PowerPoint Presentation

Anticoagulants & AntiplateletsNOOR WIJAYAHADITerminologiesAntithrombotics = Drugs which interfere with platelet functions

Anticoagulants = Drugs used to reduce the coagulability of blood

Thrombolytics (Fibrinolytics) = Drugs used to lyse thrombin clot (mainly therapeutic)

HEPARIN vs Activated clotting factorsThe Coagulation and Fibrinolytic Pathways3Figure 1. The Coagulation and Fibrinolytic Pathways. The main coagulation reactions are divided into the intrinsic and extrinsic systems. Activation of factor XII on contact with a negatively charged surface initiates the intrinsic coagulation system. (The activated form of the factor is indicated by "a.") The extrinsic coagulation system induces the formation of a complex composed of factor VII and tissue factor, which is released after tissue injury. Some of these reactions depend on calcium ions. Thrombin is formed by an enzyme complex called prothrombinase, composed of factor X, factor V, negatively charged phospholipids, and calcium ions. Intrinsic and extrinsic activation of the coagulation cascade leads to the generation of thrombin, the activation of fibrinogen, the release of fibrinopeptides, the formation of soluble fibrin, and finally, the formation of factor XIII-mediated, cross-linked, insoluble fibrin. The main fibrinolytic reactions involve the inhibition of fibrinolysis by plasminogen-activator inhibitor type 1 (PAI-1) and {alpha}2-antiplasmin. Fibrinolysis is initiated by tissue plasminogen activator (t-PA), urinary-type plasminogen activator (u-PA), and plasmin. Plasmin bound to the surface of fibrin initiates the lysis of insoluble, cross-linked fibrin, with the subsequent generation of fibrin-degradation products. Plasmin bound to the surface of fibrin is better protected from inhibition by {alpha}2-antiplasmin than is plasmin generated in the fluid phase.

Prothrombin TimeExtrinsic pathwayMonitor warfarinINRActivated Partial Thromboplastin TimeIntrinsic pathwayMonitor heparinSimplified View of the Coagulation CascadeExtrinsicIntrinsicCommon4Clotting Cascade

The blood coagulation process can be activated by one of two pathways, the tissue Factor pathway (formerly known as the extrinsic pathway) and the contact activation pathway (known as the intrinsic pathway).Tissue Factor binds to and activates Factor VII and the Tissue Factor/VIIa complex then activates Factor X and Factor IX to Xa and Ixa respectively. Factor X can also be converted to Xa by Ixa (in the presence of Factor VIII).The intrinsic pathway is activated when Factor XII comes in contact with a foreign surface. The resulting Factor XIIa then activates Factor XI, which in turn activates Factor IX. Factor Ixa then activates Factor X.Thus Factor Xa can be generated by activation of the tissue factor or contact activation pathways. Factor Xa then cleves prothrombin and the resulting thrombin converts fibrinogen to fibrin.Four of these clotting factors (Factors IX, VII, X and prothrombin) are Vitamin K dependent and therefore their activity is decreased by the Vitamin K antagonist, warfarin. The half-lives of these four Vitamin K dependent clotting factors are shown on this slide. Factor VII has the shortest half life of the Vitamin K dependent coagulation factors. However, for adequate anticoagulation one needs to reduce the other coagulation factors appropriately, including Factor II (prothrombin) which has a 60 hour half life. It takes several days after initiation of warfarin therapy to reduce Factor II and thus warfarin and heparin need to overlap for approximately 45 days when starting therapy.Thrombosis - Pathogenesis3 primary influences predispose to thrombus formation

Virchows Triad (1856):Endothelial InjuryStasisHypercoagulability

6Blood Clotting Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic PhaseVascular Phase Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulationTissue FactorPlatelet phaseblood 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 Coagulation PhaseTwo major pathwaysIntrinsic pathwayExtrinsic 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 Normally inactive and sequentially activated Hereditary lack of clotting factors lead to hemophilia -A

Intrinsic PathwayAll clotting factors are within the blood vesselsClotting slower Activated partial thromboplastin test (aPTT)

Extrinsic PathwayInitiating factor is outside the blood vessels - tissue factorClotting - faster - in SecondsProthrombin test (PT)Blood Vessel InjuryIX IXaXI XIaX XaXII XIIaTissue InjuryTissue FactorThromboplastinVIIa VIIX ProthrombinThrombinFibrinogenFribrin monomerFibrin polymerXIIIIntrinsic PathwayExtrinsic PathwayFactors affectedBy HeparinVit. K dependent FactorsAffected by Oral Anticoagulants Functions of Platelet Plug formation by passive agglutination and active aggregation later reinforced by fibrinExposure of PF3 which is clotting factor IIIMechanical clot retraction involving platelet actin and myosin - strengthens clotActive biochemicals from granules, dense granules and cytoplasmAntiplatelet activity in the bodyInvivo blockers of platelet aggregationPGI2* through cAMP* pathway NO through cGMP pathway

