TEG has been studied in various clinical settings, mostly in dogs. Although recently validated for use in horses and cats, clinical studies have yet to be published outlining the clinical utility of TEG in these species. However, published abstracts suggest that the clinical use of TEG is being focused on critically ill foals and horses with colic.49–51 There are sporadic reports of evaluation of coagulation in cattle, pigs, sheep, guinea pigs, rats, and various species of fish using TEG,52–59 but, to date there are no widely accepted guidelines to direct appropriate clinical use or interpretation of TEG tracings in these species.
VT is a serious and life-threatening complication of many underlying disease processes, including neoplasia, immune-mediated hemolytic anemia (IMHA), sepsis, heartworm disease, hyperadrenocorticism, and others; associated risk factors for the development of VT in animals are well described.60–62 Routine hemostatic assays have poor sensitivity for the detection of hypercoagulability,5,26,29,63,64 and TEG has been evaluated for its capacity to provide early, sensitive detection of hypercoagulability.26,29,50,51,63–68 Discrepancies among studies, including variability of TEG methodology and the occasional absence of concurrent hematologic data, including platelet count, fibrinogen concentration, and hematocrit, limit our ability to fully interpret and compare TEG results among studies. Interpretation is further hindered by the absence of long-term prospective studies that confirm a positive correlation between TEG tracings that indicate hypercoagulability and true risk of thrombosis in the animal. To date, hypercoagulability, as evidenced by alterations in the TEG components G and MA, has been demonstrated in dogs with parvoviral enteritis, neoplasia, DIC, and IMHA and in dogs admitted to ICU.26,29,63–65
In an early case–controlled study, 9 puppies with naturally occurring parvoviral enteritis were compared with 9 age-matched control dogs.63 Hypercoagulability was detected in all of the puppies with parvoviral entiritis, as evidenced by an increased MA using recalcified citrated blood. These puppies also had significantly increased fibrinogen concentrations compared with control puppies. Four of the dogs with parvoviral enteritis developed clinical evidence of catheter-associated VT or phlebitis.63
Underlying malignancy is considered a risk factor for thrombosis in animals and people.60–62,69–73 The proposed mechanisms of thrombus formation are not fully characterized but may include altered plasma- or cell-based procoagulant or fibrinolytic activity, increased production of cytokines, including tumor necrosis factor, interleukin-1β, and vascular endothelial growth factor, by tumor cells,72 aberrant TF expression, procoagulant factor production by neoplastic cells, and antiphospholipid antibody production.72,74 In one study using rhTF-Haemoscope TEG, 67% of dogs with malignant neoplasia had hemostatic dysfunction, defined as an altered G value. Of these dogs, 75% were hypercoagulable and 25% were hypocoagulable.64 Dogs with malignant neoplasia were significantly more likely to be hypercoagulable compared with dogs that had benign neoplasms, although 31% of the dogs with benign neoplasms were also hypercoagulable.64 Hypercoagulability was not attributable to fibrinogen concentration as there was no significant difference in the fibrinogen concentrations of dogs with malignant compared with those with benign neoplasia. No information was provided on the overall correlation between fibrinogen concentration and G/MA or the number of dogs with TEG tracings indicative of hypercoagulability that developed VT. These findings are consistent with a similar study in which people with malignant neoplasms had increased G/MA values.27
TEG tracings that indicated hypercoagulable, normocoagulable, and hypocoagulable states were also found in dogs with DIC. In 50 dogs diagnosed with DIC based on a wide battery of hemostatic assays, tracings obtained using rhTF-TEG indicated that 22% were hypocoagulable, 34% were normocoagulable, and 44% were hypercoagulable.29 Interestingly, hypocoagulable dogs had a 2.4 times greater relative risk of death within 28 days than hypercoagulable dogs. The G value was concluded to best reflect the hemostatic status of dogs with DIC, and a TEG tracing indicating hypercoagulability was considered a favorable prognostic indicator.29 In a similar study in human patients with severe sepsis with or without overt DIC, the ROTEM MCF value (equivalent to the MA value) in patients with severe sepsis did not differ significantly from the value in the healthy control group; however, patients with overt DIC had significantly decreased MCF, indicative of hypocoagulability.37
