Unfractionated and low-molecular-weight heparin for hypercoagulability in dogs and cats - Veterinary Medicine
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Unfractionated and low-molecular-weight heparin for hypercoagulability in dogs and cats
A new type of heparin, low-molecular-weight heparin, shows promise as an effective and easier-to-use form of therapy for people prone to thromboembolism. Does the same hold true for dogs and cats?


VETERINARY MEDICINE


Once unfractionated heparin binds with antithrombin, a conformational change takes place in antithrombin that accelerates its activity 1,000- to 4,000-fold.3 The principal anticoagulant effects of activated antithrombin are inactivation of activated factors X and IX. Because of the length of the molecule beyond the pentasaccharide sequence, the unfractionated heparin molecule also binds antithrombin and thrombin (activated factor II) together to form a ternary complex that inactivates thrombin (Figure 4). The anticoagulant mechanism of inactivation of activated factor X occurs only through unfractionated heparin binding to antithrombin and not through the formation of the ternary complex.16

The principal therapeutic limitations of unfractionated heparin arise from the heterogeneity of molecule sizes, which alters both anticoagulant activity and pharmacokinetic properties. Only one-third of unfractionated heparin has antithrombin-mediated anticoagulant activity. Larger unfractionated heparin molecules are cleared more quickly, resulting in an excess of lower-molecular-weight molecules. This disparity causes a nonlinear relationship between APTT and heparin activity. In addition, unfractionated heparin must be administered by subcutaneous injection three or four times a day, has a narrow therapeutic index, and may not have a predictable response in all individuals.2,14

Low-molecular-weight heparins

Low-molecular-weight heparins, first discovered in 1979, are glycosaminoglycans composed of chains of alternating residues of D-glucosamine and uronic acid.2 These products are manufactured from fragments of unfractionated heparin by a controlled enzymatic or chemical depolymerization process to form more uniform heparin chains with average molecular weights of 5,000. Similar to unfractionated heparin, the principal anticoagulant effect of low-molecular-weight heparin is due to a unique pentasaccharide sequence with a high affinity for antithrombin (Figure 4). This sequence is present in about 15% to 25% of low-molecular-weight heparin molecules.28

As with unfractionated heparin, once the pentasaccharide sequence of low-molecular-weight heparin binds with antithrombin, the function of antithrombin is catalyzed, increasing the activity of antithrombin 1,000- to 4,000-fold. But in contrast to unfractionated heparin, the relatively small size of low-molecular-weight heparin allows binding to antithrombin only, thereby avoiding concurrent binding of thrombin and the production of ternary complexes.2 Therefore, low-molecular-weight heparin causes a greater inhibition of activated factor X than does thrombin (Figure 4), while unfractionated heparin has equivalent inhibition of activated factor X and thrombin.2

Even though APTT evaluates both the intrinsic and common pathways, and factor X is a part of the common pathway, lack of thrombin (factor II) binding and subsequent formation of ternary complexes by low-molecular-weight heparin results in less of an impact on the common pathway than is seen with unfractionated heparin and explains the lack of an increase in APTT in patients treated with low-molecular-weight heparin. Because the molecules are of a similar size, they are cleared at a similar rate, resulting in a more predictable anticoagulant effect.

CLINICAL INDICATIONS AND PROTOCOLS FOR HEPARIN THERAPY

In people, prophylaxis of thrombosis is indicated for a number of conditions associated with hypercoagulability, such as pregnancy with risk of thrombosis, certain soft tissue and orthopedic surgeries, joint replacement procedures, acute spinal cord injury, multiple trauma, and ischemic stroke.2 Anticoagulant therapy is administered after established deep vein thrombosis, unstable angina, and ischemic stroke to prevent additional thromboses.2

In veterinary patients, thromboprophylaxis should be considered when conditions associated with hypercoagulability are diagnosed (Table 1). The decision to initiate thromboprophylaxis should be tempered by clinical evidence. For example, although hyperadrenocorticism is a risk factor for thromboembolic disease in dogs, if the patient is newly diagnosed, has minimal clinical signs, and is undergoing definitive treatment, the clinician may elect to delay heparin therapy. If the patient is more severely affected by the underlying disease or has multiple risk factors (e.g. hyperadrenocorticism and septicemia from a concurrent infection), the clinician would more strongly consider prophylaxis.


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Source: VETERINARY MEDICINE,
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