Thrombocytopenia is Associated with Worse Long-Term Outcomes in Sarcoidosis Patients Compared to Hypercalcemia. A Retrospective Analysis of 89 Patients

Thrombocytopenia is Associated with Worse Long-Term Outcomes in Sarcoidosis Patients Compared to Hypercalcemia. 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A Retrospective Analysis of 89 Patients Guy Dumanis, Tamir Ofek, Adi Gubbay, Coral Tal, Ilana Moshkovich, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9385075/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background. Long term survival in Sarcoidosis patients can be predicted by several clinical and laboratory parameters. Hypercalcemia serves as a predominant, negative prognostic factor. In the current study we aimed at identification of other patient characteristics influencing outcomes over a 10-year period. Methods. This was a retrospective analysis of hospitalized sarcoidosis patients in a large, tertiary medical center. Results. During a 10-year period between 2014 and 2024, data from 89 sarcoidosis patients was collected using MDClone data mining software. Overall, 13 patients suffered from hypercalcemia (median, corrected for blood albumin: 10.3 mg/dL [9.9–10.5] vs. 9.5 [9.2–9.8], p < 0.001). Patients with hypercalcemia had higher rates of renal failure (30.8% vs. 3.9%, p = 0.008), lower platelet counts (median 153 K/mcl [113–170] vs. 230 [190.7–263.5], p < 0.001), lower hemoglobin concentrations (median 10.2 g/dL [10.0–11.3] vs. 12.5 [10.8–13.6], p < 0.01), higher Urea blood levels (median 88 mg/dL [46–130] vs. 38.5 [30–47.2], p < 0.001), higher creatinine levels (median 1.48 mg/dL [1.31–1.6] vs. 0.9 [0.76–1.05], p < 0.001), and lower albumin (mean 3.07 g/dL ± 0.47 vs. 3.57 ± 0.56, p = 0.003). Hypercalcemia was associated with lower, post-discharge survival rates (median 4.8 years [2.6–7.3] vs. 7.9 [3.3–12.1], p = 0.045) and higher rates of 3-years, post-discharge mortality (30.8% vs. 7.9%, p = 0.036). In univariate analysis, hypercalcemia and thrombocytopenia were both associated with a higher risk of mortality within 3 years (HR = 4.11, 95% CI 1.16–14.57, p = 0.029 and HR = 13.92, 95% CI 3.88–49.93, p < 0.001, respectively). However, in a multivariate analysis only patient age and thrombocytopenia continued to be associated with a statistically significant higher risk of death (HR = 8.13, 95% CI 1.88–35.2, p = 0.005). Most patients suffering from thrombocytopenia did not undergo bone-marrow-biopsy, and amongst those who did, only 3 patients were diagnosed as suffering from significant haemato-pathology. Conclusion. Amongst hospitalized patients with sarcoidosis, thrombocytopenia is associated with shorter long-term survival compared to hypercalcemia. Larger studies should further establish our findings. Sarcoidosis Hypercalcemia Cytopenia Thrombocytopenia Prognosis Figures Figure 1 Background Markers of prognosis in Sarcoidosis patients . Sarcoidosis is a systemic granulomatous disorder of unknown etiology [ 1 ]. Generally, Sarcoidosis is considered as a benign disease but of potentially devastating clinical results in some patients [ 2 ]. While the lungs and intrathoracic lymph nodes are involved in more than 90% of cases, sarcoidosis is a multisystem disorder that may affect nearly any organ, resulting in a broad spectrum of clinical manifestations [ 1 ]. Hypercalcemia has long been considered as one of the metabolic characteristics of the sarcoidosis, arising, most probably, from the granulomatous component of disease, frequently endangering patient kidney functions [ 3 – 5 ]. Other than calcium metabolism, there are several markers potentially serving as prognostic factors for these patients: Zhou et al. found that serum angiotensin converting enzyme (ACE) levels and soluble interleukin-2 receptor blood levels serve as biomarkers for advanced sarcoidosis, signified by the authors as sarcoid with multiple organ involvement and abnormal calcium metabolism [ 6 ]. Hypercalcemia in Sarcoidosis . Chronic hypercalcemia has been traditionally accepted as an adverse prognostic factor in patients with sarcoidosis [ 7 ]. While hypercalcemia has been shown to be associated with decreased rates of spontaneous disease resolution [ 5 ], a separate study found that calcium serum levels in patients with active disease were comparable to those with non-active sarcoidosis and that there was no association between calcium levels and decreased quality of life [ 8 ]. Hence, the prognostic role of hypercalcemia in sarcoidosis remains unclear, especially in the context of mortality which has not been widely explored. Thrombocytopenia as part of Sarcoidosis . Hematological abnormalities are relatively uncommon in sarcoidosis [ 9 ], with lymphopenia and anemia being the most frequently reported findings [ 10 ]. Isolated thrombocytopenia, defined as a platelet count below 100×10⁹/L, is a relatively rare extrapulmonary manifestation of sarcoidosis [ 1 ]. The first occurrence of thrombocytopenia in sarcoidosis was documented in 1938, and its estimated incidence in retrospective studies was reported to be only 1% to 2% [ 11 , 12 ]. Three main pathophysiological mechanisms have been described for thrombocytopenia in sarcoidosis: immune-mediated platelet destruction, splenomegaly leading to hypersplenism, and granulomatous infiltration of the bone marrow. Immune-mediated peripheral destruction is considered the most prevalent mechanism, potentially accounting for more than 80% of sarcoidosis-related thrombocytopenia cases [ 11 ]. This mechanism is supported by bone marrow findings that frequently show megakaryocyte proliferation, suggestive of an immune destructive process [ 10 ]. Splenomegaly is observed in approximately 10% of sarcoidosis patients and may contribute to platelet sequestration and destruction through hypersplenism [ 14 ]. Granulomatous infiltration of the bone marrow, although rare, is also a reported mechanism that may potentially reduce platelet production [ 14 ]. Interestingly, complex cases may exhibit evidence of all three pathophysiological mechanisms simultaneously [ 10 ]. Sarcoidosis-associated immune thrombocytopenia (ITP) is often characterized by a severe and acute onset [ 14 ]. In clinical series, median platelet counts at presentation were often severely low, reaching 11×10⁹/L in one study, with 85% of patients having counts below 30×10⁹/L [ 11 ]. Patients may present with significant bleeding symptoms such as petechiae, ecchymosis, and mucosal bleeding [ 9 , 12 ]. The chronological relationship between the conditions varies; while sarcoidosis often precedes ITP onset (median interval of 48 months), simultaneous onset or relapse of both conditions is also frequent, occurring in up to 60% of cases [ 11 ]. Due to the rarity of this association, there are no specific guidelines for the management of thrombocytopenia in sarcoidosis [ 14 ]. Therapeutic approaches typically follow guidelines established for primary ITP, utilizing corticosteroids and intravenous immunoglobulin (IVIg) as first-line agents [ 11 , 13 ]. While early reports described sarcoidosis-associated ITP as potentially life-threatening and associated with mortality rates up to 15% due to bleeding, modern therapeutic management generally yields a favorable response, with recent series reporting no related deaths or severe bleeding episodes [ 11 ]. Despite the generally good outcome for the ITP component, the underlying sarcoidosis disease course in these patients often appears chronic, requiring prolonged corticosteroid therapy for longer than 36 months in up to 65% of cases. Furthermore, hematological abnormalities are recognized as potential indicators of severe systemic inflammatory activity. This critical finding suggests that low platelet count serves as a marker for a more severe or persistently active disease phenotype. Given the acute severity, chronic nature of the associated sarcoidosis, and the independent prognostic significance of thrombocytopenia, a comprehensive evaluation of its contribution to the risk of mortality is crucial for optimizing long-term clinical management and monitoring in sarcoidosis patients [ 11 ]. Aim of the current study . Given that pulmonary assessment, such as the results of bronchoalveolar lavage, are not directly related to prognosis [ 2 ], there is a need to identify reliable prognostic markers that could improve clinical decision-making and disease management. The present study aims to investigate prognostic factors in sarcoidosis using data from a large tertiary medical center. Specifically, we re-evaluated