Advantages of point-of-care methods in perioperative bleeding control

Perioperative bleeding management is a complex task which has significant impact on surgery outcome. Most hemostasis disorders occurring intraoperatively are acute, caused by massive bleeding, and can be explained by the principle of loss, compensation, and dilution of circulating blood volume. Disorders at the level of the hemostatic system can be assessed both by various standard laboratory tests, such as: prothrombin time, activated partial thromboplastin time, platelet count, coagulation factor concentrates, levels of antithrombin and D-dimer; or by point-of-care (POC) methods.

Standard laboratory tests have their limitations. They do not detect increased intraoperative bleeding tendency, and it is recommended to use methods such as POC, which quickly and accurately assess the patient’s coagulation status, thus enabling the administration of the appropriate therapy, as soon as possible. The most commonly used POC methods are the aggregometry methods (Multiplate, PFA-100, and Platelet Mapping Assay), used in perioperative platelet function evaluation, and viscoelastic tests (rotational thromboelastometry – ROTEM; thromboelastography – TEG), which provide a graphic representation of all hemostatic activity by measuring the time elapsed until the onset of clot formation, formation dynamics, as well as clot firmness and stability over time.

The main advantages of the POC method are: the swift availability of results (up to 15 minutes) and the very small blood sample size (up to 5 ml) necessary for performing the test; while the main disadvantages are: their cost, which exceeds the cost of performing standard laboratory tests, and their inability to detect coagulopathies, resulting from the disturbance of the patient’s normal physiological state. POC methods are very important in reducing perioperative bleeding, reducing blood transfusions, and forming adequate therapeutic algorithms.

INTRODUCTION

Perioperative bleeding management is a complex task which has significant impact on surgery outcome. For anesthesiologists, surgeons, transfusiologists, hematologists, but also for doctors of other specialties, monitoring coagulation factors and hemostasis is one of the most important tasks. Most coagulation disorders occurring intraoperatively are acute, caused by massive bleeding and can be explained by the principle of loss, compensation, and dilution of circulating blood volume. This is when disruption occurs in the values of coagulation monitoring test results, such as: prothrombin time (PT), activated partial thromboplastin time (aPTT), thromboelastography, platelet count, as well as the concentrations of antithrombin, fibrinogen, coagulation factors and D-dimer [1],[2].Perioperative bleeding depends on the type of surgical procedure, the coagulation status, and the comorbidities of the patient. Heavy perioperative bleeding is expected in cardiac, orthopedic, abdominal, and vascular surgery, but more profuse bleeding can also occur in other branches of surgery [3].Also, profuse perioperative bleeding can be the result of certain illnesses (von Willebrand disease, hemophilia A and B, thrombocytopenic purpura, etc.), but also of anticoagulation drug application (aspirin, vitamin K antagonists, ADP receptor antagonists, and others) [4],[5]. Serious bleeding, as a potential complication of all invasive procedures, and its treatment, in the form of transfusion of blood and blood products, are linked to the increase in morbidity and mortality [6].

Different strategies for treating bleeding have been described in literature. Some authors describe two strategies of bleeding treatment based either on the transfusion of fresh-frozen plasma (FFP) and red blood cell concentrates, in the ratio 1:2, or on the transfusion of the fibrinogen concentrate and red blood cell concentrates, adjusted according to the blood hemoglobin level. Other authors recommend three strategies of bleeding treatment:

1. Strategy of damage control (damage control resuscitation; damage control hematology) is the replacement of blood, FFP, and thrombocytes, in the ratio: 1:1:1;
2. Individual therapy concept, based on standard laboratory tests (PT, aPTT and platelet count);
3. Individual therapy near-patient concept, based on POC testing, whereby the coagulation status and the platelet function are tested by means of viscoelastic and aggregometry tests (TEG, ROTEM, MULTIPLATE).

Standard laboratory tests, such as PT and aPTT, are weak predictors of bleeding and are not appropriate for assessing the patient’s coagulation status. If appropriate equipment is available, the third concept can easily replace the first two therapeutic concepts [7],[8].

POINT-OF-CARE (POC) METHODS

POC methods provide information on coagulation initiation, clot stability and fibrinolysis. Results confirming coagulation disorder and its origin are obtained within a short space of time and can be carried out in any of the phases of surgical treatment: perioperatively, intraoperatively and postoperatively. On its own, none of the currently available POC methods can offer information on the coagulation system, as a whole. There are two types of POC methods: aggregometry tests and viscoelastic tests [9].

