[Late Open Semi-conversion with Endograft Preservation for (Type II) Endoleaks with Late Aneurysm Sac Enlargement after EVAR - Indications, Method and Results in Our Own Patient Collective]. / Die späte offene Semikonversion mit Prothesenerhalt bei (Typ II­)Endoleckagen mit spätem Aneurysmasackwachstum nach EVAR - Indikationen, Methode und Ergebnisse im eigenen Patientenkollektiv.

EVAR (endovascular aortic repair) is the most common method for treating an abdominal aortic aneurysm, but according to the latest findings it carries the risk of subsequent complications. These can be caused by (late) aneurysm sac growth. If conservative and surgical therapies fail to treat the aneurysm sac growth, open conversion is necessary to prevent aneurysm rupture. There are several options for open conversion, in which the EVAR prosthesis can be completely preserved or is (partially) removed. Late open semi-conversion with complete in-situ preservation of the EVAR-prosthesis and gathering of the aneurysm sac are a less invasive method than complete conversion and may be performed instead for selected patients. The aim of the present work is to present the surgical method, including indications and technical information, as well as the presentation of the results in our recent patient collective.All patients semi-converted in our department of vascular surgery and phlebology due to (type II) endoleak were included. All data are presented as n (%) or median (range).Between 6/2019 and 3/2023, 13 patients underwent semi-conversion 6 (2-12) years (median, range) after the initial EVAR. The aneurysm sac diameter at the time of semi-conversion was 69 mm (58-95 mm), the operating time was 114 min (97-147 min), the blood loss was 100 ml (100-1500 ml). Five (38%) patients received blood transfusion intraoperatively and 2 (15%) postoperatively. The stay in the intensive care unit lasted 1 (1-5) days, the hospitalisation time was 8 (6-11) days. Postoperative complications were intestinal atony (3 [23%], 1 [8%] with nausea/emesis and gastric tube insertion), anaemia (2 [15%]), hyponatraemia (2 [15%]), delirium (1 [8%]), COVID-19 infection (1 [8%]) and 1 [8%] intra-abdominal postoperative bleeding with the indication for surgical revision and the transfusion of 8 erythrocyte concentrates.Semi-conversion is a safe and practicable surgical method with few severe complications for a selected group of patients, which should be considered as an alternative to more invasive methods with (partial) removal of the EVAR-prosthesis. Further long-term studies comparing semi-conversion to full conversion are needed to demonstrate its benefits.

Atypical and rare cause of myocardial infarction: coronary subclavian steal syndrome (CSSS) treated by a carotid-subclavian bypass in a 71-year-old female patient.

BACKGROUND: The coronary subclavian steal syndrome (CSSS) is a rare complication after coronary arterial bypass graft operations (CABG) using the left or right internal mammary artery ((L/R)IMA). It results from a retrograde blood flow from the IMA into the subclavian artery (SA) due to a stenosis or occlusion of the SA proximal to the IMA origin. This "steal phenomenon" leads to a decreased blood flow in the IMA and may result in myocardial ischemia (MIS) and even myocardial infarction (MIN). Treatment options include interventional and surgical therapy. CASE PRESENTATION: We report the case of a 71-year old woman, who suffered from an acute non-ST elevation myocardial infarction (NSTEMI) 11 years after LIMA-CABG surgery and who was treated successfully with a carotid-subclavian bypass (CSB) after failed interventional therapy. CONCLUSION: CSB may be regarded as a viable treatment option for patients suffering CSSS in the case of MIS and even an acute MIN/NSTEMI, especially in the case of missing or failed interventional therapy attempts. Specialists in cardiothoracic and vascular surgery should be aware of possible CSSS conditions and know about appropriate diagnostic and therapeutic options.

Intraoperative use of transit time flow measurement improves patency of newly created radiocephalic arteriovenous fistulas in patients requiring hemodialysis.

