Management of Acquired von Willebrand Syndrome During Prolonged VV-ECMO

Acquired von Willebrand syndrome (AVWS) contributes to bleeding during extracorporeal membrane oxygenation (ECMO) support. Although it is recognized that AVWS rapidly resolves after ECMO decannulation, this approach may often be clinically unsuitable. In such cases, optimal AVWS management during ECMO support is not well established. We report our approach to managing AVWS in a patient on veno-venous (VV) ECMO for 59 days. A 19-year-old male developed hypoxemic respiratory failure from SARS-CoV-2 pneumonia. Following intubation, he progressed to VV-ECMO support for refractory hypoxemia and was started on bivalirudin for systemic anticoagulation. Two days later, he developed refractory gastrointestinal and oro-nasopharyngeal bleeding despite blood product transfusions and discontinuing bivalirudin. He was started on pantoprazole along with infusions of octreotide and aminocaproic acid. Upper endoscopy on ECMO day 5 revealed an ulcerative bleeding vessel in the duodenum that was clipped. Recurrent mucosal bleeding precluded resumption of systemic anticoagulation. On ECMO day 23, AVWS was diagnosed based on elevated von Willebrand factor (VWF) activity (207%, normal 55-189%) and antigen (234%, normal 50-210%) levels with abnormally low VWF high-molecular-weight multimers. Factor VIII complex was administered twice over the following week. Between doses, the ECMO circuit was exchanged to empirically mitigate suspected shear-related VWF consumption from the fibrin burden, and a repeat endoscopy controlled additional intestinal bleeding with local hemostatic agents. He received 36 units of red blood cells, 2 units of platelets, 2 units of plasma, and 7 pooled units of cryoprecipitate over 31 days leading into these combined interventions. In the 28 days afterwards, he received 3 units of red blood cells, 3.5 pooled units of cryoprecipitate, and no additional platelets or plasma. Our patient was maintained off systemic anticoagulation for 54 of 59 days of VV-ECMO support without any thrombotic complications occurring. With no subsequent clinical evidence of bleeding, repeat VWF testing was done two months post-decannulation and showed near-normal VWF activity (54%) and normal multimer distribution. Our patient rehabilitated well without any neurologic deficits and on discharge was requiring supplemental oxygen with sleep and strenuous activity. Avoiding systemic anticoagulation, repleting VWF, maintaining circuit integrity, and providing local hemostasis, when possible, may be a safe and effective management strategy of AVWS on ECMO support when decannulation is not a viable option.

HEMORRHAGIC PLEURAL EFFUSION IN A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA ON IBRUTINIB THERAPY

SESSION TITLE: Problems in the Pleura Case Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment of a variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL). There is an association of increased risk of bleeding with ibrutinib due to platelet dysfunction caused by the medication. Bleeding is usually non-life threating such as subcutaneous or mucosal bleeding, epistaxis, and ecchymosis. But major bleeding has been reported such as intracranial hemorrhage and gastrointestinal hemorrhage. Thoracic complications from ibrutinib are rare. Below is a case report discussing a hemorrhagic pleural effusion thought to be caused by Ibrutinib. CASE PRESENTATION: Patient is a 78-year-old male initially diagnosed with CLL on flow cytometry showing a low-grade B cell lymphoproliferative process. Patient was monitored by Hematology and when kappa light chain numbers began to rise, a bone marrow biopsy was performed showing 90% infiltration of the marrow with lymphoid cells. Patient was started on Ibrutinib therapy and responded well to treatment. A year after starting therapy, patient presented to the emergency room with increased shortness of breath and fatigue. Patient was found to be COVID-19 positive and chest x-ray showed a large right sided pleural effusion. Thoracentesis was performed draining 1650cc of bloody fluid. Fluid studies revealed a lymphocytic effusion with RBC count 1,185375, WBC of 1751. Cultures and cytology were negative. On further history, patient was without recent trauma or surgery, CTA chest was negative for pulmonary embolism. QuantiFERON Gold test was negative, indicating low likelihood of tuberculosis. Patient was not on any antiplatelet or systemic anticoagulation medications. Ibrutinib therapy was held during hospitalization and pleural effusion did not reaccumulate. Patient passed away during hospital stay secondary to respiratory failure due to COVID-19. DISCUSSION: Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib predisposes to bleeding by inhibiting BTK and Tec, which play a role in the inhibitory signaling pathway of platelet collagen receptors such as glycoprotein VI (GP VI) and C-type lectin-like receptor 2 (CLEC-2). Our patient had no other risk factors for developing a hemorrhagic effusion. CLL itself can cause malignant effusions, one study found the incidence of malignant effusions among patients with CLL to be 9%, but the effusion was noted to be serous or serosanguinous and there was pleural involvement in all patients which was not the case in our patient. CONCLUSIONS: There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. It is important to realize bleeding complications related to ibrutinib therapy can occur. Reference #1: Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TG. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost. 2017;15(5):835-847. doi:10.1111/jth.13651 Reference #2: Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388 Reference #3: Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56-63. doi:10.1016/j.critrevonc.2019.02.001 DISCLOSURES: No relevant relationships by fatima ali No relevant relationships by Joan Wiley

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.

Monitoring of Patients with Autoimmune Cytopenias during Sars-Cov-2 Vaccination Campaign: The Experience of a Reference Center

[Formula presented] SARS-CoV-2 infection and vaccination have raised concern in immune mediated diseases, including autoimmune cytopenias (AIC, i.e. autoimmune hemolytic anemia, AIHA;autoimmune thrombocytopenia, ITP;autoimmune neutropenia, AIN;aplastic anemia, AA;and their combination, termed Evans syndrome, ES). The latter are highly heterogeneous conditions with variable severity and a clinical course marked by several relapses often triggered by immune-activating events (infections, traumas, surgery, etc.) including vaccines. Some reports of ITP and AIHA post-SARS-CoV-2 vaccines have been described but no population studies have been conducted in AIC patients. Here we systematically studied a large series of 100 patients with AIC (44 AIHA, 38 ITP, 7 AIN, 6 ES, and 5 AA) prospectively followed at a reference center in Milan, Italy, who underwent SARS-CoV-2 vaccination from 24 th of March until the end of June 2021. Patients (median age 62 years, range 25-89, female/male ratio 1.7) were monitored with whole blood counts and LDH testing the week before and the week after each vaccination dose. Importantly, ongoing AIC therapy (38% of cases, including steroids, cyclosporine, eltrombopag, and complement inhibitor sutimlimab) were kept stable within the 2 weeks before vaccination. Patients mainly received Pfizer-BioNtech vaccine (N=88), followed by Moderna (N=10), and Astra-Zeneca (N=2). Table 1 summarizes hematologic trends and side effects observed after each dose in patients with ITP and AIHA. Regarding the former, a delta percentage reduction of 10% or higher was observed in up to 13% of cases after the first and the second dose, requiring therapy adjustment in 2 patients. They were two elderly male subjects on low dose eltrombopag treatment and experienced a severe/moderate relapse (platelets 28 and 21x10

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.