Acute pulmonary injury in hematology patients supported with pathogen-reduced and conventional platelet components.

ABSTRACT: Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Acquired bleeding disorders secondary to immune checkpoint inhibitors: a case report and systematic literature review.

Acquired bleeding disorders because of an autoimmune phenomenon are rare events. Acquired von Willebrand disease (aVWD) has been estimated as having a prevalence of 400 per million in the general population. Acquired hemophilia A (AHA), the most common of the acquired hemophilias, has an estimated incidence of 1.3-1.5 cases per million per year. Immune checkpoint inhibitors (ICI) targeting PD-1, PD-L1, and CTLA-4 are being used with increasing frequency for hematologic and oncologic disorders. Acquired hemophilias and aVWD have been reported with the use of ICI therapy. We performed a systematic review of the literature to identify cases of acquired bleeding disorders with ICI therapy and contribute our own institution's experience with a case of AHA after pembrolizumab therapy. Six cases of AHA, one case of aVWD, and one case of factor V inhibitor were identified in the literature. Inhibitors were successfully eradicated in five of the eight cases identified. We propose that a centralized registry, possibly through the Scientific and Standardization Subcommittee on Plasma Coagulation Inhibitors through the International Society on Thrombosis and Hemostasis (ISTH), be developed to record treatment and outcomes of this rare ICI complication in order to prognosticate risk and better understand optimal treatment strategies.

Retrospective Analysis of the Real-World Utilization of 4-Factor Prothrombin Complex Concentrate and Plasma in Oral Anticoagulant-Associated Bleeding in US Hospitals.

Real-world utilization of 4-factor prothrombin complex concentrate (4F-PCC) and plasma for the management of oral anticoagulant (OAC)-associated bleeding in US trauma hospitals was described.This is amulticenter, retrospective chart review evaluating the use of 4F-PCC and plasma in OAC reversal across medical specialties. Physicians completed a survey and extracted data from 3 to 5 patient charts. Variables of interest included medical specialty, urgency, and bleed type. Two hundred and thirty-five physicians completed the survey, and 861 patient charts were included in the study. 4F-PCC was commonly used in life-threatening or emergent indications, whereas plasma was used in emergent and urgent indications. Plasma was used mostly for patients on warfarin (53% vs 47% 4F-PCC) and 4F-PCC for those on apixaban (82% vs 18% plasma) and rivaroxaban (77% vs 23% plasma). This retrospective analysis showed that 4F-PCC was predominantly used for OAC reversal despite available specific reversal agents for some of the OAC. Although it is not recommended by any reversal guidelines, plasma is still used for OAC reversal. Plasma should be avoided in the management of OAC-associated bleeding.

Reduction of anti-A and anti-B isoagglutinin titers of group O whole blood units employing an ABO antibody immune adsorption column.

BACKGROUND: Massive hemorrhage is a leading cause of death from trauma. There is growing interest in group O whole blood transfusions to mitigate coagulopathy and hemorrhagic shock. Insufficient availability of low-titer group O whole blood is a barrier to routine use. We tested the efficacy of the Glycosorb® ABO immunoadsorption column to reduce anti-A/B titers in group O whole blood. METHODS: Six group O whole blood units were collected from healthy volunteers, and centrifuged to separate platelet poor plasma. Platelet-poor plasma was filtered through a Glycosorb® ABO antibody immunoabsorption column, then reconstituted to prepare post-filtration whole blood. Anti-A/B titers, CBC, free hemoglobin, and thromboelastography (TEG) assays were performed on pre-and post-filtration whole blood. RESULTS: Mean( ± SEM) anti-A (224 ± 65 pre vs 13 ± 4 post) and anti-B (138 ± 38 pre vs 11 ± 4 post) titers were significantly reduced (p = 0.004) in post-filtration whole blood. No significant changes were detected in CBC, free hemoglobin, and TEG parameters on day 0. Free hemoglobin increased throughout storage (48 mg/dl ± 24 Day 0 vs 73 ± 35 Day 7 vs 96 ± 44 Day 14; p = 0.14). CONCLUSIONS: The Glycosorb® ABO column can significantly reduce anti-A/B isoagglutinin titers of group O whole blood units. Glycosorb® ABO could be employed to provide whole blood with lower risk of hemolysis and other consequences of infusing ABO incompatible plasma. Preparation of group O whole blood with substantially reduced anti-A/B would also increase the supply of low-titer group O whole blood for transfusion.

