Low fibrin(ogen) levels lead to a poor clot firmness. In general, there is presently a general opinion that clot firmness may be most relevant than thrombin generation in the pathophysiology of severe postoperative bleeding in cardiac surgery.

Viscoelastic tests provide a measure of clot firmness based on the viscoelastic properties of the clot, namely, expressed in terms of “amplitude” (mm) of the formed clot. For TEG, this is represented by the maximum amplitude (MA) and for ROTEM as maximum clot firmness (MCF). However, these measures provide a combined assessment of the interaction between fibrin(ogen) and platelets and are therefore not specific for fibrin(ogen) contribution to clot firmness. To achieve this specific measure, the platelet contribution must be eliminated, and modified TEG/ROTEM assays are available. Basically, platelet contribution is blunted by a GPIIbIIIa inhibitor in functional fibrinogen (FF) TEG and by cytochalasin D in FIBTEM (ROTEM).

The resulting values of MA and MCF at FF-TEG or FIBTEM are representative of fibrin(ogen) alone contribution to clot firmness.

There is an acceptable correlation between viscoelastic tests measure of fibrin(ogen) contribution to clot firmness and fibrinogen levels as measured with the conventional Clauss method [50] (Fig. 8.3). However, the two measures are not interchangeable, since one represents fibrinogen concentration, the other a functional fibrinogen activity.

At present, it is still unclear which levels of postoperative fibrinogen should lead to fibrinogen supplementation. Some authors suggest trigger values of 1.0–2.0 g/L [51–53], while others suggest higher values in the setting of cardiac surgery [54].

A specific issue is represented by the possibility of prophylactic correction of low preoperative fibrinogen levels. The recently released guidelines for the management of severe perioperative bleeding (European Society of Anaesthesiology) [54] consider the possibility of correcting values <3.8 g/L, based on a single, small randomized controlled trial [47]. However, an analysis of the existing literature [55] has demonstrated that preoperative fibrinogen levels have a very poor (about 10 %) positive predictive power for prediction of severe postoperative bleeding. A trigger value of 3.8 g/L would lead to an unacceptable 90 % rate of superfluous treatments. Trigger values settled around 2.0 g/L seems more adequate, but however a strategy based on postoperative values is certainly more reasonable.

Fibrinogen can be supplemented using three different strategies. FFP contains fibrinogen but actually at a very variable concentration. A reasonable value can be settled at about 2 g/L [56], and therefore, the amount of FFP to increase fibrinogen levels by 1 g/L is about 30 mL/kg. Therefore, the same considerations applied to FFP as a source of factors increasing thrombin generation may be applied to FFP as a source of fibrinogen, the main problem remaining the large dose required to achieve a clinically relevant benefit.

A second source of fibrinogen is represented by cryoprecipitates. The fibrinogen content in cryoprecipitates is variable, but a value of 12 g/L seems reasonable [57]. In some countries, cryoprecipitates are the standard of care for fibrinogen supplementation in case of acquired bleeding; however, they are not available in many European countries [58].

Fibrinogen concentrate is probably the most effective treatment for fibrinogen deficiency. The high concentration (20 g/L) allows treatment without volume overload, and its purified nature limits the risks associated with FFP and cryoprecipitates. The suggested dose is 25–50 mg/kg [54]. Fibrinogen concentrate is not licensed for acquired bleeding in the UK and USA [58].

Many studies suggest to settle the fibrinogen dose on the value of MCF at FIBTEM [17–19]. A target value of 22 mm at FIBTEM is suggested, and an equation to achieve the target has been proposed [59, 60]:
However, following this equation leads to administration of large doses of fibrinogen concentrate. At present, we are lacking an evidence-based information with respect to the exact fibrinogen trigger values, targets, and dosage.

A recent RCT on postoperative fibrinogen concentrate administration demonstrated the efficacy of this strategy in reducing postoperative bleeding and transfusions [61]. This study suggested that a target MCF at FIBTEM in the range of 15–17 mm is enough to avoid severe bleeding.

Finally, FXIII has been proposed to increase clot firmness in the setting of the bleeding patient. However, a recent randomized controlled trial of FXIII supplementation in cardiac surgery failed to demonstrate any effect on bleeding and transfusions [62].

The diagnosis of thrombocytopenia is based on conventional cell count. However, thrombocytopenia may be suspected in case of low values of clot firmness (MA-MCF) with normal values of functional fibrinogen. When applying this concept, however, it should be considered that the values of MA/MCF are not linearly correlated with the real viscoelastic properties of the clot.

