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Platelets are first responders in thrombosis and hemostasis, but also central players in inflammation. Compared to platelets recruited to thrombi, immune-responsive platelets use distinct effector functions including Arp2/3-dependent migration along adhesive substrate gradients (haptotaxis), which prevents inflammatory bleeding and contributes to host defense. How platelet migration in this context is regulated on a cellular level is incompletely understood. Here, we use time-resolved morphodynamic profiling of individual platelets to show that migration, in contrast to clot retraction, requires anisotropic myosin IIa-activity at the platelet rear which is preceded by polarized actin polymerization at the front to initiate and maintain migration. Polarization of migrating platelets is coordinated by integrin GPIIb-dependent outside-in signaling via Gα13 to trigger tyrosine kinase c-Src/14-3-3ζ-dependent lamellipodium formation and functions independent of soluble agonists or chemotactic signals. Inhibitors of this signaling cascade, including the clinically employed ABL/c-Src inhibitor dasatinib, interfere predominantly with the migratory capacity of platelets, without major impairment of classical platelet functions. In murine inflammation models, this translates to reduced migration of platelets visualized by 4D intravital microscopy, resulting in increased inflammation-associated hemorrhage in acute lung injury. Finally, platelets isolated from dasatinib-treated leukemia patients prone to clinically relevant hemorrhage exhibit prominent migration defects, while other platelet functions are only partially affected. In summary, we define a distinct signaling pathway essential for migration, and provide novel mechanistic insights explaining dasatinib-related platelet dysfunction and bleeding.

Summary: Background: This study aimed to evaluate risk factors for adverse outcomes and perioperative stroke and death in patients with symptomatic carotid stenosis undergoing open endarterectomy (CEA). The second objective was to assess the predictive value of the POSSUM and V-POSSUM models for predicting morbidity and mortality from CEA in symptomatic carotid stenosis. Patients and methods: A retrospective observational study of all patients admitted to a single center who underwent CEA for symptomatic carotid stenosis was performed. 320 patients from 1999 to 2013 were included. Postoperative complications, 30-day survival, and stroke rates were recorded. The observed outcomes were compared to the POSSUM and V-POSSUM expected mortality (observed to expected ratio (O:E)). Results: The mean age was 68.1±10.0 years. 215 patients were male (67%). Risk factors for surgical complications were: age, with a higher risk in both groups of less than 60 years and more than 75 years of age (p=0.04), a higher ASA score (p=0.04), and hyperlipidemia (p=0.017). Risk factors for the combined endpoint stroke or death were a higher ASA category (p

Objective to investigate the clinical presentation, treatment options, and outcomes of the patients with isolated ruptured paravisceral penetrating aortic ulcers (PV-PAU). Methods All patients presenting with acute aortic syndrome from 2015 to 2020 were screened, of which patients with isolated ruptured PV-PAU were included in this retrospective study. Study endpoints were the assessment of treatment options, technical success, and clinical outcome. Outcome measures included major perioperative complications and mortality. Results Sixteen patients (11 men; median age 68; IQR 60- 75 years) presented with isolated ruptured PV-PAU were included in this study. The median follow-up was 25 months (range 1-51). Ruptured PV-PAUs represented 12.3% of the ruptured aortic aneurysms in all locations. PV-PAUs were found in segment A (n=8, 50%), segment B (n=5, 31%), and segment C (n=3, 19%). PV-PAUs showed a mean protrusion distance of 27±10 mm, a mean neck diameter of 21 ± 7 mm, and maximal aortic diameter of 50 ± 11 mm. Five patients (31%) showed hemodynamic instability on admission and needed intense fluid resuscitation. Of those, two patients needed urgent laparotomy with a fast transabdominal supraceliac aortic clamping, one needed an aortic balloon occlusion to obtain rapid aortic control. The open aortic repair was the most frequently performed surgery (11/16, 69%), followed by hybrid procedures (3/16) and parallel graft chimney technique (2/16). Two patients died during the follow-up, calculating for in-hospital and 1-year mortality rates of 6% and 12%, respectively. The postoperative morbidity rate was 31%. Postoperative complications included acute renal failure (31%), pneumonia (25%), and one case of ischemic colitis (6%). No spinal cord ischemia was reported. Conclusion Ruptured PV-PAU is a rare and challenging diagnostic and therapeutic entity. Open aortic repair seems to be a reliable option in treating patients with isolated ruptured PV-PAUs. Hybrid procedures and parallel stent-graft techniques can only be used in selected patients.

