ANTI-COAGULANT IN ICU DR.AMENA FATIMA

COAGULATION A CASCADE OF REACTIONS INVOLVED IN CONVERSION OF SOLUBLE FIBRRINOGEN TO INSOLUBLE FIBRIN.

Platelet plug formation :

Platelet Activation Pathways ADP Adrenaline COLLAGEN THROMBIN ADP GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation GpIIb/IIIa Aggregation GpIIb/IIIa Adhesion Platelet Multiple pathways are responsible for platelet activation. Platelets adhere to damaged blood vessels via cell surface adhesion molecules and their membrane receptors such as glycoprotein Ib/IX (GP Ib/IX), the ligand for von Willebrand factor (VWF), which in turn can activated platelets and cause conformational changes. Further, other activators including thrombin, adrenaline, ADP, and collagen can also activate platelets. When activation occurs, the glycoprotein IIb/IIIa membrane receptor (GP IIb/IIIa) is exposed. This receptor forms bridges using fibrinogen resulting in aggregation. Platelet activation also exposes a phospholipid surface (meeting place) upon which coagulation proteins carry out their reactions. The sequential activation of these coagulation factors ultimately leads to the formation of fibrin, which is a critical component in stabilizing the hemostatic plug. Thrombin when generated, plays a pivotal role in hemostasis, via both fibrin conversion and platelet activation. GpIb Adrenaline Adhesion vWF Exposed Collagen Endothelium

Targets for anti-platelet therapy ADP receptor Aspirin - Thrombin inhibitors ADP ADP receptor antagonists Clopidogrel II receptor THROMBIN receptor COX-1 Aspirin Phosphodiesterase inhibitors dipyridamole Signalling AA NSAIDs pathways TXA2 GPIIb - IIIa Fibrinogen Receptor Antagonists Fibrinogen

Coagulation cascade

Factor i – fibrinogen Factor ii – prothrombin Factor iii – tissue thrombo plastin Factor iv – calcium Factor v – labile factor (pro accelerin) Factor vii – pro covertin; stable factor Factor viii – Anti heamophilic factor ‘A’ Factor ix – Anti heamophilic factor ‘B’ or christamas factor Factor x – stuart prover factor Factor xi – plasma thromboplastin antecedent Factor xii – hagemann factor Factor xiii – fibrin stabilizing factor

Factor xiv- pre kallikrein Factor xv – HMWK(high mol. Wt. kininogen Factor xvi – vWF vonwillibrand factor Factor xvii – Anti thrombin iii Factor viii – heparin factor ii Factor xix – protien ‘c’ Factor xx – protien ‘s’

ANTI-THROMBOTIC AGENTS categories vit k antagonist Heparin- 1.UFH 2.LMWH ANTI-PLATELET AGENTS NOVEL ANTICOAGULANTS ANTI-FIBRINOLYTICS ACQUIRED INHIBITORS OF COAGULATION.

ANTI COAGULANTS DIRECT THROMBIN INHIBITORS-dabigatran,argatroban,lepirudin Indirect thrombin inhibitors-1.heparin-enoxaparin,UFH,LMWH. 2.fondaparinux VITK EPOXIDE REDUCTASE INHIBITORS-warfarin. Direct Xa inhibitors-rivaroxaban,apixaban.

Vit k antagonist Drug-warfarin MOA- inhibition of vit k dependant clotting factors(ii,vii,ix,x) Uses-stroke prevention,atrial fibrillation,pts with artificial heart valve,DVT,PE,antiphospholipidsyndrome,rarely in MI. Tests-PT (INR)

Reversal -1.stop warfarin temporarily .2. inj. Vit.k (new factors synthesis) 3.prothrombin complex concentrate(factor ii.vii,ix,x,proteinc &s) .

