Immune thrombocytopenia (ITP) occurs in 2 to 4/100 000 adults and results in variable bleeding symptoms and thrombocytopenia. In the last decade, changes in our understanding of the pathophysiology ...of the disorder have led to the publication of new guidelines for the diagnosis and management of ITP and standards for terminology. Current evidence supports alternatives to splenectomy for second-line management of patients with persistently low platelet counts and bleeding. Long-term follow-up data suggest both efficacy and safety, in particular, for the thrombopoietin receptor agonists and the occurrence of late remissions. Follow-up of patients who have undergone splenectomy for ITP reveals significant potential risks that should be discussed with patients and may influence clinician and patient choice of second-line therapy. Novel therapeutics are in development to address ongoing treatment gaps.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CAPTION(S): Table S1: Patients with reported thrombocytopenia post SARS/CoV-2 vaccination Byline: Eun-Ju Lee, Douglas B. Cines, Terry Gernsheimer, Craig Kessler, Marc Michel, Michael D. Tarantino, ...John W. Semple, Donald M. Arnold, Bertrand Godeau, Michele P. Lambert, James B. Bussel
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The inherited platelet disorders are a heterogeneous group of disorders that can be pleotropic in their clinical presentations. They may present with variable platelet counts and bleeding, making ...their diagnosis difficult. New diagnostic tools range from flow cytometric platelet function assessments to next-generation sequencing. Several platelet disorders may now be treated with gene therapy or bone marrow transplant. Improved understanding of the molecular and biologic mechanisms of the inherited platelet disorders may lead to novel targeted therapies.
This review will discuss how 2 common and morbid conditions, renal disease and liver disease, alter platelet number and function. It will review the impact of thrombocytopenia on bleeding ...complications in patients with these disorders and whether the low platelet count actually correlates with bleeding risk. Emerging data also suggest that platelets are much more than bystanders in both renal and liver disease, but instead play an active role in the pathobiology of these disorders. This review will briefly cover the emerging information on novel roles of platelets in the biology of renal and liver disease.
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of immune dysregulation characterized by derangements in first apoptosis signal-mediated apoptosis and elevations in CD3
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TCRαβ
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...CD4
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CD8
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'double negative' T cells. As our understanding of this pleomorphic disorder expands, the importance of molecular diagnosis is ever more apparent due to the growing number of disorders that may present with overlapping initial symptoms, but for which there is an ever-increasing list of therapeutic options.
This review will cover the current understanding of the molecular biology and pathophysiology of ALPS as well as describe some of the overlapping syndromes in order to better demonstrate the importance of establishing the correct diagnosis.
Going forward, international, multicenter collaboration to fully characterize ALPS and the ALPS-like disorders, including with particular focus on defining the defects for those patients with undefined ALPS, is important to both continue to improve our understanding of this disorder and to drive patient care forward to provide the best outcomes. Additionally, it is probably time to re-convene an international expert panel to re-define diagnostic criteria taking into consideration the most recent available data in order to optimize patient care.
PURPOSE OF REVIEWTo provide a comprehensive update on the current available methodologies and techniques for diagnosis of inherited platelet disorders (IPD).
RECENT FINDINGSThe contributions of many ...groups have resulted in the significant progress in the molecular diagnosis of IPD including the identification of many genes responsible for the various phenotypes. The widespread use and availability of next-generation sequencing has brought to the forefront ethical challenges associated with nontargeted sequencing as well as provided us with novel variants to functionally validate. These requirements have driven the development of novel tools for functional assessment of platelets, although none of the novel techniques beyond sequencing have yet taken clinical hold.
SUMMARYMuch work is ongoing on functional and molecular assessment of platelet disorders and the incorporation of combined assessments is likely to yield the highest diagnostic results.