The only therapeutic option is transfusion of platelet concentrates. Compensating a low platelet count with large doses of fibrinogen is a theoretical option which has never been confirmed in large studies.

Before surgery, coronary patients are usually treated with aspirin and/or P2Y12-inhibitors (ticlopidine, clopidogrel, prasugrel, and ticagrelor). Aspirin determines a mild increase in postoperative bleeding [64]; conversely, P2Y12-inhibitors are associated with patterns of severe bleeding and risk of reoperation [65, 66].

The existing guidelines suggest 5 days of drug discontinuation before surgery [67, 68], but it is admitted that even three days may be enough [67]. Platelet recovery after antiplatelet drug discontinuation is highly individual and somehow unpredictable [69]; for this reason, the use of PFTs to assess the correct timing of surgery after P2Y12-inhibitors discontinuation is considered a reasonable option [54, 70]. Conventional tests confirm that preoperative assessment of platelet function may predict postoperative bleeding: a value <40 % of ADP-dependent platelet activation at light transmission aggregometry was found predictive of severe bleeding in clopidogrel-treated patients [71].

Multiple-electrode aggregometry (MEA) has been proposed to assess ADP-dependent platelet reactivity in P2Y12-inhibitors treated patients. A study based on the Multiplate technology (Roche Diagnostics GmbH, Mannheim, Germany) proposed a minimal value of 31 [U] at the ADP test as a suitable cutoff level for admitting patients to surgery, with a negative predictive power of 92 % [72]. Subsequently, a combination of ADP test and TRAP test was found to offer better accuracy: a minimal value of TRAP test of 75 [U] in patients with an ADP test <22 [U] was associated with a 100 % negative predictive power for severe bleeding [73] MEA was found useful even to detect patients that may be operated after a time from drug discontinuation shorter than five days [74].

Other POC-PFTs have shown an association between ADP-dependent preoperative platelet function and postoperative bleeding. Modified TEG (TEG platelet mapping) may predict postoperative bleeding in clopidogrel pretreated patients [75]. A preoperative value of MAadp <42.5 mm had a 78 % sensitivity and 84 % specificity for predicting excessive bleeding [75].

The VerifyNow (Accumetrics Inc, San Diego, CA, USA) is another POC-PFT which can aid in determining the timing of cardiac surgery: preoperative values of ADP-dependent platelet inhibition >21 % in clopidogrel-treated patients have been found associated with a higher surgical revision rate and blood use in off-pump coronary surgery [76]. A previous study demonstrated an association between preoperative VerifyNow P2Y12 platelet inhibition and blood loss and blood use in coronary patients under double antiplatelet therapy until three days before surgery [77].

Recently, ROTEM has provided a ROTEM platelet device based on multielectrode aggregometry, but no data are available at present.

After surgery, PFTs show different degrees of platelet dysfunction, depending on the preoperative use of antiplatelet agents, the type of surgery, and the duration of CPB. Low levels of platelet function after surgery have been associated with postoperative bleeding [78, 79]. Algorithms including PFTs for the diagnosis of postoperative bleeding exist, including trigger values for desmopressin infusion or platelet concentrate transfusions. A recent study proposed MEA test values for triggering interventions aimed to increase platelet function: a TRAP test <50 [U] and/or an ASPI test <30 [U] and/or an ADP test <30 [U] [34]. Previously, another study suggested the following values: TRAP test <50 [U] and/or an ASPI test <20 [U] and/or an ADP test <30 [U] to trigger platelet concentrates transfusions in actively bleeding patients after cardiac surgery [36]. These values, however, are empirical and not yet validated; they have been proposed within algorithms including other POC tests to rule out other possible causes of bleeding. The combination of drug-related factors with operation-related factors makes difficult a clear determination of a specific value of postoperative platelet activity responsible for severe bleeding.

The most reasonable approach to the treatment of drug-related platelet dysfunction bleeding is the transfusion of platelet concentrates. In patients treated with ticagrelor, the transfused platelets may be attacked by the still active forms of the drug, given the pharmacokinetic of ticagrelor.

Desmopressin (0.3 μg/kg) may be used to treat surgical bleeding due to acquired platelet dysfunction, especially in the setting of acquired von Willebrand disease (aortic stenosis patients) [80] and after CPB. Despite a low level of evidence, this approach is included in the European Guidelines [54].

