treatment of hemostasis disorders

7/23/2019 Treatment of Hemostasis Disorders

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Treatment of Hemostasis DisordersWeek 4 Luyendyk

Treatment of Hemostasis Disorders Platelet inhibitors

Anticoagulants

Thrombolytic drugs

Drugs for bleeding disorders

Formation of a Localized Clot at the Site of Vessel Injury

4 Steps:1. Vasoconstriction2. Primary emostasis!. "econdary emostasis4. Acti#ation of Antithrombotic $echanisms

Step !: Vasoconstriction

%ellular res&onse of the neighboring cells$ediated by reacti#e intermediates ' (ndothelin

Step ": #rimary HemostasisTransformation of platelets into ahemostatic plu$

1. Platelet adhesion2. Platelet granule release!. Platelet aggregation and consolidation

#latelet %dhesion:


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Platelet )ill bind to collagen* )hich is mediated by glyco&roteins+,P-a and ,P-b and Von Willebrand /actor.

#latelet &ranule 'eleasePlatelets get angry and release contents

ADP* serotonin* collagen* and thrombin )ill cause&latelets to release their granule contents.

Tar$ets for %ntiplatelet Dru$s:1. ADP +Pla#i02. %ycloo0ygenase 1 +as&irin

#latelet %$$re$ation and ConsolidationDuring this &rocess T0A2 and ADP are &otent mediators of &latelet aggregation

,P--b---a is a rece&tor on the &lateletsurface that can interaction )ithbrinogen and cause &latelet aggregation.Tar$et of %ntiplatelet Therapy

,P--b---a3 brinogen interaction is criticalfor &latelet aggregation.

'e(ie): Formation of a Localized Clot at the Site of VesselInjury

!* Vasoconstrictiona. eurogenic mechanismsb. (ndothelin

"* #rimary Hemostasisa. Platelet adhesion +,P-b* VW/* %ollagen

b. Platelet granule release reaction +T+%", %D# - tar$ets of antiplatelettherapy. platelet inhi/itors0

c. Platelet aggregation and consolidation 1II/2IIIa - tar$et of antiplatelettherapy. platelet inhi/itors0

Step 3: Secondary HemostasisActi#ation of the coagulation system and a brin clot formation,oal of the coagulation cascade is to form a stable brin clot at the site of #ascular in5ury

Steps:


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1. Tissue factor e0&ression2. Thrombin acti#ation!. /ibrin &olymeri6ation

'e$ulation of the lood Coa$ulationThis series of catalytic reactions am&lies the &rocess resulting in the generation of largeamounts of brin at the site of in5ury. -t is highly regulated by multi&le anticoagulationfactors. Also* ha#e to ha#e &lasmin to break do)n the clot so that )ound healing can

occur.

5+trinsic Coa$ulation 7e8uires tissue factor +tissue thrombo&lastin* factor ---

Tissue factor binds to factor V--a

Tissue factor is &hysically se&arated from blood com&onents

Intrinsic Coa$ulation All re8uired factors are &resent in the blood

7ecent studies suggest that this &ath)ay is &rimarily acti#ated by e0trinsic

&ath)ay

/actor V--a of the e0trinsic &ath)ay acti#ates /actor -9 of the intrinsic &ath)ay

Coa$ulation Cascade %cti(ation

-n the e#ent of damage* the tissuefactor is e0&osed to the blood andnds to /actor V--a to initiate thecoagulation cascade and &roduce aclot.

'e(ie): Secondary Hemostasis1. Tissue factor e0&ression2. Thrombin acti#ationTar$et of %nticoa$ulant Therapy!. /ibrin &olymeri6ation

Step 4: %cti(ation of %ntithrom/ic 6echanisms


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7 %nticoa$ulant and %ntiplatelet 6echanisms that limit the#ropa$ation of Hemostasis

!0 #rostacyclin"0 %ntithrom/in III! Protein % and "4 Tissue factor &ath)ay inhibitor70 Tissue type plasmino$en acti(ator

#rostacyclin 1#&I"0

P,-2 from the acti#ated endothelium can inhibit&latelet acti#ation.

