Red blood cell alloimmunization in transfused patients with hereditary hemorrhagic telangiectasia: A single centre retrospective study.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a genetic blood vessel disorder which may lead to chronic bleeding and red blood cell (RBC) transfusions. Data on transfusion requirements and complications in HHT patients are sparse. STUDY DESIGN AND METHODS: Retrospective chart review was conducted at St. Michael's Hospital (SMH) in Toronto, Canada. All adults with a definite clinical diagnosis of HHT AND inpatient hospital visits between January 1, 2011 and December 31, 2020 AND had undergone transfusion compatibility testing at SMH, were identified. Data were abstracted from electronic medical records. Simple descriptive statistics were used to analyze data. Institutional Research Ethics Board approval was obtained. RESULTS: 63 HHT patients underwent compatibility testing and were subsequently transfused at SMH. Median patient age at data abstraction was 70 years (Interquartile Range [IQR]: 18) and 35 (56 %) were female. RBC alloantibodies were found in 23 transfused patients (36.5 %) and were predominantly directed against Rh and Kell antigens: Anti-E (65 %), Anti-K (39 %) and Anti-c (22 %) were most common. Excluding an outlier who received 611 RBC units during the study period, the mean number of RBC units transfused per HHT patient at SMH was 22.1 units (Standard Deviation: 40.9, IQR: 17). Six (9.5 %) transfused patients experienced at least one transfusion reaction. CONCLUSION: RBC alloimmunization rate was 36.5 % in our cohort of transfused HHT patients; this is much higher than described in the general population and another transfused HHT cohort. The most commonly observed alloantibodies were Rh and Kell, supporting our policy of prophylactic phenotypic matching for these antigens for all transfused patients with HHT.

Perioperative continuous infusions of factor VIII versus factor IX for patients with hemophilia A or B undergoing major surgery.

Continuous factor VIII (FVIII) or factor IX (FIX) infusions are commonly used for patients with hemophilia A (HA) or B (HB) undergoing surgery to secure perioperative hemostasis. To describe differences between the initial recovery and subsequent FIX and FVIII levels, and describe clinical outcomes among HB and HA patients receiving perioperative continuous infusion (CI) of recombinant FVIII and FIX concentrates. Retrospective chart review was conducted on 8 consecutive patients with HB and 7 consecutive patients with HA who underwent major surgery between 2014 and 2018 and received continuous infusions of standard half-life factor concentrate. Median initial bolus dose per kilogram was higher for HB compared to HA patients [90.8 (IQR 78.0-98.7) vs. 52.1 (IQR 48.6-55.6) IU/kg], while initial CI dose-rates were similar [4.3 (IQR 3.8-4.6) vs. 4.2 (IQR 3.8-4.4) IU/kg/h]. Median post-bolus recovery was higher for FVIII compared to FIX [1.70 (IQR 1.23-1.75) vs. 0.88 (IQR 0.75-1.00) IU/mL]. Median factor levels also were higher for FVIII on post-operative days 1 to 3. HB patients had greater mean intraoperative estimated blood loss [285.7 (range 0-1000) vs. 142.8 (range 0-400) mL] and longer median length of hospital stay [9 (IQR 8-12) vs. 5 (IQR 4-6.5) days]. Our initial evidence suggests greater in vivo yield of rFVIII compared to rFIX in the perioperative setting. We identified poorer clinical outcomes in this small cohort of perioperative HB patients indicating that they may benefit from a higher CI rate for adequate surgical hemostatic coverage.

Management of immune thrombotic thrombocytopenic purpura with caplacizumab: a Canadian, single-centre, real-world experience.

When combined with therapeutic plasma exchange (TPE) and immunosuppression, upfront universal administration of caplacizumab was shown to be effective in the management of immune thrombotic thrombocytopenic purpura (iTTP). However, access to this drug remains challenging in many jurisdictions. We retrospectively review results of a single-institution experience with caplacizumab over a 3-year period. During the study period, we treated 48 patients with iTTP, of which 11 (23%) received caplacizumab. Eight of these 11 patients (73%) were female; the median age was 45 years (IQR 37.0-58.5). All received TPE within 24 h of admission (median 9 exchanges, IQR 7.0-12.5), and high-dose steroids. Caplacizumab was initiated for a median of 6 days after admission (IQR 2.5-8.0) and continued for a median of 26 days (IQR 14.0-33.0). Five patients (45%) had refractory disease at caplacizumab initiation. Ten patients (91%) survived, reaching clinical remission. Platelet normalization was reached with a median of 4 days following caplacizumab initiation (IQR 1.5-4.0). Complications included minor bleeding (n = 1) and local allergic reaction (n = 1). No patients experienced TTP exacerbation; relapse occurred in two patients (18%) over 1-5 years of follow-up. Caplacizumab appeared to be effective and safe, despite delayed initiation and in the setting of refractory disease.

