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?


Cascade hypothesis

Figure 1
The cascade, or waterfall, hypothesis of coagulation was conceived in 1964 and separates secondary hemostasis into intrinsic, extrinsic, and common pathways (Figure 1).18 This hypothesis states that coagulation is initiated by the intrinsic pathway, which is triggered by components present in the blood, or by the extrinsic pathway in which subendothelial cell membrane protein (tissue factor) is required in addition to circulating components. According to this theory of coagulation, initiation by either the intrinsic or extrinsic pathway results in formation of activated factor X and the eventual progression to production of a fibrin clot via the common pathway.19,20 Activating the extrinsic pathway results in the formation of an activated factor VII-tissue factor complex to precipitate the formation of activated factor X, which can then feed back to amplify production of activated factor VII-tissue factor complex.

Revised hypothesis

Figures 2A & 2B
Current experimental evidence suggests a more central role for the activated factor VII-tissue factor complex (Figures 2A & 2B).21 This complex activates limited amounts of factors IX and X. While activated factor X precipitates the activation process to form thrombin, activated factor X also binds to tissue factor pathway inhibitor (TFPI), becomes inactivated, and participates in negative feedback inhibition of the activated factor VII-tissue factor complex (Figure 2A). To propagate the coagulation process, additional activated factor X production occurs through the action of activated factor IX in concert with its cofactor, activated factor VIII (Figure 2B). Thrombin-mediated production of factor XI could lead to the generation of activated factor IX to supplement that produced by the activated factor VII-tissue factor complex before its inactivation by TFPI.21

Coagulation inhibition

The coagulation cascade is inhibited by natural anticoagulants such as TFPI, the protein C and S system, and antithrombin, all of which help to limit clot formation at the site of injury.22 When TFPI is released into the circulation, it combines with activated factor X to inhibit the activated factor VII-tissue factor complex, thereby blocking the extrinsic coagulation pathway. Proteins C and S are vitamin K-dependent serine proteases that work together to inhibit the formation of thrombin through inactivation of activated factors V and VIII. Antithrombin is an alpha2-globulin that is thought to account for greater than 80% of the anticoagulant effect of plasma. It binds to and inactivates thrombin and other activated serine proteases, including activated factors VII, IX, X, XI, and XII as well as kallikrein.19,23


Figure 3
In addition to coagulation factors, blood flow and vascular endothelium are key components in hypercoagulability. The development of pathologic thrombosis can be related to Virchow's triad, which states that thrombus formation is related to one of three abnormalities: changes in the vessel wall, changes in the pattern of blood flow (flow volume), or changes in blood constituents (hypercoagulability) (Figure 3).24 In people, thromboembolic events are typically associated with more than one abnormality in Virchow's triad.


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