Reduced Time to Procedure for Gastrointestinal Bleeding After Warfarin Reversal With Four-Factor Complex Concentrate as Compared to Plasma.

Background: Bleeding is a serious adverse effect of vitamin K antagonists (VKAs). Anticoagulation reversal is required in some acute cases. This is usually accomplished by plasma transfusion or four-factor prothrombin complex concentrate (4F-PCC). The aim of this study was to gain insight into the clinical course of patients with gastrointestinal (GI) bleeding who require VKA reversal. Methods: Medical records were collected from two centers from patients who presented to the emergency department (ED) for GI bleeding and received 4F-PCC or plasma for VKA reversal between January 2015 and December 2020. ED, hospital, intensive care unit (ICU) length of stay (LOS) as well as time from admission to GI procedure were determined. Results: 4F-PCC patients (n = 49) as compared to plasma (n = 63) patients were found to have a greater number of comorbidities (average of 4.2 vs. 2.7 comorbidities/patient) and more ICU admissions (47% vs. 21%). Time to GI procedure was significantly decreased in the 4F-PCC group (median (interquartile range (IQR)) 19.47 (9.23 - 30.25) vs. 27.88 (21.38 - 45.00) h; P = 0.01). When adjusting for comorbidities, differences in time to GI procedures were also significant in favor of 4F-PCC regardless of any comorbidities (P = 0.014), in atrial fibrillation (P = 0.045) and in hypertension (P = 0.02). The 4F-PCC patients had shorter LOS in the ED and ICU. Conclusions: Our study demonstrated that compared to plasma, 4F-PCC was utilized in more acutely ill patients with higher rates of comorbidities and ICU admission. Nevertheless, the patients who received 4F-PCC had faster access to GI procedure and shorter ED and ICU LOS.

Determination of Unnecessary Blood Transfusion by Comprehensive 15-Hospital Record Review.

BACKGROUND: Although unnecessary blood component transfusions are costly and pose substantial patient risks, the extent of unnecessary blood use in a community hospital setting has not been systematically measured. METHODS: A 15-hospital observational analysis was performed using comprehensive retrospective review. Approximately 100 encounters (x¯â€¯= 103.9, standard deviation [SD] ± 7.6) per hospital (6,696 total component transfusion events) were reviewed between 2012 and 2018. Review was performed by two medical directors. Findings were supported by blind intra- and inter-reviewer double review and blind external review by 10 independent reviewers. RESULTS: Patients received an average of 4.3 (± 1.3) units. Only 8.2% (± 6.7) of patient encounters did not receive unnecessary units. Fifty-five percent (54.6% ± 13.5) could have been managed without at least one component type, while 44.6% (± 14.9) could have been managed completely without transfusion. Forty-five percent (45.4% ± 17.0) of red blood cell, 54.9% (± 19.3) of plasma-cryoprecipitate, and 38.0% (± 15.6) of plateletpheresis encounters could likely have been managed without transfusion. Between 2,713 units (40.5%) and 3,306 units (49.4%) were likely unnecessary. In patients who could have been managed without transfusion of at least one component type, unnecessary blood use was associated with a 0.38 (± 0.11)-day increase in length of hospital stay for each additional unnecessary unit received (p < 0.001). CONCLUSION: Substantial unnecessary blood use was identified, all of which was unrecognized by hospitals prior to review. Unnecessary blood use was attributed to overreliance on laboratory transfusion criteria and failure to follow common blood management principles, which resulted in potential harm to patients and avoidable cost.

INR and vitamin K-dependent factor levels after vitamin K antagonist reversal with 4F-PCC or plasma.

