New methods for bleeding monitoring

Bleeding is a potentially preventable reason of the death among patients during major surgery. Appropriate monitorization is necessary to perform optimum resuscitation. However, conventional coagulation tests have some limitations. In recent years, point of care (POC) tests has been developed to improve patient safety in the presence of clinical bleeding POC tests measure viscoelastic properties of full-thickness clot formation in the beginning of bleeding. In this review, both of advantage and disadvantage of monitorization tests during bleeding management is explained. Review Article New methods for bleeding monitoring Omer Baygin1, Ozlem Kaya1, Ayten Saracoglu1* and Kemal Tolga Saracoglu2 1Department of Anesthesiology and Intensive Care, Marmara University Medical School, Turkey 2Department of Anesthesiology and Intensive Care, Health Sciences University Medical School, Turkey Received: 22 October, 2018 Accepted: 29 October, 2018 Published: 30 October, 2018 *Corresponding author: Ayten Saracoglu, Department of Anesthesiology and Intensive Care, Marmara University Medical School, Istanbul, Turkey. Tel: +90216 6254545; Fax: +90216 6254639; Email: anesthesiayten@gmail.com


Introduction
Bleeding is one of the feared complication especially in patients undergoing consecutive anesthesia and invasive surgical procedures [1,2]. Routine laboratory coagulation tests and measurement of platelet count are the most commonly used methods to defi ne coagulation status of the patient. However, there are some limitations with conventional tests, point of care (POC) tests developed to overcome with these limitations [2].
The main goal of anesthesiologist is to prevent deterioration of hemostasis due to bleeding and bleeding complications and reduce the rate of morbidity and mortality [3,4]. The causes of perioperative bleeding may include platelet dysfunction, excessive fi brinolysis, hypothermia, preoperative anemia, lack of coagulation factors, or dilution. Among those, hyperfi brinolysis is also most important factor in the development of post-traumatic coagulopathy [3]. Bleeding monitorization is required to patient-specifi c transfusion planning and to avoid undesirable effects of excessive volume, otherwise increase the perioperative complications and risks due to unnecessary allogeneic blood transfusions [5]. Although there is no internationally accepted management protocol in bleeding patients, algorithm-based transfusion protocols depend on POC tests produce better results than individual decisions [6].
Bleeding monitoring should consist of the patient's history of bleeding and laboratory tests to reveal increased bleeding risk but cannot exclude exogenous factors [7]. Guidelines for management of bleeding monitorization suggest that the amount of platelet, activated partial thromboplastin time (a PTT), prothrombin time (PT), and fi brinogen levels should be measured [3].

History of coagulation tests
Prothrombin time was developed by Armand Quick in 1935 to evaluate liver disease, which shows the extrinsic pathway in the recalcifi ed, citrated blood sample with the addition of tissue thromboplastin and the fi rst formation of the clot form [8,9]. Activated partial thromboplastin (a PTT) time was fi rst developed in 1953 and modifi ed in 1961. A PTT refl ects the time required for clot formation in seconds, when the plasma is mixed with negatively charged phospholipids and particulate or soluble activators of contact coagulation factors.
The history of the viscoelastic tests coincides with the beginning of the 20th century and the fi rst prototype was thromboelastographic, introduced by Hastert in 1948 and developed by Haemonetics [10,11,12]. It evaluate initially coagulation factor defi ciencies detection, later anticoagulant effect, thrombocytopenia, and fi brinolysis and we could have information about the formation of the clot, the kinetics, the stability of the clot [13,14]. More information on the quality of coagulation than quantitative (numerical) values is available [11].
Rotational thromboelastometry (ROTEM) is a compact, portable point-of-care instrument introduced in 1995 (15). The working principle is like thromboelastography and there are slight differences between them [16].

