Moving toward disease modification in polycythemia vera.

Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.

The safety and performance of the Spectra Optia apheresis system platelet depletion protocol in patients with elevated platelet counts.

BACKGROUND: Thrombocytosis is a presenting and progressive clinical feature found in multiple disease states. It is characterized by high platelet (PLT) counts (>450 × 109 /L) and can lead to thrombohemorrhagic events. Thrombocytapheresis or platelet depletion (PLTD) can be performed in acutely symptomatic patients suffering from thrombocytosis and may reduce or prevent acute serious complications associated with thrombocythemia thereby enabling patients to receive potentially curative high-dose chemotherapy. METHODS: This report details the results from 2 clinical studies, one conducted in the European Union (EU) and one in the People's Republic of China, assessing the PLTD procedure on the Spectra Optia Apheresis System. The primary objective of both studies was to assess the safety and performance of the PLTD procedure in patients with elevated PLT counts. RESULTS: Data were collected from 56 participants completing 64 PLTD procedures. The mean percent change in PLT count and collection efficiency (CE1) was 55.1% and 68.5%, respectively. In the EU study, 6 participants experienced a total of 9 adverse events (AEs) and in the China study, 44 participants reported a total of 212 AEs. In both studies, the majority of AEs reported were Grade 2 or lower and no serious AEs, unanticipated adverse device effects, or AEs leading to death were reported. CONCLUSIONS: The data collected within these studies indicate that the PLTD procedure is well tolerated and effective at reducing circulating PLTs in patients suffering from thrombocytosis as evaluated by a percent decrease in PLT count, CE1, and AE incidence.

Anagrelide for platelet-directed cytoreduction in polycythemia vera: Insights into utility and safety outcomes from a large multi-center database.

Anagrelide (ANA) is a platelet-specific cytoreductive agent utilized in the guideline-directed management of high-risk essential thrombocythemia. In the context of polycythemia vera (PV), ANA is occasionally employed in clinical practice, although data has not consistently demonstrated a benefit to targeting a platelet goal as a therapeutic endpoint. The aim of the current study was to delineate the patterns of ANA use in PV, and to describe outcomes and toxicities. Within a multi-center cohort of 527 patients with PV, 48 received ANA (9 excluded for absent data). 27 (69.2%) had high-risk PV, 10 (25.6%) had prior thrombosis, and none had extreme thrombocytosis, acquired von Willebrand disease, and/or documented resistance to hydroxyurea. While ANA effectively lowered median platelet count, 43.5% of patients had an unresolved thrombocytosis at time of ANA discontinuation. Treatment-emergent adverse events-including headaches, cardiac palpitations and arrhythmias, nausea, vomiting and/or diarrhea-led to ANA discontinuation in 76.9% of patients. Further, three patients experienced arterial thromboses during a median duration of 27.5 months of ANA therapy. In conclusion, this study highlights ANA's restrictive tolerability profile which, compounded by the absence of clear advantage to strict platelet control in PV, suggests the use of ANA should be limited in this setting.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Ringing in a new future.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematologic malignancy belonging to the category of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes. While certain clinical features, including anemia and thrombocytosis, are common to both the MDS and MPN disease components, the biologic consequences of the spliceosome mutation SF3B1 results in notable clinical exceptions. Importantly, both overall and leukemia free survival are shorter for MDS/MPN-RS-T when compared to essential thrombocythemia (ET). In the case of MDS/MPN-RS-T, thrombotic risk is not associated with the presence of JAK2V617F, nor history of prior thrombosis, but is associated with the presence of the mutated spliceosome gene SF3B1. In this review, we highlight the biology, pathology, risk stratification, and treatment approach to MDS/MPN-RS-T. In particular, we focus on clinical management concepts, which are largely borrowed from MDS and MPN, including the use of cytoreduction, bone marrow stimulating agents, and the role of allogeneic stem cell transplantation. We end by highlighting unmet needs and future research priorities in MDS/MPN-RS-T.

The effects of plasma viscosity in thromboembolic events among patients with essential thrombocytosis: A case-control study.

INTRODUCTION: Essential thrombocythemia (ET) is an entity of classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by thrombocytosis with megakaryocytic hyperplasia where in the thrombocytes are increased with abnormal function.Thrombotic events are seen frequently and represent the main cause of morbidity and mortality in patients with MPNs, mainly polycythemia vera and ET. This study has aimed to research the effects of clonally increased thrombocytes on plasma viscosity (PV) levels among patients with ET and the relationship between PV and thromboembolism history, according to the hypotheses about the effects of PV in thromboembolic events among patients with ET. METHODS: A total of 55 patients were enrolled in the study group, 18 of who had been newly diagnosed with ET according to 2016 World Health Organization criteria and had not previously been treated. 37 of them had already been diagnosed with ET and had been treated. There were 47 healthy volunteers in the control group. 5 cc blood samples were taken from the patients into tubes including an anticoagulant to measure their PV levels. RESULTS: PV of the control group was found to be lower than in the study group and both each patient groups (p < 0.05). No relationship was found between the patient groups in terms of PV (p = 0.404). The mean PV levels of the 16 patients with a history of thromboembolism and the 39 patients with no such history were 2.42±0.17 cP and 2.33±0.20 cP, respectively. The mean PV levels were found to be similar according to their history of thromboembolism in all patient groups and in treated patients (p = 0.572 vs p = 0.991). CONCLUSION: We have found that PV levels were increased in clonally increased thrombocytes in patients with ET when compared with the control group. This is the first study in this field according to our knowledge.