In the bone marrow, hematopoietic stem cells (HSCs) lodge in specialized microenvironments that tightly control the proliferative state of HSCs to adapt to the varying needs for replenishment of ...blood cells while also preventing HSC exhaustion. All putative niche cells suggested thus far have a nonhematopoietic origin. Thus, it remains unclear how feedback from mature cells is conveyed to HSCs to adjust their proliferation. Here we show that megakaryocytes (MKs) can directly regulate HSC pool size in mice. Three-dimensional whole-mount imaging revealed that endogenous HSCs are frequently located adjacent to MKs in a nonrandom fashion. Selective in vivo depletion of MKs resulted in specific loss of HSC quiescence and led to a marked expansion of functional HSCs. Gene expression analyses revealed that MKs are the source of chemokine C-X-C motif ligand 4 (CXCL4, also named platelet factor 4 or PF4) in the bone marrow, and we found that CXCL4 regulates HSC cell cycle activity. CXCL4 injection into mice resulted in a reduced number of HSCs because of their increased quiescence. By contrast, Cxcl4(-/-) mice exhibited an increased number of HSCs and increased HSC proliferation. Combined use of whole-mount imaging and computational modeling was highly suggestive of a megakaryocytic niche capable of independently influencing HSC maintenance by regulating quiescence. These results indicate that a terminally differentiated cell type derived from HSCs contributes to the HSC niche, directly regulating HSC behavior.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The last 10 years have seen an explosion in the amount of data available through next-generation sequencing. These data are advancing quickly, and this pace makes it difficult for most practitioners ...to easily keep up with all of the new information. Complicating this understanding is sometimes conflicting information about variant pathogenicity or even about the role of some genes in the pathogenesis of disease. The more widespread clinical use of sequencing has expanded phenotypes, including the identification of mild phenotypes associated with previously serious disease, such as with some variants in RUNX1, MYH9, ITG2A, and others. Several organizations have taken up the task of cataloging and systematically evaluating genes and variants using a standardized approach and making the data publicly available so that others can benefit from their gene/variant curation. The efforts in testing for hereditary hemorrhagic, thrombotic, and platelet disorders have been led by the International Society on Thrombosis and Haemostasis Scientific Standardization Committee on Genomics in Thrombosis and Hemostasis, the American Society of Hematology, and the National Institutes of Health National Human Genome Research Institute Clinical Genome Resource. This article outlines current efforts to improve the interpretation of genetic testing and the role of standardizing and disseminating information. By assessing the strength of gene-disease associations, standardizing variant curation guidelines, sharing genomic data among expert members, and incorporating data from existing disease databases, the number of variants of uncertain significance will decrease, thereby improving the value of genetic testing as a diagnostic tool.
Patients with autoimmune multilineage cytopenias are often refractory to standard therapies requiring chronic immunosuppression with medications with limited efficacy and high toxicity. We present ...data on 30 patients treated on a multicenter prospective clinical trial using sirolimus as monotherapy. All children (N = 12) with autoimmune lymphoproliferative syndrome (ALPS) achieved a durable complete response (CR), including rapid improvement in autoimmune disease, lymphadenopathy, and splenomegaly within 1 to 3 months of starting sirolimus. Double-negative T cells were no longer detectable in most, yet other lymphocyte populations were spared, suggesting a targeted effect of sirolimus. We also treated 12 patients with multilineage cytopenias secondary to common variable immunodeficiency (CVID), Evans syndrome (ES), or systemic lupus erythematosus (SLE), and most achieved a CR (N = 8), although the time to CR was often slower than was seen in ALPS. Six children with single-lineage autoimmune cytopenias were treated and only 2 responded. Sirolimus was well tolerated with very few side effects. All of the responding patients have remained on therapy for over 1 year (median, 2 years; range, 1 to 4.5 years). In summary, sirolimus led to CR and durable responses in a majority of children with refractory multilineage autoimmune cytopenias. The responses seen in ALPS patients were profound, suggesting that sirolimus should be considered as a first-line, steroid-sparing treatment of patients needing chronic therapy. The results in other multilineage autoimmune cytopenia cohorts were encouraging, and sirolimus should be considered in children with SLE, ES, and CVID. This trial was registered at www.clinicaltrials.gov as #NCT00392951.
•Sirolimus monotherapy is a safe and effective steroid-sparing agent, improving autoimmune cytopenias in highly refractory patients.•Sirolimus is particularly active in ALPS and should be an early therapy option for patients who require chronic therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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