Aggregometry tests are used in perioperative platelet function assessment. They differ depending on the agonist applied for platelet activation (collagen, adenosine diphosphate, epinephrine, arachidonic acid, thrombin). The most commonly used aggregometry test is the Multiplate test.

Multiplate (multiple electrode aggregometry – MEA) is a platelet function test. It can be used for discovering platelet function disorder, monitoring antiplatelet therapy, as well as for assessing the risk of bleeding. This test uses a full blood sample in platelet aggregation function quantification, through the process of sticking the platelets from the full blood sample to metal electrodes, with two pairs of electrodes placed in each cuvette, while electrical resistance between them is continuously measured. The use of different reagents (adenosine diphosphate, collagen, arachidonic acid, ristocetin, thrombin receptor activating peptide 6 - TRAP-6) results in platelet activation via different receptors located on their surface, and, in this way, not only platelet function, but also the effect of antiplatelet therapy can be tested. Results are obtained in the form of graphs, where the surface below the curves marks the platelet function and the effect of antiplatelet therapy, with a larger surface representing better platelet function (Figures 1 and 2) [10],[11].

Figure 1. The Multiplate Curve *AUC – Area under the Curve From: Dimić N, et al. Procena obima intraoperativnog krvarenja i strategije za smanjenje rizika i nadoknadu volumena, in: Kalezić N. Perioperativna medicina 1. Medicinski fakultet, Beograd; 2020; 303-324.

Figure 2. Monitoring the effects of antiplatelet therapy From: Dimić N, et al. Procena obima intraoperativnog krvarenja i strategije za smanjenje rizika i nadoknadu volumena, in: Kalezić N. Perioperativna medicina 1. Medicinski fakultet, Beograd; 2020; 303-324

Viscoelastic tests (rotational thromboelastometry - ROTEM and thromboelastography – TEG) provide data on clot formation initiation time, clot formation dynamics, clot firmness, and clot stability over time. They enable parallel monitoring of these parameters in a single blood sample, after clot activation with different agonists, while the possibility of also detecting hyperfibrinolysis is a particular advantage [12].

The TEG test was discovered in 1948. In the beginning it was used only for assessing coagulation status during liver transplantation, while today it is used in cardiac surgery, gynecology, orthopedics, and other branches of surgery [13]. With the aid of the TEG method, information on fibrin formation, interaction between thrombocytes and fibrin, clot firmness, and fibrinolysis, is obtained. The following are used as coagulation activators: celite, kaolin, or the tissue factor. The implementation of the TEG method enables the monitoring of five parameters in different stadiums of clot formation: R value, K value, α angle, maximum amplitude (MA), and maximum amplitude after 60 minutes (MA60). Additionally, clot lysis indices are also monitored, 30 and 60 minutes after maximum amplitude (LY30; LY60). Reference values depend on the activator being used. The R value represents clotting time (CT), i.e. the interval between the moment of test initiation and the moment when fibrin starts forming. The K value represents the kinetics of clot formation, i.e. the speed of clotting at which a certain level of clot firmness is achieved (time elapsed from the beginning of clot formation until the moment when the amplitude reaches 20 mm). The α angle is the angle formed by the tangent when the amplitude is 2 mm. It represents the speed of fibrin formation (clot strengthening). The maximum amplitude (MA) represents clot firmness, which depends on the function and number of platelets as well as on their interaction with fibrin (Figures 3 and 4). This parameter is used as a marker for discovering platelet function disorder. The limitation of the TEG method is reflected in its inability to detect platelet function disorders resulting from the influence of antiplatelet drugs. This shortcoming has been overcome with aggregometry tests [11],[14]. A modification of the TEG method, whereby the tissue factor or kaolin is used as an activator, has been named the rapid TEG method (rTEG). The results of this test are available within 15 minutes and can be used in assessing the need for early transfusion of blood products [15]. With his colleagues, Spiess analyzed 1,079 patients, before and after introducing the TEG method, which was an important factor when deciding on blood and blood product replacement. They concluded that, due to early detection of coagulation disorder and timely intervention, a significant decrease in blood and all blood product replacement occurred, after the introduction of the TEG method [16]. Shore-Lesserson reached the same conclusion four years later [17],[18],[19].