%ntithrom/in IIIAntithrombin --- is a &rotein that binds to and inacti#ates se#eral &roteins in thecoagulation cascade.

o Thrombin

o -9a

o 9a

o 9-a

o 9--a

This reaction is cataly6ed by he&arin like molecules e0&ressed on the surface ofendothelial cells.

Heparin $i(en to patients pre(ents coa$ulation acti(ation /y this mechanism*

#lasminProduced from &lasminogen )hen &lasminogen is acti#ated by TPA +tissue &lasminogenacti#atorThrom/olytics acti(ate plasmino$enPlasmin degrades crosslinked brin &olymers into brin degradation &roducts

'e(ie) of %ll 4 Steps


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'is8 Factors forThrom/oem/olism

!* %/normalities in lood Flo)a. Atrial brillationb. Left #entricular dysfunction

c. -schemic:idio&athic myocardio&athyd. %ongesti#e heart failuree. ;ed rest: immobili6ation: &aralysisf. Venous obstruction from tumor:o/esityor &regnancy

"* %/normalities of Surface in Contact )ith lood(0&osure of tissue factor to the blood +not normally in contact )ith each other

a. Vascular trauma:in5uryb. eart #al#e diseasec. eart #al#e re&lacementd. Atherosclerosis

e. Acute $yocardial -nfarctionf. -nd)elling %atheters

3* %/normalities in Clottin$ Factorsa. (ndogenous anticoagulants

i. Protein % deciency +Vit 9 dependentii. Protein " deciency +Vit 9 dependentiii. Antithrombin --- deciency

b. Anti&hos&holi&id Antibody "yndromec. (strogen thera&yd. Pregnancye. $alignancy

%ntiplatelet Dru$s


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%spirin:inhibit %ects on &latelets are seen 12 days after administration and lasts

for the duration of the &latelets life s&an +?1@ days

Ticlopidine 1Ticlid0 %D# %nta$onist -nhibits ADP rece&tors on &latelets )hich &re#ents acti#ation of ,P--b---a.

o ,P--b---a &romotes &latelet aggregation

-nhibits &latelet adhesion and &latelet&latelet interactions

-ndicated as an alternati#e to as&irin to

&re#ent aninitial or recurrent thromboembolic

stroke

Also useful for myocardial reinfarctions

&ro&hyla0is Administered orally

7a&idly and )ell absorbed +B@C

(0tensi#ely metaboli6ed

7are cases of se(ere /one marro) to+icitylimits use to &atients )ho areintolerant or unres&onsi#e to as&irin.

-ncreases li#er function en6ymes


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Drug -nteractions3

o -ncreased bleeding occurs )hen gi#en )ith3

Warfarin

e&arin


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#hosphodiesterase Inhi/itors

Pre#ent degradation of cA$P by inhibit PD(

Dipyridamole 1#ersantin0 %oronary #asodilator that also inhibits &latelet aggregation.

-n combination )ith as&irin* reduces thrombosis in &atients )ith thromboticdisease

-n combination )ith )arfarin* inhibits embolism from &rosthetic heart #al#es 1mainuse0

Cilostazol 1#letal0 Antithrombotic* anti&latelet* and #asodilatory action

-nhibits PD( ty&e --- and thereby* increases cA$P le#els

=sed for intermittent claudicationand &eri&heral #ascular disease

%na$relide 1%$rylin0

7educes ele#ated &latelet counts in &atients )ith essential thrombocytosis +toomany platelets0

Ased if platelet num/er is too HI&H

-nhibits megakaryocyte de#elo&ment in the late &ostmitotic stage

Inhi/its the formation of platelets

A&&ro#ed for treatment of thrombocytosis secondary to myelo&roliferati#e

disorders* such as Polycythemia Vera and %$L to reduce the risk of stroke and $-.

