Characterization of Shear Stress Mediated Platelet Dysfunction: Data from an Ex Vivo Model for Extracorporeal Circulation and a Prospective Clinical Study.

Extracorporeal circulation (ECC) is frequently used in intensive care patients with impaired lung or cardiac function. Despite being a life-saving therapeutic option, ECC is associated with increased risk for both bleeding and thrombosis. The management of bleeding and thromboembolic events in ECC patients is still challenging partly due to the lack of information on the pathophysiological changes in hemostasis and platelet function during the procedure. Using a combination of an ex vivo model for shear stress and a sensitive and easy-to-use laboratory method, we analyzed platelet responsiveness during ECC. After shear stress simulation in an ex vivo closed-loop ECC model, we found a significantly decreased response of α-granules after activation with adenosine diphosphate and thrombin receptor activating peptide (TRAP-6) and CD63 expression after activation with TRAP-6. Mepacrine uptake was also significantly reduced in the ex vivo shear stress model.In the same line, platelets from patients under ECC with venovenous systems and venoarterial systems showed impaired CD62P degranulation after stimulation with ADP and TRAP-6 compared with healthy control on day 1, 6, and 10 after implantation of ECC. However, no correlation between platelet degranulation and the occurrence of bleeding or thromboembolic events was observed.The used whole blood flow cytometry with immediate fixation after drawing introduces a sensitive and easy-to-use method to determine platelet activation status and our data confirm that increased shear stress conditions under ECC can cause impaired degranulation of platelet.

Left ventricular assist device implantation causes platelet dysfunction and proinflammatory platelet-neutrophil interaction.

Blood flow through left ventricular assist devices (LVAD) may induce activation and dysfunction of platelets. Dysfunctional platelets cause coagulation disturbances and form platelet-neutrophil conjugates (PNC), which contribute to inflammatory tissue damage. This prospective observational cohort study investigated patients, who underwent implantation of a LVAD (either HeartMate II (HM II) (n = 7) or HeartMate 3 (HM 3) (n = 6)) and as control patients undergoing coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) (n = 10). We performed platelet and leukocyte flow cytometry, analysis of platelet activation markers, and platelet aggregometry. Platelet CD42b expression was reduced at baseline and perioperatively in HM II/3 compared to CABG/AVR patients. After surgery the platelet activation marker ß-thromboglobulin and platelet microparticles increased in all groups while platelet aggregation decreased. Platelet aggregation was more significantly impaired in LVAD compared to CABG/AVR patients. PNC were higher in HM II compared to HM 3 patients. We conclude that LVAD implantation is associated with platelet dysfunction and proinflammatory platelet-leukocyte binding. These changes are less pronounced in patients treated with the newer generation LVAD HM 3. Future research should identify device-specific LVAD features, which are associated with the least amount of platelet activation to further improve LVAD therapy.

Upregulation of cAMP prevents antibody-mediated thrombus formation in COVID-19.

Thromboembolic events are frequently reported in patients infected with the SARS-CoV-2 virus. The exact mechanisms of COVID-19-associated hypercoagulopathy, however, remain elusive. Recently, we observed that platelets (PLTs) from patients with severe COVID-19 infection express high levels of procoagulant markers, which were found to be associated with increased risk for thrombosis. In the current study, we investigated the time course as well as the mechanisms leading to procoagulant PLTs in COVID-19. Our study demonstrates the presence of PLT-reactive IgG antibodies that induce marked changes in PLTs in terms of increased inner-mitochondrial transmembrane potential (Δψ) depolarization, phosphatidylserine (PS) externalization, and P-selectin expression. The IgG-induced procoagulant PLTs and increased thrombus formation were mediated by ligation of PLT Fc-γ RIIA (FcγRIIA). In addition, contents of calcium and cyclic-adenosine-monophosphate (cAMP) in PLTs were identified to play a central role in antibody-induced procoagulant PLT formation. Most importantly, antibody-induced procoagulant events, as well as increased thrombus formation in severe COVID-19, were inhibited by Iloprost, a clinically approved therapeutic agent that increases the intracellular cAMP levels in PLTs. Our data indicate that upregulation of cAMP could be a potential therapeutic target to prevent antibody-mediated coagulopathy in COVID-19 disease.

[Levosimendan - a 20-Year Experience]. / Zwanzig Jahre Levosimendan.