Figure 3. Thromboelastography – monitored parameters From: Dimić N, et al. Procena obima intraoperativnog krvarenja i strategije za smanjenje rizika i nadoknadu volumena, in: Kalezić N. Perioperativna medicina 1. Medicinski fakultet, Beograd; 2020; 303-324

Figure 4. Examples of different disorders shown on a thromboelastogram From: Dimić N, et al. Procena obima intraoperativnog krvarenja i strategije za smanjenje rizika i nadoknadu volumena, in: Kalezić N. Perioperativna medicina 1. Medicinski fakultet, Beograd; 2020; 303-324

Rotational thromboelastometry (ROTEM) is a viscoelastic POC method whereby a sensor fixed on a rotational axis is immersed in a cuvette containing the blood sample. The loss of elasticity during blood coagulation is detected as the reflection of light on a small mirror fixed to the axis, and it is represented in the form of a thromboelastogram [20].

The following parameters are monitored with the ROTEM method:

• clotting time (CT) is the time measured from the moment when the test begins until the moment when the maximum amplitude reaches 2 mm. This value provides information on the beginning of clot formation;
• clot formation time (CFT) is the time necessary for the maximum amplitude to increase from 2 mm to 20 mm. This value provides information on fibrin polymerization and the stabilization of the clot with thrombocytes and factor XIII;
• maximum clot firmness (MCF) is the maximum amplitude registered in the test and it depends on the platelet number and function and on fibrinogen concentration;
• the α angle is the angle formed by the tangent when the amplitude is 2 mm;
• maximum clot lysis (ML) is the ratio between the minimum amplitude after achieving maximum clot firmness and the maximum amplitude;
• clot stability during maximum lysis or clot lysis index (CLI);
• maximum clotting velocity, i.e. maximum velocity (maxVel);
• time to maximum velocity (t-maxVel) [21].

For the purpose of expediting the analysis within the ROTEM method, coagulation can be activated with the tissue factor (EXTEM) or with ellagic acid (INTEM). Intrinsic coagulation pathway activators (INTEM – phospholipid and ellagic acid) and extrinsic coagulation pathway activators are used to provide information similar to that provided by aPTT (INTEM) and PT (EXTEM). In addition to performing basic screening tests (INTEM and EXTEM) it is possible to establish a differential diagnosis by adding specific reagents. By combining and comparing the results of different ROTEM tests, it is possible to detect a deficiency in one or more coagulation factors, and based on this finding, start with appropriate and timely replacement therapy [22],[23]. The time needed to perform and analyze the ROTEM test is around 10 to 20 minutes and the test can be repeated around 10 minutes after the administration of a particular coagulation factor or blood product, whereby further therapy is directed, i.e. the effect of the applied therapy is monitored [24].

ROTEM is not used for diagnosing platelet function disorder, although it can indirectly point to a disruption in the platelet number or function [25]. Also, it is not possible to detect hemostasis disorder resulting from von Willebrand disease or the use of antiplatelet drugs by applying only the ROTEM method; rather it is necessary to combine the ROTEM method and aggregometry tests [26]. Therapeutic algorithms, which are based on the ROTEM method and founded on the replacement of the fibrinogen concentrate and the prothrombin complex concentrate (PCC), but also on the application of antifibrinolytics in trauma, liver transplantation, cardiac surgery, and other branches of medicine, reduce the transfusion of allogenic blood [27]. In his clinical study, Anderson showed that, because of the introduction of the ROTEM method, the transfusion of erythrocytes, FFP, and thrombocytes was performed in a significantly reduced number of patients [28]. The ROTEM method did not demonstrate any influence on the reduction in mortality, but it did influence the reduction in perioperative blood loss, as well as blood and blood product replacement [29]. Larsen studied the diagnostic properties of the TEG method (kaolin activated) and the ROTEM method, and concluded that ROTEM provided more precise information on all the investigated coagulopathies and enabled swifter diagnostics, while the TEG method failed to show satisfactory results in differentiating between dilutional coagulopathy and thrombocytopenia induced coagulopathy, which could lead to unnecessary platelet transfusion (Figures 5 and 6) [11],[30].

Figure 5. ROTEM – Monitored parameters From: Dimić N, et al. Procena obima intraoperativnog krvarenja i strategije za smanjenje rizika i nadoknadu volumena, in: Kalezić N. Perioperativna medicina 1. Medicinski fakultet, Beograd; 2020; 303-324.

Figure 6. ROTEM – Normal finding From: Dimić N, et al. Procena obima intraoperativnog krvarenja i strategije za smanjenje rizika i nadoknadu volumena, in: Kalezić N. Perioperativna medicina 1. Medicinski fakultet, Beograd; 2020; 303-324.