Restoration of the international normalized ratio (INR) to values <1.5 is commonly targeted to achieve hemostasis in patients with major bleeding or undergoing urgent surgery who are treated using vitamin K antagonists (VKAs). However, the relationship between corrected INR and vitamin K-dependent factor (VKDF) levels for hemostasis is uncertain. We aim to examine the impact of 4-factor prothrombin complex concentrate (4F-PCC) or plasma on INR correction and VKDF restoration and evaluate the relationship between INR values and VKDF levels in patients with acute major bleeding or patients requiring an urgent surgical procedure. Adult patients treated with VKA with an elevated INR (≥2.0 within 3 hours before study treatment) who received 4F-PCC or plasma after major bleeding or before an urgent surgery or invasive procedure were included in this retrospective analysis of data from 2 prospective phase 3b randomized controlled trials. Of the 370 patients included in this analysis, 185 received 4F-PCC, and 185 received plasma. In the 4F-PCC group, 159 of 185 (85.9%) had an INR ≤1.5 at 30 minutes after the end of infusion compared with only 72 of 184 (39.1%) in the plasma group. After 4F-PCC treatment, all VKDF levels exceeded 50% activity regardless of the postinfusion INR value. However, after plasma administration, mean activity levels for factors II and X were <50% at all time points assessed within 3 hours after starting the infusion, regardless of the postinfusion INR value. This retrospective analysis demonstrated that treatment with 4F-PCC among patients treated with VKA rapidly restores VKDFs to hemostatic levels irrespective of the postinfusion INR value, whereas treatment with plasma does not.

Evaluation of a Newly Implemented Critical Thromboelastography (TEG) Value Callback System.

OBJECTIVES: Thromboelastography (TEG) measures whole blood coagulation kinetics in real time and is useful in guiding blood product transfusion. At our institution, providers have immediate remote access to TEG results. However, some critical values are occasionally missed. Our patient blood management program implemented a critical TEG value callback system to improve patient management and blood product utilization. METHODS: This retrospective, observational study assessed the data of trauma and critical care patients preimplementation (n = 20) and postimplementation (n = 100) of the callback system. Provider responses to callbacks and changes in TEG parameters after subsequent testing were compared between the two groups. RESULTS: In response to callbacks, 42% provided appropriate management and 42% ordered a repeat TEG vs 28% and 33% in the historical group (P < .0001 and P = .0002, respectively). Following callback, 90% of the TEG parameters in the study group showed an improvement vs 57% in the control group (P = .011). CONCLUSIONS: The increase in appropriate management and the improvement in TEG parameters upon repeat testing in the study group compared to the control group demonstrate the efficacy of the TEG callback system. Further studies are needed to evaluate the callback system effect on patient outcome.

Comparative risk of pulmonary adverse events with transfusion of pathogen reduced and conventional platelet components.

BACKGROUND: Platelet transfusion carries risk of transfusion-transmitted infection (TTI). Pathogen reduction of platelet components (PRPC) is designed to reduce TTI. Pulmonary adverse events (AEs), including transfusion-related acute lung injury and acute respiratory distress syndrome (ARDS) occur with platelet transfusion. STUDY DESIGN: An open label, sequential cohort study of transfusion-dependent hematology-oncology patients was conducted to compare pulmonary safety of PRPC with conventional PC (CPC). The primary outcome was the incidence of treatment-emergent assisted mechanical ventilation (TEAMV) by non-inferiority. Secondary outcomes included: time to TEAMV, ARDS, pulmonary AEs, peri-transfusion AE, hemorrhagic AE, transfusion reactions (TRs), PC and red blood cell (RBC) use, and mortality. RESULTS: By modified intent-to-treat (mITT), 1068 patients received 5277 PRPC and 1223 patients received 5487 CPC. The cohorts had similar demographics, primary disease, and primary therapy. PRPC were non-inferior to CPC for TEAMV (treatment difference -1.7%, 95% CI: (-3.3% to -0.1%); odds ratio = 0.53, 95% CI: (0.30, 0.94). The cumulative incidence of TEAMV for PRPC (2.9%) was significantly less than CPC (4.6%, p = .039). The incidence of ARDS was less, but not significantly different, for PRPC (1.0% vs. 1.8%, p = .151; odds ratio = 0.57, 95% CI: (0.27, 1.18). AE, pulmonary AE, and mortality were not different between cohorts. TRs were similar for PRPC and CPC (8.3% vs. 9.7%, p = .256); and allergic TR were significantly less with PRPC (p = .006). PC and RBC use were not increased with PRPC. DISCUSSION: PRPC demonstrated reduced TEAMV with no excess treatment-related pulmonary morbidity.

