Journal: Expert review of hematology
Recombinant IFN-α (rIFN-α) induces complete hematologic remissions in patients with myeloproliferative neoplasms (MPNs), but its use has been limited by side effects owing to the relatively high doses used. Now, low-dose rIFN-α is stressed, starting relatively early in the course of the MPNs. In polycythemia vera, this has resulted in a significant clinical, hematologic, morphologic and molecular response manifested by reduction in the JAK2(V617F) allele burden, sustained even after discontinuation of recombinant IFN. In essential thrombocythemia, platelet count reduction is prompt and durable without treatment for varying periods. In hypercellular primary myelofibrosis, rIFN-α has restored normal blood counts, reduced splenomegaly and induced morphologic marrow remissions. This article highlights our current use of rIFN-α in MPNs.
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin’s lymphoma. It can follow a heterogeneous clinical course but generally patients relapse early after standard immunochemotherapy regimens and develop resistance to subsequent therapies. For younger patients, intensive approaches followed by autologous stem cell transplantation offer excellent long-term disease control but with the possible exception of an allogenic stem cell transplant, MCL is an incurable condition. As MCL principally affects older individuals, the majority of patients are not candidates for such intensive approaches. Ibrutinib is an orally active, Bruton’s tyrosine kinase inhibitor. It inhibits signaling pathways downstream of Bruton’s tyrosine kinase that appear critical for the proliferation and survival of MCL. As a single agent it has shown extremely promising activity in relapsed and refractory MCL patients with an excellent side-effect profile. The exact role for ibrutinib in the treatment of MCL is yet to be established; however, it is likely to fundamentally change the way we treat this disease.
The recent discovery of mutations of the gene calreticulin has allowed raising the proportion of patients with essential thrombocythemia and primary myelofibrosis with known mutational abnormality up to 85-90%. Knowledge of the mechanisms by which mutated calreticulin underlie a myeloproliferative neoplasm as well as the clinical and therapeutic implications is just at the very beginning, and exciting times await research in this field.
A major advance in the management of febrile neutropenia (FN) has been the stratification of the population of adult patients with FN for the risk of complications and death. Using validated reliable predictive instruments, such as the Multinational Association for Supportive Care in Cancer score, it is possible to identify a population of ‘low-risk’ patients, who can benefit from simplified and less expensive therapeutic approaches (e.g., orally administered antimicrobial therapy and early home return). Prevention of FN by the use of granulopoietic colony-stimulating factor (G-CSF) has been successfully applied to patients at ‘high risk’ of developing FN. In addition to the aggressiveness of chemotherapy, which usually defines the ‘high-risk’ status, the role of a series of factors that increase both the risk of FN and the complications rate has been recognized and should probably be taken into consideration when selecting patients for G-CSF prophylaxis. The cost of the G-CSF is the major limiting factor for their broad use; further efforts should be made to match the cost issue with the need of protecting from the development of FN most patients treated with chemotherapy for cancer.
Incompatibility of red cell and platelet antigens can lead to maternal alloimmunization causing hemolytic disease of the fetus & newborn and fetal neonatal alloimmune thrombocytopenia respectively. As the molecular background of these polymorphisms emerged, prenatal testing using initially fetal DNA obtained from invasively obtained amniotic fluid or chorionic villus was implemented. This evolved into testing using maternal plasma as source of fetal DNA, and this is in routine use as a safe non-invasive diagnostic that has no risk to the fetus of alloimmunization or spontaneous miscarriage. These tests were initially applied to high risk pregnancies, but has been applied on a mass scale, to screen fetuses in D-negative pregnant populations as national screening programs. Fetal neonatal alloimmune thrombocytopenia management has had comparatively small take up in non-invasive testing for causative fetal platelet alleles (e.g., HPA-1A), but mass scale genotyping of mothers to identify at risk HPA-1b1b pregnancies and their treatment with prophylactic anti-HPA-1A is being considered in at least one country (Norway).
A deficiency in ADAMTS13 (A Disintegrin And Metalloprotease with ThromboSpondin type-1 repeats, member 13) is associated with thrombotic thrombocytopenic purpura (TTP). Congenital TTP is caused by a defect in the ADAMTS13 gene resulting in decreased or absent enzyme activity; acquired TTP results from autoantibodies that either inhibit the activity or increase the clearance of ADAMTS13. Despite major progress in recent years in our understanding of the disease, many aspects around the pathophysiology of TTP are still unclear. Newer studies expanded the TTP field from ADAMTS13 and inhibitory antibodies to immune complexes, cloned autoantibodies and a possible involvement of other proteases. Additionally, several new treatment strategies supplementing plasma- exchange and infusion are under investigation for a better and more specific treatment of TTP patients. In this review, we discuss the recent insights in TTP pathophysiology and describe upcoming therapeutic opportunities.
