34 | Drugs Used in Disorders of Coagulation Hemostasis -finely regulated dynamic process of maintaining fluidity of the blood -repairing vascular injury and limiting blood loss while avoiding vessel occlusion (thrombosis (thrombosis)) and inadequate perfusion of vital organs Thrombosis (or excessive bleeding) -represents a breakdown of the hemostatic mechanism Common causes of Dysregulated Hemostasis 1. ereditary or acquired defects in the clotting mechanism !. "econdary effects of infection or cancer
MECHANISMS OF BLOOD COAULA!ION COAULA!ION Vascular endothelial cell layer -lines the blood vessels -has an anticoagulant phenotype -circulate blood platelets and clotting factors do not normally adhere to it Case: Vascular injury -the -the endothelial cell layer undergoes a series of changes resulting in a more procoagulant phenotype -exposes# $ollagen and Willebrand factor %reactive subendothelial matrix proteins -effects# &latelet adherence and activation "ecretion and synthesis of vasoconstrictors &latelet-recruiting 'ctivating-molecules Thromboxane A 2 (TXA 2 -synthesied from# arachidonic acid within within platelets -a platelet activator and potent vasoconstrictor
-platelet function defects von +illebrand disease -patie -patients nts typica typically lly bleed bleed from from surfac surfacee sites sites (with (with injury injury)# )# gingival skin heavy menses Defects in #econdary Hemostasis -patients with defects in the clotting mechanism -hemophilia ' -patie -patients nts tend tend to bleed bleed into into deep deep tissue tissuess (joint (joints s muscle muscle retroperitoneum) often with no apparent inciting event and bleeding may recur unpredictably. unpredictably. "latelet -center to normal hemostasis and thromboembolic disease 'hite thrombi &s )ed thrombi 'hite thrombi - platelet-rich platelet-rich thrombi -form in the high flow rate and high shear force environment of arteries -occlusive arterial thrombi cause serious disease by producing downstream ischemia of extremeties or vital organs and can result in limb amputation or organ failure )ed thrombi (venous clots recognied pathologically) recognied pathologically) -fibrin-rich -contain large numbers of trapped red blood cells -can cause severe swelling and pain of the affected extremity -most feared consequence# pulmonary consequence# pulmonary embolism *pulmonary embolism -occurs when part or all of the clot breaks off from its location in the deep venous system and travels as an embolus through the right side of the heart and into the pulmonary arterial articulation -sudden occlusion of a large pulmonary artery can cause# acute right heart failure and sudden death -in addition lung ischemia and infarction will infarction will occur distal to the occluded pulmonary arterial segment -such emboli usually arise from the deep venous system of the proximal lower extremeties or pelvis
Adenosine di!hos!hate di!hos!hate (AD" -a powerful inducer of platelet aggregation
"latelet nidus &s *ibrin tail
#erotonin ($%HT -stimulates aggregation and vasoconstriction
"latelet nidus -dominates the arterial thrombus
Acti&ation of !latelet -results in the aggregation and formation of a platelet plug -simultaneously the coagulation system cascade is activated* resul resultiting ng in# thromb thrombin in generat generation ion and a fibrin fibrin clot clot whic whichh stabilies the platelet plug
*ibrin tail -dominates the venous thrombus
Defects in !rimary hemostasis -patients with defects in the formation of the primary platelet plug
BLOOD COAULA!ION CASCADE Bloo Bloodd coag coagul ulat ates es due due to the the tran transf sfor orma matition on of solu solubl blee fibrinogen into fibrinogen into insoluble fibrin by the enzyme thrombin Thrombin
-has a central role in hemostasis -in clotting thrombin proteolytically cleaves small peptides from fibrinogen allowing fibrinogen to polymerie and form a fibrin clot -also activates many upstream clotting factors leading to more thrombin generation and activates factor XIII (a transaminase that cross-links the fibrin polymer and stabilies the clot -a potent platelet activator and mitogen -also exerts anticoagulant effects by activating the protein C pathway (this attenuates the clotting response) Response to ascular in!ury ensures that under normal circumstances" repair of ascular in!ury occurs without thrombosis and downstream ischemia -that is# the response is proportionate and reersible