Coagulation cascade
The cell-based coagulation cascade model consists of a series of complex cellular and biochemical reactions. However routine plasma-based coagulation tests ignore cellular component of coagulation, so they are inadequate to solve bleeding problems [4].
The extrinsic pathway begins with the release of the tissue factor and allows the Factor (F)X to become active by activating the FVII. Whereas the extrinsic pathway is activated after the tissue damage, the intrinsic pathway begins as a result of damage to the blood vessels. The intrinsic pathway activates factor XII, which released after contact to the damaged vessel surface with blood, and eventually activates the FX, resulting in the activation of FXI and FIX.
Activation of FX allows the common pathway to be reached.

Standard-baside coagulation tests
Standard laboratory tests such as activated partial thromboplastin time and prothrombin time give the results obtained from the patient's plasma and do not account for other items of coagulation such as platelets and fi brin [5]. While tests such as platelet count, platelet aggregation and Clauss fi brinogen measurements, and fi brin degradation products can assess individual items of coagulation, but it does not take account of interactions in blood and contributions of the cellular content [17,18]. Those do not involve multifactorial states such as endothelial effects in clot formation, interactions of platelets with each other, and subsequent thrombin formation, and fi brinolysis. Many laboratories can provide these tests and can be used to predict transfusion and mortality [18].
While the PT measurement shows hereditary or acquired defi ciencies of FII, V, VII, X and fi brinogen; aPTT measurement reveals FVIII, FIX and FXI defi ciencies and the use of anticoagulants of direct action type [8]. The aPTT measurement shows the intrinsic pathway and common pathway whereas PT measures the extrinsic pathway and common pathway. In patients with ongoing hemorrhage, the PT measurement is superior than a PTT, due to better correlation and the absence of interaction with many situations [19].
Although standard laboratory tests are the most commonly used for bleeding monitorization, the accuracy of bleeding monitorization has not been fully demonstrated [14].
Standard laboratory tests are both time consuming and useless with long time results nearly 45 min, especially in trauma patients, which rapid evaluations are needed in the fi rst hours (19). Conversely, bedside viscoelastic tests can provide qualitative assessment of patients' coagulation status within 5-10 minutes. Hyperfi brinolysis conditions cannot be measured by standard tests. However hyperfi brinolysis in trauma patients is associated with poor prognosis [3,19]. Conventional tests are insuffi cient to investigate the acquired defi ciencies of pro-and anti-coagulants due to thrombomodulin [1].
Fibrinogen is the fi rst depleted factor in the massive hemorrhagies, which is the basis of effective coagulation.
Concentration can be measured indirectly by the Clauss method. Fibrinogen is proportional to the clotting time and is measured using calibration standards.
Standard-bedside tests do not involve hematocrit effect in effi cacious plasma volume in measurements. depends on the same principles and gives the same graphical chart [16]. These differences include optical detection system, immobilization of the cuvette, and oscillation of the needle / wire system. When ROTEM delta analyzes each parameter on separate channels, the TEG 6 and ROTEM sigma analyzes at the same time. TEG is used coalin, EXTEM is used tissue factor, and INTEM is used contact activator ellagic acid as activator [16]. VEM, also used in cases such as sepsis, has been proven in several systemic reviews, demonstrating increased severity and mortality, especially in hypocoagulation situations. It can also show the hypercoagulation state that occurs after hours or days after trauma or surgery. Platelet and enzymatic hypercoagulation can also be distinguished by new parameters derived from the VEM curve.

