Fibrinolysis, antifibrinolytics and tangled terminology

The CRASH-2 study has shown that the use of tranexamic acid (TA), an antifibrinolytic agent, reduces mortality in those with traumatic bleeding. This trial has emphasized the importance of fibrinolytic activation in causing bleeding. The widespread use of thromboelastography in monitoring traumatic coagulopathy has led to the use of a new language around fibrinolysis, which is noticeably different from the classic terminology of fibrinolysis. This author suggests that in future publications, the word “thromboelastography” or ROTEM is prefixed before the new terminology to prevent confusion. The largest trial to date of antifibrinolytics: the Clinical Randomisation of Antifibrinolytics in Significant Haemorrhage (CRASH-2) trial assessed the effects of administration of TA within 8 h of injury in trauma patients with, or at risk of substantial bleeding (1); 20,211 trauma patients from 40 countries were randomly assigned within 8 h of injury to either TA (1 g load, then 1 g over 8 h) or placebo. The primary outcome was in-hospital mortality within 4 weeks of injury. All-cause mortality was significantly reduced with TA (14.5% vs. 16%; relative risk [RR], 0.91; 95% confidence interval [CI], 0.85-0.97; P = 0.0035). Bleeding-related mortality was also reduced (4.9% vs. 5.7%, respectively) without an increase in fatal or nonfatal vascular occlusive events. As a consequence of this trial, tranexamic acid has been incorporated into trauma bleeding protocols worldwide. The most recent publication from the CRASH-2 group (2) showed that tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid was less effective and could be harmful. This was based on strong evidence that the effect of tranexamic acid on death due to bleeding varied according to time from injury. Treatment within an hour of injury produced an RR of 0.68 (95% CI, 0.57-0.82; P < 0.0001). Treatment given between 1 and 3 h showed an RR of 0.79 (95% CI, 0.64-0.97; P = 0.03). However treatment given after 3 h seemed to increase the risk of death due to bleeding RR of 1.44 (95% CI, 1.12-1.84; P = 0.004). Despite the reduction in mortality, TA did not reduce transfusion requirements in CRASH-2. Why might this be? The first most obvious conclusion is that the study was not designed to detect a reduction in bleeding. Indeed the management of blood loss during trauma is not fine-tuned to compensate for losses-blood is given empirically and not against measure blood losses. Moreover, investigators were asked to use their normal practice, and the availability of blood components is variable among the 40 countries of the countries involved, and it is widely recognized that transfusion practice varies widely between units (3). Use of blood components is only a very crude measure of bleeding especially when no trigger for transfusion and stopping transfusion were given (4). It has also been clearly established that antifibrinolytic agents reduce blood loss in patients with surgical and both normal and traumatic injury. A systematic review of randomized trials assessing tranexamic acid in patients undergoing elective surgery identified over 50 studies (5). Tranexamic acid reduced the need for blood transfusion by a third (RR, 0.61; 95% CI, 0.54-0.70). Another systematic review of randomized trials of antifibrinolytic agents given for bleeding during the postpartum period concluded that TA reduced blood loss in postpartum hemorrhage (6). The utility of antifibrinolytics in reducing blood loss in surgery and death rate in traumatic bleeding implies that activation of fibrinolysis is important in the coagulopathy of bleeding. Fibrinolysis is responsible for clot breakdown. Traditionally, definitions of fibrinolytic activation have been separated into primary and secondary fibrinolysis: primary fibrinolysis represents increased fibrinolytic activity independent of other factors, whereas secondary fibrinolysis is a consequence of activation of coagulation and thus thrombin activation, which stimulates the endothelium to produce increased amounts of tissue plasminogen activator. Hyperfibrinolysis is the term used when fibrinolytic activity is greater than fibrin formation such that clot integrity is threatened, and there is clot breakdown (7). Tranexamic acid (fra/w-4-(anunomemyl)cyclohexanecarboxylic acid) is a synthetic derivative of the amino acid lysine