&eneral 6echanisms of %nticoa$ulation


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1. Calcium Chelators: -nhibits blood coagulation in #itroa. ;+alic acid, sodium citrate, disodium edetate

2. Heparins:Accelerates action of Antithrombin --- to neutrali6e thrombin and othercoagulation factors

a. %ny dru$s that end in I@S

!. 'udins:Direct thrombin inhibitors4. Coumarin:-nterfere )ith he&atic synthesis of functional #itamin F de&endent

clotting factorsa* ?arfarin

Standard Heparin 1AFH0Source:Porcine intestinal mucosa and bo#ine lungStructure:sulfated muco&olysaccharide 1acidic molecule0'oute of %dministration:

o %ontinuous +infusion &um&

o -ntermittent +subcutaneous

o @ot oraldue to lack of absor&tion

o ot -$ due to risk of hematoma at in5ection site;nset of %ction:Immediate5ndothelial cell.protein /indin$:

o (0tensi#e3 sticky molecule

o %learance is dose de&endent because &lasma le#els of he&arin increase

considerably once binding sites are saturated +most drugs are doseinde&endent

o Dose Dependent #harmaco8ineticsTherapeutic &oal:

#rolon$ed #TT to !*72"*7 times normal6echanism of %ction

o Protease inhibitor* antithrom/in III* forms a 131 com&le0 )ith clotting factor

&roteaseso -nteraction is slo) but is stimulated !BBB foldby he&arin* )hich binds

antithrombin ---o This com&le0 inacti(ates factor IIa 1throm/in0 - main mechanism

o This com&le0 also inacti#ates factor 9a* )hich occurs earlier in cascade

Standard Heparin 1continued0Contraindications

o

;leeding disorders and disorders that &redis&ose to bleeding +hemo&hilia*thrombocyto&enia* hemorrhage* and se#eral other diseaseso Patients )ith ad#anced li#er or kidney disease* se#ere T* and certain

infections +acti#e T;* infectious endocarditiso Preferable to other anticoagulants during &regnancy due to lack of &lacental

transfer 1contrast to )arfarin0

%d(erse 5ects %ntidote: #rotamine Sulfate


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L6?H: Lo) 6olecular ?ei$htHeparins(no0aparin $W3 2@@@G@@@Dalteparin $W3 2@@@H@@@

Tin6aparin $W3 !@@@B@@@

#roperties of L6?Ho /irst a&&ro#ed for &rimary &re#ention of DVT after hi& re&lacement thera&y

o (#aluated and used for treatment of other thromboembolic diseases

o Ad#antages of =/3o Pharmacokinetics 1D;S5 I@D5#5@D5@T0

o "afety

o Also contraindicated in -T3 e&arin -nduced Thrombocyto&enia

o @ot readily re(ersed )ith protamine sulfateo $onitored by anti2


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o Venous thromboembolism &ro&hyla0is after ortho surgery

o Treatment of P(

o Treatment of DVT

o Treatment of coronary artery thromboembolism ' &romising but still under

study

Direct Throm/in Inhi/itors 1ru/ins0

D; @;T '5AI'5 %@TITH';6I@ IIIHirudin: the rudinEsGI amino acid &e&tideThis is a s&ecic thrombin inhibitor obtained from leeches

Lepirudin 17eJudan07ecombinant yeastderi#ed form of hirudin-t is a&&ro#ed for anticoagulation in &atients )ith he&arininduced thrombocyto&enia

1HIT0

Desirudin 1-&i#ask0 and i(alirudin 1Angioma00e) recombinant hirudin analogs that may be used instead of he&arins in the

future

%r$atro/an 1Aco#a02nd agent +1st is le&irudin a&&ro#ed for HIT=nlike le&irudin* it is cleared by li#er and can be used in &atients )ith end2sta$e

renal disease

?arfarin%oumarin deri#ati#e1@@C oral bioa#ailability#lasma #rotein indin$ is 5+tensi(e

o

Lo) (olume of distri/ution+albumin s&aceo Long halflife 13 hours

o Lack of urinary e0cretion of unchanged drug

6eta/olismo $etaboli6ed to inacti#e metabolites by cytochrome P4I@

+C=#"C> in li#ero Site of numerous dru$ interactions

6echanism of %ctiono -nhibitor of Vitamin 9 epo+ide reductase

o -m&airs li#ers ca&acity to &roduce reduced Vitamin F

(ssential cofactor in the &roduction of Vit F de&endent coagulationfactors %lotting factors 2*?*H*1@ are dead factors ' donKt )ork