Platelet function monitoring
Platelets are necessary as well as functional fi brinogen in clot formation and stability. When vascular endothelium is injured, formation of thrombin is required in order to maintain hemostasis. In cases where vascular endothelin is intact, it is also necessary for the inhibition of thrombus formation. Therefore platelet function is a condition that must be assessed rapidly and essential with fi brinogen for hemostatic clot formation. Platelet function tests are also useful in monitoring hereditary platelet function abnormalities and antiplatelet medications, but are ineffective in demonstrating bleeding or acquired hemorrhagic syndromes [30].
Thrombocytopenia can be obtained simply by complete blood count and can be easily corrected by platelet transfusion. However, platelet function cannot be measured by standard laboratory tests. Platelet activity can be affected by antithrombotic drugs, as well as in many medical conditions, such as in traumatic brain injury or intracranial hemorrhage. Many point of care tests can show us platelet activity. Light transmission aggregometry, platelet-rich plasma is used and is the gold standard for evaluation of platelet activation. However, the complexity of the device and the long-term outcome time limits the use of some central laboratories outside the laboratories. TEG platelet mapping is a modifi cation of TEG and platelet activation in platelets can be assessed by initiating platelet aggregation with the addition of arachidonic acid or adenosine diphosphate to the sample blood [31].
The platelet function analyzer (PFA-100) (Siemens Diagnostics, Deerfi eld, Ill., USA) uses citrated whole blood passing through disposable cartridges and obtains reliable and reproducible results. PFA-100 has sensitivity for von Willebrand disease screening and presentation of moderateto-severe platelet abnormality but it is insuffi cient to demonstrate the effects of antiplatelet agents [19]. Verify Now (Accumetrics, San Diego, CA, USA) tests are available for aspirin, thienopyridines, and glycoprotein IIb / IIIa antagonists and can be used preoperatively to assess risk of bleeding.
PFA-100 was not suffi cient fort the assessment of postoperative blood loss in patients undergoing cardiovascular surgery. In addition, research in patients receiving clopidogrel has also been in the background of evaluating blood loss in patients and in the management of blood transfusion. However, evaluation of platelet function also has high specifi city.
The Cone and Plate (let) analyzer is effective in screening primer hemostatic disorders such as von Willebrand with accumulation of platelets from whole blood on the artifi cial surface [32]. Platelet Works is a point of care device that provides an electronic impedance-based cell count used in platelet count and aggregation [33].
Whole blood aggregometry is a commercially available platelet aggregometer that can overcome above the inadequacy of conventional tests by screen fi ltration pressure method [34].
This device displays platelet aggregation by measuring wholeblood resistance while the whole blood passes through the microelectrode after platelet activation has taken place.
Multiple electrode platelet aggregometry using Wholeblood Impedance Aggregometry (Multiplate) may show risky patients in terms of postoperative platelet transfusion.  Compared with viscoelastic tests, they give better total hemostatic capacity. This provides more information on bleeding monitoring. However, as the platelet rich / poor plasma environment must be created, there is no place for rapid diagnosis.

Thrombine formation tests
However, even an experienced laboratory employee obtained the results by running for more than 1 hour. Because of that this test did not fi nd a universal application area. Viscoelastic coagulation tests evaluate the coagulation state in a static (non-current) state (not an endothelium blood vessel) in cuvette [2]. For this reason, the clinical situation must be considered in evaluating these results in vitro.

Limitations in point of care tests
Although viscoelastic POC tests may show excessive bleeding after cardiopulmonary bypass, effi cacy of predicting bleeding is still controversial. Defi nition of the thrombosis with these devices is time-consuming and does not have a standardization for extended clinical use [37].
TEG and ROTEM ensure that results are obtained 370C and are therefore missing in the prediction of coagulation disorders in hypothermic patients [17]. Point-of-care tests are less precise, with more variation in results. In general, research on price-performance is lacking.

Conclusion
Routine plasma-based tests may also be inadequate to demonstrate coagulopathic bleeding. Point of care tests play an important role in optimizing treatment by ensuring correct product delivery at the right time in the presence of clinical bleeding. They are also effective in the rapid assessment of bleeding especially intraoperatively and can also measure all coagulation parameters in a compact machine at bedside in many areas of medicine. TEG and thromboelastometry are still an important and rapidly developing part of the medicine. POC tests can be used to monitor the treatment of anticoagulants, hyper-and hypocoagulation, and reduce the use of blood products accurately and cheaply.