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?

Hypercoagulability refers to an increased risk of thrombus formation.1 In people, hypercoagulability can be either a congenital or an acquired condition. Congenital hypercoagulability occurs when certain anticoagulant factors such as protein C, protein S, or antithrombin are deficient or because of mutations such as factor V Leiden mutation or prothrombin gene mutation.2,3 Factors causing acquired hypercoagulability include obesity, prolonged recumbency or immobilization, cigarette smoking, contraceptive drugs, pregnancy, malignancy, air travel with prolonged periods of limited activity, tamoxifen therapy, and cardiovascular disease.2,3 Frequently, congenital hypercoagulability in an individual remains undiagnosed until an acquired cause of hypercoagulability occurs concurrently, precipitating a thrombotic event.

Clinical awareness of factors predisposing dogs and cats to hypercoagulable states is increasing. Many conditions have been associated with venous thromboembolic disease in dogs and cats4-7 and arterial thromboembolic disease in cats (Table 1).8-12

Table 1 Diseases or Factors Associated with Thromboembolic Events in Dogs and Cats

With our increased awareness of hypercoagulable states, novel anticoagulant strategies for veterinary use are receiving more attention.13-15 Heparin plays an important role in the prophylaxis of and therapy for venous thromboembolism in people. The traditional therapeutic heparin compound has been unfractionated heparin, but recently a class of heparins known as low-molecular-weight heparins has been developed and FDA-approved for use in people.16 Low-molecular-weight heparins offer therapeutic advantages over unfractionated heparin in people, including less frequent dosing, less intensive therapeutic monitoring of drug effect, and reduced risk of hemorrhage, heparin-induced thrombocytopenia, and paradoxical thrombosis.17 In addition, low-molecular-weight heparins can be administered more easily on an outpatient basis in people than unfractionated heparin can because of once-daily administration.2,17 However, limited information exists in the literature concerning the efficacy and potential therapeutic benefit of low-molecular-weight heparins for treating veterinary patients in the clinical setting.

The goal of this article is to review the physiology of hemostasis, the pathophysiology leading to hypercoagulability, and the mechanism of action, pharmacokinetics, laboratory monitoring, and clinical indications for use of unfractionated heparin and low-molecular-weight heparins.


Hemostasis is the process of forming a blood clot to seal an injured vessel and the subsequent removal of this clot when the injury is resolved. The clot prevents ongoing blood loss and also initiates blood vessel repair. Hemostasis can be separated into several phases, which include the formation of a platelet plug (primary hemostasis), stabilization of the platelet plug with cross-linked fibrin (secondary hemostasis), and destruction of the clot by fibrinolysis (tertiary hemostasis).18

Cascade hypothesis

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.

Figure 1

Revised hypothesis

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

Figures 2A & 2B

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


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.

Figure 3


Definitive diagnosis of hypercoagulability has been a challenge to both researchers and clinicians. Standard coagulation testing (prothrombin time, activated partial thromboplastin time [aptt], and thrombin time) assesses the presence and function of coagulation factors, but hypercoagulability does not correlate with shortened coagulation times.19

Antithrombin activity, protein C assay, and platelet aggregation studies

Antithrombin activity of 60% to 75% of the normal control value for the species is associated with hypercoagulability; however, animals with conditions that predispose them to hypercoagulability may have normal antithrombin activity, and antithrombin activity can be decreased secondary to thrombus formation even in the absence of hypercoagulability.24 Furthermore, antithrombin measurement is not widely available for routine and rapid clinical use.

Likewise, although protein C deficiency has been associated with hypercoagulability in people, a protein C assay is also not routinely available to veterinarians. Platelet aggregation studies are mainly helpful to monitor the effectiveness of antiplatelet therapy rather than to detect hypercoagulability. A variety of other tests used to detect hypercoagulable states in people (e.g. detection of lupus anticoagulant, genetic tests for enzyme defects) are simply not available for veterinarians.


