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Coagulopathy and plasma transfusion in critically ill patients

Müller, M.C.A.

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Citation for published version (APA):Müller, M. C. A. (2014). Coagulopathy and plasma transfusion in critically ill patients.

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Download date: 03 Jun 2020

Chapter 2

The utility of thromboelastometry (ROTEM) or 

thromboelastography (TEG) in non-bleeding ICU patients

Kirsten Balvers, Marcella C.A. Müller, Nicole P. Juffermans

Annual Update in Intensive Care and Emergency Medicine 2014; 583-591

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Introduction

A hypocoagulable state is highly prevalent in critically ill patients. An International Normalized Ratio (INR) of >1.5 occurs in 30% of patients, associated with increased mortality [1]. Also, of critically ill patients, up to 40% develops thrombocytopenia during their intensive care unit (ICU) stay [2-4], associated with increased length of stay, need for transfusion of blood products and increased mortality [5]. A hyper-coagulable state is also associated with adverse outcome, as well as with increased thrombo-embolic events [6]. Disseminated intravascular coagulation (DIC) develops in 10 to 20% of ICU patients. A hypercoagulable state contributes to organ failure and is associated with a high mortality, ranging from 45% to 78% [7].Coagulopathy is thought to result from an imbalance between activation of coagula-tion and impaired inhibition of coagulation and fibrinolysis. Activation is triggered by tissue factor, which is expressed in reaction to cytokines or endothelial damage. Impaired inhibition of coagulation is the consequence of reduced plasma levels of antithrombin (AT), depressed activity of the protein C system and decreased levels of tissue factor pathway inhibitor (TFPI). A decrease in the fibrinolytic system is due to increased levels of plasminogen activator inhibitor type 1 (PAI-1) [8,9]. This dis-turbance between components of the coagulation system leads to a variable clinical picture, ranging from patients with an increased bleeding tendency (hypocoagulable state) to those with DIC with (micro-) vascular thrombosis (hypercoagulable state).Assessment of coagulation status in patients is complex. Global coagulation tests, including activated partial thromboplastin time (aPTT) and prothrombin time (PT), are used clinically. However, these tests are of limited value and their ability to accu-rately reflect in vivo hypocoagulable state is questioned [10]. Also, aPTT/PT reflects a part of the coagulation system and does not provide information on the full balance between coagulation, anti-coagulation and fibrinolysis. Hypercoagulable state can be assessed by increased levels of d-dimers, but specificity is limited [10]. Impaired function of the anticoagulant system can be diagnosed by measuring plasma levels of naturally occurring anticoagulant factors AT, protein C and TFPI. However, these are not readily available for clinical use. Apart from the DIC score, there are no diag-nostic tests which evaluate a hypercoagulable state. Also, markers of the activity of the fibrinolytic system are not used at the bedside [10].

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TEG/ROTEM tests

Rotational thromboelastography (TEG/ROTEM) is a point of care test, which evalu-ates whole clot formation and degradation. The thromboelastogram arises through movement of the cup (TEG) or the pin (ROTEM). As fibrin forms between the cup and the pin, this movement is influenced and converted to a specific trace. The trace reflects different phases of the clotting process. Major parameters are R (reaction/clotting) time, the period from the initiation of the test until the beginning of clot formation. K-time is the period from the start of the clot formation until the curve reaches an amplitude of 20 mm. Kinetics of fibrin formation and cross-linking is expressed by the α-angle, which is the angle between the baseline and the tangent to the TEG/ROTEM curve. Clot strength is represented by the maximal amplitude (MA) of the trace. The degree of fibrinolysis is reflected by the difference between the maximal amplitude and the amplitude measured after 30 and/or 60 minutes. To describe these visco-elastic changes, both systems have their own terminol-ogy (table 1). Both generate similar data. The technique is developed in the 1940s, but until recent, clinical application has been limited. However, technical develop-ments have led to standardization and improved reproducibility of the method [11]. Also, the availability for bedside evaluation and a changing view regarding the use of blood and haemostatic therapy in massive bleeding, have both contributed to a renewed interest in this technique.

