Heparin: Consider monitoring AT III with long-term therapy

Q:

Please provide a brief review on the clinical usefulness of heparin products in dogs and cats.

A: Heparin has antithrombotic and anticoagulatory activity. Fractionatingheparin and using the low molecular weight forms appear to have advantagesover unfractionated heparin. Unfractionated heparin is a heterogeneous mixtureof anionic sulfated mucopolysaccharides. The variability in molecular compositionand biologic activity necessitates standardization of drug concentrationby bioassay of anticoagulant activity (expressed as units). Low molecularweight heparins are produced by chemical or enzymatic depolymerization resultingin various products with the usual molecular weight being in the range of4,000 to 8,000 daltons.

The following articles describe heparin and its use in clinical practice- Carr AP: Heparin: an update. Proc 20th Annual Forum ACVIM 20:574-576,2002.

Physiologic effects

The reversible binding of heparin to antithrombin III (AT III) is responsiblefor most of the anticoagulatory and antithrombotic effect of heparin. Affinityfor AT III is dependent upon molecular size, with larger molecules beingmore effective. Binding to AT III causes a conformational change in theAT III molecule that enhances its inhibitory effect on activated coagulationfactors, especially thrombin and activated factor X.

The rate of inactivation can increase 2000-fold to 10,000-fold. Afterinactivation, heparin dissociates from the complex and is available forfurther interactions. In a pharmaceutical heparin preparation, 30-50 percentof the heparin molecules bind to AT III. For thrombin to be inactivated,it must be bound to AT III via heparin (acting almost as a template). Althoughthe heparin is free to interact again after inactivation of thrombin byAT III, AT III is consumed. Simultaneous binding of factor X to AT III andheparin is not required for inactivation.

The inactivation of thrombin by unfractionated heparin increases itsanticoagulatory ability and also the bleeding tendency seen. At higher dosages,heparin can also bind to heparin cofactor II, which only inhibits thrombin.

Heparin also binds to endothelial cell walls, imparting a negative charge,which makes it more resistant to platelet attachment. In addition, heparinadministration leads to an increase in the levels of tissue factor inhibitor.These effects all contribute to the anticoagulatory and antithrombotic actionof heparin and vary with the individual heparin fractions. Low-molecular-weightfractions of heparin do not inactivate thrombin because they are not largeenough to bind thrombin and AT III concurrently. They do inactivate factorX and also cause the release of tissue factor pathway inhibitor and tissueplasminogen activator.

Influencing platelet function

Low molecular weight heparins have the ability to influence plateletfunction. A classic in-vivo model of platelet function is cyclic blood flow.

In this model, an artery is damaged by crushing and then banded to mimican area of atherosclerotic damage. As platelets adhere, blood flow slowstill it resumes when the platelets are dislodged by pressure.

This occurs in a cyclic pattern. Drugs that inhibit platelet functionwill terminate cyclic blood flow. Heparin has only a limited effect on cyclicblood flow, if at all; however, low molecular weight heparins do have aneffect in this regard. The antithrombotic effects of low molecular weightheparins are seen without appreciable anticoagulation effects as demonstratedby clotting assays.

Variety of effects

Heparin and heparin-like molecules have a variety of effects. Unfractionatedheparin has significant effects in regard to immune function. Heparin administrationreduces leukocyte-endothelial interaction as well as leukocyte migration.

By limiting the accumulation of inflammatory cells in tissue, inflammationis reduced. Leukocytes have a heparinase that is used to circumvent theendogenous GAG layer of the endothelium, heparin binds to endothelium therebyreplacing this barrier.

Selectins (molecules expressed that are needed for leukocyte adhesion)are also affected. Some of the positive effects of heparin and low molecularweight heparins are derived from inhibition or blockade of P-selectin. Complementactivation is also reduced by heparin and heparin-like molecules. Heparinand similar compounds protect against free radicals, which would also aidin reducing tissue damage. Heparin also reduces the production and releaseof endothelin-1, a powerful vasoconstrictor. An additional effect of heparinthat does not seem to be related to hemostasis is the ability to liberatelipoprotein lipase, which lowers serum triglyceride levels.

Beneficial effects of heparin on glomerular disease have been observed.Heparin appears to be able to facilitate removal of antigen deposits fromglomeruli. In addition, its anti-inflammatory properties help reduce furtherglomerular injury.

