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Anticoagulants and Thrombolytic Agents

Anticoagulants and Thrombolytic Agents

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Published by: anaeshkl on Apr 07, 2012
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Coagulation cascade
After injury to a vessel wall, tissue factor is exposed onthe surface of the damaged endothelium.
The interaction of tissue factor with plasma factor VIIactivates the coagulation cascade, producing thrombin bystepwise activation of a series of proenzymes
The coagulation cascade is regulated by naturalanticoagulants, such as tissue factor pathway inhibitor TFPI, the protein C and protein S system, andantithrombin, all of which help to restrict the formationof the hemostatic plug to the site of injury.
Effects of thrombin
converts soluble fibrinogen to fibrin
activates factors V, VIII, and XI, which generates morethrombin
stimulates platelets
 by activating factor XIII, thrombin favours theformation of cross-linked bonds among the fibrinmolecules, stabilizing the clot
Activated platelets
An activated platelet exposes surfacereceptors for specific clotting factors,such as factor Va, and anionic phospholipids that function as bindingsites for factor Xa.
An analogous system exists for  binding factor IXa.
Endogenous inhibitors of coagulation
antithrombin III
from a family of serine proteaseinhibitors (serpins)
glycose aminoglycans (GAGs)
highly sulphated sugars bind toantithrombin by ionic interaction
associated with surfaces of endothelialcells and subendothelial structures
smaller heparin molecules inhibit Xamore effectively
tissue factor pathway inhibitor(TFPI)
inhibits Xa by forming a complex thatcan also inhibit VIIa bound to TF, butnot free VII
important for blocking the effect of TFwhere it is expressed on endothelialcells and subendothelial structures
proteins C and S
thrombin in conjunction withthrombomodulin, activates protein C
Protein C proteolytically cleaves VIIIaand Va (major cofactors that help produce Xa and IIa), with protein Sacting as cofactor 
in septic patients, activated protein C(available as a recombinant product)inhibit DIVC that occurs in smallvessels
 protein C may down-regulateinflammatory cytokines
thrombomodulin
a constituent of the endothelial cellmembrane, very small amounts are present in blood
 binds thrombin and begins thesequence of protein C activation
functions as cell-basedinhibition of coagulation
 probably facilitates thrombincatabolism
Anticoagulants and thrombolytic agents
 NC Hwang 2008
 
Thrombus formation at the site of damaged vesselsPlatelet factors
 platelet factor 1:coagulation factor V
 platelet factor 2:thromboplastic material
 platelet factor 3:platelet thromboplastin
 platelet factor 4:antiheparin factor 
 platelet factor 5:fibrinogen coagulation factor 
 platelet factor 6:antifibrinolytic factor 
 platelet factor 7:platelet cothromboplastin
Platelet membrane glycoproteins
GP Ia: receptor for subendothelium
GP Ib: receptor for von Willebrand
GP IIb: receptor for von Willebrand, fibrinogen
GP IIIa: receptor for von Willebrand, fibrinogen
Prothrombin time
monitoring of extrinsic coagulation pathway
normal range between 9 to 15 seconds
"normal" varies according to batch of thromboplastin intest reagent in different laboratories, hence the use of International Normalised Ratio (INR)
for a person on full anticoagulant therapy, the PT should be 2 to 3 times the laboratory "control" value (INR of 2-3)
 prolonged PT (more than 3 times control value)
 bile duct obstruction
cirrhosis
disseminated intravascular coagulation
hepatitis
malabsorption
warfarin therapy
> 10% deficiency in any of the following
Vitamin K, VII, X, II, V, I
Partial thromboplastin time
monitoring of intrinsic and common coagulation pathways
 partial thromboplastin time (PTT):30–45 s
activated partial thromboplastin time (APTT):25–39 s
value will vary between laboratories
 patients receiving anticoagulant therapy usually willhave value within 1.5 to 2.5 times control values
not valid for patients on low molecular weight heparintherapy (anti Xa heparin assay)
 prolonged PTT may indicate
cirrhosis
disseminated intravascular coagulation (DIC)
factor XII deficiency
hemophilia A (factor VIII deficiency)
hemophilia B (factor IX deficiency)
hypofibrinogenemia
malabsorption (inadequate absorption of nutrients from the intestinal tract)
von Willebrand's disease
lupus anticoagulant
decreased aPTT can occur due to:
digitalis
tetracyclines
antihistamines
nicotine
elevated factor VIII
tissue inflammation or trauma
Fibrinolytic system
Anticoagulants and thrombolytic agents
 NC Hwang 2008
 