Initiation of Clotting" !#e !issue Fa$tor%&IIa Co'(le) + (T*%factor V,,a !ath-ay -the tissue factor that is the main initiator of blood coagulation -is a transmembrane protein uniquitously expressed outside the vasculature but not normally expressed in an active form within vessels 2 *actor Xa and *actor Va -forms the prothrombinase complex on activated cell surfaces which catalyes the conversion of prothrombin $factor II) to thrombin $factor IIa) . Thrombin -in turn activates upstream clotting factors primarily factors , , and resulting in amplification of thrombin generation / The T*%factor V,,a%cataly0ed acti&ation of factor Xa -is regulated by tissue factor pathway inhibitor (/0&) $ %hus" after initial actiation of factor X to Xa by %&-'IIa" a further propagation of the clot is by feedbac( amplification of thrombin through the intrinsic pathway factors V,, and ,X -this provides an explanation of why patients with deficiency of factr , or ----hemophilia ' and haemophilia respectively----have a severe bleeding disorder 23/4# %he coagulation mechanism in io does not occur in solution" but is localized to actiated cell surfaces epressing anionic phospholipids such as phosphatidylserine" and is mediated by Calcium bridging between two anionic phospholipids and gamma-carboyglutamic acid residues of the clotting factors -this is the basis for using calcium chelators to preent blood from clottin in a test tube" such as# %ethylenediamine tetraacetic acid (45/') or citrate Abtithrombin (AT -is an endogenous anticoagulant and a member of the serine protease inhibitor (serpin) family
-it inactivates the serine proteases# IIa" IXa" Xa" Xia" and XIIa "rotein C and !rotein # -endogenous coagulants that attenuate the blood clotting cascade by proteolysis of the two cofactors 'a and 'IIIa efects in natural anticoagulants result in an increased ris( of enous thrombosis 1utation in factor V (factor V eiden -most common defect in the natural anticoagulant system -results in resistance to inactivation by the protein $ protein " mechanism
Fi*rinol+sis *ibrinolysis -the process of fibrin digestion by the fibrin-specific protease plasmin /he fibrinolytic system is similar to the coagulation system in that the precursor form of the serine protease plasmin circulates in an inactive form as plasminogen t%"A (tissue !lasminogen acti&ator -released by endothelial cells in an injury -converts plasminogen to plasmin "lasmin -remodels the thrombus and limits its extension by proteolytic digestion of fibrin "lasminogen and !lasmin -both have specialied protein domains (kringles) that bind to exposed lysines on the fibrin clot and impart clot specificity to the fibrinolytic process (only observed at physiologic leels of t&') -at the pharmacologic leels of t-&' used in thrombolytic therapy clot specificity is lost and a systemic lytic state is created with attendant increase in bleeding risk 3egati&e )egulators of *ibrinolysis -endothelial cells synthesie and release plasminogen actiator inhibitor $+,I)# inhibits t-&' - . antiplasmin# circulates in blood at high concentrations and under physiologic conditions will rapidly inactivate any plasmin that is not clot-bound* however this regulatory system is overwhelmed by therapeutic doses of plas minogen activators Disseminated intra&ascular coagulation (D,C -generalied intravascular clotting and bleeding -happens when the hemostatic system careens out of control if the coagulation and fibrinolytic systemsare pathologically activated
-may follow massive tissue injury advanced cancers obstetric emergencies such as abruption placentae or retained products of conception or bacterial sepsis Tissue !lasminogen acti&ator4 stre!to5inase -all activate the fibrinolytic system
uro5inase4
and
Decreased fibrinolysis -protects clots from lysis and reduces the bleeding of hemostatic failure Aminoca!roic acid -is a clinically useful inhibitor of fibrinolysis He!arin and the oral anticoagulant drugs -do not affect the fibrinolytic mechanism
BASIC ,HA-MACOLO. OF !HE AN!ICOAULAN! D-US %he ideal anticoagulant drug would preent pathologic thrombosis and limit reperfusion in!ury" yet allow a normal response to ascular in!ury and limit bleeding
%in t#e a*sen$e of #e(arin0 t#ese rea$tions are slo1 %in t#e (resen$e of #e(arin0 t#e+ are a$$elerated 2%fold Acti&e he!arin molecules bind tightly to antithrombin and cause a conformational change -exposes its active site for more rapid interaction with the proteases (the activated clotting factors) He!arin -functions as a cofactor for the antithrombin-protease reaction without being consumed /nce the antithrombin-protease comple is formed" heparin is released intact for renewed binding to more antithrombin H1' (High%molecular -eight -aka# 70 -fractions of heparin with high affinity for antithrombin markedly inhibit blood coagulation by inhibiting all three factors especially thrombin and factor a
,ndirect thrombin inhibitors -so-named because their anti-thrombic effect is exerted by their interaction with a separate protein antithrombin
1' (o-%molecular -eight -shorter-chain -fractions of heparin inhibit activated factor but have less effect on thrombin than the 8+ species -in comparison with 70 have equal efficacy increased bioavalability from the subcutaneous site of inhection and lessfrequent dosing requirements (once or twice daily is sufficient) -such as# eno)a(arin0 dalte(arin0 and tina(arin %are effective in several thromboembolic conditions
