Acute Inflammatory Recovery-A Matter of Sophisticated Interaction of Two Cell Populations?

Inflammation is the physiologic response to cellular or tissue damage initiated by various pathologic conditions including the consequences of trauma, infection, or ischemia. An increase in white blood cell (WBC) counts and levels of other acute phase reactants are cardinal signs of an inflammatory reaction, characteristically induced by exogenous molecules derived from pathogens or endogenous molecules activated by tissue stress or damage.1 Platelets (PLTs) have been shown to play a decisive role in angiogenesis, allograft vasculopathy, and tumor growth, all inflammatory diseases mediated by interactions among endothelial cells, PLTs, and WBCs.2,3 Activated PLTs secrete proinflammatory mediators such as cytokines, chemokines, and growth factors from their granules. They also express a series of surface adhesion receptors leading to interactions between PLTs and both endothelial and immune cells4 (Figure 1).FIGURE 1.: Interaction of platelets with endothelial cells and activated immune cells via simultaneous P-selectin and CD40 binding. Nonnucleated platelets contain dense granules with serotonin, ADP, and a-granules containing proinflammatory cytokines, including RANTES, TNF-α, PDGF, and vWF. Surface receptors, including glycoprotein receptors, lead to collagen binding, vWF, and fibrinogen activation (modified from Mezger et al3). ADP, adenosine diphosphate; GP, glycoprotein; PAR, protease-activated receptor; PDGF, platelet-derived growth factor; PSGL-1, P-selectin glycoprotein ligand 1; RANTES, regulated on activation normal T cell expressed and secreted; TNF-α, tumor necrosis factor alpha; vWF, von Willebrand factor.Foy et al5 hypothesized in their work published in Nature Communications that successful inflammatory recoveries from diverse pathologic conditions share some common core dynamics. To test this assumption, they analyzed multivariate temporal relationships in clinical laboratory studies from patients responding to multiple types of infections, ischemia, and trauma associated with surgery. First, the authors analyzed inflammatory responses in patients with nonemergent cardiac surgery, the rational being the involvement of a significant inflammatory challenge because of sternotomy and cardiopulmonary bypass. Results revealed a strong inflammatory response with correlating markers, including WBCs and PLTs, suggesting co-regulation of blood cell populations and serum markers. By using a phase plane analysis—a visual display of characteristics of certain kinds of differential equations6—the authors validated their hypothesis and were able to show that there is a robust WBC-PLT trajectory during inflammatory recovery from cardiac surgery with uncomplicated recoveries being characterized by an exponential decay from a maximum WBC followed by delayed linear growth of PLTs. Interestingly, this finding was independent of variables including patient age and gender, preoperative risk, and other clinical characteristics. Next, the authors analyzed 6 relevant surgical procedures, including cesarean sections, colectomies, hip arthroplasties, hysterectomies, Whipple procedures, and limb amputations, revealing a WBC-PLT recovery trajectories that were comparable among all surgeries. Encouraged by these consistent findings across a broad spectrum of surgical patients, the authors investigated whether the pattern persisted in nontraumatic inflammatory conditions including coronavirus disease 2019, Clostridium difficile colitis, and sepsis. Additionally, they analyzed 2 types of ischemia, including myocardial infarction and stroke. Again, a very similar basic response shape was identified in all patient cohorts with WBC and PLT kinetics of recovering patients in each cohort, which was well explained by exponential WBC decay and delayed linear PLT growth. Finally, the authors set out to test whether their WBC-PLT trajectory can assess individual patient risks. To get this point across, the authors present a convincing analysis of 2 cardiac surgery patients illustrating how the WBC-PLT recovery shape can be used to identify high-risk patients with an “expected” postoperative course while identifying latent findings predictive of adverse events. Relevant to the overall cardiac surgery cohort, this means that patients outside the 80th percentiles of position and direction had a 32× relative risk of adverse outcomes by postoperative day 3. Moreover, across all the 12 investigated inflammatory patient cohorts, deviation from the WBC-PLT-trajectory was associated with a 5× to 33× higher relative risk of adverse outcomes. Despite these intriguing data and sophisticated statistical analysis, some questions remain: first and foremost, this study is a retrospective analysis with all its limitations regarding missing data and potential unknown confounders. Moreover, there is no information about the effects of specific treatments or interventions, including antibiotics or antiviral drugs and therapeutic antibodies in the coronavirus disease 2019 patient cohort.7,8 Additionally, it would be very interesting to know if WBC-PLT trajectories may also predict recovery. Therefore, prospective studies with detailed analyses are needed to define these correlations more precisely and to determine whether therapeutic interventions will lead to improved patient outcomes. It would also be interesting to know what effects were detected after intra-/postoperative platelet transfusions on the WBC-PLT trajectory. Finally, further studies should elucidate whether the pattern of the inflammatory response identified in this study is present in other inflammatory diseases, including infections, autoimmunity, and transplantation. Investigations focusing on transplant immunology seem exquisitely interesting, as PLTs interact with cells of the innate immune system and endothelial cells. Their importance throughout all phases of solid organ transplantation includes subendothelial tissue remodeling9 and immune cell interactions with the potential of therapeutic approaches targeting thromboinflammation. Taken together, the authors have identified a universal trajectory of human acute inflammatory recovery defined by exponential decay of WBCs and delayed linear increase in PLTs. This response pattern appeared in the setting of various traumatic, infectious, and ischemic inflammatory stimuli, irrespective of patient demographics and baseline risk and was robust across multiple years of clinical care. Therefore, it may help provide a clinically useful personalized benchmark for tracking individual patient recovery with relevance for transplantation and ultimately offer novel therapeutic opportunities in diseases featuring platelet abundance.