Clotting factors are delayed b/c it has no effect on clotting factors already in circulation Pharmacokinetics: 99% is bound to albumin

in blood Initial response 8-12 h & several days for peak 1 Tx uses: Prevention of venous thrombosis & PE, thromboembolism in pts with prosthetic heart valves Prevention of thrombosis during atrial fibrillation Monitoring: PT/INR, 12/2-4.5 Monitor frequently for the first 4 weeks & if anything changes (drug regimen, diet etc) Monitor levels 5 hrs after IV and 24hrs after SQ Overdose: -Tx with vitamin K1 (phytonadione) PO, IV (avoid SQ),Infuse slowly -Vitamin K3 (menadione) no effect on warfarin -If vit K1 does not work use whole blood, fresh-frozen plasma AE: Hemorrhage

Main drugs that may interact with warfarin: Heparin, Aspirin, Acetaminophen 2 -Antiplatelet drugs- drugs that prevent platelet aggregation Aspirin Clopidogrel (Plavis) Ticlopidine (Ticlid) Tirofiban (Aggrastat), Eptifibatide (Integrilin), Abciximab (ReoPro) -Others Dipyridamole (Persntine) Cilostazol (Pletal) 2 -ASPIRIN- MI and Stroke prophylaxis IRREVERSIBLE inhibition of cycloxygenase which is needed to aspirin last for the life of the

synthesize TXA2 so the effect of platelet.

2 AE: GI bleeding, hemorrhagic stroke 2 -ADP RECEPTOR ANTAGONISTS- Clopidogrel (Plavix)- Stroke - Ticlopidine (Ticlid)- Stroke (both use the word base pid)

and MI

-blocks adp receptors on platelet surface, thus preventing aggregation. (irreversible)

>coagulation- is a property of plasma, and is the conversion of soluble fibrinogen into insoluble fibrin > Blood is kept in liquid form by the aid of the endothelium. Endothelial cells produce antiplatelet agents such as, nitrous oxide, adp dephosphatase, and PGI2 (prostacyclin, a prostaglandin). Platelets are very sensitive to ADP. ADP activates platelets and platelet aggregation. These antiplatelet agents don't allow platelets to stick to the endothelial surface (which would cause platelet plug). In order to stick, platelets must be in an active state, but antiplatelet agents bind to the receptors on the surface of the platelets, inactivating them. >Healthy endothelium is a tissue which is antithrombotic, and an anticoagulant. > Healthy endothelial cells will not tolerate the presence of activated coagulation factors. They will kill them because otherwise, there would be increased risk of undue solidification of blood. >Healthy endothelial cells do this by expressing HEPARIN SULFATE. Heparin sulfate binds with antithrombin 3 and forms a complex that breaks down thrombin, and coagulation factors 9 and 10. >Healthy endothelial cells also express thrombomodulin, which binds with thrombin to activate protein C which eats/digest activated factor 5 and 8. (Thrombin is usually a procoagulant, but when bound to thrombomodulin, it is an anticoagulant.) >Healthy endothelium produces TPA, tissue plasminogen activator, which activates plasminogen into plasmin. Plasmin breaks down fibrin into fibrin degradation products. > Healthy endothelial cells produce vasodilators, when these cells are injured, they produce vasoconstrictors. When a vessel is injured vasoconstriction occurs via means of neurogenic constriction and myogenic (smooth muscle) constriction. >Injured endothelial cells will produce endothelin which vasoconstriction. causes

>Injured endothelial cells also secrete von Willebrand factor which is very sticky and on one side sticks to the subendothelial extracellular matrix/collagen while the other side sticks/hooks to platelets (binds with the Gp1b receptors on the platelet). This is called patelet adhesion, the process by which platelets stick to a non platelet surface. >Activated platelets secrete TxA2 (thromboxin A2), a platelet aggregator. vasoconstrictor and