6nfractioned he!arin (6*H4 o-%molecular%-eight he!arin (1'H4 and fonda!arinux $synthetic pentasaccharide) -bind to antithrombin and enhance its inactivation of factor Xa
Dalte!arin4 tin0a!arin4 and dana!aroid -an 98+ heparanoid containing heparin sulfate dermatan sulfate and chondroitin sulfate -specified in anti-factor a units
6nfractioned he!arin (6*H and to a lesser etent" o-% molecular%-eight he!arin (1'H -also enhance antithrombin6s inactivation of thrombin
Monitoring of He(arin Effe$t
,ll anticoagulants and fibrinolytic drugs hae an increased bleeding ris( a their principle toicity
Indire$t !#ro'*in In#i*itors
a"TT or "TT (acti&ated !artial thrombo!lastin time -close monitoring of this is necessary in patients receiving 70
HE,A-IN C#e'istr+ / MOA He!arin -a heterogeneous mixture of sulphated mucopolysaccharides -binds to endothelial cell surfaces and a variety of plasma proteins -its biologic activity is dependent upon the endogenous anticoagulant antithrombin Antithrombin -inhibits clotting factor proteases especially thrombin (a) a and a by forming equimolar stable complexes with them
"rotamine titration or anti%Xa units -determines the levels of 70 Anti%Xa units -determines 9+ heparin levels
!o)i$it+ A5 Bleeding and Mis$ellaneous Effe$ts 7leeding -major adverse effect of heparin -risk can be decrease by# % scrupulous patient selection %careful control of dosage
%close monitoring 8lderly -omen and !atients -ith renal failure -more prone to hemorrhage He!arin -of animal origin -accelerates the clearing of postprandial lipemia by causing the release of lipoprotein lipase from tissues 1iscellaneous effects: -increased loss of hair -reversible alopecia -long-term heparin therapy is associated with osteoporosis and spontaneous fractures -long-term use of heparin is associated with mineralocorticoid deficiency
B5 He(arin%Indu$ed !#ro'*o$+to(enia H,T (He!arin%induced thrombocyto!enia -is a systemic hypercoagulable state that occurs in 1:; of individuals treated with 70 for a minimum of < days 9reatest ris5s -"urgical patients -ndividuals treated with 70 of bovine origin compared with porcine heparin o- ris5s -pediatric population -pregnant women (relatively rare) -individuals treated exclusively with 98+ "oints considered in all !atients recei&ing he!arin -platelet counts should be performed frequently -thrombocytopenia appearing in a time frame consistent with an immune response to heparin should be considered suspicious for / -any new thrombus occurring in a patient receiveing heparin therapy should raise suspicion of / +atients who deelop 0I% are treated by discontinuance of heparin and administration of a direct thrombin inhibitor
-significant thrombocytopenia -purpurea -severe hypertension -intracranial hemorrhage -infective endocarditis -active tuberculosis -ulcerative lesions of the = tract -threatened abortion -visceral carcinoma -advanced hepatic or renal disease He!arin should be a&oided in !atients: -who have recently had surgery of the brain spinal cord or eye and in patients who are undergoing lumbar puncture or regional anesthetic block -should only be used in pregnant women only when clearly indicated
Ad'inistration / Dosage The follo-ing strategy is recommended: -prior to initiating anticoagulant therapy of any type the integrity of the patient6s hemostatic system should be assessed by a careful history of prior bleeding events and baseline &/ and &//. -if there is a prolonged clotting time the cause of this (deficiency or inhibitor) should be determined prior to initiating therapy and treatment goals stratified to a risk-benefit assessment 12 Continuous I' administration .2 3ow dose prophylais ia subcutaneous administration *because of danger of hematoma formation at the in!ection site" heparin 456% 78'8R be administered I7%R,456C53,R39 *onda!arinux -synthetic pentasaccharide molecule -avidly binds antithrombin with high specific activity resulting in efficient activation of factor a -effective in the prevention and treatment of venous thromboembolism -appears to not cross-react with pathologic / antibodies in most individuals -it is currently being tested in clinical trials to serve as an alternative anticoagulant in /
Contraindi$ations
)i&aroxaban -orally active anticoagulant that do not require monitoring -first oral factor a inhibitor to reach phase clinical trials
Contraindications -ith !atients: -/ -hypersensitivity to the drug -active bleeding -hemophilia
-e6ersal of He(arin A$tion -4xcessive anticoagulant action of heparin is treated by discontinuance of the drug -if bleeding occurs administration of# "rotamine sulfate is indicated
