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Expert Review of Hematology Apr 2023Erythrocytosis is associated with an elevation of the hemoglobin level above 16.5 g/dL in men and above 16 g/dL in women and an elevation of the hematocrit level above... (Review)
Review
INTRODUCTION
Erythrocytosis is associated with an elevation of the hemoglobin level above 16.5 g/dL in men and above 16 g/dL in women and an elevation of the hematocrit level above 49% in men and > 48% in women. In primary erythrocytosis, the defect is a clonal disorder in the myeloid compartment of the bone marrow, leading to an increased red cell production. Secondary erythrocytosis is the result of external stimuli to the bone marrow, leading to the production of red cells in excess. Secondary erythrocytosis is more common than primary erythrocytosis and has a broad differential diagnosis.
AREAS COVERED
This review will discuss secondary erythrocytosis, its causes, clinical presentation, and both diagnostic and therapeutic approaches.
EXPERT OPINION
Although secondary erythrocytosis is more common than PV, there are still challenges and difficulties associated with the distinction between these two conditions. Moreover, there is a paucity of data and guidance when it comes to the management of certain congenital and acquired conditions. A pragmatic approach is recommended in order to identify the cause for this condition. Treatment should be directed at the management of the underlying cause.
Topics: Male; Humans; Female; Polycythemia; Bone Marrow; Erythrocytes; Diagnosis, Differential; Erythropoietin
PubMed: 36927204
DOI: 10.1080/17474086.2023.2192475 -
Best Practice & Research. Clinical... Nov 2022Twin anemia polycythemia sequence (TAPS) is a consequence of unequal sharing of red blood cells between monochorionic twins resulting in anemia in the donor and... (Review)
Review
Twin anemia polycythemia sequence (TAPS) is a consequence of unequal sharing of red blood cells between monochorionic twins resulting in anemia in the donor and polycythemia in the recipient twin. Prenatally TAPS can occur spontaneously or complicate incomplete laser surgery for twin transfusion syndrome. While there may be clinical overlap with twin transfusion syndrome or selective fetal growth restriction, diagnosis relies on Doppler measurement of middle cerebral artery peak systolic velocities. Significantly discordant velocities are diagnostic, while severity staging is based on signs of cardiovascular compromise. Conservative management, fetoscopic laser coagulation, selective twin reduction, fetal blood and exchange transfusion, and delivery may be selected guided by the gestational age of diagnosis, the severity of the condition, the likelihood of success, and the patients' priorities. Prenatal curative treatment that minimizes the risk for prematurity and residual morbidity at birth is most likely to offer the greatest short-term and long-term benefits.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Polycythemia; Fetofetal Transfusion; Pregnancy, Multiple; Anemia; Fetoscopy; Pregnancy, Twin; Twins, Monozygotic
PubMed: 35450772
DOI: 10.1016/j.bpobgyn.2022.03.012 -
Current Opinion in Hematology Mar 2023Development of hepcidin therapeutics has been a ground-breaking discovery in restoring iron homeostasis in several haematological disorders. The hepcidin mimetic,... (Review)
Review
PURPOSE OF REVIEW
Development of hepcidin therapeutics has been a ground-breaking discovery in restoring iron homeostasis in several haematological disorders. The hepcidin mimetic, rusfertide, is in late-stage clinical development for treating polycythemia vera patients with a global phase 3 trial [NCT05210790] currently underway. Rusfertide serves as the first possible noncytoreductive therapeutic option to maintain haematocrit control and avoid phlebotomy in polycythemia vera patients. In this comprehensive review, we discuss the pathobiology of dysregulated iron metabolism in polycythemia vera, provide the rationale for targeting the hepcidin-ferroportin axis and elaborate on the preclinical and clinical trial evidence supporting the role of hepcidin mimetics in polycythemia vera.