Levosimendan is a calcium sensitizer and opens adenosine triphosphate-dependent potassium channels. Since 20 years, it is approved for acute decompensated heart failure. It has been tested in many clinical trials for treatment of at-risk patients in cardiac surgery, right ventricular failure, pulmonary hypertension, weaning of extracorporeal systems, cardiogenic shock, septic shock, ARDS and others.Levosimendan has diverse positive effects next to positive inotropy. It improves ventriculoarterial coupling, increases peripheral perfusion, increases kidney glomerular filtration rate, coronary blood flow and it reduces preload and afterload as well as pulmonary capillary wedge pressure.Due to the opening of potassium channels, it also acts on mitochondria resulting in organ protection. Levosimendan acts anti-apoptotic. These positive effects were described in many small studies. Although this sounds like a promising drug for a variety of settings, results of several multicentre randomized placebo-controlled studies were frustrating. This review resumes some facts of levosimendan in different diseases.

Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS.

BACKGROUND: The COVID-19 pandemic reached Germany in spring 2020. No proven treatment for SARS-CoV-2 was available at that time, especially for severe COVID-19-induced ARDS. We determined whether the infusion of mesenchymal stromal cells (MSCs) would help to improve pulmonary function and overall outcome in patients with severe COVID-19 ARDS. We offered MSC infusion as an extended indication to all critically ill COVID-19 patients with a Horovitz index <100. We treated 5 out of 23 patients with severe COVID-19 ARDS with an infusion of MSCs. One million MSCs/kg body weight was infused over 30 minutes, and the process was repeated in 3 patients twice and in 2 patients 3 times. RESULT: Four out of 5 MSC-treated patients compared to 50% of control patients (9 out of 18) received ECMO support (80%). The MSC group showed a higher Murray score on admission than control patients, reflecting more severe pulmonary compromise (3.5 ± 0.2 versus 2.8 ± 0.3). MSC infusion was safe and well tolerated. The MSC group had a significantly higher Horovitz score on discharge than the control group. Compared to controls, patients with MSC treatment showed a significantly lower Murray score upon discharge than controls. In the MSC group, 4 out of 5 patients (80%) survived to discharge and exhibited good pulmonary function, whereas only 8 out of 18 patients (45%) in the control group survived to discharge. CONCLUSION: MSC infusion is a safe treatment for COVID-19 ARDS that improves pulmonary function and overall outcome in this patient population.

Vasopressor Therapy in Cardiac Surgery-An Experts' Consensus Statement.

Hemodynamic conditions with reduced systemic vascular resistance commonly are observed in patients undergoing cardiac surgery and may range from moderate reductions in vascular tone, as a side effect of general anesthetics, to a profound vasodilatory syndrome, often referred to as vasoplegic shock. Therapy with vasopressors is an important pillar in the treatment of these conditions. There is limited guidance on the appropriate choice of vasopressors to restore and optimize systemic vascular tone in patients undergoing cardiac surgery. A panel of experts in the field convened to develop statements and evidence-based recommendations on clinically relevant questions on the use of vasopressors in cardiac surgical patients, using a critical appraisal of the literature following the GRADE system and a modified Delphi process. The authors unanimously and strongly recommend the use of norepinephrine and/or vasopressin for restoration and maintenance of systemic perfusion pressure in cardiac surgical patients; despite that, the authors cannot recommend either of these drugs with respect to the risk of ischemic complications. The authors unanimously and strongly recommend against using dopamine for treating post-cardiac surgery vasoplegic shock and against using methylene blue for purposes other than a rescue therapy. The authors unanimously and weakly recommend that clinicians consider early addition of a second vasopressor (norepinephrine or vasopressin) if adequate vascular tone cannot be restored by a monotherapy with either norepinephrine or vasopressin and to consider using vasopressin as a first-line vasopressor or to add vasopressin to norepinephrine in cardiac surgical patients with pulmonary hypertension or right-sided heart dysfunction.

The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation.

