Global Hemostasis: New Approaches to Patient Diagnosis and Treatment Monitoring

Welcome to this special issue of Seminars in Thrombosis and Hemostasis. Characteristically, each new issue is devoted to a particular theme of relevance to thrombosis and hemostasis. The current issue focuses on new approaches to patient diagnosis and treatment monitoring of global hemostasis.

The concept and application of global hemostasis has been with us for some time and is now undergoing resurgence due to renewed interest and improved methodologies and instrumentation. This is perhaps best reflected by thromboelastography (TEG), which considers most aspects of hemostasis, including coagulation as well as the fibrinolytic components. Hence this methodology is the primary focus of the current issue. In addition, global hemostasis can be represented by other methodologies, such as thrombin generation and overall hemostasis potential, and a selection of articles covering these topics is also included in this issue. Standardization is critical when it comes to global hemostatic tests, particularly in clinical scenarios where decision making regarding diagnosis and management is of utmost importance. Accordingly, this issue includes a selection of articles that deal with standardization issues, quality assurance, and quality control from different perspectives. These approaches, for global hemostatic tests as well as other tests of hemostasis, validate test performance and ensure that results are correct. Because tissue factor is a key player in triggering hemostasis, this issue also provides an article discussing the contribution of tissue factor to global hemostatic assays. In the area of global hemostasis, animal studies have contributed greatly to our understanding of TEG and other global hemostatic assays and have highlighted the value of such studies at both clinical and experimental levels, so this issue also includes an overview of the veterinary experience for TEG. Some of the more critical areas for TEG are its utilization in trauma patients, pregnancy and its complications, and potentially in hemophilia monitoring. Accordingly, this issue offers selected articles in cover these specific areas. As guest editor for this issue, I hope you make the most of this “global dose” of hemostasis and find this update both profitable and enjoyable.

Wegner and Popovsky[1] begin this issue with the critical statement that in hemostasis “one size does not fit all.” Indeed, using TEG (a vesicohemostatic assay [VHA] available since 1948)[2] is quite different than other conventional tests because it monitors the various phases of clot formation and lysis time from the time of initial clot formation, including the rate of clot development, maximum clot strength, and clot lysis. This provides the clinician with a tool for making informed therapeutic decisions. Currently, two VHA devices are available for clinical use, the TEG (Thromboelastograph; Haemoscope Corp., Niles, IL, USA) and the ROTEM (Rotation Thromboelastometer; Pentapharm GmbH, Munich, Germany). Both devices measure the changes in a clot's physical properties by monitoring the movement of a pin suspended in activated blood, but with some small technical differences.[3] Sample types and other modifiers play a role in the speed and type of kinetics of generation of a clot including tissue factor, kaolin and corn trypsin inhibitor. In addition to the standard technique, the TEG-based PlateletMapping assay (Haemoscope Corp., Niles, IL) discussed by the authors has helped predict the bleeding risk in acute cases by measuring platelet responsiveness to adenosine diphosphate while the patient receives drugs like clopidogrel.[4] The article provides a rich overview of the clinical application of TEG in bleeding and thrombotic disorders and projects this to improved decisions regarding the appropriate treatment of those hemostatic abnormalities.

The article that follows by Chitlur and Lusher[5] discusses the first serious worldwide effort toward standardization of TEG with respect to preanalytical and analytical factors. Up until 2005, a major criticism of this technology was that it is not well standardized and that different investigators use different techniques and sample modifiers that make comparison of data difficult.[6] [7]

Chitlur and Lusher update us on the work in progress in this regard. The article explains how the international TEG/ROTEM Working Group was formulated and provoked interest in performing standardization exercises. Twelve laboratories from four countries grouped their efforts, obtained support from the International Society on Thrombosis and Haemostasis, and began blind testing among all participating laboratories of panels of normal pools as well as samples containing factor VIII–deficient plasma. Future exercises will be directed to use whole blood samples because they are more physiological.