Immune thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening blood condition characterized by low platelets, anemia, and formation of blood clots in the small blood vessels. The condition results from a patient's immune system attacking a blood protein called ADAMTS13. The standard treatment for iTTP is plasma exchange (which replaces ADAMTS13) and medications, which suppress the immune system. Recently, a new medication, caplacizumab, has been shown to improve outcomes in iTTP, if combined with a standard treatment. However, this drug is expensive, and not readily available in all parts of the world, including Canada. In this article, we present the first Canadian experience with caplacizumab. Due to its limited access, the drug is frequently used in patients who are refractory to standard treatment or presented with severe organ damage. This contrasts with previously published studies, where it has been used upfront and in all patients with TTP. We find that caplacizumab may be safe and effective in this setting, demonstrating a low mortality rate and rapid recovery in most patients. While upfront and universal use of caplacizumab in the treatment of iTTP is optimal, our approach could be used in settings, where access to this medication is restricted.

The Impact of Brain Metastases and Associated Neurocognitive Aspects on Health Utility Scores in EGFR Mutated and ALK Rearranged NSCLC: A Real World Evidence Analysis.

BACKGROUND: In lung cancer, brain metastases (BM) and their treatment are associated with high economic burden and inferior health-related quality of life. In the era of targeted therapy, real world evidence through health utility scores (HUS) is critical for economic analyses. MATERIALS AND METHODS: In a prospective observational cohort study (2014-2016), outpatients with stage IV lung cancer completed demographic and EQ-5D-3L surveys (to derive HUS). Health states and clinicopathologic variables were obtained from chart abstraction. Patients were categorized by the presence or absence of BM; regression analyses identified factors that were associated with HUS. A subset of patients prospectively completed neurocognitive function (NCF) tests and/or the FACT-brain (FACT-Br) questionnaire, which were then correlated with HUS (Spearman coefficients; regression analyses). RESULTS: Of 519 patients with 1,686 EQ-5D-3L-derived HUS, 94 (18%) completed NCF tests and 107 (21%) completed FACT-Br; 301 (58%) never developed BM, 24 (5%) developed first BM during study period, and 194 (37%) had BM at study entry. The sample was enriched (46%) for EGFR mutations (EGFRm) and ALK-rearrangements (ALKr). There were no HUS differences by BM status overall and in subsets by demographics. In multivariable analyses, superior HUS was associated with having EGFRm/ALKr (p < .0001), no prior radiation for extracranial disease (p < .001), and both intracranial (p = .002) and extracranial disease control (p < .01). HUS correlated with multiple elements of the FACT-Br and tests of NCF. CONCLUSION: Having BM in lung cancer is not associated with inferior HUS in a population enriched for EGFRm and ALKr. Patients exhibiting disease control and those with oncogene-addicted tumors have superior HUS. IMPLICATIONS FOR PRACTICE: In the setting of EGFR mutations or ALK rearrangement non-small cell lung cancer (NSCLC), a diagnosis of brain metastases no longer consigns the patient to an inferior health state suggesting that new economic analyses in NSCLC are needed in the era of targeted therapies. Additionally, the EQ-5D questionnaire is associated with measures of health-related quality of life and neurocognitive scores suggesting this tool should be further explored in prospective clinical studies.

Relapse of immune thrombotic thrombocytopenic purpura (iTTP) possibly triggered by COVID-19 vaccination and/or concurrent COVID-19 infection.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that may be triggered by inflammation, including infection or vaccination. Since the start of the COVID-19 pandemic, several case reports were published on de novo or relapsed immune TTP (iTTP) in COVID-19-infected patients. Case reports of iTTP episodes following vaccination against COVID-19 are also emerging. We report a case of relapsed iTTP in a patient who received Moderna mRNA-1273 SARS-CoV-2 vaccine and developed concurrent severe COVID-19 infection. The patient's iTTP was successfully managed with caplacizumab, therapeutic plasma exchange and high-dose steroids. We summarise published cases of iTTP associated with COVID-19 infection or vaccination.

Evaluating hemostatic thresholds for neuraxial anesthesia in adults with hemorrhagic disorders and tendencies: A scoping review.