BACKGROUND: The autologous arteriovenous fistula is the primary choice to establish hemodialysis access without high failure rates. Intraoperative ultrasound flow measurements of newly created autologous arteriovenous fistulas represent a possibility of quality control and may therefore be a tool to assess their functionality. The aim of our study was to correlate intraoperative blood flow with access patency. METHODS: Between March 2012 and March 2015, intraoperative transit time flow measurements were collected on 89 patients. Measurements were performed 5-10 min after the creation of a standardized anastomosis using 3-6 mm flow probes. To examine the correlation between intraoperative blood flow and access patency, groups of patients with high (> 200 mL/min) versus low flow (< 200 mL/min) were enrolled. Patients were assessed clinically and with ultrasound every 3 months. Data were analyzed retrospectively. RESULTS: In the current short-term follow-up, including 89 patients (age 62 ± 3 years), 61 (68.5%) of the autologous arteriovenous fistulas were currently being used in an observation period ranging from 3 months to 3 years (mean observation period 546 ± 95 days) postoperatively. The intraoperative blood flow in patients with functioning autologous arteriovenous fistula (78) was significantly higher than that of patients without functioning autologous arteriovenous fistulas (407 ± 25 vs 252 ± 42 mL/min, respectively; p < 0.005) (11). CONCLUSION: The intraoperative measurement of blood flow is a useful tool to predict the outcome of maturation in autologous arteriovenous fistula. With this method, technical problems can be detected and corrected intraoperatively. Routine implementation of intraoperative flow measurements has to be examined by prospective controlled trials.

Adductor Canal Compression Syndrome in a 46-Year-Old Female Patient Leading to Acute External Iliac, Femoral, and Popliteal Artery Thrombosis and Critical Ischemia: A Case Report.

The adductor canal compression syndrome is one of the several rare nontraumatic causes of arterial occlusions, which may lead to critical ischemia of the lower limb. We report the case of a 46-year-old athletic woman, who suffered from activity-related paresthesia and sharp pain in the left upper and lower leg for 2 years. Imaging and neurological investigations of the spine remained without pathological findings that would explain the patient's complaints. Actually, the patient presented with symptoms of critical lower limb ischemia. Magnetic resonance angiography revealed nearly complete thrombotic occlusion of the common femoral artery and the arteries of the lower leg. An emergency surgery was performed, revealing an external compression of the superficial femoral artery in the adductor canal. Subsequently, a thrombectomy was performed and a venous bypass graft was installed. No postoperative complications occurred, the patient recovered well and could return to her activities of daily living about 3 weeks after the surgery. The adductor canal compression syndrome results from a local anomalous musculotendinous band or hypertrophic musculature surrounding the passing structures. It mainly occurs in athletes exposed to repetitive stress, especially runners and skiers, and may lead to thrombosis followed by critical lower extremity ischemia. The lack of obvious symptoms during routine physical examination often impedes rapid diagnosis and timely therapy. Considering the high thrombotic risk, attention should be paid to this rare cause of lower limb pain to prevent the patient from critical lower extremity ischemia and potential limb loss due to consecutive acute thrombotic occlusions.

Analysis of the influence of antithrombin on microvascular thrombosis: anti-inflammation is crucial for anticoagulation.

PURPOSE: Microvascular thrombosis during septic conditions is of essential clinical relevance, but the pathomechanisms are not yet completely understood. The purpose of this study was to study the distinguished differentiation of the interactions of inflammation and coagulation using antithrombin (AT), a mediator of anticoagulation and anti-inflammation. METHODS: Using a thrombosis model in a cremaster muscle preparation of male C57Bl/6J mice (n = 83), we quantitatively assessed microvascular thrombus formation by using intravital fluorescence microscopy. Experimental groups consisted of animals treated with AT or with tryptophan(49)-blocked AT (TrypAT), which exerts only anticoagulant but no anti-inflammatory effects. To further see whether endothelial glycosaminoglycan (GAG) binding with consecutive prostacyclin (PGI2) release is mandatory for the anticoagulant process of AT, animals were administered heparin or indomethacin either alone or in combination with AT. RESULTS: The antithrombotic capacity of AT significantly differs in the experimental groups in which anti-inflammation was antagonized. This is given by the significantly prolonged occlusion times (p < 0.05) and higher patency rates in case of application of AT alone; while all other groups in which the anti-inflammatory action of AT was blocked by TrypAT, heparin or indomethacin revealed thrombus kinetics comparable to controls. CONCLUSIONS: The anti-inflammatory influence of AT is essentially linked to its anticoagulant effect in the microvascular system. Those specifications of the active profile of AT characterize the intimate interactions of the anticoagulant and anti-inflammatory pathways. This might be of relevance for AT as a therapeutic agent in critically diseased patients and the clinical understanding of microvascular thrombosis.