> PGI2(antiplatelet) and TxA2 (platelet aggregator). are in constant competition. If one should prevail, its mechanism will take place. > Aspirin (salicylic acid) keeps platelets inactivated by inactivating the enzyme cyclooxygenase on the platelet plasma membrane (enzyme that converts arachadonic acid into TxA2). Platelets will lose the capability to produce TxA2, therefore, platelets cannot aggregate. >Activated platelets undergo a release reaction. Platelets will secrete Alpha and Delta granules. Delta granules produce SAC- seratonin, ADP, and Calcium. Seratonin produces vasoconstriction. ADP is a platelet activating chemical substance. Calcium tightly fixes the coagulation factors on the phospholipid surface of platelets and to each other. It does this because coagulation factors are enzymes/proteins, which contain amino acids, namely glutamate, which is carboxylated negatively charged (COO-). Calcium is positive and so it binds to them. Without calcium, coagulation reactions cannot occur. Coagulation factors are inactive enzymes that activate each other down the coagulation cascade >Alpha granules are like factories. Although most coagulation factors come from the liver, some coagulation factors come from alpha granules. Alpha granules release CFs, fibrinogen, and platelet derived growth factors (these growth factors will diffuse around the injured tissue, GFs will lead to mitosis/multiplication of smooth muscle at the injury site, GFs will attract fibroblasts which will multiply to make more collagen and permanently seal the injured area. > The chemicals that platelets release bind to/activate other platelets and attract them to the injured site to bind to other platelets. >Gamma carboxylation of coagulation factors depends on Vitamin K. Vitamin K dependent enzyme make the coagulation factors gamma carboxylated at glutamate point. Only these gamma carboxylated coagulation factors can work in the future. >Platelet plugs are formed by platelet adhesion (when platelets stick to non platelet surfaces), platelet release reactions (the chemicals that are released from platelets that activate other platelets and call them near), and platelet aggregation (the sticking of platelets to each other). This initial plug is loose. The initial platelet plug is called a primary hemostatic plug/ primary platelet plug. > After the primary platelet plug has formed, the platelets start expressing platelet factors. These factors favor the coagulation process. On this plug, fibrin is deposited, forming a tight plug or secondary hemostatic plug/secondary platelet plug.

>Coagulation occurs via 2 pathways. The intrinsic and extrinsic pathways. The end is always the same coagulation. >Intrinsic pathway- pathway that leads to coagulation without addition of any external substance to the blood. Coagulation occurs under certain circumstances. >Extrinsic pathway- pathway that leads to coagulation with of thromboplastin or tissue factor. the addition

>When injury occurs, both pathways are activated. Intrinsic pathway is activated when blood comes in contact with activated platelets. Extrinsic pathway is activated by thromboplastin/TF, which is secreted from activated platelet cells and injured endothelial cells. Intrinsic Pathway > Exposed sub-endothelium/injured endothelial cells, or activated platelet sites activate the hangman factor/ contact factor/factor XII into factor XIIa. >Factor XIIa will activate factor XI. Factor XIIa -> factor IX. Factor IXa in the presence of phospholipids on the surfaces of platelets, calcium, and XIII, will activate factor X. Factor Xa IN THE PRESENCE OF PHOSPHOLIPIDS, CALCIUM AND FACTOR V. acts on PROTHROMBIN/ FACTOR II and converts it into THROMBIN.THROMBIN CONVERTS FIBRINOGEN (FACTOR I) INTO FIRBIN MONOMERS. FIBRIN MONOMERS ARE DEPOSITED ONTO PLATELET PLUGS. THROMBIN IS T HE MASTER!! :) > THROMBIN also activates TSF/ Thrombin stabilizing factor/ factor XIII. XIIIa induces cross linking of fibrin within and on the surface of the platelet plug. Extrinsic pathway >T.F. will convert VII into VIIa. VIIa can also activate PRESENCE OF CA++ AND PHOSPHOLIPIDS. >Extrinsic pathway is fast. Intrinsic pathway is slow. >SECONDARY PLATELET PLUG IS BIG AND WHEN PRESENT INSIDE THE CIRCULATION IT IS CALLED A THROMBUS. WHEN IT IS PRESENT OUTSIDE THE CARDIOVASCULAR SYSTEM, IT IS CALLED A CLOT. >HEMOSTASIS IS THE STOPPING OF BLODD AFTER INJURY. THIS OCCURS IN SEVERAL STEPS 1- VASOCONSTRICTION IX and X IN THE

