Evaluation of an automated von Willebrand factor glycoprotein IbM activity assay compared with 3 alternative von Willebrand factor activity assays.

Background: To overcome deficiencies of the traditional von Willebrand factor (VWF) ristocetin cofactor activity assay (VWF:RCo), several automated assays for VWF platelet-binding activity have been developed. Information on the performance of these assays and their diagnostic utility remains limited. Objectives: To validate the VWF:glycoprotein IbM assay INNOVANCE VWF Ac and compare it with an automated VWF:RCo assay as well as with an automated assay and a manual VWF:Ab assay and to generate reference ranges and analyze reproducibility of the VWF:glycoprotein IbM assay. Methods: Clinical sites enrolled healthy subjects and patients representing the intended use population; VWF activity assays were performed, and results were analyzed. The performance of the INNOVANCE VWF Ac assay was also compared between the BCS XP System and the CS-2500 and CS-5100 analyzers. Results: The INNOVANCE VWF Ac assay correlated well with the VWF:RCo assay and the automated HemosIL VWF:Ab assay, with Pearson coefficients of >.9 and a predicted bias of ≤5.0 IU/dL at VWF levels of 30 IU/dL and ≤5.8 IU/dL at the levels of 50 IU/dL, but correlation and bias were not as good when compared with the REAADS manual VWF:Ab assay. Reference ranges observed for healthy subjects correlated well with previously published findings. Reproducibility of the INNOVANCE VWF Ac assay on the BCS XP System and the CS analyzers was excellent, as was correlation among devices. Conclusion: The characteristics of the INNOVANCE VWF Ac assay regarding comparability with other VWF activity assays, reference ranges, and precision support the use of this assay for evaluation of patients with concern for von Willebrand disease.

Recombinant ADAMTS13 for Immune Thrombotic Thrombocytopenic Purpura.

In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis. However, the potential benefits of recombinant human ADAMTS13 (rADAMTS13) in patients with iTTP remain unknown. Here, we report the clinical use of rADAMTS13, which resulted in the rapid suppression of disease activity and complete recovery in a critically ill patient whose condition had proved to be refractory to all available treatments. We also show that rADAMTS13 causes immune complex formation, which saturates the autoantibody and may promote its clearance. Our data support the role of rADAMTS13 as a novel adjunctive therapy in patients with iTTP.

How I diagnose and treat thrombocytopenia in geriatric patients.

ABSTRACT: Thrombocytopenia in older individuals is a common but diagnostically challenging condition that has variable clinical impact to those who are affected. Diagnostic approach requires evaluation of the preexisting clinical conditions, detailed review of medications, and assessment for disorders that warrant urgent treatment. In this article, we describe a systematic approach to diagnosis of thrombocytopenia and present a schematic review for management strategies. Three clinical scenarios are presented that are relevant for their prevalence and management challenges in an older adult population. The first scenario addresses primary immune thrombocytopenia (ITP) and reviews different treatment options. The second one addresses complications of thrombocytopenia in management of the myelodysplastic syndrome. The last one reviews diagnostic challenges of drug-induced ITP.

Observational cohort study of long-term outcomes of liver transplantation in haemophilia.

INTRODUCTION: Gene therapy is now a reality for individuals with haemophilia, yet little is known regarding the quality-of-life impact of factor correction. As few data exist, and recognizing the analogy to liver transplantation (OLTX), we identified OLTX+ and OLTX- men in the ATHNdataset to compare post-OLTX factor VIII and IX on quality of life (QoL) by Haem-A-QoL and PROMIS-29. METHODS: OLTX- were matched to OLTX+ by age, race, and haemophilia type and severity. Deidentified demographic data, including post-transplant factor levels, genotype and target joint disease were analysed by descriptive statistics. Haem-A-Qol and PROMIS-29 were compared in OLTX+ and OLTX- by student's t-test and univariate regression models. RESULTS: Of 86 people with haemophilia A (HA) or haemophilia B (HB) cared for at 10 haemophilia treatment centers (HTCs), 21 (24.4%) OLTX+ and 65 (75.6%) OLTX- were identified. OLTX+ and OLTX- had a similar frequency of target joint disease (p = .806), HA genotypes, null versus non-null (p = .696), and HIV infection (p = .316). At a median 9.2 years post-OLTX, median FVIII, .63 IU/mL [IQR 0.52-0.97] and FIX, .91 IU/mL [IQR .63-1.32], Haem-A-QoL, PROMIS-29, and HOT scores were comparable. Severe HA/HB had lower post-OLTX 'dealing with haemophilia' scores (p = .022) and higher 'sports and leisure' (p = .010) and 'view of yourself' scores (p = .024) than OLTX+ non-severe participants. Non-caucasian OLTX+ had significantly lower scores in sports and leisure (p = .042), future expectations (p = .021) and total score (p = .010). CONCLUSION: Nine years after OLTX, QoL is comparable to OLTX-, but significantly better in OLTX+ with severe than non-severe disease and in caucasians than non-caucasians.