Produced in vascular endotheliumAnticoagulant drugsDrug ClassPrototypeActionEffectAnticoagulantParenteralHeparinInactivation of clottingFactorsPrevent venousThrombosisAnticoagulantOralWarfarinDecrease synthesis ofClotting factors Prevent venousThrombosisAntiplateletdrugsAspirinDecrease plateletaggregationPrevent arterialThrombosisThrombolytic DrugsStreptokinaseFibinolysisBreakdown ofthrombi

Mohler E. N Engl J Med 2007;357:293-296Atherosclerotic Plaque Disruption and Platelet Activation16Figure 1. Atherosclerotic Plaque Disruption and Platelet Activation. The disruption of an atherosclerotic plaque results in exposure of highly thrombogenic material. In patients with atherothrombosis, the activation of platelets and coagulation are inseparable, reciprocally self-amplifying processes. The inhibition of platelets alone does not block the coagulation activators. GP denotes glycoprotein, ADP adenosine diphosphate, and COX-1 cyclooxygenase-1.Copyright restrictions may apply.

Schulman, S. P. JAMA 2004;292:1875-1882.Sites of Action17AntiplateletNSAIDS inhibit cyclooxygenase and decrease TxA2 synthesis (irreversibly with Aspirin)Ticlopidine and Clopidogrel ADP induced platelet aggregation & platelet-fibrinogen interaction irreversibly blocked Cilostazol: PDIII inhibitor increases cytoplasmic cAMP GP IIb/IIIa blockers : Abciximab,Eptifibatide, Tirofiban Dextran : interferes with platelet aggregationAntiplatelet phamaceuticalscontdDipyridamole# Increases PGI2 release from the endothelium # Inhibits platelet phosphodiesterase - builds up platelet cAMP and decreases cytoplasmic Ca2+

# Inhibits RBC uptake of adenosine* which is an inhibitor of platelet reactivity

# Inhibits the formation of TxA2 by blocking Tx synthetase

Antiplatelet drugsExample: AspirinPrevents platelet aggregation /adhesionClinical use - prevents arterial thrombusMyocardial infarction (MI), stroke, heart valve replacement and shunts Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine

Mechanism of actionAspirin inhibits cyclooxygenase (COX)COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins)Inhibits platelet aggregationProphylactic use of AspirinLow dose daily.Prevents ischemic attack (ministroke) and MI335 mg/day reduced the risk of heart attack in patients over 50More than 1000 mg/day NO EFFECTContraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency

Coagulation CascadeThree steps:Initiation Phase: Starts with VIIa/TFEnds with formation of IIa Amplification PhaseActivation of V, VIII, XIII, XI and Fibrinogen by IIa, if the IIa is not neutralised by ATIII or Thrombomodulin Propagation PhaseRefers to the phase during which activated factors Va, VIIIa, and IXa attach to the platelets and the platelets release PF3In-vivo Antithrombotic Mechanisms Antithrombin IIIInhibits IIa, IXa, Xa, XIa, XIIa, XIIIa and Plasmin by binding to their active siteWhen heparin bind to AT III the active sites of the clotting factors are further compromisedAcquired AT III deficiency: DIC, OCP, sepsis, c/c heparin RxProtein C & SIIa + Protein C Protein Ca Va & VIIIa inactivationProtein S is a co-factor for activated Protein C (Protein Ca) Tissue factor pathway inhibitor (TFPI)Inhibits VIIa/TF complex and XaCirculates in Plasma or contained in Platelets or on EndotheliumHeparin may release it from the surface of endothelial cellsFibrinolysisThe Fibrinolytic SystemPlasminogen

tPA Urokinase (endothelium) PAI-1PAI-2

Thrombin(IIa) Plasmin

(2 antiplasmin) PICross-linked fibrin polymer

Fibrinogen fibrinPolymer

FDPD-Dimer

Anticoagulant pharmaceuticalsStandard Heparin (Unfractionated Heparin) (mol.wt 5000- 30,000 Da; av.15,000 Da)Derived from porcine intestinal mucosa or beef lung, prepared as Na+ or Ca2+saltsAT III inhibits IIa, IXa, Xa, XIa, XIIa, XIIIa and Plasmin by binding to their active site. When heparin binds to AT III the active sites of the clotting factors are further compromisedRoutes: IV, SC, Intra nasal. Never IM or Oral*Peak plasma levels after SC inj. 2-4 hrs.Strongly anionic, hence rapidly bound to proteins.t1/2 90 min

