Platelet Transfusion is Not Associated with the Better Outcomes of Patients with Sepsis-Induced Thrombocytopenia: A Propensity Score-Matching Analysis.

Background: The association of platelet transfusion and short-term mortality in patients with sepsis-induced thrombocytopenia remains unclear. Therefore, we intended to explore whether platelet transfusion could make a difference for patients with sepsis-induced thrombocytopenia. Methods: The study was based on the Medical Information Mart for Intensive Care (MIMIC) III database. Sepsis patients were divided into those with or without platelet transfusion (Platelet Transfusion group [PT group] and No Platelet Transfusion group [NPT group], respectively) during hospital stay. The primary outcome was 28-day all-cause mortality, and secondary outcomes were length of ICU stay (LOS-ICU) and survival days of 28. Propensity-score matching was used to reduce the imbalance. Results: We included 1733 patients: 296 patients in the PT group and 1437 patients in the NPT group. Overall, 655 patients died by day 28. After propensity score matching, 294 paired patients constituted each group. 28-day mortality did not decreased in PT patients comparing to NPT patients (120 [40.54%] vs. 535 [37.23%] deaths; P=0.29). LOS-ICU was similar between PT group and NPT group (5.84[2.68-11.78] vs. 4.94[2.18-12.72]; P=0.44). After confounders were adjusted for, it showed no difference between PT group and NPT group in 28-day mortality (hazard ratio [HR], 1.28;95% condence interval [CI], [0.96, 1.17]; P=0.09) or lOS-ICU (odd ratio [OR], 0.09; 95%CI, [-1.45, 1.62]; P=0.91). Survival at 28 days showed no difference between the groups according to Kaplan-Meier survival estimates. After propensity score matching, platelet transfusion was also not associated with 28-mortality or LOS-ICU. Conclusions: In the propensity score-matched analysis, there is no evidence that platelet transfusion is benecial for patients with sepsis-induced thrombocytopenia, neither 28-mortality nor LOS-ICU.

showed no difference between the groups according to Kaplan-Meier survival estimates. After propensity score matching, platelet transfusion was also not associated with 28-mortality or LOS-ICU.
Conclusions: In the propensity score-matched analysis, there is no evidence that platelet transfusion is bene cial for patients with sepsis-induced thrombocytopenia, neither 28-mortality nor LOS-ICU.

Background
Sepsis is the most common diseases in the intensive care unit (ICU), de ned as a life-threatening syndrome of organ dysfunction caused by dysregulated host response to a severe infection(1), considered a major cause of health loss worldwide. According to a recent scienti c publication, there were about 48.9 million cases and 11 million sepsis-related deaths worldwide in 2017, which accounted for almost 20% of all global deaths (2).
Clinically, platelet count decreased is very common among patients with sepsis admitted to the ICU. The incidence of sepsis-induced thrombocytopenia is around 25% on ICU admission(3) and approximately 55% during the hospital stay(4). Studies con rmed that platelets play a crucial role in in ammatory balance, immune responses, tissue repair and regeneration, beyond their important role in hemostasis and thrombosis (5)(6)(7). Based on recent studies, thrombocytopenia is closely associated with multiple organ dysfunction syndrome, prolonged ICU stay and high mortality in sepsis patients (8,9). Besides, thrombocytopenia was an early prognostic marker for ICU patients in the rst 24h of septic shock onset (10). And non-resolution of thrombocytopenia was associated with increased 28-day mortality in this population (9).
In general, accompanied by control of infection and improvement of the patient's conditions, sepsisinduced thrombocytopenia is gradually returning to be normal. Recently, several studies showed that recombinant human thrombopoietin (rhTPO) can lead to the quick recovery of the platelet count and improve the prognosis of patients with sepsis-induced severe thrombocytopenia (11)(12)(13). And platelet transfusion is the most common clinical therapy to increase platelet counts. In theory, one standard unit dose of platelet transfusion can elevate platelet counts by 20 X 10 9 /L. However, because of resource scarcity, transfusion-related immune and infectious complications, platelet transfusion is limited in clinical practice and has a rigorous indication in sepsis patients (14,15), which in return restricts large prospective clinical trials conducted to explore the impact of platelet transfusion on sepsis-induced thrombocytopenia.
According to a recent large registry study, it showed that platelet transfusion were not associated with increased risk of death in critically ill patients (16). Nonetheless, there has been no large study of platelet transfusion in severe sepsis-induced thrombocytopenia to investigate whether platelet administration can improve the prognosis of sepsis patients. Therefore, in this study, we aimed to determine the possible association between platelet transfusion with outcomes including 28-day mortality and length of ICU stay.