Immunotactoid hepatopathy: A novel entity with histologically proven recurrence post liver transplantation.

Immunotactoid deposition is a rare fibrillary deposition disease that is primarily seen in the kidney and is associated with paraproteinemia. Here, we report a case of hepatic immunotactoid deposition in a 67-year-old male with a history of smoldering myeloma and chronic kidney disease who underwent liver transplantation for metabolic dysfunction-related cirrhosis. Immunotactoid deposition was first identified in the explanted liver and recurred in the allograft within only 7 weeks following transplantation, presenting as ascites with normal liver function tests. The patient's posttransplant course was complicated by proteinuria and renal failure requiring dialysis. Histologic examination of both native and allograft livers demonstrated pink amorphous material occupying sinusoidal spaces that were Congo-red negative and immunoglobulin M Kappa-restricted. Electron microscopy revealed characteristic deposits of electron-dense bundles of hollow microtubules with a 40 nm diameter within the sinusoids and space of Disse, consistent with immunotactoids. Therapy of the patient's underlying plasma-cell dyscrasia utilizing a daratumumab-based regimen showed decreased serum paraproteins, resolution of ascites, and improved kidney function, no longer requiring dialysis, without inducing rejection. The patient continues to respond to treatment 10 months posttransplant.

Real-world safety and effectiveness of recombinant porcine sequence factor VIII in acquired haemophilia A: A non-interventional, post-authorization safety study.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII, susoctocog alfa) is indicated for the treatment of bleeding episodes in adults with acquired haemophilia A (AHA). AIM: To provide long-term real-world safety and effectiveness data for rpFVIII in the management of AHA bleeding episodes. METHODS: US PASS (NCT02610127) was a multicentre, uncontrolled, open-label, post-marketing safety surveillance study conducted in adults with AHA. Data were collected retrospectively or prospectively for 180 days after rpFVIII treatment. The primary outcome was the incidence of treatment-related serious adverse events (SAEs). Secondary outcomes included haemostatic effectiveness of rpFVIII and rpFVIII utilization. RESULTS: Fifty-three patients were enrolled from December 2015 to June 2019 (prospective, n = 30; retrospective, n = 23). Six patients experienced seven treatment-related SAEs (incidence 12.0%). The most common treatment-related SAE was FVIII inhibition (inhibiting antibodies to rpFVIII; incidence 8.0%, 95% CI: 2.2-19.2). Five patients reported seven thromboembolic events; one was an SAE and possibly related to rpFVIII. Of bleeding events treated with rpFVIII, 80.3% (57/71) of bleeds resolved with rpFVIII. The median (range) dose of rpFVIII per infusion was 50 (10-300) units/kg, with a median (range) of 6.0 (1-140) infusions and a median (range) time from bleed onset to bleed resolution of 14.0 (2.0-132.7) days. CONCLUSION: In this real-world study of rpFVIII for AHA, no new safety signals were identified compared with previous clinical trial findings. Eighty percent of bleeds resolved with rpFVIII treatment.

Durable remission of thrombotic thrombocytopenic purpura in the setting of pembrolizumab therapy.