Evaluation of solvent/detergent-treated plasma safety and efficacy in orthotopic liver transplant and thrombotic thrombocytopenic purpura patients: A single center experience.

BACKGROUND: Solvent/detergent-treated, pooled plasma (SDP) is approved for use in orthotopic liver transplantation (OLT) and thrombotic thrombocytopenic purpura (TTP) patients; however, studies evaluating safety and effectiveness of SDP in these populations are limited. METHODS: This prospective study included two cohorts: OLT patients (n = 40) who received either SDP (n = 20) or FFP (control group) (n = 20), and TTP patients (n = 20) who received either SDP (n = 10) or FFP (control group) (n = 10) throughout hospitalization. Medical, laboratory, and blood bank records were retroactively assessed for both cohorts for differences in clinical outcomes, laboratory values, and transfusion data from admission to discharge. RESULTS: In the OLT cohort, significant changes in AST and ALP were observed in the control group as compared to SDP (p < .05 each), and creatinine levels improved significantly in the SDP group as compared to the control group (p < .05) from admission to discharge. In the TTP cohort, platelet counts were significantly improved within the control and SDP groups from admission to discharge, but there were no significant differences between groups (p = .31). LDH levels improved between admission and discharge for both groups (70% decrease in the control group, p < .001, and 80% decrease in the SDP group, p = .001). There were no significant differences detected in clinical outcomes in either cohort. CONCLUSIONS: As evidenced by the lack of adverse events in either cohort and similar clinical outcomes, we conclude that SDP is comparable in safety and effectiveness to FFP in OLT and TTP patients. Further studies are needed to evaluate the potential for improved safety with SDP.

Essential Role of Rho-Associated Kinase in ABO Immune Complex-Mediated Endothelial Barrier Disruption.

ABO immune complexes (ABO-IC) formed by ABO-incompatible antigen-antibody interaction are associated with hemolysis and platelet destruction in patients transfused with ABO-nonidentical blood products. However, the effects of ABO-IC on endothelial cells (EC) are unclear. ABO-IC were formed in vitro from normal donor-derived plasma and serum. Human pulmonary artery EC (HPAEC) were cultured and treated with media, ABO-identical and -non-identical plasma, and ABO-IC. EC barrier integrity was evaluated using transendothelial electrical resistance (TEER), scanning electron microscopy (SEM), vascular endothelial (VE)-cadherin and phalloidin staining, and Rho-associated Kinase (ROCK) inhibitor treatment. TEER revealed significant/irreversible barrier disruption within 1-2 h of exposure to ABO non-identical plasma and ABO-IC; this occurred independently of EC ABO type. Treatment with ABO-IC resulted in decreased VE-cadherin staining and increased phalloidin staining in a time-dependent manner, suggesting that the resultant increased EC barrier permeability is secondary to actin stress fiber formation and loss of cell surface VE-cadherin. Inhibition of ROCK was effective in protecting against IC-induced barrier disruption even two hours after ABO-IC exposure. ABO-IC causes increased EC barrier permeability by decreasing cell surface VE-cadherin and promoting stress fiber formation, which is preventable by inhibiting ROCK activation to protect against EC contraction and gap formation.

In Vitro and In Vivo Comparison of Hemoglobin and Electrolytes Following the Collection of Cell Saver Blood Washed with Either Normal Saline or Plasma-Lyte A.

