Physician perspectives about the diagnosis and management of acute chest syndrome.

BACKGROUND: Acute chest syndrome (ACS) is the leading cause of mortality, accounting for 25% of all deaths among individuals with sickle cell disease (SCD). There is a lack of evidence-based laboratory and clinical risk stratification guidelines for the diagnosis and management of ACS. STUDY DESIGN AND METHODS: To better understand physician practices for the management of ACS in the United States, we created an ACS Working Group including hematology and transfusion medicine physicians from four different SCD treatment centers in the United States. The working group created a physician survey that included physician demographics and ACS diagnostic criteria that they had to rate. The survey also included three case scenarios to assess physician attitudes about the management of ACS. Management options included supportive and preventive strategies in addition to transfusion therapy options. RESULTS: Out of 455 physicians who received the survey, 195 responded (response rate = 43%). The respondents were primarily hematology/oncology physicians. The responses showed wide variability among physicians in how diagnostic criteria for ACS are used and how physicians risk-stratify ACS patients in their practice. The responses also reflected variability in the use of transfusions for ACS. DISCUSSION: Based on our results, we conclude that ACS is diagnosed and managed inconsistently among expert physicians, especially in their transfusion practices due to a lack of consensus on risk stratification criteria. Our data suggest an urgent need for well-designed prospective studies to provide evidence-based guidelines and minimize management variability among physicians who care for individuals with SCD and ACS.

Plasma Adsorption with the MTx.100 Column in Critically Ill COVID-19 Patients: A Prospective Study and Propensity Score Analysis.

BACKGROUND: Early in the COVID-19 pandemic, patients with severe disease admitted to the intensive care unit (ICU) had a high incidence of mortality. We aimed to investigate whether plasma adsorption with the MTx.100 Column could improve survival. METHODS: We performed a prospective, single-arm, multicenter, Emergency Use Authorization (EUA) trial in patients admitted to the ICU with severe COVID-19 who were worsening despite standard therapy. The primary outcome was all-cause mortality on day 28. Outcomes were analyzed using both a pre-specified performance goal (PG), and a propensity score-matched (PSM) analysis from the highest enrolling center, in which patients treated with the standard of care (SOC) plus the MTx.100 Column (n = 70) were compared to a contemporaneous cohort treated at the same center with SOC only (n = 244). FINDINGS: Between May 21, 2020, and November 2, 2021, 107 patients with severe COVID-19 (mean age 58.1) at 7 US centers were enrolled and had at least one plasma adsorption treatment initiated. All-cause mortality on day 28 was 37.4% (40/107), an improvement over the prespecified PG (88.1%, p < 0.0001). There were no serious adverse events attributable to the MTx.100 Column or plasmapheresis. Improvements in most metabolic and inflammatory markers were also noted. The PSM analysis showed that survival odds were three times higher for MTx.100 Column-treated patients (95% CI: 1.56-5.88) than for those treated with SOC only. INTERPRETATION: The MTx.100 Column treatment in severe COVID-19 resulted in a lower mortality than SOC by both pre-specified PG and PSM analysis. TRIAL REGISTRATION: clinicaltrials.gov (NCT04358003).

Bortezomib in relapsed/refractory immune thrombotic thrombocytopenic purpura: A single-centre retrospective cohort and systematic literature review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.

A case of hyperhemolysis syndrome in sickle cell disease and concomitant COVID-19.

BACKGROUND: Hyperhemolysis syndrome (HHS) is an uncommon transfusion reaction described in several hematologic disorders, including sickle cell disease (SCD). HHS is characterized by a decline in hemoglobin (Hb) values below pre-transfusion levels following transfusion of red blood cells (RBCs), coupled with laboratory markers consistent with hemolysis. The proposed pathophysiologic mechanisms underlying HHS include increased phosphatidylserine expression, macrophage activation, and complement dysregulation. Many pathophysiologic mechanisms thought to contribute to HHS have been similarly described in cases of severe COVID-19. CASE REPORT: A 28-year-old male with a history of HbSS presented with shortness of breath, right-sided chest pain, and a two-day history of fever. Polymerase chain reaction (PCR) detected SARS-CoV-2 infection with the omicron variant. The patient required an RBC transfusion (pre-transfusion hemoglobin [Hb]5.8 g/dL) with an immediate post-transfusion Hb of 6.3 g/dL. However, Hb rapidly declined to 1.7 g/dL, and lactate dehydrogenase (LDH) rose to 8701 u/L. The absolute reticulocyte count of 538 × 109/L correspondingly fell to 29 × 109/L. Despite additional RBC transfusions and initiation of immunosuppressive therapy, he expired on Day 9(D9). CONCLUSION: Given the similarities in their proposed pathophysiology, patients with SCD and concomitant SARS-CoV-2 infection may be predisposed to developing HHS.

