The current study demonstrated that higher TMA scores were associated with mortality after 30 days and poor neurologic outcome in patients undergoing TTM after OHCA. Increased TMA score was an independent predictor of 30-day mortality and unfavorable neurologic outcomes. This was consistent with a previous study for severe sepsis and septic shock in which sepsis patients who died 30 days after ED admission had significantly higher TMA scores than those who survived, with increased TMA scores being significant predictors of 30-day mortality . Clinically, sepsis is characterized by a systemic inflammatory response accompanying an infection [10, 24]. In contrast, the ROSC after CA induces systemic ischemic reperfusion injury and consequently leads to sterile inflammatory damages after ischemic/reperfusion injury in the entire body without infection [3, 25].
It is difficult to completely understand the exact pathophysiologic processes underlying the clinical relationship between TMA score and poor outcomes after OHCA. However, several hypotheses could be proposed in this study. First, PCAS can be a contributing factor to the high mortality rate and severe brain damage of patients who achieve ROSC after CA [2, 3]. The systemic and sterile inflammation is the most important component of PCAS [8, 25]. Second, whole-body ischemia/reperfusion induced by endothelial injury contributes to thrombotic occlusion of the vessels following activation of coagulation and impairment of fibrinolysis [26, 27]. Several studies have demonstrated that aggregation, deformability, and the shape of RBC are altered in critical illness and different diseases .
Given the development and changes in the morphological characteristics of schistocytes, the TMA score was developed to screen for TAMOF in critically ill patients as a rapid, simple marker . With respect to erythrocytes, the hemorheological state after ischemia and reperfusion may negatively impact the deformability and aggregation behavior of RBCs through several complex process including acute phase reactions, free radical and inflammatory response, hemodynamic deteriorations, and coagulopathy . Yu et al assessed the rheological properties of RBC after ischemic/reperfusion and reported that stiffer erythrocytes resulting from reduced deformability help increase vascular resistance by limiting movement to small tissue capillaries. This eventually leads to no-reflow phenomenon from the cells being trapped in capillaries . Accordingly, the unfavorable neurologic outcome is attributed to the cerebral microvascular occlusion that causes the no-reflow phenomenon . Many animal and clinical studies demonstrated a more severe degree of microvascular changes is associated with poor outcomes including severe hypoxic brain injury, immediate death without ROSC, and high mortality .
In patients who achieve ROSC after CA, PCAS mimics the immunologic and coagulation disorders in severe sepsis . the development of disseminated intravascular coagulation (DIC) as a serious disease results in an increased tendency of bleeding, microvascular thrombosis, thrombocytopenia, and multiple organ dysfunction, consequently affecting the clinically unfavorable outcomes of patients with PCAS . DIC and TMA show similar laboratory findings and presenting symptoms . Although microvascular thrombosis is mainly caused by platelet activation in both DIC and TMA, DIC is significantly associated with all coagulation and fibrinolysis systems, while TMA is significantly associated with vascular endothelial cells . Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are known as the classic forms of TMA . Despite differences in the mechanisms of underlying DIC and TMA , several different conditions, such as atypical hemolytic uremic syndrome, DIC, and drug toxicities, can be also considered as different forms of TMA . It is difficult to use the schistocyte count as a complete indicator for the initial diagnosis and confirmation of TMA and DIC . Various conditions including severe infection, pregnancy, and leukemia frequently produce schistocytes [13, 35]. Nevertheless, the International Council for Standardization in Hematology (ICSH) guideline states that presence of > 1% schistocytes without other moderate changes in RBCs upon a peripheral blood smear can be considered as a critical criterion for the diagnosis of TMA .
