced cystitis  Gynecological bleeding – fibroids, PPH

 Calcium complexing agents sodium oxalate sodium edetate