Successful Management of an Infected Aortic Stent Graft in a Liver Transplanted Patient.

We report on a 57-year-old female liver transplanted patient who underwent endovascular aneurysm repair because of an infrarenal abdominal aortic aneurysm. Two months later, she developed an infection, and positron emission tomography computed tomography detected a paraprosthetic abscess. Explantation of the endoprosthesis and aortic reconstruction with a Y-shaped silver graft was made. The patient was discharged on the 12th postoperative day and shows up regularly in our outpatients department in a good clinical condition. After meticulous research of the current literature, this is the first published case of the successful management of an infected endovascular aortic stent in a liver transplanted patient.

Antithrombin reduces inflammation and microcirculatory perfusion failure in closed soft-tissue injury and endotoxemia.

BACKGROUND: Closed soft-tissue trauma leads to activation of the coagulation cascade and is often complicated by systemic inflammation and infection. Previous investigations have shown potent anti-inflammatory properties of antithrombin. We herein report on the action of antithrombin on skeletal muscle injury in experimental endotoxemia. MATERIALS AND METHODS: By using a pneumatically driven computer-controlled impact device, closed soft-tissue trauma was applied on the left hind limb of pentobarbital-anesthetized rats. Six hours later, endotoxemia was induced by intraperitoneal injection of Escherichia coli lipopolysaccharide. An equivalent volume of physiological saline was given in controls. At the same time point, treatment of animals was started by intravenous injection of antithrombin (250 IU/kg body weight) or vehicle solution. Twenty-four hours after trauma, the extensor digitorum longus muscle was microsurgically exposed and analyzed by means of high-resolution multifluorescence microscopy. RESULTS: Traumatic soft-tissue injury with additional endotoxemia was characterized by nutritive perfusion failure (functional capillary density: 379±20cm/cm;), tissue hypoxia (nicotinamide adenine dinucleotide autofluorescence: 77±4 aU), and enhanced leukocyte-endothelial cell interaction (773±35 cells/mm;). Therapeutic intervention with antithrombin 6 hrs after trauma restored nutritive perfusion and tissue oxygenation (functional capillary density: 469±22cm/cm; nicotinamide adenine dinucleotide autofluorescence: 61±5 aU [p < 0.05]) and reduced inflammatory leukocyte adherence (237±20 cells/mm; [p < 0.05]) toward values found in nontraumatized controls (functional capillary density: 573±13cm/cm; nicotinamide adenine dinucleotide autofluorescence: 56±2 aU; leukocyte adherence: 204±20 cells/mm;). CONCLUSION: Antithrombin ameliorates microcirculatory dysfunction and tissue injury in traumatized animals during endotoxemia. Furthermore, a reduced inflammatory cell response helps to prevent leukocyte-dependent secondary tissue injury.

Chromogranin a as serum marker for gastroenteropancreatic neuroendocrine tumors: a single center experience and literature review.

The aim of this study was to assess the clinical sensitivities of the tumor markers chromogranin A (CgA), urinary 5-hydroxyindoleacetic acid (5-HIAA) and alkaline phosphatase (AP) in neuroendocrine tumors (NETs) of the GastroEnteroPancreatic-(GEP-) system depending on tumor primary location and metastatic spread. In a retrospective single-center series, sensitivities were evaluated in serum samples from 110 patients with midgut (n = 62) and pancreatic (n = 48) NETs. CgA levels were analyzed by a commercially-available immunoradiometric assay (CIS-bio) during routine follow-up in the years 2000-2009. CgA showed a higher sensitivity for midgut (68%) than pancreatic (54%) NETs. A higher CgA sensitivity and significantly higher median CgA values were found in patients with liver metastases than in those without, and in patients with hepatic and additionally extra-hepatic metastases than in those with hepatic and nodal metastases alone, respectively. We found an overall sensitivity for elevated 5HIAA excretion of 69% for midgut NETs and a significant correlation between median CgA and 5-HIAA values. The sensitivity of AP and the correlations of AP/CgA-data-pairs were low in both midgut and pancreatic NETs, although highest for metastatic pancreatic NETs. The sensitivity of CgA measurement depends on the NET primary location and spread of disease. 5-HIAA and CgA showed comparable sensitivity in midgut NETs, while AP does not seem to be useful as a tumor marker in GEP-NETs.