The third article in this issue by MacDonald and Luddington[8] analyzes in great detail the factors affecting the TEG trace. TEG can have a wide range of normality. This is inevitable as a test becomes more “global.” Using whole blood means the test can be influenced by all components of the whole blood including white and red cell content and composition, platelet number and function, fibrinogen concentration, as well as coagulation protein function and balance. Ideally, TEG would be used in the monitoring of change within an individual rather than to obtain a diagnostic measurement related to a general reference range. Several preanalytical and postanalytical factors can affect the TEG trace including age, sex,[9] and hematocrit;[10] native whole blood versus citrated; type of sample modifier such as kaolin, tissue factor[11] or corn trypsin inhibitor; the presence of heparin when blood is withdrawn from indwelling lines; and pH and temperature during the assay.[12] The article also discusses the interpretation of TEG in the context of various clinical and pathological conditions including blood component therapy, antiplatelet drug therapy, monitoring heparin and fibrinogen administration, in addition to the use of the assay in monitoring hemostasis in liver disease, trauma, and obstetrics.

Gonzalez and colleagues[13] then address coagulation status and thromboprophylaxis management in the trauma patient and the emerging role of point-of-care TEG. They also discuss the challenges resulting from incorporating TEG into clinical practice. The article addresses the differences between the “classic” view of the intrinsic and extrinsic coagulation cascades and the recent cell-based model of coagulation that incorporate important interactions of the cellular and plasma components to clot formation.[14] The authors then move on to review and update blood component therapy for postinjury coagulopathy and the diagnosis and treatment of hypercoagulability of traumatic critical illness. Through a detailed discussion, the article covers the goal-directed transfusion therapy guided by TEG and risk stratification of postinjury hypercoagulability. The authors conclude that the potential benefits of TEG are contingent on accurate interpretation of results, which requires a significant learning curve for the clinician to translate these potential benefits into clinical practice. The article notes two ongoing randomized prospective clinical trials: one to evaluate the usefulness of TEG as a screening test for hypercoagulability and monitoring of thromboprophylaxis and another to evaluate the efficacy of their current TEG protocol in managing postinjury coagulopathy in the context of massive transfusions.

The article by Othman and colleagues[15] reviews hemostasis and the use of TEG for monitoring hemostasis during normal pregnancy[16] and pregnancy-related complications.[17] The article begins with a detailed overview of hemostatic changes during normal pregnancy and in relation to gestational age, discusses why there is a need for a global test for hemostasis, and highlights the value of TEG in the diagnosis and management of pregnancy complications. The authors highlight the debate in the literature regarding the pros and cons of using global tests such as TEG in the obstetric ward and support investment into further clinical and experimental studies to promote utilization in this regard.

Wiinberg and Kristensen[18] then overview the available veterinary experience in using TEG. The authors explain that TEG has a very similar scope and limitations in animals as those observed in humans. TEG has been used to diagnose hypercoagulability in animals with disseminated intravascular coagulation,[19] various types of cancer,[20] and critical illness.[21] The ability to detect and monitor animals with various types of coagulopathies using TEG has been well established, both clinically and in experimental studies. The authors discuss the issue of establishing reference ranges for TEG parameters in different species, highlighting the challenge involved and recommending that each laboratory establish its own reference values as well as clinically relevant cut-off values. It is also noted that various blood constituents and biological variations have an impact on TEG measurements. The applications of TEG in veterinary medicine including congenital and acquired coagulopathy in both clinical and experimental studies, monitoring anticoagulant and procoagulant pharmacological agents, and guiding transfusion therapy are also reviewed.

Kitchen and coworkers[22] discuss the UK experience in quality assurance and quality control for TEG/ROTEM. The UK NEQAS for blood coagulation[23] has undertaken a series of exercises evaluating the provision of External Quality Assessment (EQA) material for these devices. Four studies using lyophilized plasmas as the test and up to 18 TEG and 10 ROTEM users have been involved testing two samples per study. Although results report limited EQA provision for these devices, it is important that such studies continue and expand to ensure the ongoing reliability of TEG results from different laboratories.

Tissue factor (TF)[24] and its inhibitor tissue factor pathway inhibitor (TFPI)[25] play an essential role in the regulation of coagulation and hemostasis. Several assays are available to measure TF including conventional plasma-based assays, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and TF microparticles. Accordingly, the article by Kasthuri et al[26] reviews the role of TF and TFPI in coagulation, the available assays to measure them, and their interpretations, including the role of TEG.

