Blood Vessel Injury IX IXa XI XIa X Xa XII XIIa Tissue Injury Tissue Factor Thromboplastin VIIa VII...

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