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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 polymerXIII
Intrinsic Pathway Extrinsic Pathway
Factors affectedBy HeparinVit. K dependent FactorsAffected 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, TenecteplaseC. 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 responsePlasmin 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 hemorrhageKnown structural cerebral vascular lesionKnown malignant intracranial neoplasmIschemic stroke within 3 monthsSuspected aortic dissection Active bleeding or bleeding diathesis
Relative Uncontrolled hypertensionMajor surgery within 3 weeks Recent internal bleedingFor streptokinase prior allergic reaction PregnancyActive peptic ulcerCurrent 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 A2 INHIBITORS Aspirin
ADP RECEPTOR INHIBITORS Ticlopidine Clopidogrel Prasugrel
GLYCOPROTEIN IIB/IIA INHIBITORS Abciximab Eptifibatide
PHOSPHODIESTERASE INHIBITORS Cilostazol
GP
GP
GPIa
GPIIb/IIIa
Fibrinogen
GPIIb/IIIa
Platelet..…
.............
………………
Granules
TXA2
ADP5-HT
Aspirin
ClopidogrelTiclopidine
Abciximab
GPIb
Collagen
Vascular Endothelium
vWF
Mechanism & Pharmacological effects Aspirin and most other NSAIDs inhibit the synthesis of prostaglandins: Decrease endothelial synthesis of PGI2 (prostacyclin) Decrease thromoboxane A2 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 75-325 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) K1 and K2
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