Table 1: TEG and ROTEM parameters

ROTEM TEGTime to initial fibrin formation CT RClot strengthening, rapidity of fibrin build up CFT K

a aClot strength, represents maximum dynamics of fibrin and platelet bonding

MCF MA

Clot breakdown,fibrinolysis at fixed time (min)

LI30, LI45, LI60

CL30, CL60

TEG/ROTEM may also facilitate diagnosis of clotting abnormalities in the critically ill. Detecting a hypocoagulable state, TEG/ROTEM may be a useful tool in the assess-ment of the risk of bleeding peri-operatively or prior to an invasive procedure. This

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could lead to a more tailored transfusion strategy, with an efficient use of blood products.Also, TEG/ROTEM may diagnose a hypercoagulable state. With TEG/ROTEM, a hyper-coagulable state can be detected by high maximal amplitude (MA), shortened reac-tion time, increased alfa angle and total cloth strength G (defined as (5000xMA)/(100-MA), table 2). Assessment of a hypercoagulable state could lead to prognos-tication of multiple organ failure (MOF) and risk for thrombo-embolic events. Also, another potential advantage could be a more tailor made administration of thera-pies that interfere with the coagulation system. Difficulties in identifying responders from non-responders may in part have contributed to conflicting results from trials evaluating the effect of strategies that interfere with the coagulation system [12-15].

Table 2: Changes in hypercoagulable state and hypocoagulable state of ROTEM and TEG parameters

Parameters Hypercoagulable state Hypocoagulable stateReaction time, R or CT Shortened ProlongedClot formation time, K or CFT Shortened ProlongedAlpha angle, Angle or α Increased DecreasedMaximum amplitude, MA or MCF Increased Decreased

Utility of TEG/ROTEM to detect sepsis-induced coagulopathyROTEM clearly demonstrates a hypercoagulable state during endotoxemia [16]. In vitro, endotoxin-induced hypercoagulability was demonstrated with TEG. In experi-ments where LPS was infused in healthy volunteers, a hypercoagulable state meas-ured by TEG had a strong correlation with plasma levels of prothrombin fragments F1+2 [17,18]. In sepsis patients however, TEG/ROTEM measurements have shown dif-ferential results. Several studies observed no changes in parameters [19-22], other studies reported a hypercoagulable [23] or hypocoagulable state [24]. A few stud-ies also reported patients showing both a hyper- and hypocoagulable state [25-28]. Taken together, results are heterogeneous. Also, there is a lack of clarity on interpre-tation of the test results.To date, no studies have compared conventional coagulation tests such as PT/aPTT to TEG/ROTEM in sepsis patients. However, the utility of thromboelastography to detect DIC has been evaluated. It seems that thromboelastography can predict

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DIC. Patients with DIC present with hypocoagulable state [26]. This may be due to a decrease in coagulation factors used for formation of micro thrombi. In line with this, sepsis patients who met the ISTH DIC criteria showed a hypocoagulable state when compared to healthy controls, while patients without DIC showed a non-signif-icant trend towards hypercoagulation [25]. Also, patients with an underlying disease known to be associated with DIC and ISTH DIC scores ≥5 had significantly prolonged reaction and K times and decreased alpha-angle and MA (signs of a hypocoagula-ble state) compared to patients with low ISTH DIC scores. The authors developed a score, defined as the total number of parameters (R, K, MA, and alpha) that were deranged in the direction of a hypocoagulable state. With this score, the discrimina-tory value of thromboelastometry to detect DIC improved [29]. Impaired fibrinolysis in sepsis may contribute to a hypercoagulable state. Inhibition of the fibrinolytic system was found to discriminate sepsis from postoperative controls [19,28,30].In terms of prognostication, a hypercoagulable state was not found to be a predic-tor of outcome. In contrast, the finding of a hypocoagulable state was repeatedly shown to be associated with a poor outcome. The TEG MA value is an independent predictor for 28-day mortality on admission [27]. Hospital mortality was predicted by a hypocoagulable state due to a deficit in thrombin generation [30]. A hypoco-agulable state measured with TEG is found to be associated with a pro-inflamma-tory response [19,24]. Also, the degree of a hypocoagulable state is associated with severity of organ failure in sepsis [19,22].Taken together, results are heterogeneous. Timing of measurements may be rel-evant to these observations, as a hypocoagulable state may be more outspoken in the acute phase of sepsis and return to normal values towards discharge of ICU, or even to enhanced clot formation.

Use of TEG/ROTEM to guide anticoagulant treatment in sepsis patientsIn sepsis, activation of coagulation is a crucial step in the pathophysiological cascade of sepsis, with concomitant low levels of circulating natural anticoagulants [8,9]. From this perspective, various treatment modalities that interfere with the coag-ulation system have been studied (e.g. rhAPC, AT and heparin) [12-15]. However, efficacy has been questioned. It can be hypothesized that TEG/ROTEM may help to identify patients likely to respond to therapies that target coagulopathy. To date,

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there are no studies which have addressed this question. Only a few small patient series evaluated TEG/ROTEM measurement during anticoagulant medication. ROTEM parameters did not change during anticoagulant medication. Also, treat-ment with antithrombin did not induce changes in the ROTEM measurements [23].