Database introduction
This was a retrospective study based on an online international database, Medical Information Mart for Intensive Care III (MIMIC III), compromising the information of 46,520 critically ill patients admitted to the Beth Israel Deaconess Medical Center from 2001 to 2012 (17).
All the patients in the database were de-identi ed, and the need for informed consent was waived.
One author (AZ) obtained access to this database (certi cation number 35752875) and was responsible for data extraction.

Study Population And De nitions
Septic patients with a platelet count level ≤ 50 X 10 9 /L were eligible for inclusion in our study. And sepsis was de ned according to the third sepsis de nition (1), which was extracted as suspected infection and an acute change in total Sequential Organ Failure Assessment (SOFA) score ≥ 2 points. Patients who were readmitted to the ICU, only the rst ICU admissions were included. For patients younger than 18 years or older than 89 years were excluded. The primary outcome was 28-day mortality. The secondary outcome was length of ICU stay (LOS-ICU).
Propensity Score Matching PSM was used to minimize the imbalance of the confounding factor between the PT and NPT groups. A one-to-one nearest neighbor matching algorithm was applied with a caliper width of 0.02 in our study. The following variables were selected to generate the propensity score: age, gender, SOFA, Simpli ed Acute Physiology score II (SAPSII), platelet count, platelet transfusion, diabetes mellitus, hypertension, chronic pulmonary, congestive heart failure, cancer.

Management Of Missing Data
Variables with missing data are common in the MIMIC III database. For C-response protein, serum lactate, albumin and procalcitonin values, more than 20% were missing and were removed from this analysis. For other continuous variables with missing values less than 5%, the missing values were replaced by the mean or median values.

Statistical analysis
Continuous variables were expressed as means with standard deviations or medians with interquartile ranges (IQRs), as appropriate. Student's t test, analysis of variance, Wilcoxon rank-sum test, or Kruskal-Wallis test were used, as appropriate. Categorical data were shown as frequencies and proportions and compared using the X2 test. The association between platelet transfusion and 28-day mortality was determined by logistic regression including the baseline as the covariate and the group as a xed factor. The survival outcomes comparisons between the groups were analyzed by the log-rank test. PSM was used to minimize the imbalance between groups. A two-tailed test was performed, and P < 0.05 was considered to indicate statistical signi cance. All statistical analyses were performed using the R package (version 3.6.3).

Baseline characteristics
Data on 1733 patients were included. The ow chart of patient selection is presented in Additional le 1.

