Compensates the reduction of oxygen-carrying capacity by the anemia by increasing cardiac output (limited response)
Adaptation to the low intrauterine oxygen tension by increasing hematocrit through Hb F (70 % in the neonate). Transfusion increases the risk of retrolental fibroplasia and necrotizing enterocolitis
More catabolism linked to decreased erythropoietin production: infant physiologic anemia (8–12 weeks of life)
Immunosuppression state: maternal antibodies could create a graft-versus-host disease (GVHD) and increase risk for infection (CMV)
Risk of anemia due to multiple blood drawn. Limit the volume and number of draws
Higher susceptibility to citrate intoxication
Efforts need to be made to decrease the number of transfusions and exposure to donors (use of pediatric units)
There is a reduction in the coagulation factors—vitamin K-dependent factors, contact factors, and natural coagulation inhibitors
Hypofibrinolysis and primary hemostasis are enhanced besides a deficient platelet function
Hemostatic balance is adequate besides prolonged cephaline time during the first 3–6 months of life
Comparison Between Neonatal and Adult Hemostasis
There are qualitative and quantitative differences between neonates and adults (see Table 11.2).
Table 11.2
Comparison between neonatal and adult hemostasis
Component | Neonatal function | Effect on the hemostasis |
|---|---|---|
Coagulation factors | ↓ F II, VII, IX, XI, XII ± Fibrinogen, F V ↑ F VIII | ↓Thrombin generation |
Primary hemostasis | ↑vWF ↓ Platelet function | ↑ Primary hemostasis |
Fibrinolysis | ↓ Plasminogen, t-PA, y α2 antiplasmin ↑PAI | Hypofibrinolysis |
Natural coagulation inhibitors | ↓AT, proteins C y S | ↓ Inhibition capacity of activated coagulation proteins |
Due to these developmental differences, activated partial thromboplastin time (aPTT) is prolonged during the first 3 months of life without increasing the risk of bleeding. Despite this fact, newborns have a good balance between procoagulant factors and natural anticoagulants with adequate hemostasis that allows undergoing surgery without an increased risk of bleeding. Other coagulation test like bleeding time is decreased, while the thromboelastogram shows a hypercoagulable trace with shortening of the reaction time (Miller et al. 1997b).
Congenital Heart Disease and Coagulation
Congenital heart disease is associated with coagulation anomalies. Platelets turnover anomalies with increased peripheral destruction and a higher rate of young “sticky” platelets associated with significantly reduced levels of large multimer von Willebrand factor that improve postcorrective surgery.
Cyanotic heart disease has been particularly associated with defects in coagulation. The increase red cell production secondary to chronic hypoxemia decreases platelet synthesis in an inverse related ratio. In addition, platelet life span is shorter with a decreased adhesion and aggregation properties. Recently, Gertler et al. (2014) in a study of platelet function in cyanotic pediatric patients by multiple electrode aggregometry showed that there was no clinically significant effect of cyanosis on baseline and perioperative platelet function, chest tube drain, and the number of exposures to blood products. The authors concluded that children under 1 year of age do not require a different approach with regard to platelet transfusions, independent of cyanosis.
Low cardiac output and liver congestion can decrease the production of coagulation factors especially the vitamin K-dependent ones (II, VII, IX y X). This deficit is also associated with reduced fibrinogen levels, antithrombin III (ATIII), factors V and VII, and proteins C and S that has been seen in patients with hypoplastic left heart syndrome usually before first-stage palliation but occasionally post Fontan completion. Controversy exists regarding the hypocoagulable state in pediatric patients with congenital heart disease. Is it real of just a technical artifact from traditional coagulation test and/or thromboelastogram (Spiezia et al. 2013). The fact is that the quantity of plasma, coagulation factors, and anticoagulant proteins in these patients is decreased in relationship with polycythemia. The reduction of pro- and anticoagulant factors associated with the peculiar physiology has a higher incidence of both thromboembolic events and bleeding complications. Due to this fact, this patient population requires a heightened vigilance and proactive therapy (Eaton and Iannoli 2011).