Use of TEG/ROTEM in patients with induced hypothermiaInduced hypothermia is a common therapy in survivors of a cardiac arrest [31-33]. However, hypothermia is associated with coagulopathy, prolongation of aPTT and PT [33,34] and an increased risk of bleeding [35]. A test that reliably detects hypo-thermia induced coagulopathy would be helpful in identifying patients who have an increased bleeding risk while being cooled and sedated. Unfortunately, little is known about the value of TEG/ROTEM in these patients.Spiel et al. observed that ROTEM measurements showed a prolonged CT at 1 hour after infusion of 4°C cold crystalloid solution. All other parameters remained within reference values. An important limitation of this study is that all measurements were performed at 37°C [33]. TEG parameters were evaluated also in patients after cardiac arrest. On the contrary, the TEG was performed at isothermal conditions and a hypocoagulable state was detected by TEG [36].

Use of TEG/ROTEM in patients with brain injuryAfter severe traumatic brain injury and neurosurgery, up to 45% of patients develop a coagulopathy [37-39]. Given the serious consequences of intracranial bleeding, instant assessment of coagulation status is desirable. Two small trials have stud-ied the value of TEG to detect coagulopathy in these patients, which mostly found test results within reference values. However, the functional response of platelets as measured in a platelet mapping™ (TEG-PM) assay, was significantly lower in brain injury patients than in control groups, with a particular low response in those patients who developed bleeding complications [40]. Furthermore, a hypocoagula-ble state on admission to the ICU is associated with worse outcome in patients with traumatic brain injury and intracranial bleeding [41].

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Utility of TEG/ROTEM to detect a hypercoagulable state and prognosticate organ failure in trauma patientsPatients who survive the acute phase of trauma are prone to develop a hyperco-agulable state with increased risk for thrombo-embolic events and DIC [1]. Conven-tional coagulation tests are not able to detect such a hypercoagulable state. Also, there is debate as to whether the syndrome DIC is applicable to coagulation abnor-malities in trauma. With TEG/ROTEM, a hypercoagulable state can be detected by high maximal amplitude (MA) and shortened reaction time (table 1). Several reports demonstrate a hypercoagulable state in severely injured patients with TEG/ROTEM. In trauma and burn patients admitted to the ICU, TEG was found to be more sensi-tive in detecting a hypercoagulable state than conventional clotting assays [42,43]. A high MA was found to be an independent contributor of mortality in multiple logistic regression analysis [42]. A hypercoagulable state measured by TEG predicted the development of thrombo-embolic events in trauma patients [44] although not all studies have confirmed this finding [45]. It should be noted that the finding of a hypercoagulable state is not specific for venous thrombo embolism.A study on the use of ROTEM to prognosticate the occurrence of multiple organ failure in a cohort of trauma patients is currently underway.

Considerations

In several non-bleeding critically ill patient populations, evidence supporting the use of TEG/ROTEM to diagnose a hypocoagulable or hypercoagulable state is limited at this stage, mostly because of heterogeneity of the included studies in design, use of control groups and chosen endpoints. Heterogeneity of results can also be caused by differences in disease severity, as changes were more outspoken during severe illness. Timing of TEG/ROTEM measurements may greatly influence results, as coagulopathy is a dynamic process, e.g. evolving from subtle activation of coagu-lation to overt DIC in sepsis and from a hypocoagulable to a hypercoagulable state in trauma. Performing sequential measurements will probably provide better insight in the development of coagulation derangements.Another important issue is that no uniform definitions exist of a hypocoagulable and a hypercoagulable state. Reference values for non-bleeding patients with disorders

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of coagulation are not widely assessed and cut off values are often not defined in studies. To compare patient categories and possibly investigate therapeutic inter-ventions in the coagulation system, validated universal reference values and defini-tions are essential. A study on TEG reference intervals has been recently completed (NCT01357928). Presumably, as patients groups are relatively small, evaluation of larger patient groups may yield more clear results.

Conclusion

TEG/ROTEM can detect coagulopathy in the critically ill. Whether these tests are useful as diagnostic tools remains to be investigated when reference values and clear definitions have been established.TEG/ROTEM may be useful for prognostication of outcome. A hypocoagulable status seems to be an independent predictor for organ failure and mortality in sepsis, also after correction for disease severity. In patients with brain injury, a hypocoagulable state on admission to the ICU is also associated with worse outcome. In patients who survive the acute phase of trauma, a hypercoagulable state as detected by TEG/ROTEM is a common finding. These tests could be helpful in identifying those patients at risk for thrombo-embolic complications, as a hypercoagulable state pre-dicted the development of thrombo-embolic events in the majority of studies. Fur-ther research on this topic is forthcoming.

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