bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombocytopenia and bleeding in pediatric oncology patients
Authors: Bercovitz Rachel S. , Josephson Cassandra D. 
Published: October 2019

Abstract
Prophylactic platelet transfusions are the standard of care for patients with hypoproliferative thrombocytopenia after receiving chemotherapy or radiation for the treatment of malignancy, for BM replacement by leukemia or solid tumor, or in preparation for a hematopoietic stem cell transplantation.1 During this time of thrombocytopenia, these patients may receive both prophylactic platelet transfusions, which are given to prevent potentially life-threatening bleeding when a patient's platelet count drops below a predetermined threshold, and therapeutic platelet transfusions, which are given to treat active or recurrent bleeding. In the 1950s, the invention of the plastic blood bag allowed for the production and storage of platelet concentrates,2 and in the 1960s, it was recognized that prophylactic platelet transfusions effectively reduced hemorrhagic death in patients with newly diagnosed leukemia.3,4 In 1962, Gaydos published the paper that is frequently credited with the inception of the 20 000/μL platelet transfusion threshold.5 Despite a half-century of experience with prophylactic platelet transfusions, there are still insufficient data to provide clinicians with evidence-based guidelines specific to pediatric oncology and hematopoietic stem cell transplantation (HSCT) patients.
Pharmacologic tools to reduce bleeding in surgery
Authors: Schulman Sam 
Published: October 2019

AbstractStrategies to reduce blood loss and the need for transfusions in surgery include enhancement of coagulation, inhibition of fibrinolysis, and an improved decision algorithm for transfusion based on bedside monitoring of global hemostasis. The synthetic antifibrinolytic drug tranexamic acid has emerged as an effective alternative in this respect for orthopedic and cardiac surgery. Although it seems less effective than aprotinin, it has not been associated with the increased risk of mortality of the latter. Thromboelastography to monitor the global hemostatic capacity and to guide the appropriate use of blood components in cardiac surgery is also effective in reducing the need for transfusion. Patients on antithrombotic drug therapy may need reversal before surgery to avoid excessive blood loss, or intraoperatively in cases of unexpected bleeding. Available options are protamine for unfractionated or low-molecular-weight heparin, recombinant activated factor VII for fondaparinux, prothrombin complex concentrate for vitamin K antagonists and possibly for oral factor Xa inhibitors, dialysis and possibly activated prothrombin complex concentrate for oral thrombin inhibitors, desmopressin for aspirin and possibly for thienopyridines, and platelet transfusions for the latter.
Antithrombotic therapy: triple therapy or triple threat?
Authors: Mega Jessica , Carreras Edward T. 
Published: October 2019

Abstract
Antithrombotic therapy plays an essential role in the management of some of the most common and morbid medical conditions. Triple oral antithrombotic therapy (TOAT) is defined as the administration of both therapeutic oral anticoagulation (OAC) and dual antiplatelet therapy (DAPT) to patients with indications for both treatments. The current societal guidelines regarding TOAT are derived from observational studies and some trials of the use of warfarin in addition to antiplatelet therapy in patients with atrial fibrillation and a recent acute coronary syndrome or percutaneous coronary intervention. The general apprehension to administer TOAT is due to the heightened concern for bleeding, rendering warfarin's pharmacokinetic properties concerning. Newer anticoagulant agents may serve as appealing alternatives, and further investigations are warranted. The results of the recent trials that have studied the use of these agents in atrial fibrillation and acute coronary syndrome offer some useful applications to TOAT. Ultimately, selecting the most favorable antithrombotic strategy is going to involve weighing the risks and benefits for each patient.
Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura
Authors: Hovinga Johanna A. Kremer , Lämmle Bernhard 
Published: October 2019