the prognostic significance of metabolic and hematologic biomarkers in sarcoidosis patients over a long follow-up period. Methods Study variables . We analyzed data from hospitalized sarcoidosis patients, including demographic variables (age at hospitalization, gender, smoking status, and weight) clinical background (relevant comorbidities and chronic medication use) and laboratory parameters collected at the time of hospitalization. Serum calcium levels were corrected for hypoalbuminemia using the following formula: "Corrected calcium (mg/dL)"="Serum calcium"+0.8×(4-"Serum albumin"). For patients with albumin levels below 4 g/dL, corrected calcium values were used. Hypercalcemia was defined as calcium levels, corrected or uncorrected, greater than 10.4 mg/dL. Thrombocytopenia was defined as a platelet count below 100 × 10⁹/L, and anemia as a hemoglobin concentration below 10 g/dL. The study's primary clinical outcomes included three-year mortality rate following hospitalization and overall mortality after discharge. Statistical analysis . Patients were categorized according to the presence or absence of hypercalcemia. Categorical variables were compared between groups using the Chi-square test or Fisher’s exact test, as appropriate. Continuous variables were assessed for normality using the Shapiro–Wilk test. Normally distributed variables were compared using the independent samples t-test, while non-normally distributed variables were compared using the Mann–Whitney U test. Survival analyses were performed using Cox proportional hazards regression models to evaluate associations between study variables and mortality outcomes. Both univariable and multivariable models were constructed. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported for all Cox regression analyses. Kaplan–Meier survival curves were generated to illustrate overall survival according to the presence of thrombocytopenia, anemia, and hypercalcemia, and differences were compared using the log-rank test. Data were retrieved using MDClone's ADAMS platform, a self-service query tool that provides comprehensive patient-level data of wide-ranging variables in a defined time frame around an index event (mdclone.com). All statistical analyses were performed using R software (version 4.4.2). A two-sided p value < 0.05 was considered statistically significant. Results Study cohort . Following an approval by the Institutional Review Board (IRB approval # 1713-25-SMC), patients electronic medical records (EMRs) were reviewed and relevant data was retrieved. Over a 10-year period, data from 89 hospitalized patients diagnosed with sarcoidosis were collected. Table 1 presents the baseline, demographic data of the entire cohort, background comorbidities, chronic medication use, laboratory parameters, and clinical outcomes, according to their calcium blood levels. Patients were categorized into two groups: those with hypercalcemia (13 patients with albumin-corrected calcium above 10.4 meq/L) and those with normal calcium levels (76 patients). Demographic characteristics (gender, age upon index hospitalization, smoking status and weight) were not different between the two calcium groups. In terms of comorbidities, rates of ischemic heart disease, diabetes, heart failure, malignancy, dementia, hyper- and hypothyroidism and background anemia did not differ between the two study groups. Chronic Kidney Disease (CKD) was more prevalent in the hypercalcemia group (30.8% vs. 3.9%; p = 0.008). The chronic use of both Angiotensin Converting Enzyme Inhibitors (ACE-I) and Thiazide diuretics did not significantly differ between the two study groups. Regarding laboratory parameters, the hypercalcemia group showed markedly elevated levels of urea and creatinine (median 88 [46, 130] vs. 38.5 [30, 47.25], p < 0.001 and median 1.48 [1.31, 1.6] vs. 0.9 [0.76, 1.05], p < 0.001 respectively). Additionally, patients with hypercalcemia had lower concentrations (g/dL) of albumin (mean 3.07 ± 0.47 vs. 3.57 ± 0.56, p = 0.003), lower hemoglobin (g/dL, median 10.19 [10.03, 11.31] vs. 12.5 [10.79, 13.56], p = 0.005) and lower platelets counts (K/per mcl, median 153 [113, 170], vs. 230 [190.75, 263.5], p < 0.001). Liver function tests, Lactate dehydrogenase (LDH) levels and white blood cell counts were not significantly different between the two study groups. In terms of clinical outcomes, patients in the hypercalcemia group had significantly shorter median, post discharge survival(4.8 years [2.6, 7.3] vs. 7.9 years [3.27, 12.1], p = 0.045). These patients also had a significantly higher rate of post discharge, 3-years mortality (30.8% vs. 7.9%, p = 0.036). Table 1 Study patients according to hypercalcemia status Variable Whole cohort [n = 89] Hypercalcemia* P value No [n = 76] Yes [n = 13] Calcium (mg/dL, median [IQR]) 9.60 [9.20, 9.90] 9.50 [9.20, 9.83] 10.30 [9.90, 10.50] < 0.001 Demographic background Gender; M (N (%)) 40 (44.9) 31 (40.8) 9 (69.2) 0.1 Age; years (mean (SD)) 59.2 (15.6) 58.2 (15.4) 65.4 (15.9) 0.12 Smoking; N (%) 2 (2.2) 2 (2.6) 0 (0) 1 Weight; Kg (mean (SD)) 75.9 (15.6) 75.8 (15.6) 77.0 (16.2) 0.82 Clinical background, N (%) IHD 14 (15.7) 12 (15.8) 2 (15.4) 1 Hypertension 33 (37.1) 28 (36.8) 5 (38.5) 1 Diabetes 27 (30.3) 21 (27.6) 6 (46.2) 0.2 Cardiac failure 2 (2.2) 1 (1.3) 1 (7.7) 0.27 Malignancy 9 (10.1) 7 (9.2) 2 (15.4) 0.61 Dementia 1 (1.1) 1 (1.3) 0 (0) 1 Hypo/hyperthyroid 4 (4.5) 4 (5.3) 0 (0) 1 Epilepsy 1 (1.1) 0 (0) 1 (7.7) 0.15 Renal failure 7 (7.9) 3 (3.9) 4 (30.8) < 0.01 Anemia 16 (18) 13 (17.1) 3 (23.1) 0.67 Chronic medication use, N (%) ACEi 14 (15.7) 13 (17.1) 1 (7.7) 0.68 Thiazides 5 (5.6) 4 (5.3) 1 (7.7) 0.55 Laboratory parameters Urea (mg/dL, median [IQR]) 41 [32, 54] 38.50 [30, 47.25] 88 [46, 130] < 0.001 Creatinine (mg/dL, median [IQR]) 0.95 [0.79, 1.20] 0.90 [0.76, 1.05] 1.48 [1.31, 1.60] < 0.001 ALT (IU/L, median [IQR]) 21 [15, 37] 21 [14.75, 37.50] 21 [15, 31] 0.97 AST (IU/L, median [IQR]) 24 [19, 34] 23 [18, 34] 26 [24, 32] 0.16 LDH (IU/L, median [IQR]) 232 [189, 306] 223 [183, 292] 278 [248, 352] 0.065 Bilirubin (median [IQR]) 0.60 [0.47, 0.85] 0.59 [0.47, 0.85] 0.65 [0.50, 0.76] 0.95 Albumin (g/dL, mean (SD)) 3.50 (0.58) 3.57 (0.56) 3.07 (0.47) 0.003 WBC; max (K/mcl, median [IQR]) 8.8 [6.5, 12.5] 8.8 [6.4, 12.5] 8.8 [6.8, 10.9] 0.87 Platelets (K/mcl, median [IQR]) 219 [174, 260] 230 [190.7, 263.5] 153 [113, 170] < 0.001 Hemoglobin (median [IQR]) 11.85 [10.4, 13.2] 12.5 [10.8, 13.6] 10.2 [10.0, 11.3] 0.005 Clinical outcomes Median [IQR] Survival post admission; years 7.40 [3.10, 10.40] 7.90 [3.27, 12.10] 4.80 [2.60, 7.30] 0.045 Mortality 3 years post admission; N (%) 10 (11.2) 6 (7.9) 4 (30.8) 0.036 * Corrected Ca = measured Ca + 0.8 (4 - measured albumin); if albumin < 4. IHD = Ischemic heart disease, COPD = chronic obstructive pulmonary disease, ALT = alanine transaminase, AST = aspartate transaminase, LDH = lactate dehydrogenase, WBC = white blood cells. Abbreviations: ACE = angiotensin-converting enzyme; ACE-I = ACE inhibitor; AKI = acute kidney injury; Ca = albumin-corrected serum calcium; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; ICU = intensive-care unit; IQR = inter-quartile range; IV = intravenous; SD = standard deviation As presented in Table 2 , hypercalcemia, age, malignancy and thrombocytopenia were all associated with increased hazard ratio for mortality within 3 years of admission. In a multivariate analysis, only age and thrombocytopenia remained independently associated with this clinical outcome (HR = 1.06 [1.00, 1.11], p = 0.042 and HR = 7.04 [1.46, 33.99], p = 0.015, respectively). Table 2 Univariate and multivariate analysis of mortality within 3 years from discharge Variable Univariate Multivariate HR [95%CI] P-value HR [95%CI] P-value Hypercalcemia 4.11 [1.16, 14.57] 0.029 1.72 [0.36, 8.15] 0.493 Age 1.07 [1.01, 1.13] 0.019 1.06 [1.00, 1.11] 0.042 Malignancy 7.34 [2.07, 26.09] 0.002 2.92 [0.72, 11.88] 0.135 Thrombocytopenia 13.92 [3.88, 49.93] 10.4 meq/ml, Thrombocytopenia < 100K/mcl, Anemia < 10 g/dL. Figure 1 present the crude, accumulated mortality of sarcoidosis patients according to the existence of hypercalcemia (Fig. 1a), anemia (Fig. 1b) and thrombocytopenia (Fig. 1c). Discussion Hypercalcemia is a known phenomenon associated with sarcoidosis, affecting approximately 6–11% of patients, with its pathophysiology thoroughly described in the literature [ 15 ]. Although initial presentation of hypercalcemia is rarely seen [ 16 ], its presence may indicate an acute disease phase and a high disease burden. Persistent hypercalcemia is