BACKGROUND: There is a small but growing number of thrombotic thrombocytopenic purpura (TTP) cases attributed to immune checkpoint inhibitor therapy, with nivolumab and ipilimumab therapy being the most frequently described in the literature. STUDY DESIGN AND METHODS: This report evaluates the course of a patient with a history of metastatic adenocarcinoma of the lung who developed TTP following treatment with the PD-1 inhibitor Pembrolizumab. The patient was treated with six sessions of therapeutic plasma exchange and appeared to be in remission. Exacerbation occurred 4 days later, and seven more sessions of plasma exchange were performed along with four total doses of Rituximab, and a steroid taper with monitoring of platelet counts and ADAMTS13 activity. RESULTS: His platelet count recovered to a peak of 318,000 UL with an ADAMTS13 activity of 77% at the time of discharge. The patient has been following up regularly for outpatient testing with no TTP relapse as of the completion of this report. DISCUSSION: This is one of a few cases of Pembrolizumab-associated TTP reported in the literature with successful complete remission following treatment. Plasma exchange in this setting may be an especially beneficial therapeutic intervention because of the removal of both the anti-ADAMTS13 antibody as well as the immune system upregulating anti-PDL1 monoclonal antibody with replacement of ADAMTS13 from donor plasma. Longer duration of plasma exchange and monitoring for normalization of ADAMTS13 levels in addition to platelet count before cessation of treatment may improve durable remission rates in this entity.

Inhibin-Positive "Cholangioblastic" Variant of Intrahepatic Cholangiocarcinoma: Report of 3 New Patients With Review of the Literature.

Cholangiocarcinoma is the second most common primary liver malignant neoplasm. It usually affects older individuals in their seventh decade of life with no gender predilection. Recently, a distinct subtype of cholangiocarcinoma has emerged with 2 proposed names: "cholangioblastic" and "solid tubulocystic." This variant predominantly occurs in younger women who lack the common risk factors for patients diagnosed with cholangiocarcinomas, such as older age and chronic liver disease or cirrhosis. We describe 3 new patients with a cholangioblastic variant of intrahepatic cholangiocarcinoma. At the time of diagnosis, the patients were aged 19-, 46-, and 28-year-old; 2 females and 1 male (the 46-year-old). None of our patients had a history of chronic liver disease or known predisposing factors for liver tumors. Tumor size ranged from 2.3 to 23 cm in greatest dimension. Histological examination of these tumors demonstrated reproducible morphology characterized by trabecular, nested, and multicystic patterns with micro and macro follicles filled with eosinophilic material. The immunohistochemical profile showed that the tumor cells were positive for keratin 7, inhibin, synaptophysin, and albumin in situ hybridization, while negative for HepPar1, arginase, and INSM1. All tumors lacked conventional intrahepatic cholangiocarcinoma/adenocarcinoma morphology. We also review the literature and emphasize that neuroendocrine tumors should be recognized as a major diagnostic pitfall of this variant.

Hereditary thrombotic thrombocytopenic purpura and COVID-19: Impacts of vaccination and infection in this rare disease.

Introduction: Severe COVID-19 is associated with an important increase of von Willebrand factor and mild lowering of ADAMTS13 activity that may, in the presence of a strong inflammatory reaction, increase the risk of acute thrombotic thrombocytopenic purpura (TTP). Although acute episodes of immune-mediated TTP associated with COVID-19 or SARS-CoV-2 vaccination have been reported, data about clinical evolution of hereditary TTP (hTTP) during the pandemic are scarce. Method: We conducted a survey among adult patients of the International Hereditary TTP Registry about SARS-CoV-2 vaccination, COVID-19, and occurrence of acute hTTP episodes. Results: Of 122 adult hTTP patients invited to participate, 86 (70.5%) responded. Sixty-five had been vaccinated (75.6%), of which 14 had received in addition a booster, resulting in 139 individual vaccine shots. Although vaccinations in patients on plasma prophylaxis were done within 1 week of the last plasma infusion, all 23 patients treated with plasma on demand were vaccinated without prior plasma infusions. One patient on uninterrupted weekly plasma infusions presented within 3 days from his second vaccination with neurological symptoms and computed tomography scan 9 days later showed subacute ischemic/hemorrhagic frontal lobe infarction. A second male patient developed acute myocarditis after his second dose of mRNA-1273 vaccine. Twelve (14%) patients had COVID-19, associated with an acute hTTP episode in three of them: one patient had a transient ischemic attack, one a stroke, and a pregnant woman was hospitalized to intensify plasma treatment. Discussion: The risk of an acute episode triggered by COVID-19 seems higher than following vaccination in hTTP patients, who can be safely vaccinated against SARS-CoV-2.