Antovic[27] then discusses the overall hemostasis potential (OHP) in plasma. Unlike other global measurements that reflect thrombin generation, clot formation, or fibrin degradation, the OHP assay can be used for evaluating overall coagulation and fibrinolysis in the examined sample. The assay is based on repeated spectrophotometric registration of the fibrin aggregation curve (i.e., absorbance as a function of time) in platelet-poor plasma (PPP) containing small amounts of exogenous thrombin, tissue-type plasminogen activator (tPA), and calcium chloride. The OHP can be useful in monitoring hypercoagulability, hypocoagulability, and anticoagulant and antithrombotic treatment. The highly significant correlations between OHP levels and rising concentrations of different coagulation factors indicates its usefulness in monitoring therapy such as recombinant factor VII therapy in hemophilia. This test can use both fresh and frozen-thawed plasma samples, but major limitations are that it requires addition of small amounts of thrombin and the lack of large controlled clinical studies.

Salvagno and Berntorp[28] continue this issue's global hemostatic “marathon” by discussing the thrombin generation assay (TGA). They review to what extent TGA can be expected to reflect the clotting function of blood, the development and use of different TGA systems for detecting changes in the kinetics of thrombin generation, and focus on the test's clinical usefulness for patients with different types of hemophilia or von Willebrand's disease.

The final article in this issue by Kluft and Meijer[29] deals with EQA for TGA. The ECAT (External Quality Control of Diagnostic Assays and Tests) provides an international EQA Program (EQAP) for laboratories working in the field of hemostasis and thrombosis. ECAT started as a small-scale program only in Western Europe, but today >1000 laboratories from ~20 countries participate.[30] The EQAP has explored the analysis of pooled normal plasmas, microparticle (MP)-depleted plasmas, and factor XII–deficient patient plasma in surveys with 4 to 11 participant laboratories. Results show interlaboratory variations between 11% and 57% for all TGA methods. Variations were mainly related to the normal pooled plasma used. The different sensitivities of TGA to MPs and contact activation predict that they will associate differently with clinical situations and indicate that future ECAT surveys should include samples with variation in MPs and contact activation.

A few final words: The availability of a global test that can detect, predict, and monitor hemostatic status would be attractive for both clinicians and researchers and in both clinical and experimental studies. As the technology develops with different instruments, analysis software, reagents, and applications, it is important to understand how to interpret the data generated. It is also critical to learn how to set up reference ranges and control groups and more importantly to become aware of the limitations of each technique. The validation of each assay using internal and external quality control measures and development of standardization methods is vital to moving these techniques confidently and on a wide scale to the point-of-care setting to aid diagnosis and treatment monitoring in various fields.

I sincerely thank all the contributors to this special issue of Seminars in Thrombosis and Hemostasis for their excellent contributions and collaboration during the production of this issue. On behalf of all the contributors, I hope that you enjoy this update on global hemostasis and that these reviews enrich your view of global hemostatic tests and their optimal utilization in both clinical and research fields.