ADVANTAGES AND SHORTCOMINS OF THE POC METHODS

As opposed to standard laboratory tests, only a very small amount of blood (up to 5 ml) is necessary for performing the POC methods, without additional processing or preanalytical delay. This is especially important in patients who have been bedridden for a longer period of time in intensive care units, and who require daily (sometimes even more frequent) coagulation status assessment. At the same time, standard laboratory tests, which sometimes require taking up to 20 ml of blood, may worsen the hemostasis potential of the patient. The blood sample needed for performing POC methods can be taken to the laboratory; POC methods can be carried out in the immediate proximity of the patient (near-patient); they can be performed in the operating theatre, in intensive care units, or even in the field [31]. However, their main advantage is quick availability of results [32]. In comparison with standard laboratory coagulation tests, which can take from 40 up to 90 minutes, which is unacceptable in situations of acute bleeding, since the results do not reflect the current state of the coagulation system, POC tests can provide information on the patient’s coagulation status within 15 minutes. Thus, POC tests are an almost immediate clinical representation of the patient’s coagulation status [33]. This is why it is an unwritten rule that, when it is not possible to perform POC diagnostic methods, whose application can make up for the shortcomings and limitations of standard coagulation tests, decisions on blood and blood product replacement during an operation, are made on the basis of clinical signs [13],[34].

Viscoelastic tests enable early assessment of the need for massive transfusion and for guided therapy with specific hemostatic drugs, coagulation factor concentrates, and blood products [35]. Several cohort studies have shown that hemostatic therapy based on POC testing is connected with a reduced need for blood transfusion (replacement), a reduced incidence of adverse effects caused by transfusion, as well as with a better final outcome [36]. These tests help doctors recognize patients who are at increased risk of bleeding, and who can greatly benefit from the cell-saver method, as well as patients who would benefit from prophylactic antifibrinolytic application [37].

Patients with acute coronary syndrome are often recommended to stop antiplatelet therapy several days prior to cardiac surgery. However, discontinuing these drugs significantly increases the risk of early graft or stent thrombosis after cardiac surgery, which is why antiplatelet drugs are, nevertheless, applied until the day of the surgery, even though this increases the risk of perioperative and postoperative bleeding [38]. Application of dual antiplatelet therapy (aspirin and clopidogrel) can lead to platelet aggregation disorder, and it is also connected to increased blood loss, increased risk of surgical reintervention, and prolonged recovery time in an intensive care unit, where POC methods play a significant role [39].

Perioperative platelet function assessment in cardiac surgery, and in other branches of surgery as well, can be performed with the aid of the Multiplate or the TEG test. Hemostatic therapy guided in this way is linked to a decrease in postoperative bleeding, a decreased need for blood product replacement, improved surgery outcomes, decreased financial costs, and a significant decrease in mortality [40]. The use of transfusion algorithms based on POC methods has demonstrated a decrease in the need for blood product replacement and a decrease in blood loss in cardiac surgery [41]. In a recent cohort study, which included 3,865 cardiac surgery patients, firstline therapy based on the transfusion of the fibrinogen concentrate and the prothrombin complex concentrate, and guided by the application of POC methods (ROTEM and Multiplate) was closely connected with a significant decrease in the need for allogenic blood transfusion, a reduction of massive transfusion incidence, reoperation and thromboembolic complications, as well as with economic savings [27],[42]. Patients with surgical bleeding who require urgent re-exploration are identified more easily with the aid of POC methods than with standard laboratory tests, which can show abnormal values up to several hours after cardiac surgery [43].

In major surgery procedures, in case of intraoperative bleeding, the decision on blood product replacement is made based on the clinical assessment of the patient’s status. Intraoperative bleeding is a dynamic process with potentially life-threatening consequences, which, together with the administration of crystalloid fluids, results in the hemodilution and depletion of coagulation factors [44]. While the hemoglobin concentration and platelet count are determined within 15 minutes, obtaining standard laboratory test results takes from 45 to 90 minutes [31]. POC methods need significantly less time for coagulation status assessment [45]. Basing the decision on blood product replacement during intraoperative bleeding on POC methods contributes to a significant reduction in blood product replacement, a reduction in all the possible consequences and risks which this method entails, as well as to a significant improvement in the outcomes of the surgical procedure [46]. Experience has shown that, in serious acute bleeding, therapeutic algorithms need to be directed towards increasing the value of the ROTEM analysis parameters, above the normal reference range [47].

