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?


The effect of low-molecular-weight heparin therapy is poorly correlated with APTT, reflecting the reduced inhibition of activated factor II (thrombin) compared with the anti-activated factor X activity.14 In people, the drug activity of low-molecular-weight heparin is predictable enough that hospitalization and intensive monitoring to determine dosage is often unnecessary.2 In dogs and cats, studies in normal, healthy animals demonstrate shortened dosing intervals compared with people to achieve similar anti-activated factor X activity, and prospective controlled clinical trials in animals with naturally occurring diseases have not yet been reported.14,43,50 Low-molecular-weight heparins are renally excreted, so the drug kinetics will be altered in patients with renal disease. In those patients, carefully monitor anti-activated factor X assays to assess response to treatment, and tailor the dose or frequency as is appropriate for the degree of decline of renal function.49

If the thromboembolic event or the underlying disease process contributing to hypercoagulability has resolved, the clinician may elect to discontinue heparin therapy. Rebound hypercoagulability has been seen with discontinuation of heparin because of the reduction in antithrombin that occurs with heparin use. To avoid rebound hypercoagulability, heparin should be tapered over several days to a week rather than stopped abruptly.24 Concurrent anticoagulation via platelet function inhibition (e.g. aspirin) has been demonstrated to reduce the risk of rebound hypercoagulability in people.51

Heparin and platelet effects

Heparin-induced thrombocytopenia is a serious immune-mediated complication of heparin therapy in people that has not yet been reported in animals. This complication can occur after the administration of either unfractionated heparin or low-molecular-weight heparin, but it is less common with low-molecular-weight heparin.52,53 The serious nature of this problem is found in the paradoxical thrombocytosis to which it leads in people, resulting in severe thrombotic complications within days of initiating heparin therapy.53

In people experiencing heparin-induced thrombocytopenia, antibodies form to complexed heparin-platelet factor 4. These antibodies activate platelets to cause platelets to release prothrombotic microparticles. Platelets are consumed and thrombocytopenia ensues; however, the microparticles promote excessive thrombin generation, resulting in thrombosis. Circulating antigen-antibody complexes also interact with monocytes to increase production of tissue factor and to induce endothelial injury to further exacerbate thrombosis.53 No distinguishing clinical features exist to predict which individuals will develop this response.

In dogs, unfractionated heparin was administered at 1,000 IU/kg subcutaneously and did not have a clinically important effect on platelet count, aggregability, or capillary bleeding time.15


Heparin overdose can occur in spite of regular clinical monitoring. The clinical sign of excessive anticoagulation therapy is bleeding, so patients receiving heparin therapy should be monitored carefully for signs of hemorrhage. The effects of overdose can be countered to some degree by administering protamine sulfate. Protamine is a simple, low-molecular-weight, cationic protein that occurs naturally in fish sperm.34 Protamine is strongly basic, and heparin is strongly acidic; protamine complexes with heparin to form a stable, inactive salt. The recommended dose is 1 to 1.5 mg protamine for every 100 u unfractionated heparin, and it is administered by a slow intravenous infusion.34 Likewise, overdosage of low-molecular-weight heparin can be treated with protamine at 1 mg protamine for every 100 u dalteparin or 1 mg protamine for every 1 mg enoxaparin given (Table 2).31,34

Rapid intravenous injection of protamine can cause acute hypotension, bradycardia, pulmonary hypertension, and dyspnea, so the intravenous injection should occur over several minutes. Heparin-induced bleeding (heparin rebound effect) can sometimes recur several hours after heparin has been neutralized with protamine, either from release of heparin from the extravascular compartment or release from the heparin-protamine complex as the complex undergoes fibrinolysis. Protamine has a mild, transient anticoagulant activity at high doses.34


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