Update to the structured MRI report for primary staging of rectal cancer : Perspective from the SAR Disease Focused Panel on Rectal and Anal Cancer.

OBJECTIVE: To review existing structured MRI reports for primary staging of rectal cancer and create a new, freely available structured report based on multidisciplinary expert opinion and literature review. METHODS: Twenty abdominal imaging experts from the Society of Abdominal Radiology (SAR)'s Disease Focused Panel (DFP) on Rectal and Anal Cancer completed a questionnaire and participated in a subsequent consensus meeting based on the RAND-UCLA Appropriateness Method. Twenty-two items were classified via a group survey as "appropriate" or "inappropriate" (defined by ≥ 70% consensus), or "needs group discussion" (defined by < 70% consensus). Certain items were also discussed with multidisciplinary team members from colorectal surgery, oncology and pathology. RESULTS: After completion of the questionnaire, 16 (72%) items required further discussion (< 70% consensus). Following group discussion, consensus was achieved for 21 (95%) of the items. Based on the consensus meeting, a revised structured report was developed. The most significant modifications included (1) Exclusion of the T2/early T3 category; (2) Replacement of the term "circumferential resection margin (CRM)" with "mesorectal fascia (MRF)"; (3) A revised definition of "mucinous content"; (4) Creation of two distinct categories for suspicious lymph nodes (LNs) and tumor deposits; and (5) Classification of suspicious extra-mesorectal LNs by anatomic location. CONCLUSION: The SAR DFP on Rectal and Anal Cancer recommends using this newly updated reporting template for primary MRI staging of rectal cancer.

Turning a Corner in ME/CFS Research.

This collection of research papers addresses fundamental questions concerning the nature of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), the problem of disbelief and lack of knowledge and understanding of the condition among many doctors and the origins of this problem, and its impact on patients and their families. We report briefly the growing knowledge of the underlying pathological processes in ME/CFS, and the development of new organizations, including Doctors with ME, the US ME/CFS Clinical Coalition and EUROMENE, to address aspects of the challenges posed by the illness. We discuss the implications of COVID-19, which has much in common with ME/CFS, with much overlap of symptoms, and propose a new taxonomic category, which we are terming post-active phase of infection syndromes (PAPIS) to include both. This collection of papers includes a number of papers reporting similar serious impacts on the quality of life of patients and their families in various European countries. The advice of EUROMENE experts on diagnosis and management is included in the collection. We report this in light of guidance from other parts of the world, including the USA and Australia, and in the context of current difficulties in the UK over the promulgation of a revised guideline from the National Institute for Health and Care Excellence (NICE). We also consider evidence on the cost-effectiveness of interventions for ME/CFS, and on the difficulties of determining the costs of care when a high proportion of people with ME/CFS are never diagnosed as such. The Special Issue includes a paper which is a reminder of the importance of a person-centred approach to care by reviewing mind-body interventions. Finally, another paper reviews the scope for prevention in minimizing the population burden of ME/CFS, and concludes that secondary prevention, through early detection and diagnosis, could be of value.

Our Evolving Understanding of ME/CFS.

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the 'hallmark' symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes. We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Annual incidence and severity of acute episodes in hereditary thrombotic thrombocytopenic purpura.

Hereditary thrombotic thrombocytopenic purpura (hTTP) is a rare thrombotic microangiopathy characterized by severe congenital ADAMTS13 deficiency and recurring acute episodes causing morbidity and premature death. Information on the annual incidence and severity of acute episodes in patients with hTTP is largely lacking. This study reports prospective data on 87 patients from the Hereditary TTP Registry (clinicaltrials.gov #NCT01257269) for survival, frequency, and severity of acute episodes from enrollment until December 2019. The 87 patients, followed up for a median of 4.2 years (range, 0.01-15 years), had a median age at overt disease onset and at clinical diagnosis of 4.6 years and 18 years (range, 0.0-70 years for both), respectively. Forty-three patients received regular plasma prophylaxis, whereas 22 did not, and treatment changed over time or was unknown in the remaining 22. Forty-three patients experienced 131 acute episodes, of which 91 (69%) occurred in patients receiving regular prophylaxis. This resulted in an annual incidence of acute episodes of 0.36 (95% confidence interval [CI], 0.29-0.44) with regular plasma treatment and of 0.41 (95% CI, 0.30-0.56) without regular plasma treatment. More than one-third of acute episodes (n = 51) were documented in children <10 years of age at enrollment and were often triggered by infections. Their annual incidence of acute episodes was significantly higher than in patients aged >40 years (1.18 [95% CI, 0.88-1.55] vs 0.14 [95% CI, 0.08-0.23]). The prophylactic plasma infusion regimens used were insufficient to prevent acute episodes in many patients. Such regimens are burdensome, and caregivers, patients, and their guardians are reluctant to start regular plasma infusions, from which children particularly would benefit.

