Prof. Aboubakr ElnasharEmail: elnashar53@hotmail.com

• Vascular Phase• Platelet Phase• Coagulation Phase• Fibrinolytic Phase

1. Vascular Phase

• V.C• Exposure to tissues activate tissue factor

and initiate coagulation

Tissue Factor

2. Platelet phase

• Blood vessel wall (endothelial cells) prevent platelet adhesion & aggregation

• Platelets contain receptors for fibrinogen and von Willebrand factor.

• After vessel injury: Platelets adhere & aggregate• Release permeability increasing factors (e.g. vascular

permeability factor, VPF)• Loose their membrane & form a viscous plug

3. Coagulation Phase

• 2 major pathways• Intrinsic pathway• Extrinsic pathway

• Both converge at a common point• Clotting factors:13 soluble Biosynthesis is dependent on Vitamin K1& K2 Most are proteases Normally inactive & sequentially activated

Intrinsic Pathway• All clotting factors are

within the blood vessels• Clotting: slower• aPTT

Extrinsic Pathway• Initiating factor is outside the blood

vessels: tissue factor• Clotting: faster in Seconds• 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 polymerXIII

Intrinsic Pathway Extrinsic Pathway

Factors affectedBy Heparin

Vit. K dependent FactorsAffected by Oral Anticoagulants

ThrombiAcc to location & composition

Arterial• Occur in areas of rapid flow

(arteries)• In response to an injured or

abnormal vessel wall• White • Composed: primarily of platelets, also fibrin &

occasional leukocytes• Associated withMI Strokeischemia

Venous•Occur primarily in the venous circulation•In response to venous stasis or vascular injury •Red•Composed almost entirely of fibrin & erythrocytes•Associated withCongestive Heart Failure, CancerSurgery.

4. Fibrinolysis

Enhance degradation of clotsActivation of endogenous proteasePlasminogen (inactive form) is converted to Plasmin (active form)Plasmin breaks down fibrin clots

Drug Class Prototype Action Effect1. Anticoagulant Parenteral

Heparin Inactivation of clottingfactors

Prevent DVT

Oral Warfarin Decrease synthesis ofclotting factors

Prevent DVT

2. Antiplatelet

Aspirin Decrease plateletaggregation

Prevent arterialthrombosis

3. Thrombolytic Streptokinase Fibinolysis Breakdown ofthrombi

I. Anticoagulants1. Heparin

StructureMucopolysaccharide MetabolismPartially in the liver by heparinase to uroheparin, which has

only slight antithrombin activity. 20-50 % is excreted unchanged. {The heparin polysaccharide chain is degraded in the gastric

acid} administered IV or SC. Heparin should not be given IM } danger of hematoma

formation{ .

Unfractionated heparin (UFH)Mol weight:3000-30000Mechanism of action:•Primarily: interaction with antithrombin III: alters the molecular configuration of antithrombin III, making it 1,000 to 4,000 times more potent as an inhibitor of thrombin formation: limits conversion of fibrinogen to fibrin: prolongs aPTT•Also inhibits the effects of factor Xa on the coagulation cascade & limits platelet aggregation. Half-life:IV: 1 hr SC: 3 hrs.

UFH inactivate factor IIa through formation of a tertiary complex (unlike LMWH).

UFH binds more to plasma proteins, endothelium and macrophages: reduced bioavailability & greater patient variability to a given dose.

UFH inactivates factors IIa and Xa & affects the aPTT (measure of anti-factor IIa activity).

Heparin-induced thrombocytopenia 20% . Diagnosis: platelet count falls below the lower limits of normal or by 50% but remains in the normal range. a.Type 1Mild, rarely dropping below 100,000 platelets/ML. Platelet count monitoring is important, but therapy usually can continue {platelet count returns to normal even with continued use}. {platelet activation & is not immune-mediated}.b. Type 27 to 14 days after starting therapy. Platelet counts frequently drop to 20,000/ML. {an immune response caused by antibodies to the heparin-platelet factor 4 complex}.

It is related to: Mol wt, dose & duration of therapy. immediate withdrawal of all forms of heparin is mandatory. Platelet concentration should be monitored at least every 2 days.