HeparincontdComplicationsHemorrhageesp. intracranial, intraspinal, intraocularHeparin resistanceseen in a/c thrombotic processes with consumption of AT III. Rx FFP !!Maternal osteoporosis on c/c useHIT Syndrome: spectrumThrombocytopenia without thrombosisHypotension & Transient reversible platelet aggregationIrreversible platelet aggregation: White clot syndrome Heparin antibodiesLMWHM.Wt 2000-8000 Da ( avg 4500 Da )- prepared from SH by fractionation, enzymatic degradation or chem modifnCommercial preprn : Enoxaparin, Dalteparin, Ardeparin, Tinzaparin, FondaparinuxRoutes : SC (OD)High anti-Xa and low anti-IIa activity greater antithrombotic and lower anticoag activityLow anti-IIa activity, hence, aPTT, TT, ACT not ideal for monitoring. Anti-Xa assay idealLess complicated, dose independent clearance and more predictable anticoagulant response than SH. Hence lab monitoring not requiredFondaparinux: synthetic, specific inhibitor of Xa, used for Px in THR & TKR. Long elimination t 1/2 (20 hrs). Renal clearanceAnticoagulation with SH & LMWH contdOther uses:To prevent catheter thrombosis: 2-5 U/mlIf sample collected from indwelling catheter, blood to be discarded prior to collection of the sample = 3 times the volume of catheter.For ABG: 1000 U/ml. Dont exceed 1/10th the volume of blood, since heparin is itself acidic. may alter resultsTemporary vascular occlusion: 100 U/kgFor CPB & ECMO: 300 U/kg. Monitor ACT. Reverse with Protamine 1mg / 100 U Heparin

Coumarin derivativesDicumarol and WarfarinIndirect anticoagulants- interfere with hepatic synthesis of Vit K- dependent clotting factorsUsed for Px and Rx in thrombophlebitis, AF, PTE, AMI, mechanical prosthetic valves and valvular heart diseaseA typical regimen: warfarin started at 5mg/day x 7days, then maintenance dose 2.5 to 7.5 mg OD depending upon required INRMonitored using Prothrombin time & INRFactors affecting coumarin potencyINCREASE PTReduced clearanceDisulfiramMetronidazolecotrimoxazoleReduced albumin bindingPhenylbutazoneAdditive hemostatic effectAspirin, HeparinLiver disease, Vit. K deficiencyIncresed turnover of Vit.KClofibrate, Hypermetabolic state

DECREASE PTAccelerated clearanceBarbituratesRifampin

Reduced absorptionCholestyramin Coumarin resistance

Fibrinolytics Plasminogen activatorsPreparations:Anistreplase (t 100 minutes)Streptokinase (t 83 minutes)Urokinase (t 20 minutes)Reteplase (t 15 minutes)Alteplase (t 3 minutes)Streptokinase: bacterial enzyme indirect activator of plasminogen: SK first forms a complex with Plasminogen. It is this complex which activates subsequent plasminogen. Dose in AMI: 1.5 million units I.V over 1 hour Urokinase: product of renal tubular cell direct activator of plasminogen. Fibrinolyticscontd..Major problem: hemorrhageCauses:NOT related to residual activityDefective fibrin polymerisation due to FDPs: can be a problem upto 24 hrs despite t1/2 of 3 hrs Platelet aggregation inhibition by FDPsDecreased concentration of factors I,V & VIIIRx of hemorrhage due to fibrinolytics:Discontinue administration Antagonise residual effect: Aprotinin or EACAAfter residual effect wanes: FFP / CryopptFibrinolyticscontd..Some basic facts to be remembered:Heparin should be added in the post-thrombolytic pd. till hospitalised followed by warfarin therapy till 3 months, as Plasminogen is most effective if it lies within the fibrin matrix during clot formation. Clots formed during the period of thrombolysis are resistant to subsequent thrombolysis. Reperfusion arrhythmia: so must repeat an ECG post-thrombolysisAvoid coughing, straining, HTN post-thrombolysisNo IM inj.Sampling through indwelling cathetersLower limb BP cuffs: risk of embolisation of dissolving clotsLocal infusions of thrombolytics may have major systemic effects: Do Not Underestimate !