The pandemia of coronavirus disease 2019 (COVID-19) has caused more than 355,000 confirmed deaths worldwide. However, publications on postmortem findings are scarce. We present the pulmonary findings in four cases of fatal COVID-19 with a spectrum of lung pathology reflecting disease course and duration, invasive therapies, and laboratory features. Early disease is characterized by neutrophilic, exudative capillaritis with microthrombosis and high levels of IL-1beta and IL-6. Later stages are associated with diffuse alveolar damage and ongoing intravascular thrombosis in small to medium-sized pulmonary vessels, occasionally with areas of infarction equivalents, accompanied by laboratory features of disseminated intravascular coagulation. In late stages, organizing pneumonia with extensive intra-alveolar proliferation of fibroblasts and marked metaplasia of alveolar epithelium can be observed. Viral RNA is encountered in the lung, with virus particles in endothelial cells and pneumocytes. In many patients, multi-organ failure with severe liver damage sets in finally, possibly as consequence of an early-onset pro-inflammatory cytokine storm and/or thrombotic microangiopathy.

Multi-Modal Characterization of the Coagulopathy Associated With Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation is used to stabilize severe cardiocirculatory and/or respiratory failure. However, extracorporeal membrane oxygenation is associated with a coagulopathy characterized by thromboembolic and hemorrhagic complications. This study aimed to characterize the pathomechanism of the extracorporeal membrane oxygenation-associated coagulopathy and identify options to optimize its monitoring and therapy. DESIGN: Prospective observational clinical trial. SETTING: ICU of a university hospital. PATIENTS: Patients treated with venovenous extracorporeal membrane oxygenation (n = 10) due to acute respiratory distress syndrome and patients treated with venoarterial extracorporeal membrane oxygenation (n = 8) due to cardiocirculatory failure. One patient per group (venovenous extracorporeal membrane oxygenation or venoarterial extracorporeal membrane oxygenation) had surgery before extracorporeal membrane oxygenation. INTERVENTIONS: Blood was sampled before, and 1, 24, and 48 hours after extracorporeal membrane oxygenation implantation. Point-of-care tests (thrombelastometry/platelet aggregometry), conventional coagulation tests, whole blood counts, and platelet flow cytometry were performed. MEASUREMENTS AND MAIN RESULTS: Even before extracorporeal membrane oxygenation, plasmatic coagulation and platelet aggregation were impaired due to systemic inflammation, liver failure, anticoagulants (heparins, phenprocoumon, apixaban), and antiplatelet medication. During extracorporeal membrane oxygenation, hemodilution and contact of blood components with artificial surfaces and shear stress inside extracorporeal membrane oxygenation additionally contributed to coagulation and platelet defects. Fibrinogen levels, fibrin polymerization, platelet activation, and microparticle release were increased in venovenous extracorporeal membrane oxygenation compared to venoarterial extracorporeal membrane oxygenation patients. Point-of-care results were available faster than conventional analyses. Bleeding requiring blood product application occurred in three of 10 venovenous extracorporeal membrane oxygenation patients and in four of eight venoarterial extracorporeal membrane oxygenation patients. No thrombotic events were observed. In-hospital mortality was 30% for venovenous extracorporeal membrane oxygenation and 37.5% for venoarterial extracorporeal membrane oxygenation patients. CONCLUSIONS: The extracorporeal membrane oxygenation-associated coagulopathy is a multifactorial and quickly developing syndrome. It is characterized by individual changes of coagulation parameters and platelets and is aggravated by anticoagulants. The underlying factors of the extracorporeal membrane oxygenation-associated coagulopathy differ between venovenous extracorporeal membrane oxygenation and venoarterial extracorporeal membrane oxygenation patients and are best diagnosed by a combination of point-of-care and conventional coagulation and platelet analyses. Therapy protocols for treating extracorporeal membrane oxygenation-associated coagulopathy should be further validated in large-scale prospective clinical investigations.

[Anesthesiology and Outcome - Impact of the Perioperative Process]. / Anästhesie und Outcome: Einfluss der perioperativen Prozesse.

In recent years, the role of the anesthesiologist has turned tremendously from the "anaesthesia doctor" into a perioperative physician and risk specialist. Patients are older, multimorbid, and are called up for more and more extensive surgery and interventions. Socioeconomic aspects have grown in importance. The anesthesiologist, paving the way for a good outcome, is involved in nearly all perioperative processes: preoperative evaluation, definition and optimization of preoperative and intraoperative conditions, management of modern intraoperative anesthesia as well as postoperative medically indicated, effective and efficient treatment of partially highly complex patients. The individual perioperative process steps in this way are examined in accordance with established guidelines and the increase in current requirements. Finally, a special emphasis is placed on the perception that the perioperative process has not been completed with the end of surgery - postoperative outcome is not least adversely affected by postoperative complications on the normal ward. The risk of death after complications, "failure to rescue", should be identified early and treated promptly.