Antithrombin therapy in pancreas retransplantation and pancreas-after-kidney/pancreas-transplantation-alone patients.

Antithrombin (AT) is a coagulatory inhibitor with pleiotropic activities. AT reduces ischemia/reperfusion injury and has been successfully used in patients with simultaneous pancreas kidney transplantation. This study retrospectively analyzes prophylactic high-dose AT application in patients with solitary pancreas transplantation traditionally related to suboptimal results. In our center, 31 patients received solitary pancreas transplantation between 7/1994 and 7/2005 (pancreas retransplantation, PAK/PTA). The perioperative treatment protocol was modified in 5/2002 now including application of 3000 IU. AT was given intravenously before pancreatic reperfusion (AT, n = 18). Patients receiving standard therapy served as controls (n = 13). Daily blood sampling was performed during five postoperative days. Standard coagulatory parameters and number of transfused red blood cell units were not altered by AT. In AT patients serum amylase (p < 0.01) and lipase (p < 0.01) on postoperative days 1, 2 and 3 were significantly reduced. Our actual perioperative management protocol including high dose AT application in human solitary pancreas transplantation reduced postoperative liberation of pancreatic enzymes in this pilot study. Prophylactic AT application should deserve further clinical testing in a randomized controlled trial.

Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding.

INTRODUCTION: Prothrombin complex concentrates are recommended for rapid reversal of vitamin K anticoagulants. As they normalize levels of vitamin K dependent clotting factors and re-establish hemostasis, they may also be used as adjunctive therapy in patients with major bleeding. The aim of this study was to retrospectively evaluate the efficacy of prothrombin complex concentrates in the surgical setting. METHODS: The case notes of 50 patients requiring urgent oral anticoagulation reversal (n = 12) or with severe perioperative coagulopathic bleeding (n = 38) who received an infusion of prothrombin complex concentrate (Beriplex P/N(R) 500) at the surgical department of the University of Munich Hospital, Germany were retrospectively reviewed. Efficacy of prothrombin complex concentrate application was evaluated using the Quick test, reported as an international normalized ratio, hemodynamic measurements and requirement for blood products. Safety assessments included whole blood hemoglobin levels and specific parameters of organ dysfunction. RESULTS: Baseline characteristics were comparable, except that mean baseline international normalized ratio and hemoglobin levels were significantly higher (P < 0.01) in anticoagulation reversal than in bleeding patients. In anticoagulation reversal, the international normalized ratio was significantly reduced (from 2.8 +/- 0.2 at baseline to 1.5 +/- 0.1, P < 0.001) after one prothrombin complex concentrate infusion (median dose 1500 IU; lower quartile 1,000, upper quartile 2,000). No major bleeding was observed during surgery after prothrombin complex concentrate administration. Only one patient received platelets and red blood cell transfusion after prothrombin complex concentrate administration. In bleeding patients, infusion of prothrombin complex concentrate (median dose 2,000 IU; lower quartile 2,000, upper quartile 3,000) significantly reduced the INR from 1.7 +/- 0.1 at baseline to 1.4 +/- 0.1 (P < 0.001). This decrease was unrelated to fresh frozen plasma or vitamin K administration. Bleeding stopped after prothrombin complex concentrate administration in 4/11 (36%) patients with surgical bleeding and 26/27 (96%) patients with diffuse bleeding. Hemoglobin levels increased significantly from baseline in bleeding patients (P < 0.05) and mean arterial pressure stabilized (P < 0.05). No thrombotic events or changes in organ function were reported in any patient. CONCLUSIONS: Prothrombin complex concentrate application effectively reduced international normalized ratios in anticoagulation reversal, allowing surgical procedures and interventions without major bleeding. In bleeding patients, the improvement in coagulation after prothrombin complex concentrate administration was judged to be clinically significant.

A critical analysis of laparoscopic appendectomy: how experience with 1,400 appendectomies allowed innovative treatment to become standard in a university hospital.