Although changes in the microcirculation are known to play an important role in the severity of organ damage after CA, only few studies have investigated the characteristic changes for RBC deformability after CA and ischemic/reperfusion injury . To investigate rheological changes of RBCs after ischemic-reperfusion injury, Lee et al. evaluated the RBC deformability by three-dimensional shapes of RBCs after asphyxial CA in rats using three-dimensional laser interferometric microscopy. They did not find changes in three-dimensional shapes and cell deformability in RBCs during CPR and in 60 min after ROSC . Nemeth et al. demonstrated that the erythrocyte deformability significantly deteriorate 1–3 days after limb ischemic/reperfusion . The limited number of studies prompts us to refer to the significant association between sepsis and DIC. The increased development of schistocyte may be closely associated with the severity of sepsis and septic shock. Moreover, the increased rigidity and decreased deformability of RBCs during sepsis are clinically relevant for sepsis patients as they significantly influence outcomes . Specifically, this progressive decrease of RBC deformability, which occurs over the next 2 to 8 days since the onset of infections, is closely associated with multiple organ dysfunction [37, 38]. Given that PCAS has similar clinical characteristics to severe sepsis with respect to systemic and sterile inflammation, the increase in the number and changes in the characteristics of schistocytes may also be similar to severe sepsis and septic shock [8, 25]. Unlike the study by Lee et al. that simply evaluated changes in three-dimensional shapes and cell deformability in RBCs during CPR and in 60 min after ROSC , we used the TMA score, which represents changes in the morphological characteristics of schistocytes, to predict 30-day mortality and unfavorable neurologic outcomes for patients undergoing TTM after OHCA. To the best of our knowledge, this is the first study to report increased TMA score, which reflects significant changes in the morphological characteristics of schistocytes, within 12–24 h after ED admission. Importantly, we found that increased TMA score is a reliable predictor of clinical outcomes in patients undergoing TTM after OHCA.
Ko et al. reported that the optimal cutoff values of TMA scores at time-0 and time-24 were 2 and 3 in patients with sepsis and TMA scores ≥ 2 at time-0 and ≥ 3 at time-24 increased the predictability of 30-day mortality . Similarly, in the present study, a TMA score ≥ 2 at time-12 was closely associated with the increased predictability of 30-day mortality and unfavorable neurologic outcome in patients undergoing TTM after OHCA. Therefore, microvascular dysregulation and mechanical damage by RBC injury in ischemic reperfusion injury can play an important role in the formation of schistocytes . Further prospective, multicenter trials are required to validate the prognostic value of cell deformability in RBCs in 12 h and 24 h after admission in patients with PCAS undergoing TTM after OHCA.
Some studies suggested that the automated counting of RBC fragments is helpful as a routine screening tool, with good agreement with microscopy and other several advantages [13, 35]. The TMA score is a simple and rapidly measurable marker in clinical practice . In our study, the specific automated hematology analyzer can automatically measure TMA score during a CBC count and report the TMA score without additional costs, time, or laboratory tests [17, 18]. During the early stage of TTM after OHCA, the TMA score can be valuable because it can indicate the changes in the morphological characteristics of schistocytes rather than the absolute schistocyte counts . Our findings support that the TMA score can improve the predictability for the prognosis and risk stratification of patients undergoing TTM after OHCA. This is in line with the findings of another study that the TMA score can be a useful ancillary marker during clinical decision in the early stage TTM after OHCA .
The current study has several limitations. First, the possibility of selection bias cannot be eliminated. Although we used a prospective CP with a predetermined standardized protocol, we retrospectively analyzed this using a cohort derived from the CP of a single center. Second, we could not directly compare between TMA scores from an automated hematology analyzer and the schistocyte count determined manually through a microscope. As we stated in our previous study, the TMA score was created based on significant changes in the morphological characteristics of schistocytes and is determined automatically. Finally, we could not investigate the association between ADAMTS-13 activity and TMA score. The present study evaluated the usefulness of the TMA score for predicting the severity of organ failure in patients undergoing TTM after OHCA. ADAMTS-13 activity is a critical factor in the pathophysiology of the classic form of TMA. Although we used a prospective registry of the CP, we could not measure ADAMTS-13 activity because it was not a mandatory biomarker in this registry. Further prospective, multicenter trials are required to validate the usefulness of the TMA scores as a prognostic factor in patients undergoing TTM after OHCA.