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抗凝和溶栓

Anticoagulants and Thrombolytics
S. Ramakrishnan
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
Platelets and Thromboemolism
Arteries : White Thrombus
Platelets adhere
Release ADP
More adhesion/ aggregation
Reduced blood flow (stasis)
Fibrin clot
Veins low pressure : Red thrombus is formed
Especially in valve pockets
Contains a long tail of fibrin
Can detach and form emboli
Coagulation Phase
Two major pathways
Intrinsic pathway
Extrinsic pathway
 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)
Prothrombin time (PT)
Tissue Thromboplastin factor III

Mix with phospholipid extract

Add calcium and blood sample

Determine clotting time


Generally 12 - 14 seconds
Used to detect defects in extrinsic pathway
Activated partial thromboplastin time (APTT)
Blood sample + EDTA or Citrate

No clot ( recalcification will result in clot in about 2 - 4 min)

Add calcium
Mix with negatively charged phospholipid
Kaoline (aluminum silicate)

Determine clotting time
Generally clotting occurs in 26 to 33 seconds

Used to detect defects in the intrinsic pathway
Diagnosis of coagulation defects
Prolonged APTT   Defective Intrinsic Pathway
No change in PT


No change in APTT   Defective Extrinsic Pathway
Prolonged PT


Prolonged APTT   Defective in Common pathway
Prolonged PT  
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 Pathway
Extrinsic Pathway
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
Activation
Inactive XI
Active XIa
XIIa
+
Thrombosis
Arterial Thrombosis :
Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia
 Venous Thrombosis :
Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated with  Congestive Heart Failure, Cancer,  Surgery.

Anticoagulant drugs to treat thromboembolism
Drug Class Prototype Action   Effect
Anticoagulant
Parenteral
Heparin
Inactivation of clotting
Factors
Prevent venous
Thrombosis
Anticoagulant
Oral
Warfarin
Decrease synthesis of
Clotting factors
 Prevent venous
Thrombosis
Antiplatelet
drugs
Aspirin
Decrease platelet
aggregation
Prevent arterial
Thrombosis
Thrombolytic
Drugs
Streptokinase
Fibinolysis
Breakdown of
thrombi
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
Heparin mechanism of action
Heparin
Antithrombin III
Thrombin
Oral anticoagulants : warfarin, dicumarol
Coumarins - warfarin, dicumarol
Isolated from clover leaves
Structurally related to vitamin K
Inhibits production of active clotting factors
Absorption rapid - binds to albumin
Clearance is slow - 36 hrs
Delayed onset 8 - 12 hrs
Overdose - reversed by vitamin K infusion
Can cross placenta - do not use during late pregnancies

Mechanism of action
Descarboxy Prothrombin
Prothrombin
Reduced Vitamin K
Oxidized Vitamin K
NADH
NAD
Warfarin
Antiplatelet drugs
Aspirin
Prevents platelet aggregation /adhesion
Clinical use - prevents arterial thrombus
Myocardial infarction (MI), stroke, heart valve replacement and shunts
 Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine

Mechanism of action
Aspirin inhibits cyclooxygenase (COX)
COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)
Inhibits platelet aggregation
Prophylactic use of Aspirin
Low dose daily ( 180 mg/day)
Prevents ischemic attack (ministroke) and MI
335 mg/day  reduced the risk of heart attack in patients over 50
More than 1000 mg/day NO EFFECT
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
 Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency
 


Drug interaction- prototype Warfarin
Drugs that Increase
Warfarin Activity
Decrease binding to
Albumin

Inhibit Degradation

Decrease synthesis of
Clotting Factors
Aspirin, Sulfonamides


Cimetidine, Disulfiram

   Antibiotics (oral)
Category                      Mechanism                Representative Drugs
Drug interaction- prototype Warfarin
Drugs that promote
bleeding
Inhibition of platelets  Aspirin

Inhibition of clotting              heparin
Factors        antimetabolites
Drugs that decrease
Warfarin activity
Induction of metabolizing Barbiturates
Enzymes   Phenytoin

Promote clotting factor Vitamin K
Synthesis   OC
Reduced absorption  cholestyramine
    colestipol
Fibrinolysis
 Enhance degradation of clots
Activation of endogenous protease
Plas


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