Relevance of early diagnosis in polycythemia vera and essential thrombocythemia: A single center's experience.

OBJECTIVES: This work aims to describe the proportion of patients with polycythemia vera (PV) or essential thrombocythemia (ET) and thrombosis prior to the diagnosis who had erythrocytosis or thrombocytosis prior to the thrombosis. PATIENTS AND METHODS: This is a retrospective review of 63 patients with PV and 130 with ET. RESULTS: In regard to PV, we found prior erythrocytosis in 7 (11.1%) of the 17 cases (27%) with thrombosis prior to diagnosis. In ET, we found prior thrombocytosis in 10 (7.7%) of the 25 cases (19.2%) with thrombosis prior to diagnosis. The median time between the laboratory finding and thrombosis was 8.2 months and 11.8 months for PV and TE, respectively. In both entities, patients with thrombosis prior to diagnosis had significantly lower survival. CONCLUSION: A significant proportion of patients with thrombosis prior to the diagnosis of PV and ET present with erythrocytosis or thrombocytosis prior to the episode of thrombosis. This could allow for anticipating diagnosis and treatment.

Thrombocytosis in children and adolescents-classification, diagnostic approach, and clinical management.

Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor's effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.

Differential diagnostic and treatment difficulties in a patient with acquired von Willebrand syndrome.

BACKGROUND: Acquired von Willebrand syndrome (AVWS) is a rare, frequently underdiagnosed and underestimated bleeding disorder. Careful personal and family history and late-onset mucocutaneous bleeding could help clarify the etiology of bleeding deficiency. CASE PRESENTATION: An 82-year-old male patient was admitted to our clinic with a severe nosebleed on 30.05.2018. Laboratory results revealed thrombocytosis, elevated white blood cell count and high LDH. Basic coagulation parameters were normal. He was referred to our clinic, where a bone marrow biopsy was taken. His personal and family history had no mention of bleeding disorders, nor was he on anticoagulant therapy. We detected elevated VWF antigen and decreased VWF ristocetin cofactor activity. Loss of high molecular weight multimers was detected by using agarose gel electrophoresis. These laboratory results were indicative of AVWS. Hydroxyurea treatment was initiated, leading to a gradual decrease in platelet count. The histological examination revealed essential thrombocytosist while mutation analysis was JAK2/CALR/MPL negative. However, due to severe nosebleeds, the patient was hospitalized and needed blood transfusion. A cardiological check-up revealed the progression of aortic valve stenosis. After, balloon-dilation a transcatheter aortic valve implantation was performed. As a result, VWF activity and activity to antigen ratio returned to normal as did multimeric structure. In July 2019, the follow-up examination showed that the patient was in a satisfactory condition, with normal hematological parameters, and no new nosebleed episode occurred. CONCLUSIONS: The patient complained of recurring nosebleeds, which stopped completely after the resolution of both underlying conditions successful cytoreductive treatment of triple-negative ET and transcatheteric aortic valve replacement.

Quality of Life in Myeloproliferative Neoplasms: Symptoms and Management Implications.

Myeloproliferative neoplasms include essential thrombocythemia, polycythemia vera, and myelofibrosis. They are characterized by abnormal myeloid proliferation. Patients suffer from debilitating constitutional symptoms and splenomegaly. There have been advances in understanding the impact on quality of life in myeloproliferative neoplasms. Owing to the chronicity of these diseases, symptoms are considered in response criteria for clinical trials. This review wills cover how quality of life is measured in patients with myeloproliferative neoplasm. We review the impact of treatment options, including JAK inhibitors, allogeneic stem cell transplantation, and medications in development. We discuss nonpharmacologic methods of improving symptoms and quality of life.

[Pseudohyperkalemia and thrombocytosis]. / Pseudo-hyperkaliémie et thrombocytose.

INTRODUCTION: Hyperkalemia is common in medicine and requires rapid management. Besides the easily evoked causes such as renal failure, adrenal insufficiency, cell lysis or iatrogenic causes, false or pseudo-hyperkalemia should not be forgotten. OBSERVATIONS: Three patients (1 man, 2 women, aged 78, 84, 88) were managed for thrombocytosis (between 1306 and 2404 G/L) and non-symptomatic hyperkalemia (between 6.1 and 7.7mmol/L) are reported. Kalemia on blood collected in heparin tube was normal (4.4-4.6mmol/L). Therefore, no specific treatment for this pseudohyperkalemia was required. CONCLUSION: The combination of thrombocytosis and non-symptomatic hyperkalemia should suggest the diagnosis of pseudohyperkalemia and should prompt for a control of kalemia on blood collected in heparin tube. The recognition of this diagnosis is important in order to avoid unnecessary and potentially deleterious treatment of hyperkalemia.