Fibrinolyticscontd..Contraindications:Absolute Cerebrovascular hmg at any timeNon hmgic stroke or other CVA within past yearSBP >180mmHg; DBP >110 mmHgSuspicion of Aortic dissectionActive internal bleeding (excluding menses)RelativeINR 2 on current anticoagulantRecent (< 2 wk.) history of surgery or invasive procedureProlonged ( > 10 min )CPCRKnown bleeding diathesisPregnancyHmgic ophthalmic condition (eg. hmgic diabetic retinopathy)Active peptic ulcerhistory of severe HTN, now adequately controlledhistory of having received SK within 5 days to 2 years

Neuraxial block along with anticoagulants: Recommendations AntiplatelesNSAIDs alone and NAB are compatibleThe effect of ticlopidin and clopidogrel should be allowed to dissipate (7 days) before NABGPIIb/IIIa inhibitors: NAB 8 hrs after tirofiban and eptifibatide, and 48 hrs after abciximab Concurrent use of SH, LMWH, or anticoagulants increase the risk of bleeding (holds true for all subsequent anticoagulants)FibrinolyticsNAB not recommended upto 10 daysIf NAB is undertaken, monitor neurologically atleast q2hConfirm adequate fibrinogen and low FDP levels before removing the catheters contd..Oral anticoagulantsStop anticoagulants and allow normalization of INR prior to performance of NABPreop warfarin: if initial dose >24 hrs earlier or a second dose was given, check INR before NAB Warfarin @ 5mg/day for >36 hrs and receiving epidural analgesia should have INR checked daily and before catheter removalIf epidural catheter present, withold / reduce warfarin if INR > 3Remove catheter if INR < 1.5If INR > 1.5 and catheter removed, monitor neurologically for at least 24 hrs.

Contd..Standard heparinMinidose, SCNo CI to performance of NABConsider delaying initiation of heparin till after institution of the NABAfter 4 days of SH confirm whether HIT has occurredI.V Heparin for intraop anticoagulationA gap of 4-6 hrs required between heparin and NABConsider minimal concentrations of local anesthetics to permit early detection of neurological changesDelay initiating heparin till 1 hr after needle placement for NABRemove epidural cath 1 hr before any subsequent i.v dose of heparin (assuming 12 hrly dosing ) or 4 hr after the last dose of heparinDifficult needle placement / bloody tap not an indication for cancellation, but frequent postop monitoring of neurological status mandatory contd..LMWHA gap of 24 hrs required between Fondaparinux administration and NAB. For catheter removal same interval recommendedA gap of 12 hrs required between LMWH and performance of NAB. In renal failure the interval should be longer (16-18 hrs)Remove epidural cath 24 hr after last dose of LMWH and do not administer subsequent dose for next 2 hrDifficult needle placement / bloody tap not an indication for cancellation, but important to delay subsequent dose of LMWH for 24 hrsConsider minimal concentrations of local anesthetics to permit early detection of neurological changesConsider single dose SAB

Prompt recognition of epidural hematoma is confirmed by CT or MRI followed by emergency decompressive laminectomy within 8 hrs

Anticoagulants and periop considerationsAdvantages of stopping an anticoagulant should outweigh the risksPostop bleeding due to warfarin administration is rarely fatal or associated with major morbidity whereas the consequences of venous or arterial embolism may be fatalAnticoagulation decreases the risk of VTE by 80%, the risk of arterial TE in patients with mechanical heart valves by 75%, and risk of ATE in patients with nonvalvular AF by 66%Rebound hypercoagulation state may develop by discontinuing warfarin, super-added by the prothrombotic effect of surgery .Surgery increases risk of VTE but not ATE in patients with AF or mechanical heart valves Patients on warfarin periopIn cases where change over to alternative anticoagulant not done before sx:INR 2-3: 4 scheduled doses of warfarin withheld to allow INR to fall to 1.5 before sxINR measured day before sx to see responseIf INR 1.8 at this time, inj. Vit. K SC (not IM)If INR 1.5 perform surgery After surgery:Warfarin takes 3-4 days to reach INR to 2. So Rx started soon after surgery

With the above regimen patients can have subtherapeutic levels for 2 days before and after surgery. Yet these levels can still provide partial protection against thromboembolism

Patient on warfarin for VTEDuring first 30 days:Elective surgery should be avoidedIf not possible, substitute with I.V Heparin before and after surgery while INR