One test that can help detect hypercoagulation is thromboelastography, which provides information about coagulation, from initiation to clot formation (including clot quality) and fibrinolysis.25

A thromboelastography tracing provides four primary values. The first two values, R and K, are measures of the time to clot generation.1 The R value is a measure of the precoagulation time and is thought to represent the intrinsic pathway. The K value is the clot formation time, and it is affected by factor II and VIII activities, platelet count and function, thrombin formation, fibrin precipitation, fibrinogen concentration, and hematocrit.1 The third value, which is the angle or alpha value, reflects the rate of clot formation and is affected by the same factors that influence K. The fourth value is the maximum amplitude, which reflects the clot's maximum strength. It is affected by fibrin and fibrinogen concentrations, platelet count and function, thrombin concentration, factor VIII activity, and hematocrit.1 These four values are used to calculate a coagulation index that indicates hypercoagulability or hypocoagulability.

The advantage of this technology is the global view of hemostasis that it provides, but this test is not practical for use with clinical patients outside of select academic environments. In people, thromboelastography can be performed intraoperatively to guide blood product and anticoagulant administration.25 In animals, thromboelastography is currently used primarily as a research tool because of the procedure's technical demands.5,26


When hypercoagulability is suspected or thromboembolism is diagnosed, heparin therapy is often indicated. Unfractionated and low-molecular-weight heparins achieve similar anticoagulant effects by enhancing antithrombin activity but differ in their ability to bind and inhibit thrombin. This difference causes variations in drug use and monitoring that are important in clinical patients.

Unfractionated heparin

Heparins, which are glycosaminoglycans, were first discovered in 1916.27 There is considerable heterogeneity of molecules, with a molecular weight range of 5,000 to 30,000; the average molecular weight of unfractionated heparin is 12,000 to 15,000.2 Anticoagulant activity is due to a unique pentasaccharide sequence with a high affinity for binding to antithrombin (Figure 4). This sequence occurs in about one-third of unfractionated heparin molecules. Distribution of the sequence in the molecule is random.

Figure 4

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.


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.

Lack of heparin absorption (either unfractionated or low-molecular-weight heparin) after oral ingestion necessitates intravenous or subcutaneous administration. Intramuscular injection can produce large hematomas, so it is avoided. In people, more bleeding occurs when unfractionated heparin is administered by repeated intravenous injection compared with a continuous intravenous infusion.17 But in general, the efficacy and safety of subcutaneous and intravenous heparin are comparable. However, if immediate anticoagulant activity is required and the subcutaneous route is selected, then an initial intravenous bolus should be administered because the anticoagulant effect of heparin is delayed by one to two hours after subcutaneous injection.17

Unfractionated heparin

Because unfractionated heparin is highly negatively charged, it binds to a number of plasma proteins as well as proteins secreted by platelets and endothelial cells. Some heparin-binding proteins are acute phase reactants and are increased in patients with thromboembolic disease.17 The variability of plasma concentrations of heparin-binding proteins in patients with thromboembolic disease causes the unpredictable anticoagulant response of unfractionated heparin and, occasionally, heparin resistance, necessitating increased dosing.17

Indications and contraindications. Little information exists in the literature regarding the clinical use of unfractionated heparin and outcomes when used in patients thought to be hypercoagulable. Cranial vena cava thrombosis in dogs has been treated with unfractionated heparin with generally poor outcomes.6 In one study, a group of dogs with immune-mediated hemolytic anemia was prospectively identified and treated with unfractionated heparin at 300 IU/kg four times a day to prevent thromboembolic events and subsequently monitored for anti-activated factor X activity. It was found that the unfractionated heparin dose used was generally inadequate to attain the target anti-activated factor X activity. Two of three dogs that died during the study had thrombi at necropsy. Additionally, no change was identified in survival at discharge or one month after discharge compared with a control group.29

In a retrospective study, dogs identified with immune-mediated hemolytic anemia were divided into two groups: dogs receiving heparin prophylaxis and those not receiving heparin prophylaxis. Dogs in the heparin-treated group were less likely to survive hospitalization than were those not receiving heparin.30 Since no statistically significant difference was found between the two treatment groups with regard to initial packed cell volume, total bilirubin concentration, or neutrophil count or toxicity, the authors proposed that the difference in survival between the two groups occurred because heparin treatment blocked the binding of endogenous heparan sulfate to antithrombin, thus the anti-inflammatory effects of this endogenous interaction were lost.30

Heparin therapy in cats is commonly initiated after arterial thromboembolism in an effort to stop additional thromboembolic events. Both unfractionated heparin and low-molecular-weight heparin have been recommended for therapy.31