Abstract
The regulation of VWF multimer size is essential in preventing spontaneous microvascular platelet clumping, a central pathophysiologic finding in thrombotic thrombocytopenic purpura (TTP). In the majority of TTP patients, ADAMTS13, the principal regulator of VWF size, is severely deficient. Today, 2 forms of severe ADAMTS13 deficiency are recognized. The acquired form is caused by circulating autoantibodies inhibiting ADAMTS13 activity or increasing ADAMTS13 clearance. Pathogenic anti-ADAMTS13 Abs are mainly of the IgG class, predominantly of subclass IgG4, and inhibitory Abs recognize a defined epitope in the ADAMTS13 spacer domain. The reasons underlying the failure to maintain immunologic tolerance to ADAMTS13, however, are still poorly understood. Constitutional ADAMTS13 deficiency leading to hereditary TTP, also known as Upshaw-Schulman syndrome, is the result of homozygous or compound heterozygous ADAMTS13 gene mutations.
Cancer-associated thrombosis: updates and controversies
Authors: Khorana Alok A. 
Published: October 2019

Abstract
Emerging data have enhanced our understanding of cancer-associated thrombosis, a major cause of morbidity and mortality in patients with cancer. This update will focus on recent findings, including the phenomenon of incidental venous thromboembolism (VTE), novel approaches to risk assessment, and the results of randomized clinical trials focusing on prophylaxis of cancer outpatients. Incidental VTE is an important contributor to rates of cancer-associated VTE and, in terms of outcomes, appears to be as consequential for patients as symptomatic VTE. Multiple biomarkers have been studied, with the highest level of evidence for prechemotherapy elevated platelet counts, elevated leukocyte counts, and low hemoglobin. Other candidate biomarkers, including D-dimer and tissue factor, are currently being evaluated. A recently validated risk score for chemotherapy-associated VTE has now been evaluated in more than 10 000 cancer patients in a variety of clinical settings and trials and is ready for clinical use (Level 1 clinical decision rule). Several randomized clinical trials in solid-tumor patients with low-molecular-weight heparins and semuloparin, an ultra-low-molecular-weight heparin, demonstrate clearly that outpatient thromboprophylaxis is feasible, safe, and effective. Selecting the appropriate patients for prophylaxis, however, continues to be a matter of controversy.
Novel therapeutic strategies: hypomethylating agents and beyond
Authors: Santini Valeria 
Published: October 2019

Abstract
The treatment of symptomatic and high-risk myelodysplastic syndrome (MDS) spans several therapeutic goals and options. Key to the successful therapy of these heterogeneous diseases is careful characterization and diagnosis, including clinical, cytogenetic, biological, and molecular evaluation of individual patients. Any novel management strategy in MDS must be based on accepted and validated prognostic scoring systems, such as the International Prognostic Scoring System (IPSS), and should take into account predictive parameters of response to the available therapeutic agents and individual comorbidities. For IPSS lower-risk MDS patients, several first-line options are available, including erythropoietic stimulating agents, lenalidomide, and immunosuppressive drugs. Sequential therapy is advisable whenever response is lost, and the activity of azacitidine and decitabine in first- or second-line therapy is relevant, especially in patients with symptomatic cytopenias and anemia. Hypomethylating agents have a central role in therapy of IPSS higher-risk MDS patients. These agents include azacitidine and decitabine, which allow treatment of very elderly and frail patients, resulting in hematological improvement and transfusion independency in roughly half, and for azacitidine a demonstrated significant prolongation of survival. Because hypomethylating agents are not curative, they are not satisfactory for younger MDS patients, for whom a transplantation strategy should be planned. Although hypomethylating agent therapy is used extensively, a growing number of MDS patients fail to respond or progress. The future challenge is not only to find treatment regimens that target the dysplastic clone(s) so that durable remissions are achieved (particularly in high-risk patients with short survival and/or increased leukemic transformation rates), but also to also identify active salvage regimens.
Intermediate-risk acute myeloid leukemia therapy: current and future
Authors: Döhner Konstanze , Paschka Peter 
Published: October 2019