considered one of the key indications for treatment initiation in sarcoidosis [ 5 ]. In addition, it was previously demonstrated that hypercalcemia serves as negative prognostic indicator in sarcoidosis, correlating with chronic-persistent disease, higher ACE levels, older age, hypergammaglobulinemia, and extrapulmonary involvement of organs such as the spleen, bone, and kidneys [ 17 ]. In this study, we aimed to establish whether hypercalcemia at the time of diagnosis of sarcoidosis is associated with an increased mortality rate compared to normocalcemic patients. Thus, reinforcing its role as a prognostic factor in sarcoidosis. In this study, 13 patients (14.6%) were identified with hypercalcemia. As shown in Table 1 , normocalcemic patients had a significantly longer median survival of 7.90 years, whereas patients with hypercalcemia demonstrated a significantly lower median survival of 4.80 years (p = 0.044). A Kaplan-Meier survival curve demonstrated a statistically significant difference in survival between the two groups (p = 0.0046). Moreover, 3-years mortality was significantly increased in the hypercalcemic group compared to the normocalcemic group (30.8% vs. 7.9%, p = 0.036). While 5-year mortality remained higher in the hypercalcemic group compared to the normocalcemic group (30.8% vs. 14.5%), the difference was not statistical significance (p = 0.221). This may suggest a short-term effect of hypercalcemia on survival, although over the long-term follow up (of 5 years) it has no impact on survival. These results should be taken into consideration when evaluating the role of hypercalcemia as a prognostic factor in sarcoidosis patients. In the multivariate analysis for 3-year and 5-year survival, hypercalcemia was not found to be a statistically significant risk factor for mortality (p = 0.078, 0.254, respectively). However, this could be due to the small sample size. Larger cohort studies are needed to determine the role of hypercalcemia in the course of sarcoidosis. These findings highlight the importance of early recognition of hypercalcemia in sarcoidosis to optimize outcomes and reduce mortality risk. Sarcoidosis patients with hypercalcemia demonstrated significantly different clinical characteristics and laboratory parameters compared to those without hypercalcemia. Among all examined comorbidities (Table 1 ), only renal failure demonstrated a statistically significant difference between groups (30.8% vs 3.9%, p = 0.008), suggesting the consequential relationship between renal dysfunction and hypercalcemia, potentially mediated through dysregulation parathyroid hormone secretion leading to tertiary hyperparathyroidism. Accordingly, laboratory findings associated with severe renal impairment such as hyperphosphatemia (4.3 vs. 3.81 P < 0.001), elevated serum creatinine (1.48 vs. 0.9 P < 0.001), increased serum urea (88 vs. 38.5 P < 0.001), decreased hemoglobin (10.19 vs. 12.5 P = 0.005) and hypoalbuminemia (3.07 vs. 3.57 p = 0.003) were all statistically significant in the hypercalcemic cohort. Our results suggest that thrombocytopenia may serve as a negative prognostic factor for survival in sarcoidosis patients. Thrombocytopenia was significantly associated with higher 3-year mortality rates in both uni- and multivariate analyses. To confirm the relationship between thrombocytopenia and the primary sarcoidosis diagnosis in our cohort, we reviewed the medical records of all 89 patients. Most did not undergo a bone-marrow-biopsy, and amongst those who did, only 3 patients were diagnosed with significant haemato-pathology. As described earlier, thrombocytopenia in sarcoidosis patients could arise from different etiologies. However, our findings are more suggestive for immune-related thrombocytopenia rather than bone marrow pathologies associated with sarcoidosis infiltration.. Conclusions In addition to the “classic” risk factors for poor prognosis of sarcoidosis patients, thrombocytopenia should not be overlooked. After exclusion of alternative hematologic diagnoses, thrombocytopenia may serve as a cause for earlier, more intensive investigations and treatment for sarcoidosis patients who might otherwise remain under routine follow-up only. This assumption should guide future, controlled comparative studies to explore the clinical significance of thrombocytopenia in this patient population. Abbreviations HR Hazard ratio MCL microliter ACE angiotensin converting enzyme ITP immune thrombo–cytopenia IVIG intra venous immune globulins CI Confidence interval IRB institutional review board EMR electronic medical record CKD chronic kidney disease LDH Lactate dehydrogenase IHD Ischemic heart disease COPD chronic obstructive pulmonary disease ALT alanine transaminase AST aspartate transaminase WBC white blood cells AKI acute kidney injury eGFR estimated glomerular filtration rate ICU intensive–care unit IQR inter–quartile range IV intravenous SD standard deviation Declarations Ethics approval and consent to participate: This study was approved by the Sheba medical center Institutional Review Board (IRB approval # 1713-25-SMC). Informed consent was waived due to the retrospective nature of this study. Consent for publication: All authors gave their consent for this publication. Availability of data and materials: All research data is available with the corresponding author upon request under the terms and conditions of the IRB. Competing Interests: All authors declare they have no competing interests. Funding: This research had no funding resource to disclose. Authors' contributions: All authors contributed to research conceptualization, methodology and data curation. All authors contributed to data analysis, writing of the preliminary manuscript and the final submission. Acknowledgements: N/A References Pasli M, Lovell KK, Vulasala SSR, Hairr ML, Bandaru RR, Khalilullah MZ et al. Severe Thrombocytopenia in a 30-Year-Old African American Male With Newly Diagnosed Sarcoidosis: A Case Report. Cureus. 2023. https://doi.org/10.7759/cureus.34135 Kraaijvanger R, Janssen Bonás M, Vorselaars ADM, Veltkamp M. Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects. 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Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 07 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers invited by journal 05 May, 2026 Editor assigned by journal 27 Apr, 2026 Editor invited by journal 24 Apr, 2026 Submission checks completed at journal 24 Apr, 2026 First submitted to journal 24 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9385075","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":637680724,"identity":"b5be2724-d650-437c-b7fe-a18a25cd7be5","order_by":0,"name":"Guy Dumanis","email":"","orcid":"","institution":"Chaim Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Guy","middleName":"","lastName":"Dumanis","suffix":""},{"id":637680725,"identity":"1042775f-fa59-4256-a721-fc9238bfa62b","order_by":1,"name":"Tamir Ofek","email":"","orcid":"","institution":"Chaim Sheba Medical 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Center","correspondingAuthor":false,"prefix":"","firstName":"Ilana","middleName":"","lastName":"Moshkovich","suffix":""},{"id":637680729,"identity":"b9ff600c-0db2-4a3d-848c-5c8bd64c1530","order_by":5,"name":"Noam Klegar","email":"","orcid":"","institution":"Chaim Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Noam","middleName":"","lastName":"Klegar","suffix":""},{"id":637680730,"identity":"b37abdc0-c084-4d58-94df-ed86fcb5f3df","order_by":6,"name":"Paz Agam Ohayon","email":"","orcid":"","institution":"Chaim Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Paz","middleName":"Agam","lastName":"Ohayon","suffix":""},{"id":637680731,"identity":"8e601881-14b4-4068-aec6-fd35514b830b","order_by":7,"name":"Noa Tennenhaus","email":"","orcid":"","institution":"Chaim Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Noa","middleName":"","lastName":"Tennenhaus","suffix":""},{"id":637680732,"identity":"6af0024b-77ad-4960-9239-2b7eea14bd3f","order_by":8,"name":"Gad Segal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIiWNgGAWjYLCCBxUMCQwSDAzMQLYMiAECPHz4tCScQWjh4YFpYcOnJbENixYGXFrk29svfkicV5fHL938gLmgwo7HXrqB+cXHNgYZXFoMzpwplkjcdrhYcs4xA+YZZ5J5eGQOsFnObMPtMAOJnASglgOJG24kGDDztjEDHZbAZsxzBrcW+flvkn8kzqlL3H8j/QMz7796wloYbrAfk0hsYE7cIJEDtKXhMEgL82OeCjwOO5PDZpFw7HDijDtnCg7zHDvOw3MjsY1xRoUEboe1H39840NNXWL/7PaNj3lqquXYZyQf/vDBwMaeH5fDGHgM4MwDEIqxDRg1EthVgwH7Awwh5g941I+CUTAKRsHIAwCAhlOEoeJzowAAAABJRU5ErkJggg==","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Gad","middleName":"","lastName":"Segal","suffix":""},{"id":637680733,"identity":"f990725b-a202-48e3-87af-5f233456dc11","order_by":9,"name":"Yigal