that competitively inhibits the activation of plasminogen to the serine protease plasmin via binding to kringle domains. Tranexamic acid is also a competitive inhibitor of tissue plasminogen activator. Tranexamic acid blocks the lysine-binding sites of plasminogen, resulting in an inhibition of plasminogen activation and fibrin binding to plasminogen and therefore to an impairment of fibrinolysis (8). Perhaps the success of tranexamic acid in reducing mortality in traumatic bleeding should not be surprising as the potent stimuli of tissue plasminogen activator from the endothelium are adrenaline, vasopressin, histamine, hypoxic stress, and thrombin (9,10)-all present in varying degrees in a bleeding trauma patient. And yet activation of fibrinolysis in trauma and surgery has been surprisingly poorly studied in the past. Increased levels of fibrin degradation products (usually D-dimers, which are the breakdown product of cross-linked fibrin) are measured crudely by near-patient testing to exclude venous thromboembolism and can be measured precisely by enzyme-linked immunosorbent assays. Using D-dimer enzyme-linked immunosorbent assays D-dimer levels have been shown to increase perioperatively especially in cardiac surgery and liver transplantation (11). Brohi et al. (12) showed that D-dimer concentrations are raised in trauma patients at the time of hospital admission (median prehospital time 28 min), with the highest values in the most severely injured patients. A similar study from Japan (13) also noted increased fibrin degradation products in severely injured trauma patients. Future studies to study activation of fibrinolysis in bleeding patients using modern research assays are still required. Instead, over the last few decades, most of our information on surgical and traumatic injury comes from the use of thromboelastography, where assessment has shown that thromboelastographic detection of increased fibrinolytic activation is associated with risk of death (14). However, a new language has arisen in the field in thromboelastography, which uses the old terminology in new ways (Table 1). With the thromboelastogram (TEG), fibrinolysis is measured by the decrease in maximal amplitude over 30 min after the maximal amplitude has been reached (Lys30). The normal range is less than 7.5% The R, K, a angle, and MA variables can also be incorporated into a coagulation index (CI) as defined by the equation: CI = -0.6516R 0.3772K + 0.1224MA + 0.0759a 7.7922 (15). The CI functions as an overall assessment of coagulation, with values less than -3.0 said to signify a hypocoagulable sample and values over +3.0 said to signify a hypercoagulable sample. It is said that a LY30 greater than 7.5% with a CI less than 1.0 represents primary fibrinolysis; whereas a LY30 at greater than 7.5% with a CI greater than 3.0 represents secondary fibrinolysis. However, more recently, the term primary fibrinolysis has been applied when greater than 15% estimated percent lysis is detected in TEG in bleeding trauma patients (16). This was seen in one study on 34% of patients requiring massive transfusion after traumatic injury and significantly correlated with risk of death. Schochl et al. (14) used the term hyperfibrinolysis for increased lysis on the rotational thromboelastometry (ROTEM), again greater than 15% of maximal amplitude, and such changes were associated with poor prognosis. Thus, it seems that the trauma world is developing a different language around increased fibrinolytic activity as detected by TEG and ROTEM compared with traditional usage. While Lys30 has been shown to correlate with increased fibrinolysis with an old assay for fibrinolytic activity-the euglobulin lysis time (17), the relevance of these terms to conventional measurements such as tissue plasminogen activator levels at present is unclear, and it remains uncertain how much fibrinolysis is actually occurring undetected when the Lys30 is less than 7.5%. In view of the justified current interest in fibrinolysis and bleeding, and to prevent confusion and retain mutual understanding between the fields, this author would plea that the term 'TEG or “ROTEM” is used when describing results from thromboelastographic traces, e.g., TEG hyperfibrinolysis. Also the term primary fibrinolysis in TEG terminology sits uneasily with the classic term, perhaps the term TEG hyperfibrinolysis can be used instead?