When bleeding is associated to primary hyperfibrinolysis, the use of an antifibrinolytic agent is appropriate. Several studies and meta-analyses have shown the synthetic lysine analogues and aprotinin to be effective in reducing bleeding and the need for blood transfusion during high-risk cardiac surgery, as compared with placebo [95–99]. However, the blood conservation using antifibrinolytics in a randomized trial (BART) demonstrated a strong and consistent negative mortality trend associated with aprotinin compared to lysine analogues, leading to aprotinin withdrawal worldwide by manufacturer in 2007 [100]. The synthetic lysine analogues tranexamic acid (TXA) and epsilon-aminocaproid acid (EACA) inhibit in a reversible way the fibrinolytic enzyme plasmin. Both are indicated to reduce the number of patients who require blood transfusion and to reduce total blood loss after cardiac operations. However, these agents are slightly less potent drugs, and the safety profile of these drugs is less well studied compared with aprotinin [66].

A wide range of dosages of antifibrinolytic drugs has been proposed [101]. Suggested TXA doses during cardiac surgery varies from a loading dose of 12.5 mg/kg followed by an infusion of 6.5 mg/kg/h [102] up to higher doses such as 20 g administered during a period of 12 h [103]. Often, the chosen regime is not denoted by pharmacokinetic studies. It has been observed that plasma levels are maintained over the therapeutic level for most of the duration of cardiopulmonary bypass with a regime of 10 mg/kg loading dose followed by an infusion of 1 mg/kg/h for up to 2 h after arrival in intensive care unit. The dosing of TXA is important because its side effects are dose related [104]. The administration of high doses of TXA has been associated to a higher rate of seizures in the postoperative period [104, 105]. The safer scheme and optimal dosing regimen for lysine analogues in cardiovascular surgery has still to be established [101]. Currently, a new antifibrinolytic drug CU-2010 is in clinical development [106].

Monitoring the fibrinolytic activity can be made by the determination of D-dimers, FDP, and XDP plasma levels or using viscoelastic tests. The D-dimer, FDP, an XDP levels are not quickly and immediately available. Besides, D-dimers are not useful to determine the etiology of coagulopathy in situations of perioperative bleeding, as its concentration is usually increased postoperatively in all patients [81]. Viscoelastic hemostatic assays such as TEG and ROTEM are the current most useful clinical hemostatic test used in perioperative setting to determine hyperfibrinolytic status in bleeding patients. However, it has been argued that the viscoelastic tests only detect the most severe forms of systemic hyperfibrinolysis, but lower degrees of fibrinolysis may critically influence the outcome too [107].

The TEG parameters of lysis are the Ly30 and Ly60 (percentage of lysis 30 and 60 min after maximum amplitude respectively) and the EPL (estimated percent lysis parameter). Both parameters measure the decrease in amplitude of the trace as a function of time and reflect the loss of clot integrity due to clot lysis [108]. ROTEM parameters of lysis are maximum lysis (ML) [%] and clot lysis index 30 or 60 min after maximum clot firmness (CLI30; CLI60) [%]. Monitoring can be performed in EXTEM or HEPTEM tests that allow for timely detection of hyperfibrinolysis even under the conditions of anticoagulation with heparin during cardiopulmonary bypass. In addition, the APTEM test consists in a specific ROTEM assays that test the in vitro effect of antifibrinolytics (i.e., aprotinin) in a whole blood sample of a bleeding patient [109]. According to some published protocols in cardiac surgery, hyperfibrinolytic state needing antithrombotic therapy is diagnosed in the presence of EPL >7.5 % in TEG analysis [110] or CLI60 <85 % according to ROTEM analysis during or after CPB [36].

Exposure to CPB puts in jeopardy the fragile hemostatic balance of the young. The mechanisms of intraoperative coagulation alterations are the same as for adult patients, but the impact they have on the children hemostasis is more pronounced. On CPB levels of coagulation, factors and platelet counts are lower than the adult ones because the preoperative coagulation alterations sum up with coagulation factors consumption and massive dilution by CPB priming. In an average adult, the CPB priming volume is 1/3–1/4 of total blood volume (i.e., 1000–1500 mL of priming to 4200–4500 mL of total blood volume). For a newborn, it can be 1–1.5 times the total blood volume (i.e., 250–300 mL of priming volume to 200–250 mL of total blood volume). In a study in neonates, at the initiation of CPB, the authors found 50 % decrease in circulating coagulation factors and antithrombin levels, as well as 70 % of platelet count reduction [131].