Professional Documents
Culture Documents
Objectives
To learn how Blood Clots are formed. How the blood clots are broken down ? What drugs can be used to regulate clotting ? How to rectify clotting deficiencies
Blood
clots - Thrombus Thrombus dislodge from arteries and veins and become an embolus. Venous emboli can block arterioles in the lung and pulmonary circulation
Thromboembolism
Classes of Drugs
Prevent coagulation Dissolve clots Prevent bleeding and hemorrhage Hemostatic Overcome clotting deficiencies ( replacement therapies)
Blood Clotting
Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase
Vascular Phase
Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation
Tissue Factor
Platelet phase
Non-nucleated - arise from magakaryocytes blood vessel wall (endothelial cells) prevent platelet adhesion and aggregation platelets contain receptors for fibrinogen and von Willebrand factor after vessel injury Platelets adhere and aggregate. Release permeability increasing factors (e.g. vascular permeability factor, VPF) Loose their membrane and form a viscous plug
Veins low pressure : Red thrombus is formed Especially in valve pockets Contains a long tail of fibrin Can detach and form emboli
Coagulation Phase
Both converge at a common point 13 soluble factors are involved in clotting Biosynthesis of these factors are dependent on Vitamin K1 and K2 Most of these factors are proteases Normally inactive and sequentially activated Hereditary lack of clotting factors lead to hemophilia -A
Intrinsic Pathway All clotting factors are within the blood vessels Clotting slower Activated partial thromboplastin test (aPTT)
Extrinsic Pathway Initiating factor is outside the blood vessels - tissue factor Clotting - faster - in Seconds Prothrombin test (PT)
Intrinsic Pathway
Blood Vessel Injury XII XI IX X Factors affected By Heparin Prothrombin Fibrinogen XIII XIIa XIa IXa Xa
Extrinsic Pathway
Tissue Injury Tissue Factor Thromboplastin
VIIa X Thrombin
VII
Activation
XIIa
Inactive XI
Active XIa
Thrombosis
Arterial Thrombosis :
Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated with Congestive Heart Failure, Cancer, Surgery.
Venous Thrombosis :
Anticoagulant Warfarin Decrease synthesis of Oral Clotting factors Antiplatelet drugs Thrombolytic Drugs Aspirin Decrease platelet aggregation
Streptokinase Fibinolysis
Heparin
Sulphated carbohydrate Purified from bovine lungs Different size Active in vitro and in vivo Administration - parenteral- Do not inject IM only IV or deep s.c. Half-life 1 - 5 hrs - monitor aPTT Adverse effect - hemorrhage - antidote protamine sulphate
Thrombin
Mechanism of action
Descarboxy Prothrombin Prothrombin
Warfarin
Antiplatelet drugs
Aspirin Prevents platelet aggregation /adhesion Clinical use - prevents arterial thrombus
Mechanism of action
Aspirin
inhibits cyclooxygenase (COX) COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins) Inhibits platelet aggregation
High dose inhibits prostacyclin synthesis in cells surrounding vessels. PS normally prevents platelet aggregation. Therefore, inhibition of PS leads to abrogation of the prophylactic benefit of Aspirin
Aspirin, Sulfonamides
Fibrinolysis
Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form) Plasmin breaks down fibrin clots
Fibrinolysis
Streptokinase - bacterial product - continuous use - immune reaction Urokinase - human tissue derived - no immune response Tissue plasminogen activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE Lysine analog- inhibits proteases
Dipyridamole (Persantine)
20, 50 mg Lyophilized powder - reconstitute for iv Parenteral : 250000 - 1.5 million units per vial . Lyophilized powder. Reconstitute for iv Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml for injection
Urokinase ( Abbokinase)
Due to HIV risks in blood products recombinant proteins of the factors are made.
Gelatin sponge (Gelfoam) Gelatin film Oxidized cellulose ( Oxycel) Microfibrillar collagen (Avitene) Thrombin