Heparin: Consider monitoring AT III with long-term therapy
A: Heparin has antithrombotic and anticoagulatory activity. Fractionating heparin and using the low molecular weight forms appear to have advantages over unfractionated heparin. Unfractionated heparin is a heterogeneous mixture of anionic sulfated mucopolysaccharides. The variability in molecular composition and biologic activity necessitates standardization of drug concentration by bioassay of anticoagulant activity (expressed as units). Low molecular weight heparins are produced by chemical or enzymatic depolymerization resulting in various products with the usual molecular weight being in the range of 4,000 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.
The reversible binding of heparin to antithrombin III (AT III) is responsible for most of the anticoagulatory and antithrombotic effect of heparin. Affinity for AT III is dependent upon molecular size, with larger molecules being more effective. Binding to AT III causes a conformational change in the AT III molecule that enhances its inhibitory effect on activated coagulation factors, especially thrombin and activated factor X.
The rate of inactivation can increase 2000-fold to 10,000-fold. After inactivation, heparin dissociates from the complex and is available for further interactions. In a pharmaceutical heparin preparation, 30-50 percent of 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). Although the heparin is free to interact again after inactivation of thrombin by AT III, AT III is consumed. Simultaneous binding of factor X to AT III and heparin is not required for inactivation.
The inactivation of thrombin by unfractionated heparin increases its anticoagulatory 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, heparin administration leads to an increase in the levels of tissue factor inhibitor. These effects all contribute to the anticoagulatory and antithrombotic action of heparin and vary with the individual heparin fractions. Low-molecular-weight fractions of heparin do not inactivate thrombin because they are not large enough to bind thrombin and AT III concurrently. They do inactivate factor X and also cause the release of tissue factor pathway inhibitor and tissue plasminogen activator.
Influencing platelet function
Low molecular weight heparins have the ability to influence platelet function. 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 mimic an area of atherosclerotic damage. As platelets adhere, blood flow slows till it resumes when the platelets are dislodged by pressure.
This occurs in a cyclic pattern. Drugs that inhibit platelet function will terminate cyclic blood flow. Heparin has only a limited effect on cyclic blood flow, if at all; however, low molecular weight heparins do have an effect in this regard. The antithrombotic effects of low molecular weight heparins are seen without appreciable anticoagulation effects as demonstrated by clotting assays.
Variety of effects
Heparin and heparin-like molecules have a variety of effects. Unfractionated heparin has significant effects in regard to immune function. Heparin administration reduces leukocyte-endothelial interaction as well as leukocyte migration.
By limiting the accumulation of inflammatory cells in tissue, inflammation is reduced. Leukocytes have a heparinase that is used to circumvent the endogenous GAG layer of the endothelium, heparin binds to endothelium thereby replacing this barrier.
Selectins (molecules expressed that are needed for leukocyte adhesion) are also affected. Some of the positive effects of heparin and low molecular weight heparins are derived from inhibition or blockade of P-selectin. Complement activation is also reduced by heparin and heparin-like molecules. Heparin and similar compounds protect against free radicals, which would also aid in reducing tissue damage. Heparin also reduces the production and release of endothelin-1, a powerful vasoconstrictor. An additional effect of heparin that does not seem to be related to hemostasis is the ability to liberate lipoprotein 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 from glomeruli. In addition, its anti-inflammatory properties help reduce further glomerular injury.
Kinetics in action
The pharmacokinetics and pharmacodynamics of heparin is complex. Most of an administered dose of heparin is bound extensively to endothelial cells, macrophages and plasma proteins, which act as storage pools. The heparin on the endothelium is then internalized by endocytosis.
Once storage pools are saturated, free heparin appears in the plasma and is excreted slowly by the kidney. Heparin is metabolized by the liver and by the reticuloendothelial system. These factors cause the kinetics of heparin to be highly variable between individuals and within individuals.
A fixed heparin dose cannot be expected to produce a uniform level of anticoagulation or antithrombotic effect. Because most of heparin effectiveness is dependent on AT III, low levels of AT III will result in reduced anticoagulant activity. Biologic half-life of heparin is variable and depends on the dosage administered and the route of administration.
Subcutaneous administration leads to slow release of heparin and has an 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 molecular weight 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 subcutaneous TID 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.
Traditionally, monitoring of heparin therapy has depended on detecting its anticoagulant effect. This can be done with ACT, thrombin time or APTT.
With the advent of low molecular weight heparin therapy, other assays have become necessary since the effects on these hemostatic assays are considerably reduced.
Generally, the anti-factor IIa or anti-factor Xa activity assay is used, although these tests only measures one activity effect of heparin. It has been shown that correlation between anti-factor Xa levels and standard clotting tests is poor, even when using unfractionated heparin.
As a result, anti-factor Xa assays would be the preferred way to monitor heparin therapy.
Heparin has a variety of uses in veterinary medicine. The predominant use of heparin in veterinary medicine has been in management of disseminated intravascular 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 heartworm adulticide treatment. Use in burn victims and animals with ulcerative colitis is helpful too. More novel use includes treatment of pemphigus vulgaris.
Administration guidelines for heparin dosage vary widely. Both high-dose and low-dose regimens have been developed, their applicability will depend on the clinical indication.
High-dose heparin therapy aims to increase APTT 1.5 to 2.5 times the baseline level or ACT 1.2 to 1.4 times the baseline level. Its primary clinical indication is the treatment of established thromboemboli.
The amount of heparin required to achieve this goal will vary with each individual and, because the pharmacokinetics are nonlinear, will vary with each dose administered. Heparin can be administered intravenously or subcutaneously. Intramuscular injections should be avoided as it can cause significant hematoma formation.
In dogs 150-250 U/kg three times daily and in cats 250-375 U/kg three times daily will usually suffice. A higher loading dose may be of benefit. Regular and frequent monitoring of clotting times is essential. Low-dose heparin regimens are generally 75 U/kg three times daily in small animals and 25-100 U/kg three times daily in horses. This regimen is thought to be especially useful in the management of DIC. The effect on APTT should be minimal with low-dose heparin therapy; yet antithrombotic efficacy should be maintained. Bleeding tendencies also are reduced.
Low-molecular weight heparins have been used in dogs as well, primarily in experimental models. There are considerable differences in the various products that are available so that global dosage recommendations are difficult to make.
Excessive anticoagulation leading to hemorrhage is the primarily adverse side effect from heparin administration. Intramuscular administration is contraindicated, as it may lead to extensive hematoma formation. Because AT III is consumed when thrombin is inactivated, AT III activity will decrease in animals treated with regular heparin as well as low molecular weight heparin. With prolonged therapy, monitoring of AT III should be considered as well.