BACKGROUND: Although advantages of laparoscopic appendectomy (LA) have not yet been proved, there is increasing evidence that LA provides diagnostic and therapeutic advantages as compared to conventional surgery. This article reports the introduction of LA in a university hospital where LA now represents the standard operative procedure in patients with suspected appendicitis. METHODS: Consecutive patients with appendectomy were prospectively included in the surgical database from 5/1991 to 10/2005. Operating time skin-to-skin in minutes, conversion from laparoscopy to open appendectomy, and complications requiring reoperation as well as surgical expertise were recorded. RESULTS: After initial performance of LA by four experienced specialists in laparoscopic surgery between 1991 and 1994, LA was routinely implemented from 1995 to 2005. Laparoscopic appendectomy was performed in 1,012 patients, and conventional appendectomy in 449 patients, with a LA rate of about 90% in recent years. Intraoperative conversion was deemed necessary in 62 patients (6.2 %) by 40 surgeons among the 103 surgeons who performed LA over 14 years with a mean operative time of 57 +/- 2 min. Between 1995 and 2005 about 25%-30% of LAs were performed as the first LA for the respective surgeon. Laparoscopic appendectomy was associated overall with a reduced length of stay in the hospital compared to open appendectomy (LA: 4.4 +/- 0.1 days versus 6.6 +/- 0.2 in open appendectomy; p < 0.001). CONCLUSIONS: This analysis provides evidence that LA can be introduced in an university hospital with acceptable results despite low operation numbers per surgeon and a liberal teaching policy. The LA procedure, which is associated with a 2%-4% rate of reoperation, may serve as laparoscopy training for young surgeons.

Sublethal trauma model with systemic endotoxemia for the study of microcirculatory disorders after the second hit.

BACKGROUND: Experimental models often cannot simulate the clinical situation in traumatized patients where the septic second hit finally leads to multiple organ dysfunction syndrome and death. We present an experimental animal model combining initial standardized soft tissue trauma to the left hindlimb of rats with subsequent sublethal systemic endotoxemia. MATERIALS AND METHODS: This study characterizes the influence of trauma and systemic endotoxemia on nutritive blood flow, inflammatory cell-cell interaction and tissue cell integrity in the traumatized region. RESULTS: At 24 h after local tissue contusion, in vivo analysis of the skeletal muscle microcirculation by means of high resolution fluorescence microscopy revealed intravascular leukocyte accumulation and impairment of nutritive perfusion with tissue hypoxia. Moreover, muscle tissue damage was characterized by myocyte cell apoptosis. Additional systemic exposure of animals to E. coli lipopolysaccharide at 6 h after soft tissue contusion caused a drop in arterial blood pressure as well as coagulatory disorders, as given by marked thrombocytopenia and reduced thromboplastin times. In double-hit exposed animals, skeletal muscle microcirculation presented with an aggravation of inflammation, perfusion failure, and apoptotic cell death after 24 h. CONCLUSIONS: This model more closely resembles the scenario of polytraumatized patients with the risk of secondary infections and, thus, is suited to characterize anti-inflammatory drugs with respect to their potential to interfere with microcirculatory disorders and elaboration of disseminated intravascular coagulation after trauma.

Activated protein C reduces tissue hypoxia, inflammation, and apoptosis in traumatized skeletal muscle during endotoxemia.