Heparin is ineffective in the absence of adequate antithrombin concentrations, so heparin would not be expected to work as a prophylactic anticoagulant in animals with diseases associated with antithrombin deficiency (e.g. protein-losing nephropathy or enteropathy). Reports identify that administering unfractionated heparin results in the decline of antithrombin activity within 24 hours of administration.32,33 In a retrospective series of critically ill animals in an intensive care unit, antithrombin activity was normal (> 90%) in three of 24 dogs. A significant decrease in antithrombin activity from baseline occurred within 24 hours of heparin and plasma administration. Administering plasma alone failed to increase antithrombin activity in the dogs in this study.33 Unfractionated heparin administration also decreased antithrombin activity in a group of healthy research dogs with normal antithrombin activity at the outset of the study.32

Treatment and monitoring. Several unfractionated heparin dosing schedules exist for prophylaxis of thromboembolism in dogs and cats (Table 2).29,34 Unfractionated heparin is usually administered subcutaneously every six to eight hours.35 In people, treatment is monitored most commonly by APTT. In certain instances, APTT might not provide an accurate evaluation of anticoagulation status because of interfering substances in the patient's blood (e.g. plasma proteins or certain clotting factors) or laboratory variability (reagents and timing).36 Human clinical pathology laboratories can improve the predictability of APTT testing to evaluate heparin drug activity by correlating APTT values with plasma heparin concentrations by using in vitro or ex vivo testing; however, this correlation would have to occur with each new batch of testing supplies for APTT and is not practical in the veterinary setting.

Table 2 Commonly Reported Dosage Recommendations for Unfractionated Heparin and Low-Molecular-Weight Heparin Products and Protamine Sulfate

Studies have shown that dogs and cats, like people, have variable responses to unfractionated heparin and require individualized dosing regimens and monitoring to achieve a target drug concentration and avoid bleeding complications.37,38 In addition, APTT reagents are also variable when being used to evaluate canine samples, necessitating monitoring by the same laboratory using the same reagents over time to accurately evaluate therapeutic response.14,39-41 In dogs, the desired APTT target range is 1.5 to 2.5 times greater than the patient baseline.34 Heparin activity can also be assessed by evaluation of active factor X. In this test, heparin binds with antithrombin included in the reagent. Bovine active factor X is also included in the reagent, and the heparin-antithrombin complexes neutralize active factor X. The remaining active factor X is inversely proportional to the heparin content of the sample. The target range for heparin activity as measured by the active factor X assay (also referred to as the anti-activated factor X assay) is 0.3 to 0.6 U/ml for people.36 This assay is not widely available to practicing veterinarians but has been reported in research and academic practice settings. Anti-activated factor X assay is essential as a monitoring tool when low-molecular-weight heparins are administered to animals with renal insufficiency since the drug is renally cleared and renal disease alters reported kinetics.

Low-molecular-weight heparin

In people, low-molecular-weight heparins elicit a more predictable anticoagulant response than does unfractionated heparin because of better bioavailability, a longer half-life, and dose-independent clearance. The half-life of low-molecular-weight heparin is two to four times longer than that of unfractionated heparin. Low-molecular-weight heparins are less likely to bind plasma proteins than is unfractionated heparin, thus increasing bioavailability. Low-molecular-weight heparins are cleared primarily by renal elimination, and their biological half-life is increased in patients with renal disease.17 Administration of low-molecular-weight heparin results in less bleeding than does unfractionated heparin in people. In dogs, the half-life of dalteparin, one type of low-molecular-weight heparin, has been found to be shorter than in people.42 Cats demonstrate more rapid kinetics with low-molecular-weight heparin, necessitating dosing three to four times a day.43

Types and indications. Three different low-molecular-weight heparins have been approved in the United States for use in people: enoxaparin (Lovenox—Sanofi Aventis), dalteparin (Fragmin—Pfizer), and tinzaparin (Innohep—Pharmion).2 Of these, enoxaparin and dalteparin are commonly available and have been used in dogs and cats.31

