Safe and effective administration of multiple recombinant factors on VA-ECMO via post-oxygenator pigtail during acute massive pulmonary hemorrhage

Introduction: Massive bleeding on extracorporeal membrane oxygenation (ECMO) is associated with multiple coagulation defects, including depletion of coagulation factors and development of acquired von Willebrand syndrome (AVWS). The use of recombinant factors, in particular recombinant activated factor VII (rFVIIa, Novoseven), to treat severe refractory hemorrhage in ECMO has been described. However, the use of multiple recombinant factors has been avoided in large part due to concern for circuit complications and thrombosis. Here, we describe the safe and effective administration of rFVIIa and recombinant von Willebrand factor complex (vWF/ FVIII, Humate-P) via post-oxygenator pigtail catheter on VA-ECMO for the treatment of massive pulmonary hemorrhage. Case Description: A 21-month-old (13.4 kg) girl with a recent history of COVID-19 infection presented to an outside hospital with parainfluenza bronchiolitis resulting in acute refractory hypoxemic respiratory failure (oxygenation index 58), refractory septic shock, and myocardial dysfunction. She was cannulated to VA-ECMO and subsequently diagnosed with necrotizing pneumonia from Pseudomonas and herpes simplex infections. Her course was complicated by a large left-sided pneumatocele and bronchopleural fistula requiring multiple chest tubes. She also had right mainstem bronchus obstruction from necrotic airway debris and complete right lung atelectasis. She was noted to have prolonged episodes of mucosal and cutaneous bleeding (oropharynx, chest tube insertion sites, peripheral IV insertion sites) associated with absent high molecular weight von Willebrand multimers consistent with AVWS. Tranexamic acid infusion was initiated and bivalirudin anticoagulation was discontinued. VA-ECMO flows were escalated to 140-160 ml/kg/min to maintain circuit integrity and meet high patient metabolic demand in the absence of anticoagulation. On ECMO day 26, she underwent bronchoscopy to clear necrotic debris from her airway to assist with lung recruitment. The procedure was notable for mucosal bleeding requiring topical epinephrine and rFVIIa. Post-procedure, she developed acute hemorrhage from her right mainstem bronchus, resulting in significant hemothorax (estimated 950 ml) with mediastinal shift, increased venous pressures, desaturation and decreased ECMO blood flow rate, necessitating massive transfusion of 2,050 ml (150 ml/kg) of packed red blood cells, platelets, plasma and cryoprecipitate. An airway blocker was placed in the mid-trachea to control bleeding. In addition to transfusion of appropriate blood products and continuation of tranexamic acid infusion, she was given both rFVIIa (100mcg/kg) and vWF-FVIII (70 units vWF/kg loading dose on the day of hemorrhage, followed by 40 units vWF/kg every 12 hours for 3 additional doses). Both products were administered over 10 minutes through a post-oxygenator pigtail to allow the product to circulate throughout the patient prior to entering the ECMO circuit. The circuit was closely monitored during administration and no changes to circuit integrity were noted in the subsequent hours while hemostasis was achieved. The ECMO circuit remained without thrombosis for 9 days after the bleeding event. Discussion: Balancing anticoagulation and hemostasis is a central challenge in maintaining ECMO support, especially given the prevalence of acquired coagulopathies such as AVWS. For our patient, AVWS contributed to mucosal bleeding necessitating cessation of anticoagulation and utilization of a high ECMO blood flow strategy to minimize circuit clot burden. This was further complicated by absent native lung function and minimal myocardial function, resulting in complete dependence on ECMO. An acute massive pulmonary hemorrhage was treated with multiple recombinant factors (rFVIIa and vWF/FVIII), that are often avoided on ECMO. To minimize clotting risk to the circuit and to maximize transit of these factors to our patient, we added a post-oxygenator pigtail for administration. While this approach was the result of extreme circumstances, th use of a post-oxygenator pigtail for administration of recombinant factors may represent a viable strategy for refractory hemorrhage while on ECMO.