Clinical Evaluation and Preoperative Laboratory Testing
The most common laboratory testing used to evaluate coagulation in our patients is the PT, INR, aPTT, fibrinogen, and platelet count. During the perioperative period, the use of these testing has been questioned since they are not predictive of perioperative hemorrhage (Dzik 2004; Chee et al. 2008; Samkova et al. 2012). The abnormal results rate of “traditional” testing is 0.4–46 % which changes patient management in only 0–7 % and detects complications in only 0–8 % of the patients. There is no evidence in adult and pediatric medical literature that these preoperative testing improves patients outcome. In addition in major pediatric surgery, 64 % of PT and 94 % of aPTT of intraoperative measurements were outside the reference range, while impaired CT was observed in 13 and 6.3 % of ExTEM and InTEM ROTEM clotting times. The correlation between PT and aPTT to ExTEM and InTEM was poor. The recommended thresholds for PT and aPTT might overestimate the need for coagulation therapy (Haas et al. 2012). A good structured questionnaire about bleeding history has a better predictive value for perioperative hemorrhage than any other coagulation testing (Chee et al. 2008).
Coagulopathy and Cardiac Bypass
Cardiac surgery is one of the surgical procedures that affect more the hemostatic milieu. Patients with cardiomyopathy are hypercoagulable and require anticoagulant and/or antiplatelet therapy, which need to be held in the preoperative period. Following cardiopulmonary bypass (CPB), the balance is shifted to coagulopathy. Recent advances in CPB circuits reduce the inflammatory activation, but they still remain profoundly nonphysiologic. High-dose heparin avoids thrombosis of the CPB circuit, but low level of intravascular and intracircuit coagulation continues through bypass. The exposure of blood to the negatively charged surfaces of the CPB circuit triggers fibrinogen binding to the circuit, platelet, and coagulation activation (via factor XII). Once the platelets have been activated, they are not functional for the postoperative hemostasis. The extrinsic pathway is activated through the release of tissue factor during surgery in the surgical field. Both coagulation pathways activate thrombin with thrombotic and antithrombotic effects (Eaton and Iannoli 2011). The mechanical effect caused by the pump turbulence and active oxidation damages platelets and consumes coagulating factors. In addition the hemodilution effect by the CPB priming on the coagulating factors and platelets produces a hypocoagulable state upon CPB wean and through the postoperative period. In 5–7 % of the CPB runs the endothelium reacts to the surgical trauma releasing TPA (tissue plasminogen activator), which in hypocoagulable state causes a state of primary fibrinolysis. The activation of the coagulation by the CPC circuit, microembolic production, and tissue debris makes the patient prone to hypercoagulable state after heparin reversal with protamine and blood product use. CPB is a profoundly pro-inflammatory state with activation of multiple inflammatory humoral (e.g., interleukins, complement, etc.) and cellular mediators (e.g., monocytes and neutrophils). The inflammatory system and coagulation interact at many different levels by reducing inflammation, which reduces the activation of coagulation and vice versa (Cappabianca et al. 2011).
Monitoring of Coagulation
Laboratory-Based Coagulation Test
As previously stated, during the perioperative period, the use of traditional laboratory testing has been questioned since they are not predictive of perioperative hemorrhage. Furthermore, traditional testing in the perioperative period has been questioned due to the slow turnover (45–60 min) which by the time the results are back the patient situation may be completely different due to empiric administration of blood products and medication. It should not come to a surprise since traditional coagulation testing was not designed for quick coagulation diagnosis in the surgical period. The purpose of traditional testing is to predict isolated coagulation defects such as hemophilia (aPTT) and/or treatment with oral anticoagulants vitamin K antagonist (PT/INR). Prothrombin time and aPTT are based on nonphysiological situation, testing ex vivo fibrin formation after artificial stimulation. Citrated blood is centrifuged; plasma is recalcified and activated in a crystal tube in which several optic measurements detect the beginning of the coagulation process or fibrin formation. The velocity of thrombus formation, strength, and tendency to dissolution cannot be extrapolated from traditional testing. The effect of platelet, VWF, FXIII inhibitors, and cellular components does not affect traditional testing. Recent hemostasis model highlights the importance of platelet activation and amplification in its surface in live models of coagulation (Hoffman and Monroe 2001). Due to this fact, the role of traditional testing is limited in the live coagulation process.
