Anticoagulants

Definition An anticoagulant (an"tih-ko-AG'u-lant) is a drug that helps prevent the clotting (coagulation) of blood. These drugs tend to prevent new clots from forming or an e isting clot from enlarging. The! don't dissolve a blood clot. Anticoagulants are also given to certain people at risk for forming blood clots" such as those with artificial heart valves or who have atrial fibrillation (A'tre-al fib"rih-#A'shun). A common t!pe of stroke is caused b! a blood clot blocking blood flow to the brain. To prevent such clots" anticoagulants are often prescribed for people with conditions such as atrial fibrillation to prevent a first or recurrent stroke. $ompounds that do not allow blood to clot are called anticoagulants. These include drugs such as heparin and coumarin. %rugs that dissolve pre-formed clot including streptokinase are not referred to as anticoagulants. Anticoagulants are usuall! administered to patients with m!ocardial infarction" venous thrombosis" peripheral arterial emboli and pulmonar! emboli. The! have been used to prevent transient ischemic attacks and to reduce the risk of recurrent m!ocardial infarction. Process of clotting The circulator! s!stem has to be self-sealing" otherwise continued blood loss from even the smallest in&ur! would be life threatening. 'ormall!" all but the most catastrophic bleeding is rapidl! stopped" a process known as hemostasis. This process occurs through a progression of several steps. Hemostasis is a combination of events that occur due to ph!sical and chemical forces. The initial steps lead to a reduction in the blood flow due to the formation of a cellular plug. The later steps utili(e chemical energ! to form a blood clot" medicall! known as thrombus.

Handout Hematologi 1-6

The Physical Process

The aggregating platelets and the damaged tissue initiate the biochemical process of blood clotting or coagulation" the bod!'s ma&or defense against blood loss. Mechanism of clotting A blood clot forms as a result of concerted action of some )* different substances" most of which are plasma gl!coproteins (Table). Coagulation Factors Factor + ++ +++ +1 1 1++ 1+++ +5 5 5+ 5++ 5+++ Name ,ibrinogen 0rothrombin Tissue ,actor or thromboplastin $a22 0roaccelerin 0roconvertin Antihemophilic A factor Antihemophilic 6 factor or $hristmas factor 7tuart or 7tuart-0rower factor 0lasma thomboplastin antecedent 9ageman factor" contact factor ,ibrin stabili(ing factor 0rekallikrein factor 9igh-molecular-weight kininogen Plasma half-life (h) -) - ./ /* --34 4 3* )4 8* 84-/4 /* 34* -34/

Handout Hematologi 1-6

The phenomenon of blood coagulation is traditionall! distinguished into two pathwa!s. These pathwa!s are the intrinsic and the extrinsic pathwa!s (,igure below). The intrinsic pathwa! is defined as a cascade that utili(es onl! factors that are soluble in the plasma" whereas the e trinsic pathwa! consists of some factors that are insoluble in the plasma" e.g." membrane-bound factors (factor 1++). 9owever" the boundar! differentiating these two is becoming more and more blurred.

The characteristic feature of the coagulation pathwa! is that upon activation the individual gl!coprotein serves as a en(!me to convert the (!mogen form of the succeeding gl!coprotein to its protease form onl! in the presence of $a2) cations and on an appropriate phospholipid membrane. The activated forms of the gl!coproteins are identified b! s!mbol 'a'. 6oth the intrinsic and the e trinsic coagulation pathwa!s proceed through a common pathwa! b! forming activated factor 5. 0rothrombin is cleaved at two sites b! factor 5a to !ied thrombin (To see a structure of thrombin molecule click here). Ten -carbo !glutamic acid residues are located on the '-terminal end of the prothrombin molecule. 1itamin : is re;uired in the liver bios!nthesis of the prothrombin carbo !glutamic groups b! participating in the carbo !lation of the g-carbon of glutamic acid. These carbo ! groups are re;uired for binding calcium to prothrombin" which induce a conformation change in prothrombin enabling it to bindi to co-factors on the phospholipid surfaces during its conversion to thrombin b! factor 5a" factor 1" and platelet phospholipids in the presence of calcium. Thrombin" in turn" cleaves fibrinogen. ,ibrinogen comprises )-<= of plasma protein. Thrombin specificall! cleaves the Arg-5 (5 is mostl! Gl!) peptide bond in fibrinogen to form soluble fibrin monomers. These monomers spontaneousl! aggregate to form a pol!meric structure called "soft clot". This pol!mer is rapidl! converted to a more stable "hard clot" b! the covalent cross-linking of neighboring fibrin molecules in a reaction catal!(ed b! fibrin-stabili(ing factor (,7, or 5+++a).
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