Kinetics in action

The pharmacokinetics and pharmacodynamics of heparin is complex. Mostof an administered dose of heparin is bound extensively to endothelial cells,macrophages and plasma proteins, which act as storage pools. The heparinon the endothelium is then internalized by endocytosis.

Once storage pools are saturated, free heparin appears in the plasmaand is excreted slowly by the kidney. Heparin is metabolized by the liverand by the reticuloendothelial system. These factors cause the kineticsof heparin to be highly variable between individuals and within individuals.

A fixed heparin dose cannot be expected to produce a uniform level ofanticoagulation or antithrombotic effect. Because most of heparin effectivenessis dependent on AT III, low levels of AT III will result in reduced anticoagulantactivity. Biologic half-life of heparin is variable and depends on the dosageadministered and the route of administration.

Subcutaneous administration leads to slow release of heparin and hasan effect equivalent to intravenous heparin for the prophylaxis of thrombosis.Intravenous administration causes high initial levels with a short half-life.Low molecular weight heparins are cleared more slowly than higher molecularweight fractions and, therefore, they can be administered less frequently.Bleeding tendency is also reduced with these compounds.

Studies in dogs with low molecular weight heparins indicate that subcutaneousTID dosing is necessary to achieve stable plasma levels. There are, however,considerable differences in the various low molecular weight heparin products- each product being used needs to be investigated.

Monitoring

Traditionally, monitoring of heparin therapy has depended on detectingits anticoagulant effect. This can be done with ACT, thrombin time or APTT.

With the advent of low molecular weight heparin therapy, other assayshave become necessary since the effects on these hemostatic assays are considerablyreduced.

Generally, the anti-factor IIa or anti-factor Xa activity assay is used,although these tests only measures one activity effect of heparin. It hasbeen shown that correlation between anti-factor Xa levels and standard clottingtests is poor, even when using unfractionated heparin.

As a result, anti-factor Xa assays would be the preferred way to monitorheparin therapy.

Clinical use

Heparin has a variety of uses in veterinary medicine. The predominantuse of heparin in veterinary medicine has been in management of disseminatedintravascular coagulation (DIC) and other potentially hypercoagulable states,such as associated with hyperadrenocorticism, nephrotic syndrome and cardiomyopathy.Low-dose heparin may decrease the complications associated with heartwormadulticide treatment. Use in burn victims and animals with ulcerative colitisis helpful too. More novel use includes treatment of pemphigus vulgaris.

Administration guidelines for heparin dosage vary widely. Both high-doseand low-dose regimens have been developed, their applicability will dependon the clinical indication.

High-dose heparin therapy aims to increase APTT 1.5 to 2.5 times thebaseline level or ACT 1.2 to 1.4 times the baseline level. Its primary clinicalindication is the treatment of established thromboemboli.

The amount of heparin required to achieve this goal will vary with eachindividual and, because the pharmacokinetics are nonlinear, will vary witheach dose administered. Heparin can be administered intravenously or subcutaneously.Intramuscular injections should be avoided as it can cause significant hematomaformation.

In dogs 150-250 U/kg three times daily and in cats 250-375 U/kg threetimes daily will usually suffice. A higher loading dose may be of benefit.Regular and frequent monitoring of clotting times is essential. Low-doseheparin regimens are generally 75 U/kg three times daily in small animalsand 25-100 U/kg three times daily in horses. This regimen is thought tobe especially useful in the management of DIC. The effect on APTT shouldbe minimal with low-dose heparin therapy; yet antithrombotic efficacy shouldbe maintained. Bleeding tendencies also are reduced.

Low-molecular weight heparins have been used in dogs as well, primarilyin experimental models. There are considerable differences in the variousproducts that are available so that global dosage recommendations are difficultto make.

Adverse effects

Excessive anticoagulation leading to hemorrhage is the primarily adverseside effect from heparin administration. Intramuscular administration iscontraindicated, as it may lead to extensive hematoma formation. BecauseAT III is consumed when thrombin is inactivated, AT III activity will decreasein animals treated with regular heparin as well as low molecular weightheparin. With prolonged therapy, monitoring of AT III should be consideredas well.