Farkash","email":"","orcid":"","institution":"Ort Melton","correspondingAuthor":false,"prefix":"","firstName":"Yigal","middleName":"","lastName":"Farkash","suffix":""},{"id":637680734,"identity":"f9a9dfaa-0b79-48e7-afe1-2e1ff47349c4","order_by":10,"name":"Daniel Bendersky","email":"","orcid":"","institution":"Ort Melton","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Bendersky","suffix":""},{"id":637680735,"identity":"1c22acf0-b97d-4fa1-8408-385b73ba7b28","order_by":11,"name":"Moria Tzibin","email":"","orcid":"","institution":"Ort Melton","correspondingAuthor":false,"prefix":"","firstName":"Moria","middleName":"","lastName":"Tzibin","suffix":""},{"id":637680736,"identity":"620af499-528b-4709-af2c-696edf5b8e40","order_by":12,"name":"Reut Kassif Lerner","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Reut","middleName":"Kassif","lastName":"Lerner","suffix":""}],"badges":[],"createdAt":"2026-04-11 06:23:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9385075/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9385075/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109170735,"identity":"cb30007b-7dc6-40f6-8917-740933686c5d","added_by":"auto","created_at":"2026-05-13 08:51:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":64944,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier curves for accumulated mortality.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9385075/v1/259e4c2b265cc1c723c5bbe4.png"},{"id":109170760,"identity":"e5abba1a-e1c2-4981-8cf9-7beb2314b926","added_by":"auto","created_at":"2026-05-13 08:51:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":369956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9385075/v1/4fe0324a-714a-41aa-bbff-60382aa2feee.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Thrombocytopenia is Associated with Worse Long-Term Outcomes in Sarcoidosis Patients Compared to Hypercalcemia. A Retrospective Analysis of 89 Patients","fulltext":[{"header":"Background","content":"\u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eMarkers of prognosis in Sarcoidosis patients\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eSarcoidosis is a systemic granulomatous disorder of unknown etiology [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Generally, Sarcoidosis is considered as a benign disease but of potentially devastating clinical results in some patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While the lungs and intrathoracic lymph nodes are involved in more than 90% of cases, sarcoidosis is a multisystem disorder that may affect nearly any organ, resulting in a broad spectrum of clinical manifestations [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Hypercalcemia has long been considered as one of the metabolic characteristics of the sarcoidosis, arising, most probably, from the granulomatous component of disease, frequently endangering patient kidney functions [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Other than calcium metabolism, there are several markers potentially serving as prognostic factors for these patients: Zhou et al. found that serum angiotensin converting enzyme (ACE) levels and soluble interleukin-2 receptor blood levels serve as biomarkers for advanced sarcoidosis, signified by the authors as sarcoid with multiple organ involvement and abnormal calcium metabolism [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHypercalcemia in Sarcoidosis\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eChronic hypercalcemia has been traditionally accepted as an adverse prognostic factor in patients with sarcoidosis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. While hypercalcemia has been shown to be associated with decreased rates of spontaneous disease resolution [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], a separate study found that calcium serum levels in patients with active disease were comparable to those with non-active sarcoidosis and that there was no association between calcium levels and decreased quality of life [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Hence, the prognostic role of hypercalcemia in sarcoidosis remains unclear, especially in the context of mortality which has not been widely explored.\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eThrombocytopenia as part of Sarcoidosis\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eHematological abnormalities are relatively uncommon in sarcoidosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], with lymphopenia and anemia being the most frequently reported findings [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Isolated thrombocytopenia, defined as a platelet count below 100\u0026times;10⁹/L, is a relatively rare extrapulmonary manifestation of sarcoidosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The first occurrence of thrombocytopenia in sarcoidosis was documented in 1938, and its estimated incidence in retrospective studies was reported to be only 1% to 2% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThree main pathophysiological mechanisms have been described for thrombocytopenia in sarcoidosis: immune-mediated platelet destruction, splenomegaly leading to hypersplenism, and granulomatous infiltration of the bone marrow. Immune-mediated peripheral destruction is considered the most prevalent mechanism, potentially accounting for more than 80% of sarcoidosis-related thrombocytopenia cases [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This mechanism is supported by bone marrow findings that frequently show megakaryocyte proliferation, suggestive of an immune destructive process [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Splenomegaly is observed in approximately 10% of sarcoidosis patients and may contribute to platelet sequestration and destruction through hypersplenism [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Granulomatous infiltration of the bone marrow, although rare, is also a reported mechanism that may potentially reduce platelet production [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Interestingly, complex cases may exhibit evidence of all three pathophysiological mechanisms simultaneously [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSarcoidosis-associated immune thrombocytopenia (ITP) is often characterized by a severe and acute onset [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In clinical series, median platelet counts at presentation were often severely low, reaching 11\u0026times;10⁹/L in one study, with 85% of patients having counts below 30\u0026times;10⁹/L [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Patients may present with significant bleeding symptoms such as petechiae, ecchymosis, and mucosal bleeding [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The chronological relationship between the conditions varies; while sarcoidosis often precedes ITP onset (median interval of 48 months), simultaneous onset or relapse of both conditions is also frequent, occurring in up to 60% of cases [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDue to the rarity of this association, there are no specific guidelines for the management of thrombocytopenia in sarcoidosis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therapeutic approaches typically follow guidelines established for primary ITP, utilizing corticosteroids and intravenous immunoglobulin (IVIg) as first-line agents [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. While early reports described sarcoidosis-associated ITP as potentially life-threatening and associated with mortality rates up to 15% due to bleeding, modern therapeutic management generally yields a favorable response, with recent series reporting no related deaths or severe bleeding episodes [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite the generally good outcome for the ITP component, the underlying sarcoidosis disease course in these patients often appears chronic, requiring prolonged corticosteroid therapy for longer than 36 months in up to 65% of cases. Furthermore, hematological abnormalities are recognized as potential indicators of severe systemic inflammatory activity. This critical finding suggests that low platelet count serves as a marker for a more severe or persistently active disease phenotype. Given the acute severity, chronic nature of the associated sarcoidosis, and the independent prognostic significance of thrombocytopenia, a comprehensive evaluation of its contribution to the risk of mortality is crucial for optimizing long-term clinical management and monitoring in sarcoidosis patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAim of the current study\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eGiven that pulmonary assessment, such as the results of bronchoalveolar lavage, are not directly related to prognosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], there is a need to identify reliable prognostic markers that could improve clinical decision-making and disease management. The present study aims to investigate prognostic factors in sarcoidosis using data from a large tertiary medical center. Specifically, we re-evaluated the prognostic significance of metabolic and hematologic biomarkers in sarcoidosis patients over a long follow-up period.