Neuraxial anesthesia can be complicated by spinal or epidural hematoma and may result in permanent neurologic injury. There is a paucity of literature characterizing this serious complication in patients with congenital and acquired hemorrhagic disorders or tendencies. The objective of this scoping review was to describe the hemostatic laboratory parameters where neuraxial anesthesia has been administered with and without spinal and epidural hematoma in patients with preexisting hemorrhagic disorders and tendencies, including immune thrombocytopenia, gestational thrombocytopenia, thrombocytopenia associated with hypertensive disorders of pregnancy, platelet function disorders, von Willebrand disease, coagulation factor deficiencies, and fibrinogen disorders. A systematic search of Ovid MEDLINE, CINAHL, Embase, Scopus, and Web of Science was performed. Two authors independently reviewed all titles, abstracts, and full texts to determine study eligibility and extract data. Qualitative synthesis of 91 studies revealed significant gaps in our understanding of the risk of spinal and epidural hematoma in patients with hemorrhagic disorders and tendencies, including few studies of males and in nonobstetric settings. Most reviewed articles were small, retrospective studies at high risk for potential bias. With such low-quality data, we were unable to provide any true estimates of the risk of spinal or epidural hematoma for these patients, nor could we attribute any specific hemostatic or laboratory values to increased risk of hematoma. There is a need both for larger and more rigorously designed and reported studies on this subject and for structured, comprehensive recommendations for safe administration and removal of neuraxial anesthesia in patients with hemorrhagic disorders and tendencies.

Describing the point prevalence and characteristics of venous thromboembolism in patients with thrombotic thrombocytopenic purpura.

BACKGROUND: Arterial thromboembolic events are relatively common and well-described in patients with thrombotic thrombocytopenic purpura (TTP). However, the literature describing venous thromboembolism (VTE) in TTP is scarce. METHODS: Single-institution retrospective chart review was conducted in TTP patients over a 10-year period to describe the point prevalence of VTE. Data were analyzed using descriptive statistics. RESULTS: We identified 77 consecutive patients with 123 episodes of TTP. Of these patients, 14 (18%) experienced 16 VTEs (6 pulmonary embolisms, 6 deep vein thromboses, 4 superficial vein thromboses [SVT]). Excluding SVT, the point prevalence of VTE was 14%. All were acute and associated with admission for acute TTP. All patients were treated with plasma exchange (PLEX); 6/8 patients on concurrent PLEX at VTE diagnosis were exchanged with solvent-detergent plasma (SDP). Platelet and lactate dehydrogenase levels at time of VTE diagnosis had largely normalized from presentation values (median 175 × 109 U/L [interquartile range 130.75, 250] and 232 U/L [interquartile range 178.75, 263.5], respectively). Most VTEs (9/16) occurred while patients were not on pharmacologic thromboprophylaxis. All but one VTE was treated with anticoagulation. No VTEs were fatal or massive. CONCLUSIONS: Our data provide additional evidence that TTP patients may be at risk for VTE. It is possible that SDP exerted a prothrombotic effect. TTP-associated VTEs may be pathophysiologically distinct from arterial thromboses because they occur following hematological recovery. VTE thromboprophylaxis was not commonly used. Our findings suggest the need to implement VTE thromboprophylaxis earlier in hospitalized patients with TTP.

Improvement in Hematology Interprofessional Care: Simulation With an Emphasis on Collaboration.

Introduction: For many training programs, including hematology, there are limited structured opportunities to practice collaboration as a competency. Training is often limited to ad hoc interactions during clinical rotations. Accordingly, there is further need for immersive and standardized collaboration educational programs. This pilot study explored simulation for developing and assessing collaboration competency among hematology residents. Methods: Two standardized simulation center scenarios were developed that required residents to work in interprofessional teams. The objectives were to develop collaboration competence and confidence through experiential learning and facilitated reflection. Team members included education and simulation experts as well as hematology nurses as embedded participants. Case 1 presented a 72-year-old male with stage 4 lymphoma experiencing shortness of breath during a rituximab infusion. Case 2 presented a 68-year-old male who suffered a provoked pulmonary embolism. Both cases utilized a simulated clinic space. Pre, post, and 3-month questionnaires (self-assessed collaboration competency and simulation evaluation) were completed. Each session included structured debriefing with facilitated reflection focused on collaboration. Results: Seven senior hematology subspecialty residents participated. Despite residents entering the simulation cases with confidence in collaboration, higher collaboration confidence ratings were observed on postsimulation questionnaires (8.2 vs. 7.6 on a 10-point Likert scale). Residents demonstrated awareness of appropriate collaboration skills, but at times failed to implement knowledge into action. Facilitated reflection during the debrief helped residents critique their collaboration performance and develop improvement plans. Discussion: Simulation is a promising tool for teaching and assessing collaboration within hematology training.

Early adulthood body mass index, cumulative smoking, and esophageal adenocarcinoma survival.