Figure 11.1 shows the coagulation factors plasma level necessary to keep normal hemostasis in vivo. The relationship between coagulation time and coagulating factors is not lineal; it is exponential (Dzik 2004). Due to this fact, abnormal coagulation testing is not necessarily associated with critical plasma level of coagulation factors. Plasma levels of 20–30 % of coagulating factors are necessary to achieve a normal hemostasis, but it will require plasma levels of 40–50 % for traditional coagulation testing to be normal. Blood loss equivalent to 50 % of the blood volume replaced by crystalloids (dilution) is associated with abnormal coagulation testing but is not always associated higher propensity to bleeding. This is due to the fact that PT and aPTT are more affected by moderated decrease (to 75 %) of several factors than the decrease of an isolated factor below 50 % of its level.
Fig. 11.1
The coagulation factors plasma level necessary to keep a normal hemostasis in vivo. PT prothrombin time, aPTT activated partial thromboplastin time, NA not affected, vWF von Willebrand factor (Modified from Tanaka et al. 2009)
In the perioperative period, rarely there is an isolated decrease of a single factor; instead, usually there is generalized decrease of all factors including fibrinogen. Fibrinogen level is severalfold above the critical value of 100 mg/dl; below that is associated with bleeding tendency. This critical value is reached when there is a blood loss of 1.4 of the blood volume. When blood loss is about 2 blood volumes, critical levels of platelets and other coagulating factors is reached, and the tendency to further bleeding is enhanced (Hiippala et al. 1995). The recommended fibrinogen levels by most guidelines are higher (150–200 mg/dl) than the critical value described by the Hiippala et al. study in 1995 and are achieved sooner with lesser amount of hemodilution (Kozek-Langenecker et al. 2013; Spahn et al. 2013). It is difficult to picture that a complex process like the coagulation which requires changes in the physical properties of the blood from liquid to solid (coagulation) and from solid to liquid (fibrinolysis) can be characterized with only two coagulation tests, platelet count and fibrinogen level and D-dimer. These traditional tests do not evaluate the whole hemostatic process but only just some punctual aspects of it.
In the clinical setting either in the operating room or the intensive care unit when we are faced to a hemorrhagic patient, two questions need to be answered. First, what is the cause of the hemorrhage? Second, how can we fix it? Oftentimes this question is addressed based only on traditional coagulation testing, and the treatment is mostly empiric with overuse of blood product, which is not free of risks (Karam et al. 2015). Many times the lonely clinician is unable to answer these two questions with the right tools to achieve a goal-directed therapy with medication and/or blood products
Table 11.3 summarizes the limitations of conventional coagulation laboratory testing (Weber et al. 2013).
Table 11.3
Limitations of conventional laboratory coagulation analyses
Performed at a standardized temperature (37 °C) impeding the detection of coagulopathies induced by hypothermia |
The global test (aPTT, INR/Quick) reflects only the initial formation of thrombin in plasma and is unaffected by any of the corpuscular elements of the blood |
Conventional coagulation test does not provide any information about clot stability over time or regarding fibrinolysis |
The platelet count is purely quantitative and cannot detect preexisting, drug-induced, or perioperatively acquired platelet dysfunction |
Performing conventional laboratory analyses and reporting coagulation test results take 40–90 min after blood drawing |
Point-of-Care Monitoring
Thromboelastography (TEG®) and Thromboelastometry (ROTEM®)
The TEG/ROTEM attempt to address the initial two questions (What is the cause of the hemorrhage? How can we fix it?) by detecting the changes in the physical properties of the blood that reflect the hemostasis as a whole by the interaction of the whole blood components (Fig. 11.2).