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy variables\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eWe analyzed data from hospitalized sarcoidosis patients, including demographic variables (age at hospitalization, gender, smoking status, and weight) clinical background (relevant comorbidities and chronic medication use) and laboratory parameters collected at the time of hospitalization. Serum calcium levels were corrected for hypoalbuminemia using the following formula: \"Corrected calcium (mg/dL)\"=\"Serum calcium\"+0.8\u0026times;(4-\"Serum albumin\"). For patients with albumin levels below 4 g/dL, corrected calcium values were used. Hypercalcemia was defined as calcium levels, corrected or uncorrected, greater than 10.4 mg/dL. Thrombocytopenia was defined as a platelet count below 100 \u0026times; 10⁹/L, and anemia as a hemoglobin concentration below 10 g/dL. The study's primary clinical outcomes included three-year mortality rate following hospitalization and overall mortality after discharge.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStatistical analysis\u003c/span\u003e.\u003c/h2\u003e \u003cp\u003ePatients were categorized according to the presence or absence of hypercalcemia. Categorical variables were compared between groups using the Chi-square test or Fisher\u0026rsquo;s exact test, as appropriate. Continuous variables were assessed for normality using the Shapiro\u0026ndash;Wilk test. Normally distributed variables were compared using the independent samples t-test, while non-normally distributed variables were compared using the Mann\u0026ndash;Whitney U test.\u003c/p\u003e \u003cp\u003eSurvival analyses were performed using Cox proportional hazards regression models to evaluate associations between study variables and mortality outcomes. Both univariable and multivariable models were constructed. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported for all Cox regression analyses. Kaplan\u0026ndash;Meier survival curves were generated to illustrate overall survival according to the presence of thrombocytopenia, anemia, and hypercalcemia, and differences were compared using the log-rank test.\u003c/p\u003e \u003cp\u003eData were retrieved using MDClone's ADAMS platform, a self-service query tool that provides comprehensive patient-level data of wide-ranging variables in a defined time frame around an index event (mdclone.com). All statistical analyses were performed using R software (version 4.4.2). A two-sided p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eStudy cohort\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eFollowing an approval by the Institutional Review Board (IRB approval # 1713-25-SMC), patients electronic medical records (EMRs) were reviewed and relevant data was retrieved. Over a 10-year period, data from 89 hospitalized patients diagnosed with sarcoidosis were collected. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the baseline, demographic data of the entire cohort, background comorbidities, chronic medication use, laboratory parameters, and clinical outcomes, according to their calcium blood levels. Patients were categorized into two groups: those with hypercalcemia (13 patients with albumin-corrected calcium above 10.4 meq/L) and those with normal calcium levels (76 patients). Demographic characteristics (gender, age upon index hospitalization, smoking status and weight) were not different between the two calcium groups. In terms of comorbidities, rates of ischemic heart disease, diabetes, heart failure, malignancy, dementia, hyper- and hypothyroidism and background anemia did not differ between the two study groups. Chronic Kidney Disease (CKD) was more prevalent in the hypercalcemia group (30.8% vs. 3.9%; p\u0026thinsp;=\u0026thinsp;0.008). The chronic use of both Angiotensin Converting Enzyme Inhibitors (ACE-I) and Thiazide diuretics did not significantly differ between the two study groups.\u003c/p\u003e \u003cp\u003eRegarding laboratory parameters, the hypercalcemia group showed markedly elevated levels of urea and creatinine (median 88 [46, 130] vs. 38.5 [30, 47.25], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and median 1.48 [1.31, 1.6] vs. 0.9 [0.76, 1.05], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 respectively). Additionally, patients with hypercalcemia had lower concentrations (g/dL) of albumin (mean 3.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47 vs. 3.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56, p\u0026thinsp;=\u0026thinsp;0.003), lower hemoglobin (g/dL, median 10.19 [10.03, 11.31] vs. 12.5 [10.79, 13.56], p\u0026thinsp;=\u0026thinsp;0.005) and lower platelets counts (K/per mcl, median 153 [113, 170], vs. 230 [190.75, 263.5], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Liver function tests, Lactate dehydrogenase (LDH) levels and white blood cell counts were not significantly different between the two study groups.\u003c/p\u003e \u003cp\u003eIn terms of clinical outcomes, patients in the hypercalcemia group had significantly shorter median, post discharge survival(4.8 years [2.6, 7.3] vs. 7.9 years [3.27, 12.1], p\u0026thinsp;=\u0026thinsp;0.045). These patients also had a significantly higher rate of post discharge, 3-years mortality (30.8% vs. 7.9%, p\u0026thinsp;=\u0026thinsp;0.036).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStudy patients according to hypercalcemia status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eWhole cohort\u003c/p\u003e \u003cp\u003e[n\u0026thinsp;=\u0026thinsp;89]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eHypercalcemia*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003e[n\u0026thinsp;=\u0026thinsp;76]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003cp\u003e[n\u0026thinsp;=\u0026thinsp;13]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCalcium (mg/dL, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.60 [9.20, 9.90]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.50 [9.20, 9.83]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.30 [9.90, 10.50]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDemographic background\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender; M (N (%))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (44.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (40.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (69.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge; years (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.2 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58.2 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e65.4 (15.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking; N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight; Kg (mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75.9 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.8 (15.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.0 (16.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical background, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIHD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (37.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (36.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (38.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (27.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (46.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (10.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (15.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDementia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypo/hyperthyroid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (4.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (23.