Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (8): 3011-3016
Discordant aPTT and Anti-Xa Values and Outcomes in Hospitalized Patients Treated with Intravenous Unfractionated Heparin
ANNALS OF PHARMACOTHERAPY
2013; 47 (2): 151-158
Myelodysplastic syndromes (MDS) are a group of disorders characterized by variable cytopenias and ineffective hematopoiesis. Hematopoietic stem cells (HSCs) and myeloid progenitors in MDS have not been extensively characterized. We transplanted purified human HSCs from MDS samples into immunodeficient mice and show that HSCs are the disease-initiating cells in MDS. We identify a recurrent loss of granulocyte-macrophage progenitors (GMPs) in the bone marrow of low risk MDS patients that can distinguish low risk MDS from clinical mimics, thus providing a simple diagnostic tool. The loss of GMPs is likely due to increased apoptosis and increased phagocytosis, the latter due to the up-regulation of cell surface calreticulin, a prophagocytic marker. Blocking calreticulin on low risk MDS myeloid progenitors rescues them from phagocytosis in vitro. However, in the high-risk refractory anemia with excess blasts (RAEB) stages of MDS, the GMP population is increased in frequency compared with normal, and myeloid progenitors evade phagocytosis due to up-regulation of CD47, an antiphagocytic marker. Blocking CD47 leads to the selective phagocytosis of this population. We propose that MDS HSCs compete with normal HSCs in the patients by increasing their frequency at the expense of normal hematopoiesis, that the loss of MDS myeloid progenitors by programmed cell death and programmed cell removal are, in part, responsible for the cytopenias, and that up-regulation of the "don't eat me" signal CD47 on MDS myeloid progenitors is an important transition step leading from low risk MDS to high risk MDS and, possibly, to acute myeloid leukemia.
View details for DOI 10.1073/pnas.1222861110
View details for Web of Science ID 000315954400082
Controversies in Heparin Monitoring
AMERICAN JOURNAL OF HEMATOLOGY
2012; 87: S137-S140
Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (50): 20012-20017
Both the activated partial thromboplastin time (aPTT) and anti-Xa assay can be used to monitor unfractionated heparin (UFH). Following implementation of an anti-Xa method for heparin dosing protocols in our hospital, we became aware of many patients with discordant aPTT and anti-Xa values.To determine the frequency of discordant aPTT and anti-Xa values in a large cohort of hospitalized patients treated with UFH, as well as the demographics, coagulation status, indication for UFH, and clinical outcomes in this population.All aPTT and anti-Xa values from adults hospitalized between February and August 2009 at Stanford Hospital who were treated with UFH were analyzed. All samples were drawn simultaneously. A polynomial fit correlating aPTT and anti-Xa with a 99% confidence limit was designed. Paired aPTT/anti-Xa values were grouped according to whether the paired values fell within or outside of the concordant area. Patients were placed into groups based on concordance status, and clinical outcomes were assessed.A total of 2321 paired values from 539 patients were studied; 42% of data pairs had a high aPTT value relative to the anti-Xa value. Patients with elevated baseline prothrombin time/international normalized ratio or aPTT frequently demonstrated disproportionate relative prolongation of the aPTT. Patients with at least 2 consecutive high aPTT to anti-Xa values had increased 21-day major bleeding (9% vs 3%; p = 0.0316) and 30-day mortality (14% dead vs 5% dead at 30 days; p = 0.0202) compared with patients with consistently concordant values.aPTT and anti-Xa values are frequently discordant when used to measure UFH in hospitalized patients. A disproportionate prolongation of the aPTT relative to the anti-Xa was the most common discordant pattern in our study. Patients with relatively high aPTT to anti-Xa values appear to be at increased risk of adverse outcomes. Monitoring both aPTT and Xa values may have utility in managing such patients.
View details for DOI 10.1345/aph.1R635
View details for Web of Science ID 000324986200006
View details for PubMedID 23386070
Anemia in older persons: Etiology and evaluation
BLOOD CELLS MOLECULES AND DISEASES
2011; 46 (2): 159-165
In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.
View details for DOI 10.1073/pnas.1116110108
View details for Web of Science ID 000298034800040
View details for PubMedID 22123971
Unexplained aspects of anemia of inflammation.
Advances in hematology
2010; 2010: 508739-?