INDIRECT THROMBIN INHIBITORS 1. FONDAPARINUX 2.HEPARIN

HEPARIN UFH DRUGS: Heparin MOA- via blocking factor Xa and thrombin. TEST:APTT. REVERSAL: protamine sulphate(1mg for 100u of heparin given in previous 2-3 hrs) slow i.v

dosage For patients starting IV UFH, we suggest that the initial bolus and the initial rate of the continuous infusion be weight adjusted (bolus 80 units/kg followed by 18 units/kg per h for VTE; bolus 70 units/kg followed by 15 units/kg per h for cardiac or stroke patients) or use of a fixed dose (bolus 5,000 units followed by 1,000 units/h) rather than alternative regimens (Grade 2C).

HIT(heparin induce thrombocytopenia) Immune reaction to heparin,witin 5-14 days of therapy. Moderate thrombocytopenia, No bleeding Prothrombotic state due to platelet aggregation causing devastating arterial,microvascular or venous thrombosis. TESTS:heparin-platelet factor 4antibodies,serotonin release assay or whole blood aggregometry. Management:use of lmwh,less duration. Reversal:stop the drug,start alternative anti coagulants DANAPAROID or THROMBIN INHIBITOR SUCH AS LEPIRUDIN OR ARGATROBAN.

4T SCORE FOR HITS For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 1For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). 4 (or until heparin is stopped, whichever occurs first) (Grade 2C).

For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C).

LWMH DRUGS: Enoxaparin,daltiparin,tinzaparin. MOA:blocks factor Xa TEST: Usually no monitoring ,anti-Xa assay. REVERSAL:difficult, partially reversed by protamine (1mg for 1mg enoxaparin)

Therapeutic Dose of LMWH in Patients With Decreased Renal Function Therapeutice dose:1mg/kg 12 hrly; 1.5mg/kg 24 hrly For patients receiving therapeutic LMWH who have severe renal insufficiency (calculated creatinine clearance < 30 mL/min), we suggest a reduction of the dose rather than using standard doses (Grade 2C). 30 mg S.C /24hours

DIRECT THROMBIN INHIBITORS Drugs:dabigatran,argatoban,lepirudin,bivalirudin. MOA:blocks thrombin. TEST:not specific,normal APTT suggest no abn in hemostasis. REVERSAL:withdrawl of medication.,identification of bleeding source and control of bleeding via surgical or radiological means.,fluid replacement and maintainence of good urine output. Drug dose improvement for dabigatran in renal failre since renally excreated.

Dabigatran Drug dose improvement for dabigatran in renal failre since renally excreated. Reversal:oral activated charcoal within 2 hrs of dabigatran,hemodialysis/hemo[erfusion. Use of prothrombin complex conc or rFviia is controversial for bleeding control with dabigatran.

DIRECT XaINHIBITORS Drugs:rivaroxaban,apixaban MOA:blocks Xa TEST:normal PT suggest preserved hemostasis Reversal:not specific. Cessation of drug,supportive care.

Antiplatelet agents COX INHIBITORS: Aspirin GLYCOPROTEIN IIb/iiia INHIBITORS: abciximab, eptifibatide, tirofiban ADP INHIBITORS: Clopidogrel.

Cox inhibitor Drug:aspirin MOA:Blocks cycloxygenase to convert arachadonic acid into thromboxane (irreversible) Reversal: platelet transfusion TEST:Platelet function test

GP IIa/IIIb or ADP INHIBITORS Drugs:clopidogrel,ticagrelor,abciximab,tirofiban MOA:binds to platelet receptors P2Y12 which are ADP binding receptor,thus supresses ADP mediated activation of GP Iia/IIIb for platelet aggregation TEST:platelet function test Management:platelet transfusion if major bleeding.desmopressin,rFVIIa .

ANTI-FIBRINOLYTICS Drugs:tranexamic acid,EACA(epsilon amino caproic acid. MOA:these are lysine analogue,competitively binds to lysine binding sites on plasminogen molecule hence inhibits fibrinolysis. Uses:major bleeding ,(even with anti coagulants)

Acquired inhibitors of coagulation Auto anti bodies against factor VIII,IX,V,VWF REVERSAL:rFVIIa,PCCs,FEIBA(factor eight inhibitor bypassing activity),steroids,cyclophosphamide.,pkasmapheresis,immunoadsorption.

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