A pilot randomized trial comparing symptomatic vs. hemoglobin-level- driven red blood cell transfusions following hip fracture

BACKGROUND: The indications for transfusion have never been evaluated in an adequately sized clinical trial. A pilot study was conducted to plan larger clinical trials. STUDY DESIGN AND METHODS: Hip fracture patients undergoing surgical repair who had postoperative hemoglobin levels less than 10 g per dL were randomly assigned to receive 1) symptomatic transfusion: that is, transfusion for symptoms of anemia or for a hemoglobin level that dropped below 8 g per dL or 2) threshold transfusion: that is, patients receive 1 unit of packed RBCs at the time of random assignment and as much blood as necessary to keep the hemoglobin level above 10 g per dL. Outcomes were 60-day mortality, morbidity, functional status, and place of residence. RESULTS: Among 84 eligible patients enrolled, mean (± SD) prerandomization hemoglobin was 9.1 (± 0.6) g/ dL. The median number of units transfused in the threshold transfusion group was 2 (interquartile range, = 1–2), and that in the symptomatic transfusion group was 0 (6; interquartile range, = 0–2) (p < 0.001). Mean hemoglobin levels were approximately 1 g per dL higher in the threshold group than in the symptomatic group: for example, on Day 2, 10.3 (± 0.9) g per dL versus 9.3 (± 1.2) g per dL, respectively (p < 0.001). At 60 days, death or inability to walk across the room without assistance occurred in 16 (39.0%) of the symptomatic transfusion group and 19 (45.2%) of the threshold transfusion group. Death occurred by 60 days in 5 (11.9%) of the symptomatic transfusion group and 2 (4.8%) in the threshold transfusion group (relative risk = 2.5; 95% CI, 0.5–12.2). Other outcomes were similar for the two groups. CONCLUSIONS: Symptomatic transfusion may be an effective blood-sparing protocol associated with the transfusion of appreciably fewer units of RBCs and lower mean hemoglobin levels than are associated with the threshold transfusion policy. However, it is unknown whether these two clinical strategies have comparable mortality, morbidity, or functional status. A definitive trial is needed.     

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

Bone marrow fibrosis is the continuous replacement of blood‐forming cells in the bone marrow with excessive scar tissue, leading to failure of the body to produce blood cells and ultimately to death. Myofibroblasts are fibrosis‐driving cells and are well characterized in solid organ fibrosis, but their role and cellular origin in bone marrow fibrosis have remained obscure. Recent work has demonstrated that Gli1⁺ and leptin receptor⁺ mesenchymal stromal cells are progenitors of fibrosis‐causing myofibroblasts in the bone marrow. Genetic ablation or pharmacological inhibition of Gli1⁺ mesenchymal stromal cells ameliorated fibrosis in mouse models of myelofibrosis. Conditional deletion of the platelet‐derived growth factor (PDGF) receptor‐α (PDGFRA) gene (Pdgfra) and inhibition of PDGFRA by imatinib in leptin receptor⁺ stromal cells suppressed their expansion and ameliorated bone marrow fibrosis. Understanding the cellular and molecular mechanisms in the haematopoietic stem cell niche that govern the mesenchymal stromal cell‐to‐myofibroblast transition and myofibroblast expansion will be critical to understand the pathogenesis of bone marrow fibrosis in both malignant and non‐malignant conditions, and will guide the development of novel therapeutics. In this review, we summarize recent discoveries of mesenchymal stromal cells as part of the haematopoietic niche and as myofibroblast precursors, and discuss potential therapeutic strategies in the specific targeting of fibrotic transformation in bone marrow fibrosis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Antenatal platelet antibody testing by flow cytometry—results of a pilot study

BACKGROUND: Maternal platelet antibodies can cause fetomaternal alloimmune thrombocytopenia (FMAT), which has significant mortality and morbidity even in a first pregnancy. Prenatal diagnosis of FMAT has not previously been possible in the first affected pregnancy. STUDY DESIGN AND METHODS: Using flow cytometry, a sensitive, inexpensive test for the detection of platelet antibodies has been developed. It was adapted for use as a possible antenatal screening test, and 600 pregnant women were tested in a pilot study. RESULTS: In the study group, two women tested positive for platelet-specific IgG antibodies, one for anti-HPA- 1a and the other for anti-HPA-1a with anti-HLA. In each case, the fetus was found to be affected in utero, and treatment was initiated before successful delivery. Another woman was shown to have a platelet- reactive autoantibody without IgG specificity, and her infant was unaffected. A total of 95 (15.8%) of the women tested had HLA antibodies alone, and the majority demonstrated IgG specificity. On follow-up of 62 infants born to these women, none had thrombocytopenia; thus HLA antibodies were not shown to lead to FMAT in this study. CONCLUSION: The flow cytometry-based test for platelet antibodies can detect clinically significant maternal antibodies, and it may be that early diagnosis and treatment in utero can enhance outcome in FMAT. A population screening program is planned to determine the predictive power of this test, in addition to its sensitivity, specificity, and efficiency.     

Hereditary spastic paraplegia and Evans's syndrome

Two brothers with hereditary spastic paraplegia and Evans's syndrome are recorded. Rapid deterioration of functional motor ability followed the development of Evans's syndrome.     

Early sequelae of gunshot wounds to the spine: radiologic diagnosis

During a 6-month period, 11 consecutive patients who had delayed neurologic deterioration after sustaining a gunshot wound to the spine were prospectively evaluated clinically, radiologically, and surgically. The patients had dysesthetic burning pain in an anesthetic area, hyperhidrosis, flexor spasm, and additional motor deficit above the level of cord injury 2-22 weeks after injury. Radiologic evaluation consisted of plain radiography of the spine and metrizamide myelography followed by computed tomography. A syringomyelic cavity was found in seven patients, an arachnoid cyst in three, and osteomyelitis in one. Seven of these patients also had cord atrophy. Postoperatively, dysesthetic pain was relieved in all the patients. There was no recurrence during a 2-year follow-up. These results emphasize the need for immediate radiologic investigation in patients with gunshot wounds of the spine who have further deterioration superimposed on their initial deficit.     

Molecular mechanisms involved in receptor editing at the Ig heavy chain locus

In receptor editing, a phenomenon that has recently come to light and into favor, a rearranged VDJ or VJ gene segment encoding a variable region of an Ig chain is replaced by another. In this commentary, the molecular mechanisms involved in the editing process are examined in some detail. Editing is most likely mediated by the same V(D)J recombinase activity responsible for the formation of the original VDJ or VJ segment. An embedded heptamer, which is present near the 3' end of many VH elements, is used as the recombination signal sequence at the Ig heavy chain locus. It has been postulated that the mediation of receptor editing is the evolutionary force maintaining the embedded heptamer. Some of the evidence for and against this hypothesis is discussed.