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChronic medication use, N (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eACEi\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (15.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThiazides\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (5.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrea (mg/dL, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 [32, 54]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.50 [30, 47.25]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88 [46, 130]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dL, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.95 [0.79, 1.20]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.90 [0.76, 1.05]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.48 [1.31, 1.60]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (IU/L, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 [15, 37]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 [14.75, 37.50]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 [15, 31]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST (IU/L, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 [19, 34]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 [18, 34]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 [24, 32]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH (IU/L, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e232 [189, 306]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e223 [183, 292]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e278 [248, 352]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilirubin (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.60 [0.47, 0.85]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.59 [0.47, 0.85]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.65 [0.50, 0.76]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumin (g/dL, mean (SD))\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.50 (0.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.57 (0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.07 (0.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC; max (K/mcl, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.8 [6.5, 12.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.8 [6.4, 12.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.8 [6.8, 10.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets (K/mcl, median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e219 [174, 260]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e230 [190.7, 263.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e153 [113, 170]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (median [IQR])\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.85 [10.4, 13.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.5 [10.8, 13.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.2 [10.0, 11.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eClinical outcomes\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian [IQR] Survival post admission; years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.40 [3.10, 10.40]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.90 [3.27, 12.10]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.80 [2.60, 7.30]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMortality 3 years post admission; N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (7.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (30.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e* Corrected Ca\u0026thinsp;=\u0026thinsp;measured Ca\u0026thinsp;+\u0026thinsp;0.8 (4 - measured albumin); if albumin\u0026thinsp;\u0026lt;\u0026thinsp;4. IHD\u0026thinsp;=\u0026thinsp;Ischemic heart disease, COPD\u0026thinsp;=\u0026thinsp;chronic obstructive pulmonary disease, ALT\u0026thinsp;=\u0026thinsp;alanine transaminase, AST\u0026thinsp;=\u0026thinsp;aspartate transaminase, LDH\u0026thinsp;=\u0026thinsp;lactate dehydrogenase, WBC\u0026thinsp;=\u0026thinsp;white blood cells. Abbreviations: ACE\u0026thinsp;=\u0026thinsp;angiotensin-converting enzyme; ACE-I\u0026thinsp;=\u0026thinsp;ACE inhibitor; AKI\u0026thinsp;=\u0026thinsp;acute kidney injury; Ca\u0026thinsp;=\u0026thinsp;albumin-corrected serum calcium; CKD\u0026thinsp;=\u0026thinsp;chronic kidney disease; eGFR\u0026thinsp;=\u0026thinsp;estimated glomerular filtration rate; ICU\u0026thinsp;=\u0026thinsp;intensive-care unit; IQR\u0026thinsp;=\u0026thinsp;inter-quartile range; IV\u0026thinsp;=\u0026thinsp;intravenous; SD\u0026thinsp;=\u0026thinsp;standard deviation\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs presented in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, hypercalcemia, age, malignancy and thrombocytopenia were all associated with increased hazard ratio for mortality within 3 years of admission. In a multivariate analysis, only age and thrombocytopenia remained independently associated with this clinical outcome (HR\u0026thinsp;=\u0026thinsp;1.06 [1.00, 1.11], p\u0026thinsp;=\u0026thinsp;0.042 and HR\u0026thinsp;=\u0026thinsp;7.04 [1.46, 33.99], p\u0026thinsp;=\u0026thinsp;0.015, respectively).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analysis of mortality within 3 years from discharge\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR [95%CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR [95%CI]\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypercalcemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.11 [1.16, 14.57]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.72 [0.36, 8.15]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.493\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.07 [1.01, 1.13]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.06 [1.00, 1.11]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.042\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.34 [2.07, 26.09]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.92 [0.72, 11.88]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13.92 [3.88, 49.93]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.04 [1.46, 33.99]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.35 [0.94, 11.87]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.50 [0.31, 7.22]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.615\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eHypercalcemia, corrected for blood albumin\u0026thinsp;\u0026gt;\u0026thinsp;10.4 meq/ml, Thrombocytopenia\u0026thinsp;\u0026lt;\u0026thinsp;100K/mcl, Anemia\u0026thinsp;\u0026lt;\u0026thinsp;10 g/dL.\u003c/em\u003e \u003c/p\u003e \u003cp\u003eFigure 1 present the crude, accumulated mortality of sarcoidosis patients according to the existence of hypercalcemia (Fig.\u0026nbsp;1a), anemia (Fig.\u0026nbsp;1b) and thrombocytopenia (Fig.\u0026nbsp;1c).\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eHypercalcemia is a known phenomenon associated with sarcoidosis, affecting approximately 6\u0026ndash;11% of patients, with its pathophysiology thoroughly described in the literature [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although initial presentation of hypercalcemia is rarely seen [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], its presence may indicate an acute disease phase and a high disease burden. Persistent hypercalcemia is considered one of the key indications for treatment initiation in sarcoidosis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, it was previously demonstrated that hypercalcemia serves as negative prognostic indicator in sarcoidosis, correlating with chronic-persistent disease, higher ACE levels, older age, hypergammaglobulinemia, and extrapulmonary involvement of organs such as the spleen, bone, and kidneys [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we aimed to establish whether hypercalcemia at the time of diagnosis of sarcoidosis is associated with an increased mortality rate compared to normocalcemic patients. Thus, reinforcing its role as a prognostic factor in sarcoidosis.\u003c/p\u003e \u003cp\u003eIn this study, 13 patients (14.6%) were identified with hypercalcemia. As shown in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, normocalcemic patients had a significantly longer median survival of 7.90 years, whereas patients with hypercalcemia demonstrated a significantly lower median survival of 4.80 years (p\u0026thinsp;=\u0026thinsp;0.044). A Kaplan-Meier survival curve demonstrated a statistically significant difference in survival between the two groups (p\u0026thinsp;=\u0026thinsp;0.0046). Moreover, 3-years mortality was significantly increased in the hypercalcemic group compared to the normocalcemic group (30.8% vs. 7.9%, p\u0026thinsp;=\u0026thinsp;0.036). While 5-year mortality remained higher in the hypercalcemic group compared to the normocalcemic group (30.8% vs. 14.5%), the difference was not statistical significance (p\u0026thinsp;=\u0026thinsp;0.221). This may suggest a short-term effect of hypercalcemia on survival, although over the long-term follow up (of 5 years) it has no impact on survival.