The aim of this study was to prospectively determine the etiology of anemia in a cohort of community-dwelling older outpatients with a comprehensive hematologic evaluation. Participants were men and women age 65 and older with anemia as defined by World Health Organization criteria recruited from outpatient hematology clinics at Stanford Hospital and Clinics (SHC) and Veterans Affairs Palo Alto Health Care System (VAPAHCS). Each participant underwent a history and physical examination, followed by a comprehensive hematologic evaluation, which in all participants included complete blood count, red cell indices, review of the blood smear, and assessment of vitamin B12, folate, iron status and renal function. Additional evaluation was obtained by clinical providers as per their discretion. 190 participants enrolled and completed the evaluation. Twelve percent of participants had iron deficiency anemia. Of those with iron deficiency in whom there was follow-up information, half normalized their hemoglobin in response to iron repletion, and half did not. Thirty-five percent of participants had unexplained anemia. Those with unexplained anemia had mildly increased inflammatory markers compared to non-anemic controls, and, at the lower hemoglobin ranges had relatively low erythropoietin levels. Sixteen percent of participants were categorized as being "suspicious for myelodysplastic syndrome." Thus, even with comprehensive hematologic evaluation, unexplained anemia is common in older anemic outpatients. Iron deficiency anemia is also common and can be difficult to diagnose, and frequently the anemia is not fully corrected with iron repletion.
View details for DOI 10.1016/j.bcmd.2010.11.004
View details for Web of Science ID 000287267100007
View details for PubMedID 21208814
Anemia in the elderly: Introduction
SEMINARS IN HEMATOLOGY
2008; 45 (4): 207-209
Aging and erythropoiesis: Current state of knowledge
BLOOD CELLS MOLECULES AND DISEASES
2008; 41 (2): 158-165
Anemia of inflammation (AI), also known as anemia of chronic inflammation or anemia of chronic disease was described over 50 years ago as anemia in association with clinically overt inflammatory disease, and the findings of low plasma iron, decreased bone marrow sideroblasts and increased reticuloendothelial iron. Pathogenic features underlying AI include a mild shortening of red cell survival, impaired erythropoietin production, blunted responsiveness of the marrow to erythropoietin, and impaired iron metabolism mediated by inflammatory cytokines and the iron regulatory peptide, hepcidin. Despite marked recent advances in understanding AI, gaps remain, including understanding of the pathogenesis of AI associated with "noninflammatory" or mildly inflammatory diseases, the challenge of excluding iron deficiency anemia in the context of concomitant inflammation, and understanding more precisely the contributory role of hepcidin in the development of AI in human inflammatory diseases.
View details for DOI 10.1155/2010/508739
View details for PubMedID 20368776
Laboratory testing for heparin-induced thrombocytopenia is inconsistent in North America: A survey of North American specialized coagulation laboratories
THROMBOSIS AND HAEMOSTASIS
2007; 98 (6): 1357-1361
Many studies now document the high prevalence of anemia in the elderly and its association with poor outcomes. Study of these anemic patients reveals that in most cases the underlying abnormality is diminished erythropoieis. This analysis outlines some of the salient observations underlying the evolution of current concepts of how aging impacts erythropoiesis, and suggests areas for future exploration and research.
View details for DOI 10.1016/j.bcmd.2008.04.005
View details for Web of Science ID 000258543000004
View details for PubMedID 18514554
Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin therapy. As HIT is considered a clinico-pathologic entity, laboratory practices have an important role in diagnosing or excluding HIT. It was the objective of this study to assess the current status of laboratory testing for HIT in North America. An online survey consisting of 67 questions related to laboratory testing for HIT was developed by the North American Specialized Coagulation Laboratory Association (NASCOLA), and distributed to its 59 members. The survey included queries about HIT test ordering practices, HIT immunoassay and activation assays performed, and reporting practices. Data was collected from the 44 NASCOLA laboratories who responded. Of these sites, 88% performed immunoassays for HIT, commonly using commercial assays. However, sites varied in practices related to use of controls, immunoglobulin class of antibody detected, and in result interpretation and reporting. Platelet activation assays for HIT were performed by 36% of sites, commonly using assays of serotonin release (50%) or heparin-induced platelet aggregation (43%). Sites varied in the use of washed platelets versus platelet-rich plasma, controls, and heparin concentrations. This survey is the first comprehensive assessment of patterns of practice in HIT testing among diagnostic coagulation laboratories in North America. We observed site-specific variability of testing methods encompassing all stages of testing, including pre-analytical handling, testing methodologies, and result interpretation and reporting. The variability in HIT platelet activation assay methods among institutions indicates a need for proficiency testing to assess assay performance, and for consensus guidelines on HIT laboratory testing.
View details for DOI 10.1160/TH07-06-0401
View details for Web of Science ID 000251687400031
View details for PubMedID 18064336