Thrombocytopenia on the first day of emergency department visit predicts higher risk of acute kidney injury among elderly patients

In the current study, we discovered that thrombocytopenia was common among elderly patients who visited the ED for medical illnesses; it occurred in nearly one-fourth of these medical encounters. After the ED stay, about 40% of the elderly patients were diagnosed with AKI, and those with subsequent AKI had more comorbidities as well as poorer renal function than the patients without AKI. The regression analyses that accounted for clinical features, initial diagnoses, and laboratory data revealed that the presence of thrombocytopenia on initial evaluation predicted nearly 2-fold higher risk of subsequent AKI, and the initial platelet count was a continuous variable that also exhibited a negative correlation with the subsequent risk of AKI. The sum of these findings suggests that checking a complete blood count can be a useful approach for estimating the risk of later AKI among elderly patients who present to the ED.

The prevalence of thrombocytopenia in this study fell within the range reported by other investigators. A decade-old study suggested that only 1% of all patients admitted to a general acute care hospital had thrombocytopenia [22]. However, as clinicians have increasingly recognized the importance of blood rheology, the frequency of complete blood count testing has risen, contributing to a higher incidence of thrombocytopenia being identified. Large scale studies have suggested that on average 8–36% of in-patients have thrombocytopenia, and the number increases further to 13–68% if they received specific medications (e.g., heparin), were admitted to intensive care units, or had higher illness severity [23, 24]. Since the current study focuses on geriatric patients with a mean age of 80.7 years, the percentage of patients visiting the ED with thrombocytopenia (22.8%) in this study seems reasonable. Similarly, the incidence of AKI in our geriatric cohort approximates the rates reported in the literature, since most of them suggest that the incidence falls between 30 and 40% among patients with extremely advanced age [1, 5, 6].

Prior studies have revealed that aberrant platelet levels, both thrombocytosis and thrombocytopenia, can be important outcome determinants among patients with episodes of acute inflammation or infection. Mirsaeidi et al. reported that admission platelet counts higher than 400 × 10³/μL or lower than 100 × 10³/μL predicted a higher 30-day mortality among patients with community-acquired pneumonia [25]. Prina et al. similarly indicated that the presence of thrombocytosis increased the risk of mortality and also the incidence of respiratory complications among patients with pneumonia [26]. In the Program to Improve Care in Acute Renal Disease (PICARD) study, the researchers discovered that thrombocytopenia early in the course of hospitalization also predicted a 60 to 110% higher risk of mortality among patients with critical illnesses [27]. However, studies linking thrombocytopenia and renal complications have been sparse and available reports illustrating the relationship between thrombocytopenia and AKI have mostly focused on patients undergoing invasive procedures. Van Linden et al. reported that the occurrence of thrombocytopenia in patients undergoing aortic valve implantation was associated with an increased AKI risk [28]. Aregger et al. also discovered a higher frequency of post-procedural thrombocytopenia as a significant risk factor for AKI after trans-aortic valve implantation [12]. We hypothesized that similar finding might exist for patients who did not undergo invasive interventions, and we observed that thrombocytopenia detected during the initial evaluation of patients with medical illness alone also predicted a higher risk of developing AKI (Table 3). These results lend support to our conclusion that thrombocytopenia is an important predictor of adverse outcomes, including not only higher mortality, but also an elevated risk of AKI. Our findings further suggest that this relationship applies similarly to the elderly, a population that is more susceptible to developing thrombocytopenia and AKI from clinical insults.

The participants in this study were somewhat older than the general population, with a high proportion having multimorbidity. This is related to our hypothesis that older adults are at higher risk of developing AKI, and we specifically enrolled those with age higher than 65 years. This advanced age might be reflective of the burden of population aging on the healthcare practice in our institute. In addition, increased platelet counts can be associated with inflammatory status. However, platelet counts are also affected by factors other than inflammation, including infection processes with platelet consumption, bone marrow reserve, and hepatic diseases [29]. Patients with hepatic disease (e.g. cirrhosis) or severe infection (e.g. sepsis) tend to develop leukopenia related to bone marrow suppression or splenic sequestration [30]. In Table 1, we observed a numerically higher percentage of thrombocytopenic patients presenting with gastrointestinal/hepatic diseases and infection of unknown origin than those without thrombocytopenia, although the difference did not reach statistical significance (p = 0.23). Consequently, we propose that thrombocytopenic patients in this study might exhibit a mixture of inflammation but a relatively higher prevalence of hepatic disease and/or infection than those without thrombocytopenia, leading to leukopenia (Table 1). The advanced age of these patients might partially underlie the exaggerated differences in leukocyte counts between thrombocytopenic patients and non-thrombocytopenic ones.