OBJECTIVE: Extensive surgical trauma leads to activation of the coagulation cascade and is often complicated by systemic inflammation and infection. Activated protein C, a natural coagulatory inhibitor, was recently shown to reduce mortality in septic patients. We herein report on the actions of activated protein C on skeletal muscle injury in experimental endotoxemia. DESIGN: Prospective controlled animal study. SETTING: University animal research facility. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Closed soft tissue trauma was applied on the left hind limb of pentobarbital-anesthetized rats. Six hours later endotoxemia was induced by intraperitoneal injection of Escherichia coli lipopolysaccharide. An equivalent volume of physiologic saline was given in controls. At the same time point, treatment of animals was started by continuous intravenous application of activated protein C (24 microg/kg.hr) or vehicle solution over 18 hrs. Twenty-four hours after trauma, the extensor digitorum longus muscle was microsurgically exposed and analyzed by means of high-resolution multifluorescence microscopy. MEASUREMENTS AND MAIN RESULTS: Endotoxemia aggravated traumatized muscle injury, as evidenced by reduced nutritive perfusion, increased tissue hypoxia, enhanced leukocyte-endothelial cell interaction, and apoptotic myocyte cells (249 +/- 17 cm/cm vs. 298 +/- 22 cm/cm; reduced nicotinamide adenine dinucleotide [NADH], 149 +/- 15 arbitrary units [AU] vs. 130 +/- 13 AU; 417 +/- 79 cells/mm vs. 344 +/- 77 cells/mm and 62 +/- 9 cells/mm vs. 31 +/- 5 cells/mm). Therapeutic intervention with activated protein C 6 hrs after trama protected nutritive perfusion and tissue oxygenation (341 +/- 24 cm/cm and 115 +/- 8 AU) and reduced inflammatory leukocyte adherence (185 +/- 60 cells/mm) and cellular apoptosis (15 +/- 4 cells/mm). Of note, the protection of traumatized muscle tissue by activated protein C was also maintained during endotoxemia, as indicated by a functional capillary density of 379 +/- 10 cm/cm, a NADH-fluorescence of 102 +/- 6 AU, a leukocyte adherence of 82 +/- 12 cells/mm, and a myocyte apoptosis of 28 +/- 4 cells/mm. CONCLUSIONS: Microcirculatory injury of traumatized skeletal muscle tissue is enhanced by intravenous endotoxin application in this model of soft tissue trauma. Activated protein C ameliorates microcirculatory dysfunction and tissue injury, in particular in traumatized animals during endotoxemia.

Efficacy of antithrombin in the prevention of microvascular thrombosis during endotoxemia: an intravital microscopic study.

INTRODUCTION: The KyberSept trial in septic patients showed that antithrombin (AT) reduced 90-day mortality significantly in a subgroup of patients not receiving concomitant heparin for thrombosis prophylaxis. Microvascular thrombosis is a key pathophysiologic mechanism during sepsis, ischemia/reperfusion and disseminated intravascular coagulation (DIC). Therefore, this study investigated the antithrombotic property of AT as potential monotherapy in an experimental endotoxemia model in order to omit concomitant heparin. MATERIALS AND METHODS: Using a light/dye injury model in the ear and the cremaster muscle preparation of mice, we quantitatively assessed microvascular thrombus formation in a total of 30 endotoxemic mice by means of intravital fluorescence microscopy. Before thrombus induction animals received a single i.v. bolus of AT (100 or 250 IU/kg), heparin (100 IU/kg) or saline (NaCl). RESULTS: In NaCl-treated endotoxemic animals, light/dye exposure led to complete thrombotic occlusion in arterioles and venules within <450 s in the ear model. Heparin delayed thrombotic vessel occlusion by more than 50%. AT significantly prolonged times until thrombotic vessel occlusion in a dose-dependent manner and more effectively than heparin (p<0.05 vs. NaCl and heparin). This anti-coagulative effect of AT was especially pronounced in arterioles. Upon light/dye exposure to cremaster muscle preparations in endotoxemic mice AT also caused a 4-fold delay in microvascular thrombus growth with 827+/-77 s until complete thrombotic occlusion. CONCLUSIONS: We could characterize for the first time AT-mediated antithrombotic activity during endotoxemia in two models of phototoxicity-induced microvascular thrombosis. Our results clearly demonstrate an additional AT mechanism of action that may be responsible for beneficial effects observed during endotoxemia and DIC. This AT profile may allow future high-dose AT application without giving heparin for thrombosis prophylaxis, an intriguing strategy that is to be tested under clinical conditions.

Antithrombin and hypercoagulability in sepsis: insights from thrombelastography?

Antithrombin (AT) has been used for over 25 years to successfully treat disseminated intravascular coagulation (DIC). A four-day AT therapy in patients with DIC in the KyberSept trial has been related to a clear survival benefit in patients not receiving concomitant heparin. Gonano and coworkers performed thrombelastography (TEG) measurements in patients with severe sepsis and clearly showed hypercoagulability, as defined by five TEG parameters, compared to healthy controls. In the AT group they found a trend towards normalization of TEG parameters after treatment, although this did not reach statistical significance. This first clinical evaluation of hypercoagulability during AT treatment could not provide evidence for an attenuation of coagulopathy, an effect that might be due to high inter-individual variability.

Microcirculatory disorders in sepsis and transplantation: therapy with natural coagulatory inhibitors antithrombin and activated protein C.