REFERENCES

• 1 Wegner J, Popovsky M. Clinical utility of thromboelastography: one size does not fit all.  Semin Thromb Hemost. 2010;  36(7) 699-706
• 2 Hartert H. Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren.  Klin Wochenschr. 1948;  26(37–38) 577-583
• 3 Nielsen V G. A comparison of the Thrombelastograph and the ROTEM.  Blood Coagul Fibrinolysis. 2007;  18(3) 247-252
• 4 Hobson A R, Qureshi Z, Banks P, Curzen N. Gender and responses to aspirin and clopidogrel: insights using short thrombelastography.  Cardiovasc Ther. 2009;  27(4) 246-252
• 5 Chitlur M, Lusher J. Standardization of thromboelastography: values and Challenges.  Semin Thromb Hemost. 2010;  36(7) 707-711
• 6 Samama C M. Thromboelastography: the next step.  Anesth Analg. 2001;  92(3) 563-564
• 7 Whitten C W, Greilich P E. Thromboelastography: past, present, and future.  Anesthesiology. 2000;  92(5) 1223-1225
• 8 MacDonald S, Luddington R. Critical factors contributing to the thromboelastography trace.  Semin Thromb Haemost. 2010;  36(7) 712-722
• 9 Lang T, Bauters A, Braun S L et al.. Multi-centre investigation on reference ranges for ROTEM thromboelastometry.  Blood Coagul Fibrinolysis. 2005;  16(4) 301-310
• 10 Spiezia L, Meneghetti L, Dalla Valle F et al.. Potential role of thrombelastography in the monitoring of acquired factor VIII inhibitor hemophilia A: report on a 78-year-old woman with life-threatening bleedings.  Clin Appl Thromb Hemost. 2009;  15(4) 470-476
• 11 Othman M PS, Hopman W M, Lillicrap D. Variability of thromboelastographic responses following the administration of rFVIIa to hemophilia A dogs supports the individualization of therapy with a global test of hemostasis.  Haemophilia. 2010;  , in press
• 12 Johansson P I, Bochsen L, Andersen S, Viuff D. Investigation of the effect of kaolin and tissue-factor-activated citrated whole blood, on clot-forming variables, as evaluated by thromboelastography.  Transfusion. 2008;  48(11) 2377-2383
• 13 Gonzalez E PF, Pieracci F M, Moore E E, Kashuk J L. Coagulation abnormalities in the trauma patient: the role of point-of-care thrombelastography.  Semin Thromb Hemost. 2010;  36(7) 723-737
• 14 Hoffman M, Monroe III D M. A cell-based model of hemostasis.  Thromb Haemost. 2001;  85(6) 958-965
• 15 Othman M, Falcon B, Kadir R. Global haemostasis in pregnancy: are we utilising thromboelastography to its full potential?.  Semin Thromb Hemost. 2010;  36(7) 738-746
• 16 Cerneca F, Ricci G, Simeone R, Malisano M, Alberico S, Guaschino S. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis.  Eur J Obstet Gynecol Reprod Biol. 1997;  73(1) 31-36
• 17 Sharma S K, Philip J, Whitten C W, Padakandla U B, Landers D F. Assessment of changes in coagulation in parturients with preeclampsia using thromboelastography.  Anesthesiology. 1999;  90(2) 385-390
• 18 Wiinberg B, Kristensen A T. Thromboelastography in veterinary medicine.  Semin Thromb Hemost. 2010;  36(7) 747-756
• 19 Wiinberg B, Jensen A L, Johansson P I, Rozanski E, Tranholm M, Kristensen A T. Thromboelastographic evaluation of hemostatic function in dogs with disseminated intravascular coagulation.  J Vet Intern Med. 2008;  22(2) 357-365
• 20 Kristensen A T, Wiinberg B, Jessen L R, Andreasen E, Jensen A L. Evaluation of human recombinant tissue factor-activated thromboelastography in 49 dogs with neoplasia.  J Vet Intern Med. 2008;  22(1) 140-147
• 21 White N J, Martin E J, Brophy D F, Ward K R. Coagulopathy and traumatic shock: characterizing hemostatic function during the critical period prior to fluid resuscitation.  Resuscitation. 2010;  81(1) 111-116
• 22 Kitchen D P, Kitchen S, Jennings I, Woods T, Walker I. Quality assurance and quality control of thrombelastography and rotational thromboelastometry: The UK NEQAS for Blood Coagulation experience.  Semin Thromb Hemost. 2010;  36(7) 757-763
• 23 UK NEQAS .http://Available at: www.ukneqas.org.uk/ Accessed May 30, 2010
• 24 Mackman N, Taubman M. Tissue factor: past, present, and future.  Arterioscler Thromb Vasc Biol. 2009;  29(12) 1986-1988
• 25 Dahm A, Van Hylckama Vlieg A, Bendz B, Rosendaal F, Bertina R M, Sandset P M. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis.  Blood. 2003;  101(11) 4387-4392
• 26 Kasthuri R S, Glover S L, Boles J, Mackman N. Tissue factor and tissue factor pathway inhibitor as key regulators of global hemostasis: measurement of their levels in coagulation assays.  Semin Thromb Hemost. 2010;  36(7) 764-771
• 27 Antovic A. The overall hemostasis potential (OHP): a laboratory tool for the investigation of global hemostasis.  Semin Thromb Hemost. 2010;  36(7) 772-779
• 28 Salvagno G L, Berntorp E. Thrombin generation testing for monitoring hemophilia treatment: a clinical perspective.  Semin Thromb Hemost. 2010;  36(7) 780-790
• 29 Kluft C, Meijer P. External quality assessment for thrombin generation tests: an exploration.  Semin Thromb Hemost. 2010;  36(7) 791-796
• 30 ECAT Foundation .External quality control of diagnostic assays and tests. Available at: http://www.ecat.nl/ Accessed May 30, 2010