RECENT FINDINGS
Recently, updated results from two phase 2 clinical trials [NCT04057040 & NCT04767802] of rusfertide (PTG300) demonstrate that the drug is highly effective in eliminating the need for therapeutic phlebotomies, normalizing haematological parameters, repleting iron stores and relieving constitutional symptoms in patients with polycythemia vera. In light of these findings, additional hepcidin mimetic agents are also being evaluated in polycythemia vera patients.
SUMMARY
Hepcidin agonists essentially serve as a 'chemical phlebotomy' and are poised to vastly improve the quality of life for phlebotomy requiring polycythemia vera patients.
Topics: Humans; Polycythemia Vera; Polycythemia; Hepcidins; Quality of Life; Iron Deficiencies; Phlebotomy; Iron
PubMed: 36728649
DOI: 10.1097/MOH.0000000000000747 -
Physiology (Bethesda, Md.) Jul 2022Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude... (Review)
Review
Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude populations. Although a modest increase in blood O-carrying capacity may be beneficial for life in highland environments, erythrocytosis can also become excessive and lead to maladaptive syndromes such as chronic mountain sickness (CMS).
Topics: Altitude; Altitude Sickness; Chronic Disease; Humans; Phenotype; Polycythemia
PubMed: 35001654
DOI: 10.1152/physiol.00029.2021 -
Leukemia Aug 2021JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with... (Review)
Review
JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses both hereditary and acquired conditions. A systematic diagnostic approach begins with documentation of historical hematocrit (Hct)/hemoglobin (Hgb) measurements and classification of the process as life-long/unknown duration or acquired. Further investigation in both categories is facilitated by determination of serum erythropoietin level (EPO). Workup for hereditary/congenital erythrocytosis requires documentation of family history and laboratory screening for high-oxygen affinity hemoglobin variants, 2, 3 biphosphoglycerate deficiency, and germline mutations that are known to alter cellular oxygen sensing (e.g., PHD2, HIF2A, VHL) or EPO signaling (e.g., EPOR mutations); the latter is uniquely associated with subnormal EPO. Acquired erythrocytosis is often elicited by central or peripheral hypoxia resulting from cardiopulmonary disease/high-altitude dwelling or renal artery stenosis, respectively; EPO in the former instance is often normal (compensated by negative feed-back). Other conditions associated with acquired erythrocytosis include EPO-producing tumors and the use of drugs that promote erythropoiesis (e.g., testosterone, erythropoiesis stimulating agents). "Idiopathic erythrocytosis" loosely refers to an otherwise not explained situation. Historically, management of non-PV erythrocytosis has been conflicted by unfounded concerns regarding thrombosis risk, stemming from limited phenotypic characterization, save for Chuvash polycythemia, well-known for its thrombotic tendency. In general, cytoreductive therapy should be avoided and phlebotomy is seldom warranted where frequency is determined by symptom control rather than Hct threshold. Although not supported by hard evidence, cardiovascular risk optimization and low-dose aspirin use are often advised. Application of modern genetic tests and development of controlled therapeutic intervention trials are needed to advance current clinical practice.
Topics: Humans; Janus Kinase 2; Mutation; Polycythemia; Prognosis
PubMed: 34021251
DOI: 10.1038/s41375-021-01290-6 -
American Journal of Hematology Jun 2023JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities.
DISEASE OVERVIEW
JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities.
DIAGNOSIS
Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening. Initial assessment should also include gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list. Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity Hgb variants, 2,3-bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% Hgb saturation (P50). The latter include germline oxygen sensing pathway (HIF2A-PHD2-VHL) and other rare mutations. Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high-altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo-producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis stimulating agents, sodium-glucose cotransporter-2 inhibitors). Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation.
MANAGEMENT
Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non-clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low dose aspirin is often advised.
FUTURE DIRECTIONS
Advances in molecular hematology might result in better characterization of "idiopathic erythrocytosis" and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy.