PURPOSE OF REVIEW: Modern technologies allow visualization of microcirculatory disorders. This review describes how the coagulatory inhibitors antithrombin and activated protein C (APC) can improve microcirculation in sepsis and transplantation. RECENT FINDINGS: The effects of antithrombin and APC on microcirculatory disorders in ischemia reperfusion and experimental sepsis have been reported recently. In addition, antithrombin has recently been clinically used to reduce graft pancreatitis after pancreas-kidney transplantation, and to improve kidney perfusion. It was demonstrated that septic capillary perfusion failure as well as leukocyte-endothelial cell interactions can be reversed by high-dose prophylactic antithrombin application. APC was also highly effective in this context. Thus, APC could improve microcirculatory blood flow in septic patients as recently measured by in-vivo orthogonal polarization spectral imaging techniques. For antithrombin, comparable measurements in humans are currently not available. SUMMARY: Microcirculatory dysfunction plays a key role in the development of organ dysfunction in septic patients and after solid organ transplantation. The exogenous application of coagulatory inhibitors may provide a new important strategy for prevention and treatment of microcirculatory disorders. This mode of action may be the reason why coagulatory inhibitors could improve mortality in septic patients without directly influencing inflammatory mediator concentrations.

Antithrombin is as effective as heparin and hirudin to prevent formation of microvascular thrombosis in a murine model.

A recently published post-hoc analysis of a trial using high-dose antithrombin (AT) in septic patients (KyberSept) revealed significant reduction of lethality when no concomitant heparin was administered, whereas patients with the combination of heparin and AT did not benefit in terms of survival. Therefore, it seems feasible to study the capability of AT in prevention of microvascular thrombus formation to avoid concomitant application of heparin and AT. Using fluorescence microscopy and a light/dye-injury mouse ear model, the kinetics of thrombus formation were analyzed quantitatively in vivo upon single iv bolus of saline (control), heparin (100 IU/kg), hirudin (1 mg/kg) or AT (25, 50, 100 or 250 IU/kg) (N = 7 animals per group each). In controls, light/dye-injury induced complete thrombotic occlusion in all arterioles and venules studied. Heparin and hirudin prevented thrombotic vessel occlusion in 62% and 43% of arterioles and 11% and 28% of venules. AT-250 was found to be more effective than heparin and hirudin, because thrombus formation was completely banned in all arterioles and venules. AT-100 and AT-50 were also capable of significantly blocking thrombus formation in both arterioles and venules. In blood vessels, which finally clogged, the time for development of complete vessel occlusion was delayed after heparin, hirudin and AT-25, but in particular after AT-50 and AT-100. In conclusion, AT-mediated antithrombotic activity has been characterized in a model of phototoxicity-induced microvascular thrombosis formation, demonstrating that AT delays and prevents thrombus formation in arterioles and venules at least comparably effective as heparin and hirudin.

Single-shot antithrombin in human pancreas-kidney transplantation: reduction of reperfusion pancreatitis and prevention of graft thrombosis.

Reperfusion pancreatitis and graft thrombosis often induce early graft loss in simultaneous pancreas-kidney (SPK) transplantation. Antithrombin (AT) is a coagulatory inhibitor with pleiotropic activities that reduces experimental ischemia/reperfusion injury. This study retrospectively analyses prophylactic high-dose AT application in patients with first SPK. In an university transplantation center, 53 consecutive patients with SPK were studied without randomization. In one group, 3000 IU of AT was given intravenously before pancreatic reperfusion (AT, n = 24). Patients receiving standard therapy including postoperative AT supplementation (controls, n = 29) served as controls. Daily blood sampling was performed as a part of the clinical routine during four postoperative days. There were no differences in demographic and laboratory parameters [donor/recipient age, ischemia time, perfusion solution, body weight, mismatches] between both groups. Baseline creatinine values were lower in the control group versus AT group (P < 0.05). Coagulatory parameters and bleeding incidence were not influenced by AT, while incidence of graft thrombosis was reduced (control: 7/29; AT: 4/24; relative reduction of risk: -33%; P < 0.05). Single-shot AT application during SPK modulated serum lipase activity on postoperative days 2 and 3, and minimized risk for graft thromboses without increasing perioperative bleeding. This new concept should deserve testing in a prospective clinical trial.