Pathological and Microbiological Findings in Free-Ranging Bats in Italy

Introduction: Recent studies have shown that bats are the reservoir hosts of several novel viruses, increasing the interest in bats as potential vectors of zoonotic pathogens. Several studies investigated the presence of infectious agents in bats, but their impact on the individual host and their importance on bat mortality is largely unknown. The aim of this study was to describe the microbiological and histopathological findings in 77 deceased bats belonging to nine European species (families Vespertilionidae and Molossidae). Materials and Methods: Bat carcasses were collected in the Piedmont region (Italy) by the Unconventional Rehabilitation Centre (CANC), Torino University, and submitted to necropsy. Species, age and sex of each bat were recorded. Virological (orthoreovirus, coronavirus, flavivirus, rhabdovirus, poxvirus, kobuvirus) and histopathological examinations were performed on the main organs (liver, spleen, kidney, gut, lung, heart and brain). Results: Traumatic injuries (fractures, haemorrhages, skin lesions;43%) and predation injuries (8.4%) represented the two main causes of death. Regardless of species, age and sex, the pathological examination revealed inflammatory/degenerative lesions mainly involving liver (non-suppurative hepatitis and vacuolar degeneration;20.8%) and lung (bronchopneumonia;29.9%). Coronavirus, flavivirus, rhabdovirus and kobuvirus were not detected. Poxviruses were detected in three lungs, two with pneumonia, and 14.3% of animals were positive for reoviruses. Conclusions: This study demonstrates the importance of inflammatory lesions in bat mortality, and shows that bats can harbour infectious agents. However, there is no evidence that Italian bats may represent a severe risk for human health.

wHY DOES IT ALWAYS HAVE to BE HEMOPHILIA FAULT?

Introduction: Hemophilia A is an X-linked bleeding disease caused by coagulation factor VIII (FVIII) deficiency. Clinical presentation include bleeding and their sequalae. Hemarthrosis are the most frequent bleeding manifestation and can lead to disabling hemophilic arthropathy. However, bleeding diathesis could also be unrelated to FVIII deficiency and other causes must be taken into consideration. Methods: Case presentation: A 54-year-old man affected by severe hemophilia A, with previous inhibitors eradicated with immune tolerance induction (ITI) and suffering from a disabling hemophilic arthropathy has been followed at our center since March 1988. After on demand treatment, he started regular prophylaxis in 2003. At 25 and 27 years-old he suffered pathological fractures to both femurs, presenting with pain and functional limitation in both cases. While the first fracture was caused by osteoporosis in abuse of steroids, the second one was related to bone localization of non-Hodgkin large cell malignant lymphoma, treated with chemo and radiotherapy plus autologous stem cells transplantation and currently in clinical remission. In April 2021, 20 days after second inoculation of COVID-19 vaccination (Pfizer®), the patient developed important mucosal and cutaneous bleeding, lasting more than a week despite recombinant FVIII infusion and for which he sought medical consult. Results: Blood count analyses revealed severe immune thrombocytopenia (Platelets 3000/mmc), requiring two lines of therapy (steroid plus intravenous immunoglobulin, followed by Rituximab), always under active FVIII prophylaxis. Further investigation for thrombocytopenia revealed that the cause is a chronic lymphatic leukemia clone in the bone marrow, currently not requiring active treatment. Discussion/Conclusion: The previous case highlights how alternative bleeding cause should be considered also in hemophilia patients and how crucial is physical examination: articular or bone pain can be related to typical hemarthrosis but also to bone damage of different nature. When a bleeding episode is refractory to usual therapy, particularly in patients with severe hemophilia and a previous history, inhibitors should always be suspected. However, especially if clinical presentation is unusual (as mucosal and cutaneous diathesis) a different source should be promptly investigated for lifesaving care.