Cell saver blood is typically washed with normal saline (NS); however, recent studies have reported decreased red blood cell hemolysis and increased platelet function when a more physiologic washing solution, such as Plasma-Lyte A (PL-A) is used. We evaluated the in vitro and in vivo effects of NS compared to PL-A as washing solutions for cell saver blood in pediatric cardiac surgery. Cell saver blood was re-infused for up to 24 hours post-collection. Laboratory and clinical data were collected from infants receiving cell saver washed with either NS (n = 20) or PL-A (n = 21). Compositions of the cell saver blood were compared between groups at 5 in vitro time points and in vivo patient blood at 24 hours post-bypass. Although there were differences in in vitro laboratory values between groups; 24 hours post-bypass, in vivo results were similar. Our data supports 24-hour reinfusion of cell saver washed with either NS versus PL-A in pediatric cardiac surgery patients, and provides data on the differences in cell saver composition to guide future studies.

Preoperative anemia management program reduces blood transfusion in elective cardiac surgical patients, improving outcomes and decreasing hospital length of stay.

BACKGROUND: Anemia is an independent risk factor for hospitalization, readmission, prolonged length of stay (LOS), diminished quality of life, and mortality. A multidisciplinary program was implemented to manage anemia preoperatively as a patient blood management (PBM) initiative. METHODS AND MATERIALS: From March 2016 to August 2018, 240 patients were screened for anemia during their preoperative cardiovascular visit. About 52/240 (22%) were found to be anemic and met out inclusion criteria. Also, 45/52 (87%) had iron deficiency anemia and 7 (13%) had anemia without iron deficiency. A similar historical cohort of patients undergoing elective cardiovascular surgery with hemoglobin (Hb) < 12 g/dl from September 2014 to February /2016 (n = 52) served as control group. The primary outcome was perioperative red blood cell (RBC) transfusion. Secondary outcomes were date-of-surgery Hb, intensive care unit (ICU) and hospital LOS, complication rates, and transfusion cost. RESULTS: The two most common treatments were IV iron ± folate (n = 36/45; 80%) and oral iron (n = 9/45; 20%). As compared to historical patients, study patients had significantly higher day-of-surgery Hb (10.6 ± 1.4 vs. 9.8 ± 1.3 g/dl, p < .001), lower utilization of RBC transfusion (0.86 ± 1.4 vs. 2.78 ± 2.4, p < .001), fewer days in the ICU (2.1 ± 2.0 vs. 4.0 ± 3.5, p = .002), and shorter total LOS (6.9 ± 4.8 vs. 12.9 ± 6.8, p < .0001). Study patients also showed lower overall complication rates (p < .0001). Analysis of RBC acquisition cost and transfusion cost also showed significant saving of 69% ($293 vs. $945 and $656 vs. $2116, respectively). CONCLUSION: When corrected for type of procedures and surgeon, our pilot anemia program in elective cardiovascular surgeries showed higher day-of-surgery Hb and significant reduction in RBC transfusion rates, ICU and hospital LOS, and overall complication rates.

Updates in Anticoagulation Therapy Monitoring.

In the past six decades, heparin and warfarin were the primary anticoagulants prescribed for treatment and prophylaxis of venous thromboembolism worldwide. This has been accompanied by extensive clinical knowledge regarding dosing, monitoring, and reversal of these anticoagulants, and the resources required to do so have largely been readily available at small and large centers alike. However, with the advent of newer oral and parenteral anticoagulants such as low molecular weight heparins, factor Xa inhibitors, and direct thrombin inhibitors in recent years, new corresponding practice guidelines have also emerged. A notable shift in the need for monitoring and reversal agents has evolved as well. While this has perhaps streamlined the process for physicians and is often desirable for patients, it has also left a knowledge and resource gap in clinical scenarios for which urgent reversal and monitoring is necessary. An overview of the currently available anticoagulants with a focus on the guidelines and available tests for anticoagulant monitoring will be discussed in this article.