POC methods have an increasing role in diagnosing septic conditions. Bearing in mind that sepsis biomarkers, such as procalcitonin and interleukin-6, can be elevated in traumatized patients or patients undergoing surgical procedures, when there is no infection, the parameters of POC methods may play a role as biomarkers in early detection of sepsis in critically ill patients. Namely, in a study involving 56 patients with serious sepsis and 52 patients who had undergone surgical procedures, Adamzik demonstrated that the thromboelastometry parameter – the lysis index, was a more reliable biomarker of sepsis than procalcitonin, interleukin-6 and C-reactive protein (CRP) [48].

Current knowledge on the pathology of trauma-induced coagulopathy speaks to the great significance of hyperfibrinolysis [49]. In bleeding, fibrinogen is the first factor whose values drop below reference values [50]. The main cause of reduced clot firmness in trauma patients is, in fact, damage in fibrin polymerization, caused by a reduced concentration of fibrinogen [51]. Serious fibrinogen deficiency in trauma patients is a warning sign for possible hyperfibrinolysis [52]. ROTEM is a swift and reliable method for detecting perioperative fibrinolysis [53]. In a small retrospective study, involving 36 trauma patients, divided into two groups, the therapeutic algorithm based on FFP transfusion without the application of the ROTEM method was compared to the therapeutic algorithm based on ROTEM testing and administering the coagulation factor without FFP transfusion. A significant difference was found, with the group which was tested with the ROTEM method showing a reduction in transfusion and adverse transfusion events [54]. A prospective study, including 517 trauma patients, showed that thromboelastography enabled quick coagulation status assessment in trauma patients, swift detection of hyperfibrinogenemia, and early administration of the fibrinogen concentrate, which is linked to a much higher survival rate [55]. Additionally, the application of POC methods significantly reduces blood loss and the need for blood and blood product replacement in trauma patients. However, it does not reduce mortality [56].

Naturally, POC methods have their limitations. These are, primarily, the problem of standardization (which is an issue with standard laboratory tests as well) and the cost. The standard temperature for performing POC tests is 370 C, which may impede the detection of coagulopathies occurring in states of hypo- or hyperthermia. Also, coagulopathies resulting from normal physiological state disruption cannot be detected; for instance, abnormal blood pH value, abnormal calcium ion concentrations in the blood, or abnormal hematocrit values [57]. The cost of performing POC tests (equipment, reagents, solutions, maintenance) exceeds the cost of standard laboratory tests. Combined aggregometry and viscoelastic testing costs between 25 and 35 euros, while standard laboratory testing costs less than 10 euros. However, this difference in cost can be compensated by more rational decisions on blood and blood product replacement and application of other therapy, which are made based on POC test results [58]. In his study, Nuttal demonstrated that POC method application resulted in lesser postoperative blood loss, thereby necessitating less blood and blood product replacement [46]. In a study involving 1,422 patients, who had undergone cardiac surgery procedures, Spalding concluded that the application of POC methods led to a financial saving of 50 percent, which was the result of decreased blood and blood product replacement and a decrease in the application of other therapeutic agents [20]. In a retrospective study involving 3,865 cardiac surgery patients, Görlinger compared the financial effect of coagulation therapy application, a year before (2004) and a year after (2009) the introduction of the ROTEM method and the formation of therapeutic algorithms based on ROTEM test results in cardiac surgery patients. A saving of 34.3 percent was found after POC methods application, and it was concluded that the hospital had saved 50,000 dollars due to the application of therapeutic algorithms guided by the ROTEM method. The economic saving resulting from the reduction in blood and blood product replacement can compensate or even exceed the increase in costs resulting from coagulation factor concentrate expenditure [42].

CONCLUSION

Reference literature analysis has shown that POC testing is faster and more comprehensive than standard laboratory testing and it provides for a more efficient and cost-effective approach to treatment. Standard laboratory tests are not suitable for quick and precise perioperative identification of disorder and deficiency in coagulation factors. On the other hand, POC methods enable a quick differential diagnosis of disorder and deficiency in coagulation factors, in preexisting and newly developed coagulopathy. Therefore, it is justified to recommend the use of POC methods in creating therapeutic algorithms for the treatment of patients with specific perioperative coagulation disorders. Additionally, POC methods play a role in diagnosing sepsis, and may even be important in predicting mortality in septic patients, although the influence of these tests on reducing postoperative mortality has not definitively been confirmed. Since no single POC method can cover the whole specter of hemostasis, it is recommended to combine aggregometry with viscoelastic methods. Treatment of coagulopathies and disorders resulting from perioperative blood loss should be founded on algorithms established on the basis of POC methods