Discussion
The present study demonstrates that platelet transfusion in sepsis patients with severe thrombocytopenia is not associated with 28-day mortality or LOS-ICU. This result was robust in the PSM analysis after adjustment for covariates including platelet counts and SOFA scores. According to our ndings, it seems that platelet transfusion is not a reasonable choice to correct sepsis-induced thrombocytopenia, aiming at improving the prognosis of sepsis patients with severe thrombocytopenia.
A low platelet count, thrombocytopenia, commonly occurs in sepsis patients. According to previous research, nearly 35-59% of patients with sepsis develop thrombocytopenia (18,19), which has been recognized as an independent risk factor for mortality and a marker for disease severity (20). Moreover, it is also an important index to evaluate the prognosis of patients (21). Sepsis patients with a low platelet count or dynamic thrombocytopenia show a poor prognosis and increased mortality (22). There are several main mechanism of developing thrombocytopenia in sepsis patients: 1) bacteria and their products directly inhibit bone marrow hematopoietic function and destroy megakaryocytes, which results in decreased platelet production; 2) platelet aggregation and destruction are increased due to the host's own immunity and other factors, such as nonspeci c platelet-associated antibodies and cytokine-driven hemophagocytosis of platelets (23); 3) activated platelet mediate the reaction between leukocytes and endothelial cells by secreting cytokines, which ampli es the host in ammatory response and further reduces the number of platelet in the circulation via positive feedback; 4) uid resuscitation and surgical operation may have an in uence on platelet count.
Sepsis patients with platelet counts less than 50 x 10 9 /L are considered to have sepsis-induced thrombocytopenia (24), which has a high mortality and poor prognosis. It was reported that nonresolution of thrombocytopenia was associated with increased 28-day mortality, instead of thrombocytopenia itself (9). Currently, there is no effective treatment for this condition. Infection control, organ support therapy and immune response regulation remain the mainstream treatments. In recent years, recombinant human thrombopoietin (rhTPO) was reported improving platelet count and reducing platelet transfusion possibility among patients with severe sepsis and thrombocytopenia in a prospective study (11). In another research, it suggested that rescue therapy with rhTPO could rapidly lead to a recovery of the platelet count, increase survival days and reduce the 28-day mortality in sepsis patients with severe thrombocytopenia (25 (27). There are some evidences suggesting that platelet transfusion is associated with adverse effects including infection (28). Some experts believe that conventional platelet transfusion therapy may worsens patient's procoagulant and anticoagulant disorders. However, the other study noted that platelet transfusion was not associated with increased mortality or infective complications following rst cardiac surgery (29). A recent publication by Ning S and colleagues reported that platelet transfusions were not associated with increased risk of death in critically ill patients neither in ICU (HR, 0.78; 95%CI, 0.60-1.02; p = 0.41) nor in hospital (HR, 0.89; 95%CI, 0.68-1.09; p = 0.41) (16). In our study, we found nearly the same result among sepsis patients with thrombocytopenia, that platelet transfusion was not associated with increased risk of 28-day mortality or LOS-ICU. Regarding to our negative nding, platelet transfusion cannot bene t patients with sepsis-induced thrombocytopenia, which may also put patients into a potential risk of infection, it is reasonable to avoid unnecessary transfusions.
In present study, there are still several limitations. Firstly, as a retrospective design, the adjustment of relevant but missing data was not allowed. Although we did perform propensity score matching to reduce the imbalance, estimation of the propensity score could only be based on the acquirable data. Secondly, bacteria species and sources that were not recorded in our data could not be included in the analysis. Thirdly, patients who have been administrated with β-lactam or sulfa antibiotics, which may result in antibiotic-induced thrombocytopenia, did not excluded in this study. Lastly, well-organized prospective randomized clinical trials are required to analyze the role of platelet transfusion in sepsis-induced thrombocytopenia and identify patients most likely to bene t from platelet transfusion.

Conclusions
In our study, we found that there is no evidence that platelet transfusion is bene cial for patients with sepsis-induced thrombocytopenia, neither 28-mortality nor LOS-ICU. However, this is a retrospective study, and more further prospective studies will be need in the future to address the bene ts and harms of platelet transfusion in sepsis patients with thrombocytopenia, to distinguish different subtypes of sepsis for which platelet transfusions may be of bene t, and to develop optimal platelet transfusion thresholds to better guide clinical treatment. Declarations Figure 1 Flow chart of patient selection from the MIMIC III database Analysis of the association between platelet transfusion and 28-day mortality before PSM Description: OR: Odds ratio; SOFA: Sequential Organ Failure Assessment; SAPS II: Simpli ed Acute Physiology Score. OR was adjusted by age, male, platelet count, SOFA, SAPSII, Diabetes Mellitus, Congestive heart failure, Figure 3 The 28-day survival curves of the Platelet transfusion and No Platelet Transfusion groups before and after PSM