DRUGS USED IN COAGULATION DISORDERSANTICOAGULANTSHeparin
a heterogeneous group
a member of the heparan sulphate family of complexsugars classified under glycosaminoglycans
glycosaminoglycans or mucopolysaccharidesare polymers of repeating disaccharides
within the disaccharides, the sugarstend to be modified, with acidicgroups, amino groups, sulfatedhydroxyl and amino groups
tend to be negatively charged, becauseof the prevalence of acidic groups
heparan sulphate family of complex sugars iscomposed of long chains of alternatingdisaccharide units of uronic acid (glucuronicand iduronic acid) and glucosamine residues
the backbone structure is thendecorated by with complex patterns of sulphate and carboxyl groups at various positions, giving rise to a very stronglynegative charged molecule.
strongly acidic because of its content of covalentlylinked sulfate and carboxylic acid groups (heparinsodium)
has an extended helical conformation due tocharge repulsion by the many negativelycharged groups
naturally occurring in the secretory granules of mastcells
has no anticoagulation effect by itself 
 biologic activity is dependent upon the plasma proteaseinhibitor, anti-thrombin III (AT III) (heparin cofactor)
a specific pentasaccharide sequence containing a 3-O-sulphated glucosamine residue forms a high-affinity binding site for AT III
AT III is one of the many naturally occurringinhibitors in coagulation but its action is slow
small amounts of heparin (with AT III) inhibitthrombosis by inactivating activated Factor X(Xa) and inhibiting the conversion of  prothrombin to thrombin (II to IIa)
tight binding of heparin molecule to AT IIIcauses a conformational change in this inhibitor,which exposes the active binding site of antithrombin III for more rapid interaction withthe proteases (activated clotting factors) toinhibit the enzymes
in the absence of heparin, formation of heparin-antithrombin-protease complexes is slow, in the presenceof heparin, they are accelerated 1000-fold
heparin catalyses the antithrombin-protease reactionwithout being consumed
once the antithrombin-protease complex isformed, heparin is released intact for renewed binding to more AT III
heparin-antithrombin III complex inactivates
serine esterases
factors XIIa, XIa, Xa, IXa, IIa
 plasmin
kallilrein
only unbound Xa is sensitive to heparin activity
Xa bound to platelets in the prothrombinasecomplex is protected from the heparin action
once active thrombosis has developed, larger amounts of heparin inhibit further coagulation by inactivatingthrombin (IIa) and preventing the conversion of fibrinogen to fibrin (I to Ia)
decreased platelet aggregation
reduction of platelet membrane receptors for von Willebrand factor and fibrinogen (Ia)
inhibition of VIIIa, Va
facilitating the release of tissue plasminogenactivator (tPA), resulting in an increase in plasmin and D-dimer concentrations, both of which interfere with platelet aggregation
increased platelet aggregation
 binding of antiplatelet IgG antibodies to platelet-bound heparin, activates platelets andinduces platelet clumping (heparin-inducedthrombocytopaenia, HIT)
inhibition of VIIa-TF complex
 by releasing TFPI from endothelial cells, renalcells, carcinoma cells and lipoprotein fraction of  plasma
TFPI also inhibits Xa on TF bearing cell
releases lipoprotein lipase from capillary endothelialsurfaces
the enzyme hydrolyzes triacylglycerols inchylomicrons, very-low-density lipoproteins,low-density lipoproteins, and diacylglycerols
inhibits growth of capillary endothelial cells but potentiates the activity of acid fibroblasts growth factorson these cells
Anticoagulants and thrombolytic agents
 NC Hwang 2008

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