Redefining outcomes in immune TTP: an international working group consensus report.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.

A microfluidic analysis of thrombus formation in reconstituted whole blood samples comparing spray-dried plasma versus fresh frozen plasma.

BACKGROUND: Prompt resuscitation with plasma and other blood products reduces trauma-related morbidity and mortality. Standard storage and preparation techniques for frozen plasma limit its utility in the pre-hospital setting. Plasma can be dehydrated using hot air (spray-dried plasma), stored at room temperature and rehydrated quickly for use. The spray-dry process decreases high-molecular-weight multimers of von Willebrand factor compared with conventional plasma. The objective of this study was to compare platelet adhesion and thrombus formation in a microfluidic perfusion assay facilitated by spray-dried compared with frozen plasma using a non-inferiority design. STUDY DESIGN AND METHODS: Whole blood was centrifuged to obtain red cell concentrate, and a platelet pellet that was suspended in either spray-dried or frozen plasma to create recombined whole blood. Platelets were fluorescently labelled, and samples were flowed through a collagen-coated microchannel. Surface area coverage by platelets and thrombi was analysed and compared between each spray-dried and frozen plasma pair. RESULTS: Compared with whole blood samples containing frozen plasma, samples with spray-dried plasma had similar surface area coverage of platelets and thrombi after 180 s of flow. Even when diluted with von Willebrand factor-free plasma, there was no reduction thrombus formation. CONCLUSION: Spray-dried plasma is not inferior in supporting haemostasis compared with fresh frozen plasma in a paired analysis. It offers advantages with respect to portability and ease of preparation over frozen plasma in the pre-hospital setting. This study supports development of clinical studies to evaluate the efficacy and safety of spray-dried plasma in trauma patients.

Radiomic Texture and Shape Descriptors of the Rectal Environment on Post-Chemoradiation T2-Weighted MRI are Associated with Pathologic Tumor Stage Regression in Rectal Cancers: A Retrospective, Multi-Institution Study.

(1) Background: The relatively poor expert restaging accuracy of MRI in rectal cancer after neoadjuvant chemoradiation may be due to the difficulties in visual assessment of residual tumor on post-treatment MRI. In order to capture underlying tissue alterations and morphologic changes in rectal structures occurring due to the treatment, we hypothesized that radiomics texture and shape descriptors of the rectal environment (e.g., wall, lumen) on post-chemoradiation T2-weighted (T2w) MRI may be associated with tumor regression after neoadjuvant chemoradiation therapy (nCRT). (2) Methods: A total of 94 rectal cancer patients were retrospectively identified from three collaborating institutions, for whom a 1.5 or 3T T2w MRI was available after nCRT and prior to surgical resection. The rectal wall and the lumen were annotated by an expert radiologist on all MRIs, based on which 191 texture descriptors and 198 shape descriptors were extracted for each patient. (3) Results: Top-ranked features associated with pathologic tumor-stage regression were identified via cross-validation on a discovery set (n = 52, 1 institution) and evaluated via discriminant analysis in hold-out validation (n = 42, 2 institutions). The best performing features for distinguishing low (ypT0-2) and high (ypT3-4) pathologic tumor stages after nCRT comprised directional gradient texture expression and morphologic shape differences in the entire rectal wall and lumen. Not only were these radiomic features found to be resilient to variations in magnetic field strength and expert segmentations, a quadratic discriminant model combining them yielded consistent performance across multiple institutions (hold-out AUC of 0.73). (4) Conclusions: Radiomic texture and shape descriptors of the rectal wall from post-treatment T2w MRIs may be associated with low and high pathologic tumor stage after neoadjuvant chemoradiation therapy and generalized across variations between scanners and institutions.