Hypercoagulability was also a common hemostatic abnormality in dogs admitted to an ICU with a variety of underlying disorders and in dogs with IMHA.26,65 Eleven of 27 dogs in the ICU were classified as hypercoagulable by rhTF-TEG with supportive evidence that included decreased antithrombin activity and increased D-dimer concentration.26 The majority of dogs with IMHA had TEG tracings, obtained using recalcified citrated blood, indicating hypercoagulability with only 6 of 39 dogs classified as normocoagulable.65 One potential confounding factor in the dogs with IMHA was that all dogs in the study were pretreated with corticosteroids, which are suspected to induce a hypercoagulable state75 and alter TEG variables.68 The investigators claimed that, in this specific clinical setting, a TEG tracing indicating normocoagulability was a poor prognostic marker.65
Evidence in human clinical settings supports the hypothesis that a hypercoagulable state indicated by a TEG tracing is predictive of thromboembolic events, especially postoperatively.18,76–78 Nonetheless, the data are not consistent. In a recent review paper, the predictive accuracy of TEG results for postoperative thromboembolic events was judged to be “highly variable,” and the authors recommended further prospective studies.76 Certainly in veterinary medicine, prospective studies are warranted to better characterize the effects of fibrinogen concentration, platelet concentration, and red cell mass on TEG tracings and to determine the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of TEG tracings that indicate hypercoagulability in predicting thromboembolic events in various clinical settings.
Accurate detection of hypocoagulability with resultant increased risk of hemorrhage could guide transfusion and hemostatic therapy during and after surgery or other invasive procedures, such as liver biopsy. Coagulation assays such as PT and aPTT, fibrinogen concentration, and platelet concentration are commonly used in both veterinary and human medicine to assess the risk of bleeding as a result of a diagnostic or surgical procedure. However, a poor correlation was found in people between prolonged PT and hemorrhage after invasive procedures,4 leading to the conclusion that there was insufficient evidence to support the use of transfusion before procedures based on results of plasma-based hemostatic tests.4 Similarly, in veterinary medicine, 2 retrospective studies have demonstrated variable correlation between coagulation test results and bleeding after fine-needle aspiration and tissue-core biopsy.79,80 Given the poor capacity of these assays to predict bleeding, the use of TEG to accurately detect hypocoagulability and predict bleeding events has been evaluated.
TEG may be superior to plasma-based assays in its capacity to correctly predict hemorrhagic episodes in dogs.23,81,82 In a prospective study that compared the hemostatic phenotype in 27 dogs in hypocoagulable states, 27 in normocoagulable states, and 27 in hypercoagulable states based on results from rhTF-TEG, it was found that G value alone had a positive and a negative predictive value for bleeding of 89% and 98%, respectively. Moreover, G value more accurately predicted bleeding than the combination of platelet concentration, PT and aPTT results, D-dimer concentration, and fibrinogen concentration.23 TEG results may also predict bleeding in dogs with severe factor VIII deficiency (hemophilia A).81 In one study, bleeding was induced in anesthetized dogs with severe factor VIII deficiency and bleeding time was documented. The Haemoscope TEG component G, obtained using recalcified citrated blood, was superior to aPTT in predicting bleeding in vivo.81 TEG tracings showed incremental improvement associated with a dose-dependent response to therapy, whereas standard plasma-based assays failed to do so.81 TEG tracings may also be useful in monitoring hemostatic patterns and developing exercise regimens in dogs with severe hemophilia A; however, in this study, correlation of TEG results with hemostatic phenotype or bleeding tendency was not attempted.82 Finally, a tracing indicating hypocoagulability, obtained by rhTF-TEG, was associated with a poorer prognosis and increased mortality risk in dogs admitted to ICU with a clinical suspicion of DIC.29 These findings are supported by a new study in which a hypocoagulable state, based on kaolin-activated Haemoscope TEG tracings, in people admitted to ICU was an independent risk factor for death within 30 days.83
Monitoring anticoagulant therapy