Low-molecular-weight heparin has been found to not alter platelet aggregability in dogs.15 In a research model of deep vein thrombosis in dogs, the effects of enoxaparin and dalteparin in thrombus propagation were compared with those of unfractionated heparin. Doses were extrapolated from the human literature for all drugs. This study found that unfractionated heparin was more effective at limiting thrombus growth than either of the low-molecular-weight heparins.44 However, doses used were not based on pharmacokinetic data from dogs, and activated factor X activity was not monitored. In another study, a canine model of aortic thromboembolism was created, and the effects of enoxaparin vs. unfractionated heparin were compared with a control (saline) group. In this model, enoxaparin was found to prevent repetitive platelet-dependent thrombus formation better than unfractionated heparin.45 Regarding literature reports of veterinary clinical use of low-molecular-weight heparin, one case report exists in which low-molecular-weight heparin was administered concurrently with streptokinase in a dog with a thromboembolic event secondary to trauma in which the dog recovered.46

The anticoagulant effects of dosing of dalteparin and enoxaparin have been studied in cats.13,43,47 These studies measured the antithrombotic effect of these drugs by increased detection of inhibition of active factor X, which is a marker for heparin concentration. The studies showed that cats have a shorter duration of heparin activity than dogs or people do, necessitating dosing three to four times a day to achieve similar results. A single retrospective study reports the use of dalteparin in cats for a variety of clinical conditions associated with thromboembolism.48 The most common indication for treatment was evidence of cardiac disease predisposing cats to arterial thromboembolism. The dose averaged 98.8 U/kg, and the administration frequency was once or twice a day. Routine coagulation testing (prothrombin time, APTT) was at the discretion of the attending veterinarians and was infrequently performed. Activated factor X activity was not measured in these cats. Administration of medication was tolerated by the cats' owners. Eight cats of the 57 studied had apparent arterial thromboembolism while receiving dalteparin. The study cats were followed for variable lengths of time, and there was no control population to determine the effectiveness of therapy. Bleeding complications were infrequent; however, dalteparin's role in causing bleeding could not be determined from this report.48

Treatment and monitoring. In people, low-molecular-weight heparin is as effective as unfractionated heparin and can be used as a once-daily therapy. Treatment with low-molecular-weight heparin in people requires minimal or no therapeutic monitoring in most patient populations since the anticoagulant activity is highly correlated with dosage by body weight.17 Although low-molecular-weight heparins are considerably more expensive than unfractionated heparin, less frequent dosing, the ability to perform outpatient therapy, and a reduced need to rely on adjusting treatment with blood monitoring make using low-molecular-weight heparin economically practical in certain settings in people.17

Doses for low-molecular-weight heparin products have been extrapolated from human dosages and research in healthy animals (Table 2). The biggest difference between small animals and people is that the dosing interval for low-molecular-weight heparin is shortened in small animals. Therefore, the once-daily dosing regimens that make these drugs advantageous in people do not appear to exist for veterinary patients. When dalteparin was administered at 100 IU/kg subcutaneously in healthy dogs, the plasma half-life was two hours, and anti-activated factor X activity returned to baseline by 12 hours.49 When repeated doses of dalteparin were administered in dogs, a dose of 150 U/kg every eight hours produced anti-activated factor X assay results of 0.4 to 0.8 U/ml.42 In greyhounds, enoxaparin administered subcutaneously at 0.8 mg/kg every six hours appeared to effectively and consistently maintain therapeutic levels of anti-activated factor X activity.50 In healthy cats administered dalteparin at 180 IU/kg subcutaneously, anti-activated factor X activity peaked 95 minutes after subcutaneous administration. Enoxaparin was administered at a dosage of 1.25 mg/kg subcutaneously, and anti-activated factor X activity peaked 101 minutes after administration and returned toward baseline eight hours after administration.43

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


A variety of conditions in dogs and cats cause hypercoagulability and may benefit from prophylactic heparin therapy. Prospective, controlled clinical trials are needed to determine optimal treatment strategies. Although low-molecular-weight heparins are advantageous for treating hypercoagulability in people, the convenience of once-daily dosing for people appears to be lost in small animals. It is more expensive to treat with low-molecular-weight heparin compared with unfractionated heparin, and no evidence exists to support improved outcomes. Clinical research is ongoing to identify situations in which low-molecular-weight heparins are preferred for anticoagulant therapy in dogs and cats.

Bryan E. Harnett, DVM

Mission MedVet

5914 Johnson Drive

Mission, KS 66202


Department of Veterinary Medicine and Surgery

College of Veterinary Medicine

University of Missouri

379 East Campus Drive

Columbia, MO 65211


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