1LMU Klinikum der Universität München Medizinische Klinik und Poliklinik I München, Deutschland; 2Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland
Introduction
Every third to second patient on intensive care unit (ICU) is transfused with red blood cells during his inpatient stay due to anemia or acute blood loss (Thomas et al., Herat Lung, 2010). Augmented hematopoiesis following acute blood loss implies an increased fraction of immature, reticulated (i.e. RNA-rich) platelets (RPs) newly released from the bone marrow. Recent studies showed increased levels of RPs in patients with acute coronary syndrome (ACS) (Petzold et al., Immunity, 2022) enhancing the risk of thrombotic complications (Cesari et al., Thromb Haemost., 2013). One reason for this could be that RPs show a prothrombotic phenotype with elevated expression of central adhesion molecules (Bongiovanni et al., 2019; Petzold, Immunity) and an impaired antiplatelet response to P2Y12 inhibitors (Guthikonda et al., J Am Coll Cardiol., 2008). In this single-center, retrospective study, we analyzed the association of acute anemia and thrombotic complications in critically ill patients on cardiac ICU. Potential underlying mechanisms were studied using bone marrow imaging of anemic mice.
Methods and Results
To evaluate a potential correlation of acute anemia and thrombotic events, we analyzed all patients admitted to the cardiac ICU in the LMU hospital in Munich with cardiogenic shock between 01/2010 and 08/2023. Patients with mechanical circulatory support devices (intra‐aortic balloon pump (IABP), axial flow pumps (Impella) and veno‐arterial or veno-venous extracorporeal membrane oxygenation (ECMO)) as well as patients after platelet transfusion were excluded. In this retrospective, single-center study, a total of 968 patients were included, 63 of whom had bleeding classified to BARC 3-5. Of interest, 17.5% of patients with bleeding event experience subsequent thrombotic event (i.e. deep venous thrombosis, pulmonary embolism, myocardial infarction or stroke) compared to only 8.0% in patients without preceding bleeding event (p=0.04; Table 1).
To investigate the underlying mechanism driving enhanced risk of thrombosis, we employed an acute anemia model in C57BL/6 mice to simulate patients experiencing blood-loss on ICU. Over a period of three consecutive days, we drained 200-300μl of blood from the facial vein of the mice (Figure 1A). Following acute blood loss, anemic mice exhibited a 50% reduction in red blood cell (RBC), hemoglobin (Hgb), and hematocrit (HCT) levels (Figure 1B). Using flow cytometry, we found a 100% increase in reticulated platelet fraction with overall normal platelet counts (Figure 1C-E). To elucidate the underlying mechanism, we established bone marrow imaging under anemic conditions using multi-photon intravital microscope and assessed thrombopoiesis. Although proplatelet length, release time and growth speed were unaltered under anemic condition (Figure 1F), we found increased numbers and enlarged size of megakaryocytes (MK) within the bone marrow of anemic mice indicating that anemia promotes MKs expansion and maturation (Figure 1G-H).
Discussion
In summary, we demonstrate that bleeding serves as an independent factor contributing to an increased risk of thrombosis in patients admitted to ICU. To investigate the underlying mechanisms responsible for these clinical observations, we employed a murine model of blood loss, which confirmed the findings and attributed them primarily to an increased production of reticulated platelets resulting from enhanced MK maturation in the bone marrow.