Topics: Humans; Ion Channels; Janus Kinase 2; Oxygen; Polycythemia; Polycythemia Vera; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36966432
DOI: 10.1002/ajh.26920 -
Best Practice & Research. Clinical... Nov 2022In twin-to-twin transfusion syndrome (TTTS) communicating placental vessels on the chorionic plate between the donor and recipient twins are responsible for the chronic... (Review)
Review
In twin-to-twin transfusion syndrome (TTTS) communicating placental vessels on the chorionic plate between the donor and recipient twins are responsible for the chronic imbalance of blood flow. Evidence demonstrates that fetoscopic laser ablation is superior to serial amnioreductions in terms of survival and neurological outcome for stages II-IV TTTS. However, the optimal management of stage I TTTS remains poorly understood. It is well established that all chorionic plate anastomoses should be closed by laser ablation. Compared to the selective laser method, the Solomon technique yields a significant reduction of recurrent TTTS and post-laser twin anemia polycythemia sequence (TAPS). Over the past 25 years, survival rates after fetoscopic laser surgery have significantly increased. High volume centers report up to 70% double survival and at least one survivor in >90% cases. In this review, we discuss the controversies in the diagnosis and management of TTTS, especially, the optimal management in stage I cases, very early or late diagnosis, and the optimal laser technique. Furthermore, we will discuss a stage-related outcome after laser surgery and examine whether it is necessary at all to distinguish between stages I and II. Finally, the optimal timing as well as mode of delivery after TTTS laser treatment will be discussed.
Topics: Female; Pregnancy; Humans; Fetofetal Transfusion; Placenta; Pregnancy, Twin; Fetoscopy; Polycythemia
PubMed: 35589537
DOI: 10.1016/j.bpobgyn.2022.03.013 -
European Journal of Haematology Jul 2021Erythrocytosis, or increased red cell mass, may be labeled as primary or secondary, depending on whether the molecular defect is intrinsic to the red blood cells/their... (Review)
Review
Erythrocytosis, or increased red cell mass, may be labeled as primary or secondary, depending on whether the molecular defect is intrinsic to the red blood cells/their precursors or extrinsic to them, the latter being typically associated with elevated erythropoietin (EPO) levels. Inherited/congenital erythrocytosis (CE) of both primary and secondary types is increasingly recognized as the cause in many patients in whom acquired, especially neoplastic causes have been excluded. During the past two decades, the underlying molecular mechanisms of CE are increasingly getting unraveled. Gain-in-function mutations in the erythropoietin receptor gene were among the first to be characterized in a disorder termed primary familial and congenital polycythemia. Another set of mutations affect the components of the oxygen-sensing pathway. Under normoxic conditions, the hypoxia-inducible factor (HIF), upon hydroxylation by the prolyl-4-hydroxylase domain protein 2 (PHD2) enzyme, is degraded by the von Hippel-Lindau protein. In hypoxic conditions, failure of prolyl hydroxylation leads to stabilization of HIF and activation of the EPO gene. CE has been found to be caused by loss-of-function mutations in VHL and PHD2/EGLN1 as well as gain-of-function mutations in HIF-2α (EPAS1), all resulting in constitutive activation of EPO signaling. Apart from these, globin gene mutations leading to formation of high oxygen affinity hemoglobins also cause CE. Rarely, bisphosphoglycerate mutate mutations, affecting the 2,3-bisphosphoglycerate levels, can increase the oxygen affinity of hemoglobin and cause CE. This narrative review examines the current mutational spectrum of CE and the distinctive pathogenetic mechanisms that give rise to this increasingly recognized condition in various parts of the world.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Bisphosphoglycerate Mutase; Erythrocytes; Erythropoietin; Hemoglobins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Mice; Mutation; Oxygen; Polycythemia; Signal Transduction
PubMed: 33840141
DOI: 10.1111/ejh.13632 -
European Journal of Pediatrics Aug 2023Delayed cord clamping (DCC) at delivery has well-recognized benefits; however, current scientific guidelines lack uniformity in its definition. This parallel-group,... (Randomized Controlled Trial)