BACKGROUND: Smoking and obesity are esophageal adenocarcinoma (EAC) risk factors. However, the same risk factors may also affect biological aggressiveness and cancer outcomes. Our study evaluated the combined effects of early-adulthood obesity and cumulative smoking on the EAC survival. PATIENTS AND METHODS: In two EAC cohorts, Toronto (TO; N=235) and Boston (BO; N=329), associations between early adulthood body mass index (EA-BMI), BMI at 1year prior to diagnosis (BMI-1), and smoking with overall survival (OS) were assessed using Cox proportional hazard models, adjusted for relevant covariates. RESULTS: Both cohorts were predominantly Caucasian (89%), male (88%), ever-smokers (73%) with locally advanced/metastatic EAC (78%), and good ECOG performance status (90%); median packyears was 34; median EA-BMI, 24; median BMI-1, 25. No relationships with survival were found with BMI-1. For smoking and EA-BMI, TO, BO, and combined TO-BO analyses showed similar associations: smoking conferred worse OS in the combined TO-BO cohort, with adjusted hazard ratios (aHR) of 1.22 (95%CI: 1.15-1.43;p<0.0001) for each 20 pack-year increase. Likewise, EA-BMI ≥25 was associated with worse OS (EA-BMI of 25-<30, aHR=1.84,95%CI: 1.37-2.48; and EA-BMI>30, aHR=2.78, 95%CI: 1.94-3.99). Risk of death was also increased in remotely underweight patients with EA-BMI<18.5 (aHR=2.03,95%CI: 1.27-3.24), when compared to normal-EA-BMI (18≤EA-BMI<25). CONCLUSIONS: Two key modifiable behaviors, elevated BMI in early adulthood and heavy cumulative smoking history are independently associated with increased mortality risk in two North American cohorts of EAC patients.

Association of BRM promoter polymorphisms and esophageal adenocarcinoma outcome.

PURPOSE: Brahma (BRM) is a critical catalytic subunit of the SWI/SNF chromatin remodeling complex; expression of BRM is commonly lost in various cancer types. BRM promoter polymorphisms (BRM-741; BRM-1321) are associated with loss of BRM expression, and with cancer risk/survival. We evaluated these two polymorphisms in the overall survival (OS) of esophageal adenocarcinoma (EAC) patients. RESULTS: Of 270 patients, 37% were stage IV. Minor allele frequencies were 47-49%; 15% were double-homozygotes. When compared to the wild-type genotype, the homozygous variant of BRM-741 carried an adjusted OS hazard ratio (aHR) of 1.64 (95% CI:1.1-2.4); for BRM-1321, the aHR was 2.09 (95% CI:1.4-3.0). Compared to the double wild-type, carrying homozygous variants of both promoter polymorphisms (double-homozygote) yielded an aHR of 2.21 (95% CI:1.4-3.6). Directions/magnitudes of associations were similar in subsets by age, gender, smoking status, use of platinum agents, and disease stage, and for progression-free survival. MATERIALS AND METHODS: In a cohort of EAC patients of all stages (84% male; median age of 64 years), two BRM polymorphisms were genotyped. Cox proportional hazards models, adjusted for known prognostic variables, estimated the association of polymorphisms with OS. CONCLUSIONS: BRM polymorphisms were associated with OS in EAC in this study. Validation studies are warranted.

BRM Promoter Polymorphisms and Survival of Advanced Non-Small Cell Lung Cancer Patients in the Princess Margaret Cohort and CCTG BR.24 Trial.

Introduction: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) are associated with reversible epigenetic silencing of BRM protein expression.Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models. Promoter swap, luciferase assays, and chromatin immunoprecipitation (ChIP) experiments evaluated polymorphism function. In silico analysis of publicly available gene expression datasets with outcome were performed.Results: Carrying the homozygous variants of both polymorphisms ("double homozygotes", DH) when compared with those carrying the double wild-type was associated with worse overall survival, with an adjusted hazard ratios (aHR) of 2.74 (95% CI, 1.9-4.0). This was confirmed in the BR.24 trial (aHR, 8.97; 95% CI, 3.3-18.5). Lower BRM gene expression (by RNA-Seq or microarray) was associated with worse outcome (P < 0.04). ChIP and promoter swap experiments confirmed binding of MEF2D and HDAC9 only to homozygotes of each polymorphism, associated with reduced promoter activity in the DH.Conclusions: Epigenetic regulatory molecules bind to two BRM promoter sequence variants but not to their wild-type sequences. These variants are associated with adverse overall and progression-free survival. Decreased BRM gene expression, seen with these variants, is also associated with worse overall survival. Clin Cancer Res; 23(10); 2460-70. ©2016 AACR.