Fig. 11.2
Diagram of the coagulation process showing the areas that are unseen by conventional testing (question mark)
The coagulation process can be divided into four phases that correspond with the current coagulation process:
- 1.
Primary hemostasis is the interaction between the vascular components, platelets and vWF.
- 2.
Second is the thrombin production triggered by the activation of factor X through the tissue factor (TF)-activated factor VII (FVIIa) complex.
- 3.
Third is the thrombus formation by the polymerization of fibrin and finally the clot stabilization by the factor XIII.
- 4.
Clot lysis.
Traditional coagulation testing (PT and aPTT) just reflects the beginning of thrombin generation (Fig. 11.2). Conventional coagulation testing cannot assess primary hemostasis, clot formation, and clot lysis.
History and Nomenclature
The thromboelastography (TEG®) was described first by Hellmut Hartert in 1948 in Heidelberg, before the introduction of aPTT in clinical practice. It was fairly popular in the 1980s as a useful technique to assess the hemostatic process particularly in the beginning of liver transplant programs. In Fig. 11.3 the different stages of coagulation can be compared between traditional testing (green arrow inside the black square) and TEG®/ROTEM® which in addition assess the thrombin formation; it also shows the developing of the clot and its strength linked to platelet function, fibrin, and factor XIII. Finally, TEG®/ROTEM® shows the lysis of the clot (long arrow).
Fig. 11.3
Coagulation process (above). Conventional testing only reports the beginning of thrombin generation (Black Square). TEG®/ROTEM® report in addition to thrombin generation, clot formation, and lysis
Even though TEG® was noted to be useful since the beginning, it was troublesome for clinical use due to the management complexity and extreme sensitivity to vibration. In 1993 Haemoscope Corporation IL, USA, patented the term TEG and currently Haemoscope is a division of Haemonetics Corporation (Fig. 11.4).
Fig. 11.4
Photograph of the TEG® 5000 hemostasis analyzer and related software screenshot (Used by permission of Haemonetics Corporation)
Latterly Pentapharm GMBH, Munich, patented a new device based on similar principles and used the term ROTEM (rotational thromboelastometry) (Fig. 11.5). Both tests are similar; some have the TEG ending (thromboelastography, thromboelastogram) and others the TEM ending (thromboelastometry, themogram). Currently, the technology has improved. Management is easier and less sensitivity to vibration, so it can be used in the surgical suite.
Fig. 11.5
Photograph of the ROTEM® delta hemostasis analyzer (Used by permission of Tem international GmbH)
Operation Principles
Both devices had a similar operation principles based on measuring the changes of the viscoelastic properties of the clot associated with the polymerization of fibrin. The blood sample is placed in the tray with other reagents. In the TEG® the hanging pin is still, detecting the movement of the tray that rotates from right to left 4.75 ° on the longitudinal axis. In the ROTEM® the tray is immobile and the hanging pin spins. Once the coagulation process starts with the production of fibrin, there is a restriction of the pin on the tray that is integrated electronically and represented in a graph, which has higher amplitude when there is higher resistance to movement (Fig. 11.6).
Fig. 11.6
Illustration of the ROTEM® detection principle (Used by permission of TEM international GmbH). A whole blood sample is placed into a cuvette and a cylindrical pin is immersed. Between pin and cuvette remains a gap of 1 mm, bridged by the blood. The pin is rotated by a spring to the right and the left. As long as the blood is liquid, the movement is unrestricted. When blood starts clotting, the clot increasingly restricts the rotation of the pin with rising clot firmness. This kinetic is detected mechanically and calculated by an integrated computer to the typical curves and numerical parameters. In TEG® the principle is similar, but the tray spins while the pin is fixed (adapted from image authorized by ROTEM®).