\u003c/p\u003e \u003cp\u003eThese results should be taken into consideration when evaluating the role of hypercalcemia as a prognostic factor in sarcoidosis patients. In the multivariate analysis for 3-year and 5-year survival, hypercalcemia was not found to be a statistically significant risk factor for mortality (p\u0026thinsp;=\u0026thinsp;0.078, 0.254, respectively). However, this could be due to the small sample size. Larger cohort studies are needed to determine the role of hypercalcemia in the course of sarcoidosis. These findings highlight the importance of early recognition of hypercalcemia in sarcoidosis to optimize outcomes and reduce mortality risk. Sarcoidosis patients with hypercalcemia demonstrated significantly different clinical characteristics and laboratory parameters compared to those without hypercalcemia. Among all examined comorbidities (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), only renal failure demonstrated a statistically significant difference between groups (30.8% vs 3.9%, p\u0026thinsp;=\u0026thinsp;0.008), suggesting the consequential relationship between renal dysfunction and hypercalcemia, potentially mediated through dysregulation parathyroid hormone secretion leading to tertiary hyperparathyroidism. Accordingly, laboratory findings associated with severe renal impairment such as hyperphosphatemia (4.3 vs. 3.81 P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), elevated serum creatinine (1.48 vs. 0.9 P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), increased serum urea (88 vs. 38.5 P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), decreased hemoglobin (10.19 vs. 12.5 P\u0026thinsp;=\u0026thinsp;0.005) and hypoalbuminemia (3.07 vs. 3.57 p\u0026thinsp;=\u0026thinsp;0.003) were all statistically significant in the hypercalcemic cohort.\u003c/p\u003e \u003cp\u003eOur results suggest that thrombocytopenia may serve as a negative prognostic factor for survival in sarcoidosis patients. Thrombocytopenia was significantly associated with higher 3-year mortality rates in both uni- and multivariate analyses.\u003c/p\u003e \u003cp\u003eTo confirm the relationship between thrombocytopenia and the primary sarcoidosis diagnosis in our cohort, we reviewed the medical records of all 89 patients. Most did not undergo a bone-marrow-biopsy, and amongst those who did, only 3 patients were diagnosed with significant haemato-pathology.\u003c/p\u003e \u003cp\u003eAs described earlier, thrombocytopenia in sarcoidosis patients could arise from different etiologies. However, our findings are more suggestive for immune-related thrombocytopenia rather than bone marrow pathologies associated with sarcoidosis infiltration..\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn addition to the \u0026ldquo;classic\u0026rdquo; risk factors for poor prognosis of sarcoidosis patients, thrombocytopenia should not be overlooked. After exclusion of alternative hematologic diagnoses, thrombocytopenia may serve as a cause for earlier, more intensive investigations and treatment for sarcoidosis patients who might otherwise remain under routine follow-up only. This assumption should guide future, controlled comparative studies to explore the clinical significance of thrombocytopenia in this patient population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emicroliter\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eACE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eangiotensin converting enzyme\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eITP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune thrombo\u0026ndash;cytopenia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIVIG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintra venous immune globulins\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einstitutional review board\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eelectronic medical record\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCKD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003echronic kidney disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLDH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLactate dehydrogenase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIHD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIschemic heart disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCOPD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003echronic obstructive pulmonary disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealanine transaminase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003easpartate transaminase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ewhite blood cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAKI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacute kidney injury\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eestimated glomerular filtration rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICU\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintensive\u0026ndash;care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einter\u0026ndash;quartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintravenous\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate:\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Sheba medical center Institutional Review Board (IRB approval # 1713-25-SMC). Informed consent was waived due to the retrospective nature of this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication:\u003c/p\u003e\n\u003cp\u003eAll authors gave their consent for this publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials:\u003c/p\u003e\n\u003cp\u003eAll research data is available with the corresponding author upon request under the terms and conditions of the IRB.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting Interests:\u003c/p\u003e\n\u003cp\u003eAll authors declare they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding:\u003c/p\u003e\n\u003cp\u003eThis research had no funding resource to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003eAll authors contributed to research conceptualization, methodology and data curation. All authors contributed to data analysis, writing of the preliminary manuscript and the final submission.\u003c/p\u003e\n\u003cp\u003eAcknowledgements:\u003c/p\u003e\n\u003cp\u003eN/A\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePasli M, Lovell KK, Vulasala SSR, Hairr ML, Bandaru RR, Khalilullah MZ et al. Severe Thrombocytopenia in a 30-Year-Old African American Male With Newly Diagnosed Sarcoidosis: A Case Report. Cureus. 2023. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7759/cureus.34135\u003c/span\u003e\u003cspan address=\"10.7759/cureus.34135\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKraaijvanger R, Janssen Bon\u0026aacute;s M, Vorselaars ADM, Veltkamp M. Biomarkers in the Diagnosis and Prognosis of Sarcoidosis: Current Use and Future Prospects. Front Immunol 2020;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fimmu.2020.01443\u003c/span\u003e\u003cspan address=\"10.3389/fimmu.2020.01443\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalker MD, Shane E, Hypercalcemia. Rev JAMA. 2022;328:1624\u0026ndash;36. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/JAMA.2022.18331\u003c/span\u003e\u003cspan address=\"10.1001/JAMA.2022.18331\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerner B, Schulz E, Wieneke U, Reuss-Borst MA, Sattler B, M\u0026uuml;ller GA. Renal failure as primary manifestation of systemic sarcoidosis. 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SACE and IL-2R as serum biomarkers for evaluation of multi-organ involvement and prognosis of sarcoidosis. Respir Res 2023;24. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/S12931-023-02524-0\u003c/span\u003e\u003cspan address=\"10.1186/S12931-023-02524-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican Thoracic Society MEDICAL SECTION OF THE AMERICAN LUNG ASSOCIATION, Statement on Sarcoidosis T, HIS J OINT S TATEMENT OF THE A MERICAN T HORACIC, S OCIETY (ATS), THE E UROPEAN R ESPIRATORY S OCIETY (ERS) AND THE W ORLD A SSOCIATION OF S ARCOIDOSIS AND O THER G RANULOMATOUS D ISORDERS (WASOG.) WAS ADOPTED BY THE ATS B OARD OF D IRECTORS AND BY THE ERS E XECUTIVE. n.d.