Dosing options. Preoperative: 5,000U 2 hours before surgery. {The single preoperative dose seems to be as effective as multiple preoperative doses}.

Postoperative: 8 to 12 hrs after surgery & every 8 to 12 hrs until the patient is fully ambulatory.Antidote: Protamine sulphateMonitor: aPTTUse in pregnancy :{does not cross the placenta} safe

Low-Molecular-Weight Heparin •Molecular weight 1000-10000 Da. •Produced by concentrating the low molecular component of UFH. Enzymatic or chemical controlled hydrolysis of UFH. •The mechanism of actionPrimarily by inhibiting factor Xa, which is higher in the coagulation cascade than antithrombin: LMWH is more efficient than UFH. {the molecular configuration of antithrombin III is not altered by LMWH} thrombin conversion is minimally inhibited and aPTT is not appreciably affected.

LMWH inhibits factor Xa and minimally affects factor IIa; thus aPTT is not used to measure its anticoagulant activity.

Generic TradeManufacturerMol Wt

EnoxaparinLovenex, ClexaneRhone-Poulence-Rorer4500

TinzaparinLogiparineNovo4850

DalteparinFragminKabi6370

Half-life: 4 hrs, by any route: longer dosing interval. BioavailabilityMore consistent than that of UFH: dosing is based on lean body mass & Less thrombocytopenia.Use in pregnancy: Does not cross the placenta: safe.Dosing options. Prophylaxis: Once a dayTherapy: Twice-daily. Enoxaparin is an LMWH Moderate risk: 20 mg/dHigh risk: 40 mg/d. •Advantage Decreased need for monitoring

UFHLMWH

Mol Wt range3000-300001000-10000

Mo Wt average12000-150004000-5000

AntiXa: antiIIa activity1:12:1-4:1

aPTT monitoring requiredYesNo

Inactivation by platelet factor 4YesNo

Capable of inactivation of platelet bound factor Xa

NoYes

Inhibition of platelet function++++++

Increase vascular permeabilityYesNo

Protein binding+++++

Endothelial cell binding+++-

Dose dependent clearanceYesNo

Elimination half life50-20 min2-5 times longer

2. Oral anticoagulants • Coumarins - warfarin, dicumarol

Structure: small, lipid-soluble molecules, Structurally related to vitamin K,

isolated from clover leavesMechanism:• Inhibits production of active clotting factors• blocks the Vitamin K-dependent glutamate carboxylation of

precursor clotting factors e.g. FII, VII, IX , X Metabolism:• Absorption: rapid• Binds to albumin• Clearance is slow: 36 hrs • Delayed onset: 8-12 hr {T1/2 of clotting factors in plasma}

blocks the Vitamin K-dependent glutamate carboxylation of precursor clotting factors

Use:To prevent the formation, recurrence or extension of DVT & PENot used in pregnant women {cross placenta}Not used for arterial thrombi {No effect on platelets} Toxicity:bleeding birth defectsOverdose:Reversed by vitamin K infusionRecovery needs synthesis of new clotting factors

Warfarin tablets, 5, 3 and 1mg

Drugs that Increase Warfarin Activity

Decrease binding toAlbumin

Inhibit Degradation

Decrease synthesis ofClotting Factors

AspirinSulfonamides

Cimetidine, Disulfiram

Antibiotics (oral)

Category Mechanism Representative Drugs

Inhibition of platelets Aspirin

Inhibition of clotting HeparinFactors Antimetabolites

Drugs that promotebleeding

Induction of metabolizing BarbituratesEnzymes Phenytoin

Promote clotting factor Vitamin KSynthesis OCReduced absorption Cholestyramine

Colestipol

Drugs that decreaseWarfarin activity

HeparinWarfarinAbsorptionParentral onlyOral

Vol of distributionPlasma vol (0.07 L/kg)7.6-13.9 L

Metabolism/ClearanceHepatic metabolism & uptake by reticulo endothelial system

Also by thrombin & other clotting factors

Hepatic

Elimination t1/250-90 min36-42 hr

Protein bindingBound to antithrombin III & other serine proteases

99.4% bound to albumin

Plasma concentration (therapeutic)