Direct Oral Anticoagulants: How Do These Drugs Work, How to Monitor, and What Is Their Role in Orthopaedic Surgery.

Postoperative venous thromboembolism is a major adverse event associated with orthopaedic surgery. With the addition of perioperative anticoagulation and antiplatelet therapy, the rates of symptomatic venous thromboembolism have dropped to 1% to 3%, and as such, practicing orthopaedic surgeons must be familiar with these medications, including aspirin, heparin, or warfarin, and the use of direct oral anticoagulants (DOACs). DOACs are increasingly being prescribed due to their predictable pharmacokinetics and increased convenience, as they do not require routine monitoring, and 1% to 2% of the general population is currently anticoagulated. Although the introduction of DOACs has yielded additional treatment options, this has also led to confusion and uncertainty regarding treatment, specialized testing, and when and what reversal agents are appropriate. This article provides a basic overview of DOAC medications, their suggested use in the perioperative setting, effects on laboratory testing, and consideration for when and how to use reversal agents in orthopaedic patients.

Four-factor prothrombin complex concentrate use for on-label versus off-label indications: a retrospective cohort study.

This study aimed to characterize the utilization of four-factor prothrombin complex concentrate (4F-PCC) at a tertiary academic medical center and evaluate the incidence of thromboembolic events (TEs) and mortality when used in an on-label versus off-label context. All medical records for consecutive patients having received 4F-PCC over 61-months were retrospectively evaluated. On-label indications for 4F-PCC were defined per FDA guidance, with the remaining indications considered off-label. Three hundred sixty-nine 4F-PCC doses were administered to 355 patients, with 46.6% of administrations classified as off-label. On-label and off-label groups demonstrated similar rates of TEs (16.2% vs. 14%). On-label patients receiving repeated administrations of 4F-PCC or with a post-administration INR ≤ 1.5 had a significantly higher incidence of TE. Off-label patients with a prior history of TE were more likely to develop a TE following 4F-PCC administration. Off-label patients also had a significantly higher 30-day mortality relative to on-label patients (29.1% versus 18.3%). In conclusion, in a large cohort of patients, observed rates of off-label 4F-PCC use were high. Underlying prothrombotic risk factors were predictive of TEs in off-label patients. Moreover, patients receiving off-label 4F-PCC demonstrated higher transfusion rates. Overall, our study findings suggest that the utilization of 4F-PCC in an off-label context may convey a significant risk to patients with uncertain clinical benefits.

Central Line Access Is Predictive of Diagnostic Blood Loss and Transfusion in the Surgical Intensive Care Unit.

BACKGROUND: Most patients in the surgical intensive care unit (SICU) have anemia and undergo extensive diagnostic laboratory testing (DLT). Consequently, patients undergo RBC transfusion, and many are discharged with anemia, both of which are associated with poorer outcomes. OBJECTIVE: To characterize DLT blood loss in the SICU. MATERIALS AND METHODS: We performed a 1-year retrospective study of 291 patients admitted to a SICU. The number of draws, average volume, and estimated discard volume were recorded, along with clinical and laboratory findings. RESULTS: Patients who underwent greater amounts of DLT had lower hemoglobin levels at discharge (P ≤ .001). Admissions requiring central venous catheter (CVC) access (49.8%) demonstrated significantly higher DLT draws and rates of transfusion. CONCLUSION: Findings from this study suggest that DLT blood loss contributes to anemia in the SICU, and that the presence and duration of CVC leads to increased testing, anemia, and RBC transfusion.

Parafoveal acute middle maculopathy (PAMM) in sickle cell disease after discontinuation of hydroxyurea.