"rotamine sulfate - protamine is a highly basic positively charged peptide that combines with negatively charged heparin as an ion pair to form a stable complex devoid of anticoagulant activity 23/4# 8cess protamine 456% B8 ,'/I8: it also has an anticoagulant effect2 7eutralization of 34W heparin by protamine is incomplete
O-AL DI-EC! FAC!O- 7A INHIBI!O-S )i&aroxaban and A!ixaban -oral a inhibitors in the final common pathway of clotting -these drugs are given as fixed doses and do not require monitoring -they have a rapid onset of action and shorter half-lives than warfarin )i&aroxaban -approved for prevention of venous thromboembolism following hip or knee surgery A!ixaban -currently
in
clinical
development
7i&alirudin -another bivalent inhibitor of thrombin -is administered intraenously with a rapid onset and offset of action -also inhibits platelet activation and has been 05'-approved for use in percutaneous coronary angioplasty Argatroban -small molecule thrombin inhibitor that is 05'-approved for use in patients with / with or without thrombosis abd coronary angioplasty in patients with / -has a short-life and is given by continuous intraenous infusion and is monitored by a&// -its clearance is not affected by renal disease but is dependent on liver function -dose reduction is required in patients with liver disease -patients on argatroban will demonstrate elevated 2>s
O-AL DI-EC! !H-OMBIN INHIBI!O-S Ad&antages of oral direct thrombin inhibitors - fixed dosing and predictable anticoagulant response -make routine coagulation monitoring unnecessary -do not interact with &:?@-interacting drugs -allow for immediate anticoagulation
DI-EC! !H-OMBIN INHIBI!O-S Direct thrombin inhibitors (DT,s -exert their anticoagulant effect by directly binding to the active site of thrombin thereby inhibiting thrombin6s downstream effect Hirudin and bi&alirudin -are bivalent 5/s in that they bind at both the catalytic or active site of thrombin as well as at a substrate recognition site
Da&igatran etexilate mesylate -first oral direct thrombin inhibitor approved by the 05' -reduce risk of stroke and systemic embolism with nonvalvular atrial fibrillation -for prevention of venous thromboembolism in patients who have undergone hip or knee replacement surgery -superior to warfarin with an 2> target of !-A in preventing stroke ad systemic emboliation
,#ar'a$olog+ Argatroban and melegatran -are small molecules that bind only at the thrombin active site
Dabigatran and its metabolites -are direct thrombin inhibitors
,A-EN!E-AL DI-EC! !H-OMBIN INHIBI!O-S Hirudin -a specific irreversible thrombin inhibitor from leech saliva that is now available in recombinant form as le!irudin e!irudin -its action is independent of antithrombin which means it can reach and inactivate firbrin-bound thrombin in thrombi -has little effect on platelets or the bleeding time -like heparin it must be administered parenterally and is monitored by the a&// -approved by the 05' for use in patients with thrombosis related to heparin-induced thrombocytopenia -excreted by the kidney and should be used with great caution in patients with renal insufficiency as no anditote eists
&ollowing oral administration" dabigatran eteilate mesylate is conerted to dabigatran 23/4# $oncomitant use of etocona0ole4 Amiodarone4 ;uinidine4 and Clo!idogrel increases the effect of dabigatran )enal im!airment -results in prolonged drug clearance and may require dose adjustment -the drug should be avoided in patients with severe renal impairment
Ad'inistration / Dosage
-for preention of stro(e and systemic embolism in nonalular atrial fibrillation" 1;min" the dose is ?; mg bid -7/ 4/7I%/RI7@ I6 R8A5IR8
!o)i$it+ -bleeding -there is no antidote for dabigatran 8A-FA-IN / O!HE- COUMA-IN AN!ICOAULAN!S C#e'istr+ / ,#ar'a$o9ineti$s 'arfarin -generally administered as the sodium salt and has 1@@; bioavailability -used clinically is a racemic mixture composed f equal amounts of two enantiomorphs e&orotatory #%-arfarin is four times more potent than the dextrorotatory )%-arfarin
MOA Coumarin anticoagulants -block the gamma-carboxylation of several glutamate residues in prothrombin and factors , and as well as the endogenous anticoagulant proteins $ and " -the blockade results in incomplete coagulation factor molecules that are biologically inactive 'arfarin -there is an B- to 1!-hour delay in the action of warfarin -its anticoagulant effect results from a balance between partially inhibited synthesis and unaltered degradation of the four vitamin C-dependent clotting factors -the resulting inhibition of coagulation is dependent on their degradation half-lives in the circulation -larger initial dosesof warfarin hasten the onset of the anticoagulant effect -beyond this dosage the speed of onset is independent of the dose sie -the only difference among anticoagulant in producing and maintaining hypoprothrombinemia is the half-life of each drug
