The Cell Based Model of Coagulation A pharmacological

The Cell Based Model of Coagulation A pharmacological perspective

Topics Ø Physiology l l Cascade Model Cell Based Model Ø Pharmacology l l Anti-platelet Drugs Anti-factor Drugs Anti-cross linking Drugs Anti-fibrinolytic drugs

Part One Physiology

Hemostasis Ø Vasoconstriction Ø Platelet plug formation l l l Activation Adherence Aggregation Ø Stabilization of platelet plug l l Coagulation cascade Fibrin

Cascade Model XIIa TF XI VII XIa IX IXa VIIIa X VIIa TF X Xa Va II Fibrinogen IIa Fibrin

Intrinsic XIIa Extrinsic TF XI VII XIa IX IXa VIIIa X Common VIIa TF X Xa Va II Fibrinogen IIa Fibrin

Tests XII PT XIIa TF XI VII XIa IX IXa VIIIa VIIa TF a. PTT X X Xa Va TT II Fibrinogen IIa Fibrin

Problems XIIa C XI 2+ ? Ca TF VII XIa B IX IXa VIIIa VIIa TF A X 2+ ? Ca X Xa Va II Fibrinogen 2+ ? Ca IIa Fibrin

Cell Based Theory Ø Platelets and IIa are central Ø Sequence l l l Initiation Amplification Propagation

XII XIIa TF XI VII XIa IX IXa VIIIa X VIIa TF X Xa Va II Fibrinogen IIa Fibrin

VIIa TF Xa IIa XIa IXa VIIIa VIIa TF Xa Va IIa Fibrinogen Fibrin

Tissue factor bearing cell VIIa TF Xa Initiation Va Xa IIa Plt Amplification Xa IXa VIIIa Plt Fg Xa Va IIa Propagation Fb Subendothelial collagen Plt Fb Fb Plt v. WF

Platelet activation Ø Triggered by l l l Sub-endothelial collagen IIa ADP TXA 2 5 HT Epinephrine

Platelet activation Ø Results in; l l l Greatly increased surface area Dense granules release Ca 2+, 5 HT, TXA 2, ADP Alpha granules release factor V, fibrin, VWF

Platelet activation Ø Platelet phospholipid bilayer is actively controlled Ø Resting internal surface is procoagulant Ø Bilayer everts during activation, exposing procoagulant surface

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt IIa Propagation Fb Subendothelial collagen Plt Fb Fb Plt v. WF

Part Two Pharmacology

Part Two - Pharmacology Ø Topics l Anti-platelet Drugs l Anti-factor Drugs l Anti-cross linking Drugs l Anti-fibrinolytic Drugs

Aspirin Ø Salicylate that irreversibly acetylates COX enzymes Ø Prevents thromboxane generation Ø Thromboxane is a potent stimulator of platelet activation and aggregation

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

Clopidogrel Ø Irreversibly inactivate platelet ADP receptors Ø Thus preventing activation

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

Heparin Ø Sulfated glycosaminoglycan naturally bound to endothelial cells Ø Negatively charged + highly bound in plasma Ø Cleared by reticuloendothelial system

Heparin Ø Binds to AT III, and increases its activity 1000 fold Ø Heparin-ATIII binds to IIa, IXa, XIa and inactivates them

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

Heparin Ø Binds to Anti Thrombin III, and increases its activity 1000 fold Ø Heparin-ATIII binds to IIa, IXa, XIa and inactivates them Ø Requires AT III for its actions

Heparin Problems; Ø Thrombocytopenia Ø HITTS l l l Ig. G mediated 4 -14 days to develop Thrombosis

LMWH Ø Derived from heparin by chemical depolymerization Ø Xa: IIa activity 4: 1

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

LMWH Advantages over heparin; Ø Markedly reduced protein binding Ø Lower incidence of HITTS Ø Renal clearance Ø More effective thromboprophylaxis

Fondaparinux Ø Synthetic anticoagulant Ø Does not cause HITTS Ø Inhibits Xa Ø Renally excreted

Warfarin Ø Coumarin derivative with high oral bioavailability Ø Interferes with vitamin K regeneration

Vitamin K dependent factors Ø Factors II, VIII, IX & X Ø Carboxylation allows interaction with platelet membrane Ø Interaction requires Ca 2+

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

Warfarin Ø High protein binding Ø Hepatic clearance via inducable enzymes

Warfarin Ø Levels increased by; l l l l Protease inhibitors Macrolide antibiotics Chloramphenicol Azole antifungals Bergamottin (constituent of grapefruit juice) Verapamil Amiodarone l l l Ciprofloxacin Cyclosporin Diltiazem Ergotamine Metronidazole Norfloxacin SSRIs Fluoxetine/norfluoxetine Fluvoxamine Cimetidine Buprenorphine

Lepirudin Ø Recombinant hirudin Ø Directly binds to thrombin Ø Monitored by a. PTT

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

Lepirudin Ø Renally excreted Ø No effective antidote Ø Half-life 2 hours

Abciximab Ø Monoclonal antibody Ø High affinity for platelet IIa/IIIb receptor fibrin Ø Plasma half life 20 minutes Ø Has activity for 2 days

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

Tranexamic Acid Ø Competitive inhibitor of the activation of plasminogen Ø Renally excreted, half-life 2 hours Ø Provides survival benefit in trauma patients with hemodynamic instability

Tissue factor bearing cell VIIa TF Xa Xa Va IIa IIa Plt v. WF ADP IIa Plt TXA 2 Plt IIa Plt IXa VIIIa XIa IXa Fg Xa Va Va Plt Xa IXa VIIIa IIa 5 HT Fg IIa Plt Fb Fb Fb Subendothelial collagen Plt v. WF Plt Fb Fb Plt v. WF

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