Graph Analysis and Parameters
We are going to describe the different parameters to interpret the ROTEM® (Fig. 11.7) and TEG® (Fig. 11.8).
Fig. 11.7
ROTEM® graph and parameters (TEMogram) (Used by permission of Tem International GmbH)
Fig. 11.8
TEG® hemostasis analyzer graph and parameters (Image used by permission of Haemonetics Corporation)
The time it takes since the measurement starts to the beginning of clot formation is called R (reaction time) in TEG® and CT (clotting time) in ROTEM®. It is the line since the start of the graph until it reaches 2 mm in amplitude. It is measured in seconds, and it shows the speed in fibrin formation. It is affected by plasma coagulation factors and circulating anticoagulants.
The time it takes between the amplitude of the graph to increase from 2 to 20 mm wide is called K (clot kinetics), α angle in TEG®, and CFT (clot formation time) in ROTEM®. It is also measured in seconds, and it relates the information about the kinetics of the clot formation. It is a nonspecific parameter since it is influenced by coagulating factors, anticoagulants, fibrin polymerization, and clot stability (platelets, fibrin, and FXIII).
Maximal graph amplitude (MA in TEG®) or maximum clot firmness (MCF in ROTEM®). It is measured in mm and is one of the most important parameters since it reports the maximal clot firmness through the increase in fibrin polymerization, platelets, and FXIII. The use of FIBTEM or functional fibrinogen can differentiate between the platelets or fibrinogen contribution to the clot firmness.
ML (maximum lysis in ROTEM®) is the reduction on clot firmness after MCF in relationship with time. It is presented in a percentage of the MCF. If the clot is stable, the ML is < 15 %. Fibrinolysis is considered when the ML > 15 %. In the TEG® the parameters LY30 and LY60 measure the percentage of lysis at 30 and 60 min. LY30 is considered abnormal when > 7.5 %.
In TEG®, there is a hemostatic index (CI, coagulation index) that integrates R, K, α, and MA. Normal range for CI is −3 to +3, values < −3 represent hypocoagulable, and > 3 is hypercoagulable states.
Table 11.4 shows normal values for TEG® and Table 11.5 for ROTEM®.
Table 11.4
TEG® hemostasis analyzer table of normal values used by permission of Haemonetics Corporation
R (min) | α (degree) | K (min) | MA (mm) | LY30 (%) | CI (coagulation index) | |
|---|---|---|---|---|---|---|
Kaolín | 4–8 | 47–74 | 0–4 | 54–72 | >7.5 %fibrinolysis | < −3 hypocoagulability > +3 hypercoagulability |
R-TEG | 0–1 | 66–82 | 1–2 | 54–72 | >7.5 %fibrinolysis | |
FF | n.d. | n.d. | n.d. | 9–29 | n.d. | n.d. |
Table 11.5
ROTEM® table of normal values used by permission of Tem International GmbH
CT (sg) | α-angle (°) | CFT (sg) | A10(mm) | MCF(mm) | LI30(%) | ML(%) | |
|---|---|---|---|---|---|---|---|
INTEM | 100–240 | 70–83 | 30–110 | 44–66 | 50–72 | 94–100 | 0–15 |
EXTEM | 38–79 | 63–83 | 34–160 | 43–65 | 50–72 | 94–100 | 0–15 |
FIBTEM | n.d. | n.d. | n.d. | 7–23 | 9–25 | n.d. | n.d. |
HEPTEM | 100–240 | 70–83 | 30–110 | 44–66 | 50–72 | 94–100 | 0–15 |
APTEM | 38–79 | 63–83 | 34–160 | 43–65 | 50–72 | 94–100 | 0–15 |
Types of Testing