Bei Patienten mit peripherer arterieller Verschlusskrankheit (PAVK) kommt es zu einer ischamiebedingten Myopathie mit Veranderung der Mitochondrienfunktion. Mit hochauflosender Respirometrie (HRR) kann die Mitochondrienfunktion untersucht werden. Uberblick uber In-vivo- und In-vitro-Untersuchungsmethoden der Mitochondrienfunktion. Ausfuhrliche Beschreibung der Methodik der HRR. Darstellung der mitochondrialen Veranderungen bei PAVK. Fur die HRR wird eine Muskelbiopsie von PAVK-Patienten mit Indikation zur invasiven Behandlung oder von gesunden Probanden entnommen. Der Mitochondriengehalt im M. gastrocnemius und im M. vastus lateralis wird durch die Citrat-Synthase-Aktivitat bestimmt. Die HRR zeigt die Aktivitat der mitochondrialen Atmungskette durch Messung der Abnahme der Sauerstoffkonzentration in der Reaktionskammer. Durch Zugabe von Inhibitoren oder Substraten konnen die einzelnen Komplexe der Atmungskette untersucht werden. Bei Patienten mit PAVK im Stadium IIb nach Fontaine kommt es im Vergleich zur gesunden Kontrollgruppe zu einem verminderten Mitochondriengehalt im Versorgungsgebiet der kompromittierten Arterie bei gleichzeitig erhohter Aktivitat. Diese Veranderungen sind durch Revaskularisation reversibel. HRR erlaubt die differenzierte, quantitative Untersuchung der mitochondrialen Atmungskette. Bei PAVK kommt es zu pathologischen Veranderungen der Mitochondrienfunktion, die in vitro trotz Uberangebot von Sauerstoff und Substraten bestehen und die durch eine erfolgreiche Revaskularisation reversibel sind. Die HRR kann zur Aufklarung der Pathophysiologie der PAVK beitragen.

Recent evidence demonstrates an involvement of impaired mitochondrial function in peripheral arterial disease (PAD) development. Specific impairments have been assessed by different methodological in-vivo (near-infrared spectroscopy, 31P magnetic resonance spectroscopy), as well as in-vitro approaches (Western blotting of mitochondrial proteins and enzymes, assays of mitochondrial function and content). While effects differ with regard to disease severity, chronic malperfusion impacts subcellular energy homeostasis, and repeating cycles of ischemia and reperfusion contribute to PAD disease progression by increasing mitochondrial reactive oxygen species production and impairing mitochondrial function. With the leading clinical symptom of decreased walking capacity due to intermittent claudication, PAD patients suffer from a subsequent reduction of quality of life. Different treatment modalities, such as physical activity and revascularization procedures, can aid mitochondrial recovery. While the relevance of these modalities for mitochondrial functional recovery is still a matter of debate, recent research indicates the importance of revascularization procedures, with increased physical activity levels being a subordinate contributor, at least during mild stages of PAD. With an additional focus on the role of revascularization procedures on mitochondria and the identification of suitable mitochondrial markers in PAD, this review aims to critically evaluate the relevance of mitochondrial function in PAD development and progression.

Objective In the present study, we have reported and compared aortoduodenal fistulas (ADFs) after endovascular abdominal aortic aneurysm repair (EVAR) vs after open aortic repair (OAR). Methods We retrospectively analyzed the data from patients treated for ADFs from January 2015 to May 2020 in our hospital. The clinical data, diagnostic procedures, and surgical options were evaluated. The primary endpoints of the present study were 30-day and 1-year mortality. The secondary endpoints were major postoperative complications. Results A total of 24 patients (20 men; median age, 69 years; range, 53-82 years) were admitted with ADFs after EVAR (n = 9) or OAR (n = 15). These patients accounted for ∼4.3% of all abdominal aortic aneurysm repairs in our hospital. The median interval from the initial aortic repair and the diagnosis of ADF was 68 months (range, 6-83 months) for the ADF-EVAR group and 80 months (range, 1-479 months) for the ADF-OAR group. Three patients in the ADF-EVAR group had refused surgical treatment owing to their high surgical risk. One patient in the ADF-OAR group had undergone removal of the aortic prosthesis without replacement. Of the remaining 20 patients, 12 (ADF-EVAR group, n = 4; ADF-OAR group, n = 8) had undergone in situ replacement of the aorta and 8 (ADF-EVAR group, n = 2; ADF-OAR group, n = 6) had undergone extra-anatomic reconstruction with aortic ligation. After a mean follow-up of 26 months, no patient had experienced early limb loss. However, one case of rupture of the venous graft (ADF-EVAR), one case of aortic stump blowout (ADF-OAR), and one case of a ureteroarterial fistula with a homograft (ADF-OAR) had occurred. Overall, the incidence of postoperative complications was significantly greater after ADF-OAR (93% vs 33%; P = .036). The most frequent bacteria involved in the blood cultures were Escherichia coli (25% of patients), and Candida spp. (61%) were the predominant pathogens found on intra-abdominal smears. The in-hospital mortality rates for the ADF-EVAR and ADF-OAR group were 22% and 13%, respectively. The corresponding 1 -year mortality rates were 22% and 33%. Conclusions Patients with ADFs after EVAR or OAR have limited overall survival. In addition to the similar therapeutic approaches, we found no significant differences in postoperative mortality between these two uncommon pathologic entities. In our study, the overall postoperative morbidity seemed greater for the ADF-OAR group.