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T) - "2021 update on diagnosis, risk-stratification, and management".

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (MDS-RS-SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 109 /L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation. TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first-in-class erythroid maturation agent is now approved for the management of anemia in patients with MDS-RS and MDS/MPN-RS-T. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains to be defined.

Molecular genetics of MDS/MPN overlap syndromes.

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a heterogenous group of myeloid malignancies hallmarked by clinicopathologic features that overlap with myelodysplastic syndromes and myeloproliferative neoplasms. Formally recognized by the World Health Organization, this group includes the entities chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN with ring sideroblasts and thrombocytosis and MDS/MPN, unclassifiable. Advancements in next generation sequencing have begun to unravel the molecular underpinnings of these diseases, identifying an array of recurrently mutated genes involved in epigenetic regulation, RNA splicing, transcription, and cell signaling. Despite molecular overlap with other myeloid malignancies, each entity displays a unique spectrum of somatic mutations supporting their unique pathobiology and clinical features. Importantly, molecular profiling is becoming an integral tool utilized in routine clinical practice. This review summarizes our current understanding of the molecular pathogenesis of overlap syndromes and details the impact of somatic mutations in diagnostic, prognostic, and therapeutic decision-making.

MDS/MPN-RS-T justified inclusion as a unique disease entity?

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a disease entity characterized by anemia, bone marrow dysplasia with ring sideroblasts and persistent thrombocytosis ≥450 × 109/L with proliferation of large and morphologically atypical megakaryocytes. Although initially recognized by the World Health Organization only as a provisional entity, next generation sequencing has identified recurrent somatic mutations in SF3B1, JAK2 and other genes providing further evidence of the clonal nature of this disease and the need to recognize it as a separate entity. Despite its overlapping features with MDS with ring sideroblasts and essential thrombocythemia, MDS/MPN-RS-T is characterized by specific clinical features and distinct survival outcomes. In the current review we will describe the morphological and genomic features of MDS-RS-T and the potential diagnostic challenges and distinction from other possible conditions. We will also review how the current evidence supports its recognition as an independent disorder.

Hematologic Conditions: Platelet Disorders.

Platelets have an important role in hemostasis. Platelet disorders occur when too few or too many platelets are present, or when platelet functions are abnormal. Thrombocytopenia, defined as a platelet count less than 150,000/mcL, can be acute or chronic and congenital or acquired. Severe thrombocytopenia is associated with life-threatening bleeding and thrombotic complications. A comprehensive history and physical examination are central to the diagnostic approach. These elements should focus on identification of concurrent conditions associated with thrombocytopenia and differentiation among three mechanisms: decreased platelet production, increased platelet consumption, and platelet sequestration. Although previously thought to be the result of a single process, thrombocytopenia often is due to a combination of factors. Thrombocytosis is present when the platelet count is elevated. The principal types are essential (primary) thrombocythemia and reactive (secondary) thrombocytosis. Essential thrombocythemia is a myeloproliferative neoplasm associated with mutations of genes that regulate thrombopoiesis (eg, JAK2). It can lead to thrombotic and hemorrhagic complications. Reactive thrombocytosis frequently is encountered in the family medicine setting. It rarely causes vascular complications or requires management beyond that required for the underlying condition. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Etiologies of Extreme Thrombocytosis: A Contemporary Series.

OBJECTIVE: To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy. PATIENTS AND METHODS: We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×109/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts. RESULTS: A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT. CONCLUSION: Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.

Platelet count abnormalities and peri-operative outcomes in adults undergoing elective, non-cardiac surgery.

BACKGROUND: Anemia and transfusion of blood in the peri-operative period have been shown to be associated with increased morbidity and mortality across a wide variety of non-cardiac surgeries. While tests of coagulation, including the platelet count, have frequently been used to identify patients with an increased risk of peri-operative bleeding, results have been equivocal. The aim of this study was to assess the effect of platelet level on outcomes in patients undergoing elective surgery. MATERIALS AND METHODS: Retrospective cohort analysis of prospectively-collected clinical data from American College of Surgeons National Surgical Quality Improvement Program (NSQIP) between 2006-2016. RESULTS: We identified 3,884,400 adult patients who underwent elective, non-cardiac surgery from 2006-2016 at hospitals participating in NSQIP, a prospectively-collected, national clinical database with established reproducibility and validity. After controlling for all peri- and intraoperative factors by matching on propensity scores, patients with all levels of thrombocytopenia or thrombocytosis had higher odds for perioperative transfusion. All levels of thrombocytopenia were associated with higher mortality, but there was no association with complications or other morbidity after matching. On the other hand, thrombocytosis was not associated with mortality; but odds for postoperative complications and 30-day return to the operating room remained slightly increased after matching. CONCLUSIONS: These findings may guide surgeons in the appropriate use and appreciation of the utility of pre-operative screening of the platelet count prior to an elective, non-cardiac surgery.

Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management".

DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes. MUTATIONS AND KARYOTYPE: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both. RISK STRATIFICATION: Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation. TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.