Thromboelastography was first described more than half a century ago by Hellmut Hartert. Today there are two modern technologies that have adopted the same Hartert’s principle: thromboelastography (TEG) and thromboelastometry (ROTEM) with several advantages compared to routine clotting tests. They are easy to use as a point-of-care (POC) assay in the perioperative and emergency settings. As a global coagulation tests they provide a continuous assessment of the formation of the clot and fibrinolysis by measuring the viscoelastic properties of whole blood under the effect of a constant rotation force. Both instruments consist of a cup, in which a pin connected to a torsion wire is suspended. The movement of the torsion wire is in turn monitored. The tests generate a graphic representing the initiation, the propagation and the stabilization of the clot as well as the lysis of the clot itself. Because the viscoelastic tests are performed on whole blood, they integrate the role of cellular and non-cellular elements in the formation of the clot: platelets, red blood cells, leukocytes and enzymatic coagulation factors. The low shear rate in these instruments is comparable to that of venous circulation.
Recording repeatedly dynamic changes of haemostasis by TEG or ROTEM is useful for clinicians to distinguish between a surgical cause of bleeding or acquired/congenital coagulopathy, as well as to diagnose the type of haemostatic disorder, including hemophilia, and to evaluate the appropriate therapeutic approach.
Particularly for persons with severe hemophilia it has been shown that viscoelastic tests help to differentiate the clinical phenotype. In fact, it was shown that patients with a mild phenotype and no ‘target joint’ had a better clot formation and a higher generation of thrombin. It has been observed that about 10-15% of patients with severe hemophilia A exhibit a mild clinical phenotype and, conversely, patients with mild haemophilia may suffer from severe bleeding. In addition another aspect of phenotype determination is to differentiate severe hemophiliacs with and without inhibitors, because of the inadequate detection of the level of the coagulation factor below 1%.
This technology may induce a change in the clinical management of severe bleeding, reducing transfusion-related risks and improving patient health outcomes, as well as optimizing the use of healthcare resources.
TEG and ROTEM, either alone or associated with other rapid tests, such as the whole blood flow system of the PFA-100TM are useful to guide haemostasis with clotting therapeutic agents for specific deficiencies. Moreover this strategy may be able to reduce the total amount of blood products given patients in case of surgery or trauma compared with the empiric transfusion policy.
Salinas et al. have demonstrated the ability of kaolin-activated thromboelastography to distinguish between severe hemophilia A with and without inhibitor. A report by Chitlur et al. showed that patients with a mild phenotype and no ‘target joint’ had a better clot formation and a higher thrombin generation on TEG® 5000 than those with a more severe phenotype and ‘target joints’. Similarly the usefulness of ROTEM in mild haemophilia A patients, characterized by F8 mutations R1781H and T677I, with discrepancy between phenotype and clinical severity has been experienced.
However, while these observations encourage the use of thromboelastography in hemophilia, others have been contradictory.
Considering prophylaxis in hemophilia, patient care try to be individualized. With the latest extended half-life products, prophylaxis regimens are tailored in order to enable patients to pursue sports and other physical activities. Finally thromboelastography during prophylaxis is able to identify patients who need different timing and dosage of clotting concentrates. Further prospective studies are required to determine whether TEG/ROTEM may lead to individualize FVIII prophylaxis regimens.
Bypassing agents, such as recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC), are successful in controlling bleeding episodes in patients with inhibitors. However, these important haemostatic products are hampered by a lack of laboratory assays to evaluate adequate dosage and therapeutic responses. Many ‘in vitro’ and ‘in vivo’ studies have shown that TEG/ROTEM assays seem to be useful for monitoring the efficacy and clinical response to bypassing agents in hemophilia A patients with inhibitors.
The management of hemophilia A patients with inhibitors using bypassing agents in surgical situations is particularly demanding and challeging. Thrombin generation assays have been reported to be useful for the haemostatic management of bypassing agents in hemophilia A patients with inhibitor in the perioperative period (Dargaud et al, 2005, 2010). Nevertheless these assays are complicated, and not easily available.
A systematic monitoring protocol using ROTEM to evaluate the choice and effectiveness of bypassing agents in the perioperative period has been recently described (Furukawa et al, 2015). The ROTEM parameters improved close to normal levels after treatment with rFVIIa.
Even though aPCC resulted in a marked improvement ‘in vitro’ spiking data, it seemed to be less evident in the preoperative and perioperative setting. In the light of these results ROTEM offers a promising strategy for monitoring bypassing agents in hemophilia A with inhibitor in the perioperative period.
Nowadays pharmaceutical agents with a novel mode action and administration, such as the FVIII-mimetic bispecific antibody: emicizumab (Kitazawa et al, 2012), an anti-siRNA antibody targeting antithrombin: fitusiran (Sehgal et al, 2015) and an antibody against Tissue Factor Pathway Inhibitor (TFPI): concizumab (Chowdary et al, 2015) represent an alternative to traditional replacement therapy in hemophiliacs with inhibitor. However a limitation of these new products is the inability to measure their haemostatic effects accurately and simply.
A recent study on emicizumab demonstrated that ROTEM should be useful for haemostatic monitoring of this treatment (Yada et al, 2015b). These results indicated that further investigations using TEG/ROTEM to determine the effects of novel agents are required.
Acquired Inhibitors against FVIII (acquired hemophilia) cause an autoimmune disease that primarily affects older individuals and young women during pregnancy or peripartum/postpartum period. Half of the cases are idiopathic and bleeding is usually spontaneous, but could be life-threatening. Treatment of bleeding is the use of bypassing agents or recombinant porcine FVIII. Also in this case, preliminary observations have shown that viscoelastometry tests could be an useful opportunity.
In conclusion conventional laboratory-based clotting tests have a limited role, especially in the early management of acute haemorrhagic disorders, such as severe hemophilia. TEG/ROTEM technology provides rapid, real-time, visualized monitoring and analysis of the viscoelastic properties of clot formation and its dissolution in whole blood and the necessary analysers are readily adaptable for POC testing. However further studies are needed to better determine reproducibility and sensitivity of these assays.
Suggested Readings
Keiji Nogami. The utility of thromboelastography in inherited and acquired bleeding disorders. Br J Haematol. 2016 Aug;174(4):503-14
Wikkelsø A, Wetterslev J, Møller AM, Afshari A. Thromboelastography (TEG) or thromboelastometry (ROTEM) to monitor haemostatic treatment versus usual care in adults or children with bleeding. Cochrane Database Syst Rev. 2016 Aug 22;(8):CD007871.