0.2-0.4 U/ml1.5 mg/L

Side effectsBleeding

Thrmbocytopenia

Osteoporosis

Bleeding

Skin necrosis

Drug interactions

Treatment of bleeding

•Mild: Slow or stop infusion•Severe: Protamine 1 mg/100 u of estimated heparin remaining in body

•Mild: hold 1-2 doses, observe, restart at lower dose•Severe: Vit K or fresh frozen plasma

II. Antiplatelet DrugsActivation and aggregation of platelets is a major component of thrombosis especially in arteries

Targets for platelet inhibitory drugs:(a) inhibition of prostaglandin metabolism through inhibition of cyclooxygenase (aspirin)

(b) inhibition of ADP-induced platelet aggregation (ticlopidine)

Platelet Activation:•Endothelial damage of vessel: exposes collagen •Activated platelets release ADP, serotonin (5-HT)& thromboxane A2 (TXA2-) from arachidonic acid: platelet aggregation by causing the appearance of binding sites for fibrinogen on platelet membrane •Fibrinogen is involved: platelet to platelet adhesion (aggregation) •Thrombin causes further platelet activation by releasing platelet ADP & stimulating PG synthesis prostacyclin (PGI2) - synthesized within vessel walls inhibits thrombogenesis by increasing platelet cAMP. Nitric oxide (NO) - released by endothelium - increases cAMP

(a) NSAIDSAspirin - prototypeMechanism:inhibits cyclooxygenase (COX)COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins). Inhibits platelet aggregationlong acting because new proteins must be synthesized other NSAIDS:shorter duration because of reversible competitive inhibitory action potency varies, e.g. Naproxen, meclofenamic acid, Ibuprofen, Indomethacin, phenylbutazare

Contraindication: Patients with glucose 6-PO4 dehydrogenase deficiency

Dose:• Low dose daily (180 mg/day): Prevents ischemic attack

(ministroke) and MI• 335 mg/day: reduced the risk of heart attack in patients

over 50Use:• Prevention of recurrent infarcts in patients with myocardial

infarction, also reduces the incidence of first infarcts• low-dose aspirin, compared with placebo, reduces by

36% the risk of VTE after orthopaedic surgery• Meta-analysis of trials in surgical and medical patients: significant

reduction in DVT and PE with antiplatelet prophylaxis. (Pulmonary embolism prevention (PEP) Trial . Prevention of PE and DVTwith low dose aspirin: Lancet 2000; 355:1295–302.)

(b) Ticlopidinedecrease platelet aggregation by inhibiting ADP pathway of platelets no effect on PG metabolism used as alternative for patients intolerant to aspirin expensive (C) Other antiplatelet drugs: Dipyridamole, sulfinpyrazone

III. Thrombolytic AgentsAgents which reduce the formation of arterial platelet thrombi Mechanism:• Rapid lysis of thrombi by catalyzing the formation of plasmin from

plasminogen • Endogenous plasmin breaks down fibrin promoting clot dissolutionUse:• Emergency treatment of coronary artery thrombonís in M.I. • IV or intracoronary injection • DVT: rapid recanalization of occluded vessels Toxicity:• Bleeding (intracranial, G.I.) • Allergic reactions (i.e. streptokinase)

Streptokinase: Purified from bacteria Continuous use: immune reaction Forms a complex with plasminogen & catalyzes it: rapid conversion to plasmin Urokinase:From cultured human kidney cellsNo immune response Directly converts plasminogen to plasmintPA:Produced by recombinant techniquesNo immune reaction - EXPENSIVE Promotes conversion of plasminogen (that is found to fibrin) to plasmin In theory, selective for formed clots

Enzymatic efficiency for clot lysis

Fibrin specificity

Potential antigenicity

Average dose

Dosing administration

Cost

StreptokinaseHighMinimalYes1.5 MU1 hr IV infusionLow

AntistreplasehighMinimalYes30 u2-5 min IV infusion

Moderate

Tissue plasminogen activator

HighModerateNo100 mg15 mg IV bolus, 50 mg over 30 min, then 35 mg over 60 min

Moderate

UrokinaselowmoderateNo2 mu1 mu IV bolus,

1 mu over 60 min

high

Thank youAboubakr Elnashar