'esistance:mutations in Vitamin F e&o0ide reductase confers heritable resistance to)arfarin

?arfarin 1continued0Speed of ;nset: SL;?

o Warfarin half like 1.I days +!G hours


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o B12 hours for initial anticoagulant e>ect* se#eral days to reach ma0imum

hy&o&rothrombinemia.o The delay re&resents time to re&lace normal clotting factors )ith

incom&letely gammacarbo0ylated factors and the time to reach steady statele#els of drug

%ntidote:o Discontinue drug

o Administer large doses of (itamin 9 and fresh frozen plasmaor factor -9

concentrates containing &rothrombin com&le0

Dru$ Dru$ Interactions )ith ?arfarinDru$s that diminish the response to oral anticoa$ulants:

Inhi/ition of oral )arfarin a/sorption%holestyramine +also aects (itamin 9 a/sorption

Induction of hepatic microsomal enzymes: 1Cytochrome Inducers0;arbituates%arbama6e&ine

Primidone7ifam&inSt* Gohns ?art

Stimualtion of clottin$ factor synthesisVitamin F ' diet and bacteria5stro$ens

Dru$s that enhance the response to oral anticoa$ulantsDisplacement from plasma al/umin:

"ulfonamides

Inhi/ition of anticoa$ulant meta/olism:AmiodaroneAllo&urinol%imeditine%i&roJo0acin(rythromycin%otrimo0a6ole$etronida6ole +selecti(e for S )arfarin/lucona6ole+selecti(e for S )arfarin

'eduction in a(aila/ility of Vitamin 9:;road s&ectrum antibiotics

Ases of ?arfarino e&arin and )arfarin are both used to treat both arterial and #enous thrombi

o e&arin is used for the rst ?1@ days* )ith a !I day o#erla& )ith )arfarin* )hich

may be continued for u& to G months.o Warfarin is also used to &re#ent blood clots in &atients )ith chronic atrial brillation

Therapeutic &oal )ith ?arfarin


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o #rolon$ the #T timeabo#e normal

o 1.21.I fold increase if tissue factor +thrombo&lastin is used

o 1.I@!.I if you use human tissue factor in -7

This can be achie#ed in about1 )eek but remember that the

onset is slo)*

Limitations of ?arfarin %d(erse eect:

"erious and &ossibly fatal bleeding occurs in brain* &ericardium* stomach and

intestine

#re$nancy:

Warfarin is contraindicated 1cate$ory


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Throm/olytic Dru$sLyse thrombi by cataly6ing the formation of serine&rotease +plasmin from its &recursor 6ymogen+plasmino$en0

Throm/olytic Dru$s end in aseJ 18inase orplase0

#lasmin de$rades cross lin8ed /rin

Thrombolytic thera&y is directed to)ards the con(ersion of plasmino$en to

plasmin* )hich degrades brin and lyses thrombi.

%irculating antiplasmins&reclude the &ossibility of using &lasmin itself forthrombolytic thera&y

Plasma does not contain inhibitors of uro8inase+human kidney &rotease or the

com&le0 formed bet)een &lasminogen and strepto8inase+stre&tococcal en6yme

These acti(ators con(ert plasmino$en to plasmin inside the throm/us*

)here &lasmin is &rotected from the inhibitory e>ects of circulating anti&lasminso %cti(ate local to /ypass the systemic antiplasmin

Preferential con#ersion of brinbound &lasminogen to &lasmin also occurs )ith

tissue plasmino$en acti(ator 1t2#%0

tPA is more eEcacious than stre&tokinase or anistre&lase for thrombolytic thera&y

in myocardial infarction* but it carries a higher risk of hemorrhagic stroke.