Low-molecular-weight heparin (LMWH) is increasingly being used in veterinary medicine for treatment of thromboembolic diseases and as thrombophylaxis in animal patients at increased risk for thrombosis.84–88 Anti-factor Xa activity is considered to be the “gold standard” for monitoring the effect of heparin on coagulability; however, this assay is expensive and not readily available. TEG has been assessed for its efficacy in monitoring heparin therapy in animal and human patients.85,87–89 In recent prospective studies, healthy dogs21 and cats19 were given therapeutic doses of different heparins, including LMWH, subcutaneously. Only treatment with unfractionated heparin reached therapeutic levels as evidenced by anti-Xa activity and marked prolongation of Haemoscope TEG R time (recalcified method) with no clot formation up to 12 hours after a single subcutaneous administration. The in vitro effects of LMWH have also been tested on citrated canine blood.87 TEG tracings showed dose-dependent prolongation of R and K times and decreased clot strength using rhTF-TEG and heparinase-coated cups, whereas TEG tracings using kaolin-activated TEG and heparinase-coated cups were unremarkable, except for a prolonged R time.87 Similar results have been found in a recent study that explored the use of native Haemoscope TEG and heparinase-coated cups for monitoring LMWH for thrombophylaxis therapy in people with increased risk for deep vein thrombosis (DVT).89 The authors suggested that concurrent measurement of Haemoscope TEG using plain and heparinase-coated cups may detect anticoagulated patients at increased risk of developing DVT; however, sensitivity, specificity, positive predictive value, and negative predictive value were not calculated.89 To date, it appears that TEG may have some clinical utility for the monitoring heparin therapy in animals; however, expected TEG results will depend on the choice of activator, the choice of plain or heparinase-coated cups, and the dose and type of heparin used.
Congenital and acquired disorders of platelet dysfunction are well characterized and relatively common in animals and have been reviewed.90–92 Acquired platelet dysfunction can occur secondary to uremia, infection with various agents, such as Ehrlichia canis and FeLV, snake envenomation, neoplasia, liver disease, and drug administration, especially nonsteroidal antiinflammatory drugs (NSAID).92–98 The use of specific platelet inhibitor drugs, such as clopidogrel (platelet ADP chemoreceptor [P2Y12] inhibitor), and glycoprotein (GP) IIb/IIIa inhibitors may predispose animals to bleeding. As such, there is interest in platelet function assays that are readily accessible, reliable, and cost-effective for monitoring antiplatelet therapy or diagnosing congenital or acquired platelet disorders.99,100
Platelets have multiple physiologic activators and are a major contributor to the TEG G/MA value. Thrombin is a major and powerful platelet activator, and its presence masks the detection of platelet dysfunction that results from alteration of pathways of weaker activators, such as ADP or collagen.101 Sporadic studies have shown that TEG tracings did not differ between normal dogs and dogs with either a specific platelet dysfunction, such as Scott syndrome, or dogs that were treated with NSAID.102,103 Haemoscope TEG PlateletMapping is a modified TEG assay specifically designed to asses platelet function.101 The concept behind PlateletMapping is to eliminate the potent effect of thrombin on blood platelets during clot formation. Blood is drawn into heparin and further activated with reptilase and factor XIIIa to allow a small, polymerized fibrin clot to form in the absence of thrombin. The clot serves as a scaffold for platelet activation. Two other TEG cups are used and platelet agonists, ADP and arachadonic acids, are added to induce platelet activation. A fourth heparinase-coated TEG cup and kaolin activation are also used. Equations are derived to assess the percent MA aggregation response to an agonist. Haemoscope TEG PlateletMapping showed good correlation with optic platelet aggregometry in detecting platelet dysfunction after in vitro inhibition by antagonists of various platelet receptors, such as GP IIb/IIIa, P2Y12, and thromboxane A2 receptor.101 Preliminary data suggest that Haemoscope TEG PlateletMapping may be used to assess platelet inhibition in dogs that are treated with clopidogrel.104 The primary uses to date for TEG PlateletMapping include monitoring platelet inhibition therapy and diagnosing naturally occurring thrombocytopathies; however, this novel technique may also be able to identify platelet hyperreactivity.105 Recently, PlateletMapping was also validated for use in ROTEM analyzers.106