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGwadera Ł, Białas AJ, Kumor-Kisielewska A, Miłkowska-Dymanowska J, Majewski S, Piotrowski WJ. Calcium, Phosphate, and Vitamin D Status in Patients with Sarcoidosis\u0026mdash;Associations with Disease Activity and Symptoms. J Clin Med. 2023;12. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/jcm12144745\u003c/span\u003e\u003cspan address=\"10.3390/jcm12144745\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKorogodina A, Kaur N, Kumthekar A. Sarcoidosis-Associated Immune Thrombocytopenic Purpura and Focal Segmental Glomerulosclerosis. J Investig Med High Impact Case Rep 2022;10. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/23247096221097522\u003c/span\u003e\u003cspan address=\"10.1177/23247096221097522\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCASOS CL\u0026Iacute;NICOS CASE REPORTS 278 Medicina Interna REVISTA DA SOCIEDADE PORTUGUESA DE MEDICINA INTERNA Resumo n. d. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.24950/rspmi.545\u003c/span\u003e\u003cspan address=\"10.24950/rspmi.545\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMah\u0026eacute;vas M, Chiche L, Uzunhan Y, Khellaf M, Morin AS, Le Guenno G, et al. Association of sarcoidosis and immune thrombocytopenia: Presentation and outcome in a series of 20 patients. Medicine. 2011;90:269\u0026ndash;78. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/MD.0b013e31822618b3\u003c/span\u003e\u003cspan address=\"10.1097/MD.0b013e31822618b3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKayar Y, Kayar NB, Unver N, Ekinci I. Sarcoidosis Presenting with Severe Thrombocytopenia. Int J Respir Pulm Med. 2016;3:56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeal MS, Amado C, Paracana B, Pereira F, Sousa M, Mendes A. Immune Thrombocytopenia: A Rare Presentation of Pulmonary Sarcoidosis. Eur J Case Rep Intern Med. 2021;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.12890/2021_003060\u003c/span\u003e\u003cspan address=\"10.12890/2021_003060\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLame D, Pianelli M, Kordasti S, Morsia E, Olivieri A, Poloni A. Uncommon Presentation of Sarcoidosis with Severe Thrombocytopenia and Hemorrhagic Diathesis. Hematol Rep. 2024;16:125\u0026ndash;31. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/hematolrep16010013\u003c/span\u003e\u003cspan address=\"10.3390/hematolrep16010013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGwadera Ł, Białas AJ, Iwański MA, G\u0026oacute;rski P, Piotrowski WJ. Sarcoidosis and calcium homeostasis disturbances\u0026mdash;Do we know where we stand? Chron Respir Dis 2019;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/1479973119878713\u003c/span\u003e\u003cspan address=\"10.1177/1479973119878713\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMulkareddy V, Bhalla V, Upadhye S, Siddam P. The Diagnostic Dilemma of Sarcoidosis: A Case of Acute Hypercalcemia. Cureus 2020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7759/cureus.10399\u003c/span\u003e\u003cspan address=\"10.7759/cureus.10399\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCameli P, Caffarelli C, Refini RM, Bergantini L, D\u0026rsquo;Alessandro M, Armati M, et al. Hypercalciuria in sarcoidosis: A specific biomarker with clinical utility. Front Med (Lausanne). 2020;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fmed.2020.568020\u003c/span\u003e\u003cspan address=\"10.3389/fmed.2020.568020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Sarcoidosis, Hypercalcemia, Cytopenia, Thrombocytopenia, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-9385075/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9385075/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground.\u003c/h2\u003e \u003cp\u003eLong term survival in Sarcoidosis patients can be predicted by several clinical and laboratory parameters. Hypercalcemia serves as a predominant, negative prognostic factor. In the current study we aimed at identification of other patient characteristics influencing outcomes over a 10-year period.\u003c/p\u003e\u003ch2\u003eMethods.\u003c/h2\u003e \u003cp\u003eThis was a retrospective analysis of hospitalized sarcoidosis patients in a large, tertiary medical center.\u003c/p\u003e\u003ch2\u003eResults.\u003c/h2\u003e \u003cp\u003eDuring a 10-year period between 2014 and 2024, data from 89 sarcoidosis patients was collected using MDClone data mining software. Overall, 13 patients suffered from hypercalcemia (median, corrected for blood albumin: 10.3 mg/dL [9.9\u0026ndash;10.5] vs. 9.5 [9.2\u0026ndash;9.8], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients with hypercalcemia had higher rates of renal failure (30.8% vs. 3.9%, p\u0026thinsp;=\u0026thinsp;0.008), lower platelet counts (median 153 K/mcl [113\u0026ndash;170] vs. 230 [190.7\u0026ndash;263.5], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lower hemoglobin concentrations (median 10.2 g/dL [10.0\u0026ndash;11.3] vs. 12.5 [10.8\u0026ndash;13.6], p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), higher Urea blood levels (median 88 mg/dL [46\u0026ndash;130] vs. 38.5 [30\u0026ndash;47.2], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), higher creatinine levels (median 1.48 mg/dL [1.31\u0026ndash;1.6] vs. 0.9 [0.76\u0026ndash;1.05], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and lower albumin (mean 3.07 g/dL\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47 vs. 3.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.56, p\u0026thinsp;=\u0026thinsp;0.003). Hypercalcemia was associated with lower, post-discharge survival rates (median 4.8 years [2.6\u0026ndash;7.3] vs. 7.9 [3.3\u0026ndash;12.1], p\u0026thinsp;=\u0026thinsp;0.045) and higher rates of 3-years, post-discharge mortality (30.8% vs. 7.9%, p\u0026thinsp;=\u0026thinsp;0.036). In univariate analysis, hypercalcemia and thrombocytopenia were both associated with a higher risk of mortality within 3 years (HR\u0026thinsp;=\u0026thinsp;4.11, 95% CI 1.16\u0026ndash;14.57, p\u0026thinsp;=\u0026thinsp;0.029 and HR\u0026thinsp;=\u0026thinsp;13.92, 95% CI 3.88\u0026ndash;49.93, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). However, in a multivariate analysis only patient age and thrombocytopenia continued to be associated with a statistically significant higher risk of death (HR\u0026thinsp;=\u0026thinsp;8.13, 95% CI 1.88\u0026ndash;35.2, p\u0026thinsp;=\u0026thinsp;0.005). Most patients suffering from thrombocytopenia did not undergo bone-marrow-biopsy, and amongst those who did, only 3 patients were diagnosed as suffering from significant haemato-pathology.\u003c/p\u003e\u003ch2\u003eConclusion.\u003c/h2\u003e \u003cp\u003eAmongst hospitalized patients with sarcoidosis, thrombocytopenia is associated with shorter long-term survival compared to hypercalcemia. Larger studies should further establish our findings.\u003c/p\u003e","manuscriptTitle":"Thrombocytopenia is Associated with Worse Long-Term Outcomes in Sarcoidosis Patients Compared to Hypercalcemia. A Retrospective Analysis of 89 Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-13 08:50:58","doi":"10.21203/rs.3.rs-9385075/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-07T09:44:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"276233949588568161431532897472769609071","date":"2026-05-06T15:22:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-05T10:10:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-27T08:22:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-04-24T13:59:36+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-24T13:44:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-04-24T11:56:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ada3c711-2aa3-4916-aec3-a00fb9481830","owner":[],"postedDate":"May 13th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-07T09:44:59+00:00","index":40,"fulltext":""},{"type":"reviewerAgreed","content":"276233949588568161431532897472769609071","date":"2026-05-06T15:22:06+00:00","index":39,"fulltext":""},{"type":"reviewersInvited","content":"10","date":"2026-05-05T10:10:21+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T08:50:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-13 08:50:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9385075","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9385075","identity":"rs-9385075","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}