The rationale behind the relationship between initial thrombocytopenia and subsequent AKI is complex. Platelet count has been purported to be a marker for disease severity during acute illnesses of different nature, such as Plasmodium infection and Dengue fever [31, 32]. As inflammation/infection worsens, the consumption of platelet and thrombocytopenia may increase, and it may be compounded by local sequestration, disseminated intravascular coagulation and endothelial activation, leading to a further decline in platelet numbers [25]. An earlier presentation of thrombocytopenia during the disease course thus can be an occult indicator for ongoing inflammation, and persistent inflammation is a potential risk factor for AKI susceptibility [33]. In addition to their pro-coagulation and hemostatic effects, circulating platelets also exhibit immune-regulatory and anti-microbial ability by releasing peptides active against pathogens as well as through microorganism internalization [34]. Furthermore, an anecdotal report suggested that thrombocytopenia might directly contribute to the propagation of infection by lowering the secretion of transforming growth factor-β1 and altering cytokine repertoire [35]. Clinically, thrombocytopenia also confers a state of bleeding diathesis and increases the risk of major hemorrhage. There have been reports that thrombocytopenia elevated the risk of major bleeding complications by 4-fold among patients with acute myocardial infarction [36]. Severe bleeding with resultant hemodynamic instability is also a common predisposing event before hospital-acquired AKI. Finally, resuscitation for shock or massive fluid administration might cause dilutional thrombocytopenia, and such a clinical scenario is frequently accompanied by AKI [10, 37]. In our cohort, the predominant cause of AKI was ATN. In addition, we found that elderly patients who presented with thrombocytopenia had significantly lower leukocyte counts than the patients without thrombocytopenia (p < 0.01; Table 1), suggesting that a dilutional origin was another possible explanation. Although we did not measure inflammatory markers or assess fluid status among all the participants, we propose that thrombocytopenia might be an early marker for persistent inflammation or an excess volume status, leading to susceptibility for AKI, or it might even play a directly pathogenic role in immune-dysregulation, precipitating severe infections and resultant AKI. Based on our findings, it may be worthwhile to order an assay for platelet count among elderly patients presenting to ED for medical illnesses, for gauging their AKI risk. Avoidance of nephrotoxin exposure could also be considered for elderly patient who present to the ED with thrombocytopenia.

Our study has its strengths but is also limited in several aspects. The existence of a relationship between initial thrombocytopenia and the subsequent risk of AKI has only been reported among patients undergoing invasive procedures in the existing literature, and we confirmed the same connection in elderly patients with medical illnesses. However, the relatively modest number of cases, the absence of data about inflammatory markers, the single center study design, and the restriction of patients to those admitted to general medical wards only, reduce the generalizability of our findings. A competing risk from death during ED stay should also be considered when interpreting our results, although the mortality rate in our ED is relatively low. The lack of data on inflammatory markers and the absence of a fluid status assessment limit the interpretation of the relationship between thrombocytopenia and AKI observed in this study. In addition, depending upon clinical settings, the etiologies of AKI differ, and sepsis has been reported to be the leading cause of AKI [38]. In the current study, the possibility exists that the presence of sepsis partially accounts for the association between thrombocytopenia and the occurrence of AKI, although we have tried to adjust for this issue by considering relevant parameters including leukocyte counts and physiologic variables such as blood pressure and heart rate in the regression models. Furthermore, the extensive adjustment of known interfering variables and the existence of a dose-dependent relationship (higher AKI severity, greater decline in platelet count) strengthens the credibility of our results. Finally, results from our current approach might be influenced by the possibility that some participants would develop AKI but went unnoticed before they were admitted. A fixed time period model would be more appropriate in this regard. More studies are needed for validation.