Randomized Controlled Trial
Delayed cord clamping (DCC) at delivery has well-recognized benefits; however, current scientific guidelines lack uniformity in its definition. This parallel-group, three-arm assessor-blinded randomized controlled trial compared the effects of three different timings of DCC at 30, 60, and 120 s on venous hematocrit and serum ferritin levels in late preterm and term neonates not requiring resuscitation. Eligible newborns (n = 204) were randomized to DCC 30 (n = 65), DCC 60 (n = 70), and DCC 120 (n = 69) groups immediately after delivery. The primary outcome variable was venous hematocrit at 24 ± 2 h. Secondary outcome variables were respiratory support, axillary temperature, vital parameters, incidences of polycythemia, neonatal hyperbilirubinemia (NNH), need and duration of phototherapy, and postpartum hemorrhage (PPH). Additionally, serum ferritin levels, the incidence of iron deficiency, exclusive breastfeeding (EBF) rate, and anthropometric parameters were assessed during post-discharge follow-up at 12 ± 2 weeks. Over one-third of the included mothers were anemic. DCC 120 was associated with a significant increase in the mean hematocrit by 2%, incidence of polycythemia, and duration of phototherapy, compared to DCC30 and DCC60; though the incidence of NNH and need for phototherapy was similar. No other serious neonatal or maternal adverse events including PPH were observed. No significant difference was documented in serum ferritin, incidences of iron deficiency, and growth parameters at 3 months even in the presence of a high EBF rate. Conclusion: The standard recommendation of DCC at 30-60 s may be considered a safe and effective intervention in the busy settings of low-middle-income countries with a high prevalence of maternal anemia. Trial registration: Clinical trial registry of India (CTRI/2021/10/037070). What is Known: • The benefits of delayed cord clamping (DCC) makes it an increasingly well-accepted practice in the delivery room. • However, uncertainty continues regarding the optimal timing of clamping; this may be of concern both in the neonate and the mother. What is New: • DCC at 120 s led to higher hematocrit, polycythemia and longer duration of phototherapy, without any difference in serum ferritin, and incidence of iron deficiency. • DCC at 30-60 s may be considered a safe and effective intervention in LMICs.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Infant, Premature; Polycythemia; Aftercare; Umbilical Cord Clamping; Patient Discharge; Anemia; Iron Deficiencies; Hyperbilirubinemia, Neonatal; Constriction; Ferritins; Umbilical Cord; Delivery, Obstetric
PubMed: 37278737
DOI: 10.1007/s00431-023-05053-6 -
Seminars in Pediatric Surgery Aug 2019The increase in multiple gestation pregnancies has resulted in significant health care implications for both mother and child. Our ability to diagnose and intervene on... (Review)
Review
The increase in multiple gestation pregnancies has resulted in significant health care implications for both mother and child. Our ability to diagnose and intervene on an at-risk multi-gestation pregnancy has dramatically improved. It is important for the pediatric surgeon to be equipped with a basic fund of knowledge concerning these pregnancies. An understanding of amnionicity and chorionicity will equip the practitioner with the ability to identify which pregnancies are at risk for specific complications. This article highlights multi-gestation pregnancies that are monochorionic (single shared placenta) and can be complicated by twin-twin transfusion syndrome (TTTS), twin reversed arterial perfusion (TRAP) sequence, twin anemia polycythemia sequence (TAPS), or selective fetal intrauterine growth restriction (sIUGR). The risk of fetal demise is significant in these pregnancies. Understanding recommended surveillance and warning signs can alert surgeons to developing complications. Specialized fetal care centers possess the ability to intervene on these pregnancies in utero.
Topics: Anemia; Female; Fetal Growth Retardation; Fetofetal Transfusion; Fetoscopy; Humans; Light Coagulation; Polycythemia; Pregnancy; Twins, Dizygotic; Twins, Monozygotic; Ultrasonography, Prenatal
PubMed: 31451170
DOI: 10.1053/j.sempedsurg.2019.07.008