Purpose: Paracentral acute middle maculopathy (PAMM) is a rare ophthalmologic emergency involving the intermediate and deep retinal capillary plexus that supply the retina's middle layers. This case report describes an episode of PAMM in a patient with sickle cell disease (SCD) to demonstrate the importance of early diagnosis, review potential pathophysiologic mechanisms, and finally discuss appropriate management in this patient population. Observations: A 33-year-old black female with SCD, who had recently discontinued disease-modifying therapy with hydroxyurea, presented with a central scotoma of the left eye. Examination showed superficial opacification and whitening of the temporal perifoveal macula. After an initial diagnosis of central retinal artery occlusion she was admitted for a stroke workup. MRI was negative for stroke, and the patient was discharged after undergoing a red blood cell exchange (RBCX). Follow-up exam and optical coherence tomography (OCT) findings were more consistent with PAMM. Conclusions and Importance: To our knowledge, this is the first report of PAMM after discontinuation of hydroxyurea in preparation for pregnancy. It highlights the importance of a multidisciplinary approach when treating peripartum patients with SCD and the need for further research regarding vaso-occlusive prophylactic agents and their effects in pregnancy to minimize morbidity during family planning.

Successful use of lenalidomide to treat refractory acquired von Willebrand disease associated with monoclonal gammopathy.

Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.

Utilization of emicizumab in acquired hemophilia A: A case report.

BACKGROUND: Acquired Hemophilia A (AHA) is a rare autoimmune disorder associated with the development of autoantibodies against factor VIII (FVIII). Although obtaining hemostatic control through the use of recombinant factor VIIa, activated prothrombin complex concentrate and recombinant porcine FVIII are cornerstones in the clinical management of AHA, these therapies have several disadvantages, including a higher risk for the development of thromboembolic events, unpredictable efficacy and short half-lives. While emicizumab has been FDA licensed for use in bleeding prophylaxis for patients with Congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA, with only a few reports describing its use in this context. CASE REPORT: We report our experience with the use of emicizumab in an 83-year old male with AHA, complicated by the onset of atrial fibrillation following admission, drug-induced thrombocytopenia, infectious complications, and the identification of a low-grade lymphoproliferative disorder, in which emicizumab prophylaxis was used for bleeding prophylaxis in the context of persistently elevated inhibitor titers without evidence of thrombotic events or thrombotic microangiopathy.

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy.

Adoptive cell therapy with virus-specific T cells has been used successfully to treat life-threatening viral infections, supporting application of this approach to coronavirus disease 2019 (COVID-19). We expand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T cells from the peripheral blood of COVID-19-recovered donors and non-exposed controls using different culture conditions. We observe that the choice of cytokines modulates the expansion, phenotype, and hierarchy of antigenic recognition by SARS-CoV-2 T cells. Culture with interleukin (IL)-2/4/7, but not under other cytokine-driven conditions, results in more than 1,000-fold expansion in SARS-CoV-2 T cells with a retained phenotype, function, and hierarchy of antigenic recognition compared with baseline (pre-expansion) samples. Expanded cytotoxic T lymphocytes (CTLs) are directed against structural SARS-CoV-2 proteins, including the receptor-binding domain of Spike. SARS-CoV-2 T cells cannot be expanded efficiently from the peripheral blood of non-exposed controls. Because corticosteroids are used for management of severe COVID-19, we propose an efficient strategy to inactivate the glucocorticoid receptor gene (NR3C1) in SARS-CoV-2 CTLs using CRISPR-Cas9 gene editing.

The utility of therapeutic plasma exchange in Hyperviscosity syndrome associated with juvenile rheumatoid arthritis: A case report.

Hyperviscosity syndrome (HVS) is a life-threatening syndrome caused by high concentrations of large plasma proteins like IgM, rheumatoid factor, and other immune complexes, leading to increased blood viscosity and symptoms such as visual abnormalities, neurological impairment, bleeding diathesis, and thrombosis. While Waldenström's macroglobulinemia accounts for 80% to 90% of cases, HVS may develop in other clinical settings characterized by elevations in plasma proteins. Limited evidence currently exists describing the safety and efficacy of therapeutic plasma exchange (TPE) for the management of HVS secondary to non-neoplastic conditions. We report a case of recurrent HVS associated with juvenile rheumatoid arthritis and Felty syndrome that demonstrated improvement in clinical symptoms following initiation of TPE. These findings suggest that TPE may be utilized as an adjunct treatment option in patients with HVS secondary to autoimmune disorders.