Strepto8inase onen6ymatic &rotein &roduced by grou& % betahemolytic stre&tococci

/acilitates thrombolysis through formation of acti#ator com&le0 )ith &lasminogen

results in formation of &lasmin Plasmin degrades brin* brinogen* and &rocoagulant factors V and V---

%spirin plus strepto8inase may /e as eecti(e as t2#%

Hypersensiti(ityto stre&tokinase may occur

Aro8inaseo Parenteral thrombolytic agent +from human cultured kidney cells

o -ndicated for lysis of &ulmonary emboli* lysis of coronary artery thrombi associated

)ith e#ol#ing transmural myocardial infarctiono y&ersensiti#ity reactions occur less fre8uently than )ith stre&tokinase


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'ecom/inant Throm/olytic %$ents%lteplase: biosynthetic recombinant form of human tissue &lasminogen acti#ator +tPA

%onsiderably more e0&ensi#e than stre&tokinase Alte&lase is not associated )ith hypersensiti(ity reactions

'eteplase

7ecombinant &lasminogen acti#ator Lon$er half2life than alteplase

Tenecteplase, T@92t2#% $odied human tPA %om&ared to Alte&lase* it has a &rolonged halflife* increased s&ecicity for

brin and increased resistance to &lasminogen acti#ator inhibitor1

Ases of Throm/olytic %$ents Thrombolytic drugs )ere only used for deeein thrombosis and serious

&ulmonary embolism Today they are used for the treatment of acute &eri&heral arterial thrombosis

+including myocardial infarction &atients )ho meet certain criteria and emboli*

and for unclogging catheters and shunts -n 1HHG* a&&ro#ed for treatment of acute ischemic stroke 7ule out intracranial bleeding 1CT scan0 "e&tember 2@@1* a&&ro#ed for the restoration of function to central #enous access

de#ices Throm/olytic therapy should /e follo)ed )ith anticoa$ulant therapy )ith

heparin 1rapid onset0 and then )arfarin 1orally eecti(e0 /or myocardial infarction* as&irin may be an ad5u#ant thera&y because of its anti

&latelet e>ect.

Contraindications to Throm/olytic Therapies "urgery )ithin 1@ days "erious ,.-. bleeding )ithin ! months istory of hy&ertension 1diastolic pressure K !!B mm H$0 Acti#e bleeding or hemorrhagic disorder Pre#ious cerebro#ascular accident or acti#e intracranial &rocess Aortic dissection Acute &ericarditis

L$W Lo) $olecular Weight e&arinand /onda&arinu0

ot )arfarin because it )ill take toolong.


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Dru$s Ased in leedin$ DisordersVitamin 9:

/at soluble #itamin from green leafy #egetables

Produced by bacteria coloni6ing human intestine3 needs bile salts for absor&tion

7e8uired for $amma car/o+ylation of $lutamine residesin &rothrombin and/actors V--* -9* and 9

Treats )arfarin e0cess and #itamin F deciency Pre#ents hemorrhagic disease of Vitamin F deciency in ne)borns

#lasma Fractions. Clottin$ FactorsDeciencies in plasma coa$ulation factors can cause /leedin$ 1hemophilia0

o %oncentrated &lasma fractions treat these deciencies

o Threat of %IDS and (iral hepatitisdiscourages use of &lasma fractions in

treatment of &atients )ith hemo&hilia

'ecom/inant factors are preferred:o Antihemo&hilic factor +A/* /actor V---3 commercially &re&ared to secrete

factor V---

Fi/rinolytic Inhi/itors:%minocaproic %cid treats:

o "ystemic or urinary hy&erbrinolysis +a&lastic anemia* abru&tion &lacentae*

he&atic cirrhosiso ;leeding associated )ith neo&lastic disease +carcinoma of &rostate* lung*

stomach* or cer#i0o ;leeding follo)ing cardiac surgery

Summary:9no) the pharmacolo$y and uses of:

!* #latelet inhi/itors "* %nticoa$ulants

Recognize that heparins require antithrombin III or their mechanism o action.

"* Dru$s for /leedin$ disorders


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7ecombinant /actor B to treat emo&hilia

3* Throm/olytic dru$s

treatment of hemostasis disorders

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