2- PRIMARY PLATELET PLUG 3- SECONDARY PLATELET PLUG

> AN EMBOLUS IS A DISLODGED THROMBUS. > THROMBUS MAY EVENTUALLY UNDERGO EMBOLISATION, DISSOLUTION, ORGANIZATION, OR RECANALIZED. Platelet plug- aggregation of platelets. A clot is a platelet plug with cross-linked fibrin strands. A THROMBUS is clot that is fixed or attached to the wall of a blood vessel. An EMBOLUS is a traveling blood clot. Venous Thrombosis- slow blood flow environment. Tail of thrombus breaks free and travels in the vasculature until it lodges (embolus).embolus breaks off. Coagulation Cascade12-11 9-10 10-2 (thrombin) 2-1 (fibrinogen) Thromboembolic Drugs -Anticoagulants- drugs that prevent the conversion of fibrinogen into fibrin strands (by disrupting clotting cascade). -Heparin- IV SQ in units doesn't cross blood brain barrier. Short half life of 1.5 hours but increased in renal pts. - OD- give protamine sulfate. Immediate effect for 2 hours Tx uses: Prophylaxis of venous thrombosis, pulmonary embolism, evolving stroke, massive deep vein thrombosis (DVT), open heart surgery, pregnancy, acute MI

7AE: Hemorrhage: can be fatal, Blood loss, Thrombocytopenia Precautions: Monitor dose closely so that activated partial thromboplastin time does not exceed 2 times the control value Avoid antiplatelet drugs (aspirin, NSAIDs) Pts with hemophilia, inc capillary permeability, dissecting aneurysm, PUD, severe HTN, renal/hepatic dz.

7Contraindications: Thrombocytopenia, eye, brain, sinal cord surgery. Lumbar puncture, regional anesthesia. Laboratory Monitoring: aPTT- 40 seconds w/ hep= 60-80. Greater reduce, lesser-increase -LMW Heparin- 1st line of defense in DVT Enoxaparin (Lovenox), Dalteparin (Fragmin), Tinzaparin (Innohep) Advantage- can be given at home. Just as effective as natural hep but can be given at fixed dose, no need for aptt monitoring. (convenient) LMW hep: less likely to cause thrombocytopenia

7LMW hep preferentially inactivate factor Xa & less inactivation of thrombin than unfrac hep Tx uses:

Prevention of DVT, Tx of established DVT with or without P, Prevention of ischemic complications in pts with unstable angina or non-Q-wave MI AE: Bleeding, thrombocytopenia, neuro injury, (potential for harm is inc by antiplatelets (aspirin or ticlopidine) or warfarin 8 Anticoagulants II -Bivalirudin (angiomax), -lepirudin (Refludan), -argatroban (Acova) These drugs work by direct inh of thrombin which differ from heparin-like anticoag which inh the activity of antithrombin (indirect) Bivalirudin with aspirin is just as effective as heparin with aspirin 8 8 -Warfarin (Coumadin) Category X! Use -Not ER use. Long term due to slow DOA MOA: Antagonist of vitamin K which is needed for factors VII, IX, X & prothrombin. You need k to clot! AE: severe bleeding (fatal) [risk much higher with ticlopidine] Neutropenia, agranuloytosis, thrombotic thrombocytopenic pupurablood disorder that causes blood clots to form in small blood vessels around the body, and leads to a low platelet count. Small red/purple discoloration on the skin that do not blanch when pressure applied. 8 -GP IIb/IIIa RECEPTOR ANTAGONISTSaspirin or heparin. Expensive!! give IV in conjuction w/ hep in pregos prophylaxis

coronary

- Prophylaxis of Ischemic events in pt's w/ Acute Coronary Syndrome and those undergoing percutaneous intervention.

Tirofiban (Aggrastat), Eptifibatide (Integrilin), Abciximab (ReoPro) -Most effective antiplatelet drugs on the market

MOA: REVERSIBLE blockade of platelet GP IIb/IIIa rec which inh final step in aggregation by all factors collagen exposure, TXA2, ADP, thrombin & platelet activation factor

AE: Bleeding 9 -Thrombolytic Drugs- IV/Local(direct) - break down thrombi and are used for acute severe thrombotic conditions i.e. Acute Coronary Thrombosis, DVT, and Massive Pulmonary Emboli -MOA enzyme converts plasminogen into plasmin. Plasmin degrades fibrin clots and fibrinogen. -all tds are enzymes so they end in "ase" -Streptokinase (Streptase), -Alteplase (tPA)(Activase), -Tenecteplase (TNKase), -Reteplase, Urokinase Acute MI pts- treat withing 4-6hrs of sx onset for best results Half Life of 40-80 min due to rapid inactivation z AE- Bleeding hypotension, fever, antibody production