Despite lack of knowledge in the field, several studies have underlined the role of endothelium dysfunction and platelet activation as significant players in the development and progression of chronic obstructive pulmonary disease (COPD). Indeed, endothelium plays a crucial role in vascular homeostasis and impairment, due to the inflammation process enhanced by smoking. Chronic inflammation and endothelial dysfunction have been proved to drive platelet activity. Consequently, thrombotic risk is enhanced in COPD, and might explain the higher percentage of cardiovascular death in such patients. Areas covered: This review aims to clarify the role of endothelium function and platelet hyper-activity as the pathophysiological mechanisms of the increased thrombotic risk in COPD. Expert commentary: In COPD patients, chronic inflammation does not impact only on lung parenchyma, but potentially involves all systems, including the endothelium of blood vessels. Impaired endothelium has several consequences, such as reduced vasodilatation capacity, enhanced blood coagulation, and increased platelet activation resulting in higher risk of thrombosis in COPD patients. Endothelium dysfunction and platelet activation are potential targets of therapy in patients with COPD aiming to reduce their risk of cardiovascular events.
Objective: Retroperitoneal Hematoma (RPH) is an underdiagnosed and overlooked disease entity and has a high mortality rate if not diagnosed in a timely manner. This study aims to analyze the clinical characteristics, risk factors, treatment and the outcome of RPH cases at our medical centre.Methods: In this retrospective study, all cases who presented to the emergency room (ER) and/or admitted to our centre with the diagnosis of RPH from Jan 2016 to Dec 2018 were included (3-year data).Results: A total number of 78 RPH cases were included including both the traumatic and spontaneous bleed. The most common setting was spontaneous bleeding with no concurrent use of anti-thrombotic agents. Zone 3 (pelvic hematoma) bleed was the most common type of RPH. Most patients were successfully managed medically alone (59%). Others required surgical intervention, either laparoscopy, laparotomy or through the interventional radiological approach. There was a significant association between the need for vasopressors (OR-5.65, P-value of 0.039), spontaneous bleed (P-value of 0.001), bleed without antithrombotic agents (P-value of 0.002) with prolonged hospital stay (> 5 days). On follow-up, 83% of cases were reported to be alive. Only 2 patients died secondary to hemorrhagic shock.Conclusion: Most cases of RPH had an excellent outcome with conservative management alone.
Introduction: Uncontrolled haemorrhage with trauma-induced coagulopathy (TIC) still represents the most common cause of preventable death after trauma. Timely diagnosis and treatment including bleeding control and haemostatic resuscitation to correct TIC are important, as death from exsanguination occurs rapidly. Recognizing who requires an early massive transfusion together with the initiation of corresponding massive transfusion protocols (MTPs) is key to outcome.Areas covered: This expert review summarizes the current state of MT including the activation and termination of MTPs, complications of MT, and strategies for refinement in the administration of blood products in order to avoid harmful over-transfusion.Expert opinion: MTPs should be initiated and continued until normal physiologic parameters are reached and definitive control of bleeding is achieved. Hospitals should develop their own MTPs, guided by evidence, and according to local infrastructure, logistics, needs and patient populations. Massive transfusion, defined as > 10 units of packed red blood cell concentrates (pRBCs) within the first 24 hours of hospital admission, can be life-saving, but is not without complications. MTPs are currently being refined through targeted and early goal-directed approaches which include functional coagulation testing assays to better guide the administration of blood products and haemostatic agents once the patient is stabilized.
Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the cornerstone of curative approach to myelofibrosis (MF), although it is burdened by not negligible toxicity andac mortality.Areas covered: In this review, authors discuss the status-of-the art of HSCT in MF, emphasizing the current limits and the areas for improvement. We interrogated public databases for papers published in the last 30 years.Expert opinion: The therapeutic landscape of myelofibrosis has been revolutionized after the approval of JAK inhibitor ruxolitinib, that showed impressive efficacy in reducing splenomegaly and ameliorating symptoms and quality of life. Unfortunately, the disease-modifying activity of ruxolitinib is modest, with most patients ultimately dying due to disease progression. Identification of potential candidates to HSCT is critical in order to balance risks and expected benefits, and should rely on risk scores specifically developed to such purpose. The use of ruxolitinib as bridge to HSCT might increase the proportion of patients ultimately able to undergo the procedure and possibly improve their outcome, and represents an important area of research. Since MF is a disease of middle age, further improvements should aim to reduce toxicity of the HSCT procedure and expand the use of alternative, particularly haploidentical, donors.