AbstractIn recent years, research in molecular genetics has been instrumental in deciphering the molecular heterogeneity of acute myeloid leukemia (AML), in particular the subset of patients with “intermediate-risk” cytogenetics. However, at present, only the markers NPM1, CEBPA, and FLT3 have entered clinical practice. Treatment of intermediate-risk AML patients eligible for intensive therapy has not changed substantially. The “3 + 7” induction therapy still represents the standard of care. The addition of the immunoconjugate gemtuzumab ozogamicin to therapy has been shown to improve outcome; however, the drug is not approved for this use. A common standard for postremission therapy is the administration of repeated cycles of intermediate- to high-dose cytarabine. Allogeneic stem cell transplantation may offer a survival benefit for many patients with intermediate-risk AML. Patients are best selected based on the genetic profile of the leukemia cells and the risk associated with the transplantation itself. A myriad of novel agents targeting mutant leukemia drivers or deregulated pathways are in clinical development. In the past, many novel compounds have not met expectations; nonetheless, with the rapid developments in comprehensive molecular profiling and new drug design, there is the prospect of personalizing therapy and improving patient outcome.
Risky business of inhibitors: HLA haplotypes, gene polymorphisms, and immune responses
Authors: Reipert Birgit M. 
Published: October 2019

Abstract
The development of neutralizing antibodies against factor VIII (FVIII inhibitors) and factor IX (FIX inhibitors) is the major complication in hemophilia care today. The antibodies neutralize the biological activity of FVIII and FIX and render replacement therapies ineffective. Antibodies are generated as a result of a cascade of tightly regulated interactions between different cells of the innate and the adaptive immune system located in distinct compartments. Any event that modulates the repertoire of specific B or T cells, the activation state of the innate and adaptive immune system, or the migration pattern of immune cells will therefore potentially influence the risk for patients to develop inhibitors. This chapter reviews our current understanding of different pathways of antibody development that result in different qualities of antibodies. Potential differences in differentiation pathways leading to high-affinity neutralizing or low-affinity non-neutralizing antibodies and the potential influence of gene polymorphisms such as HLA haplotype, FVIII haplotype, and polymorphisms of immunoregulatory genes are discussed.
Flamethrowers: blood cells and cancer thrombosis risk
Authors: Pabinger Ingrid , Posch Florian 
Published: October 2019

Abstract
Cancer patients are at an increased risk of venous thromboembolism. The clotting system is activated in most cancer patients, which is reflected by specific parameters such as an increased thrombin generation and elevated D-dimer levels. Blood cells, especially WBCs and platelets, play an important role in this activation process. Neutrophils and monocytes are subpopulations of WBCs that increase the thrombotic potential by different mechanisms. Neutrophils are activated by tumor cells and can release DNA, generating highly thrombogenic neutrophil extracellular traps. Monocytes are able to synthesize and express significant quantities of procoagulant tissue factor on their surfaces upon activation. An increased risk of VTE has been found in patients with solid tumors and elevated platelet count and in those with high-grade gliomas and low platelet count. Small circulating membrane vesicles, also called microparticles (MPs), which largely derive from platelets, contribute to the procoagulant potential. Specifically, procoagulant MPs could play a role in tumor-associated thrombosis in pancreatic cancer. Interventional studies are under way that are investigating the benefits of thromboprophylaxis in patients identified to be at high risk of VTE through risk-scoring models that include blood count parameters. The “flames” thrown by blood cells, such as neutrophil extracellular traps and MPs, although exciting, still have to be investigated for their usefulness in the clinical setting.
Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress
Authors: Burt Richard , Dey Aditi , Aref Sarah , Aguiar Melanie , Akarca Ayse , Bailey Katharine , Day William , Hooper Steven , Kirkwood Amy , Kirschner Kristina , Lee Soo-Wah , Lo Celso Cristina , Manji Jiten , Mansour Marc R. , Marafioti Teresa , Mitchell Rachel J. , Muirhead Robert C. , Cheuk Yan Ng Kenton , Pospori Constandina , Puccio Ignazio , Zuborne-Alapi Krisztina , Sahai Erik , Fielding Adele K. 
Published: October 2019

Key Points
MSCs can become cancer-associated fibroblasts and transfer mitochondria to rescue B-ALL cells from ROS-inducing chemotherapy. Rescue of B-ALL cells is overcome by microtubule inhibitors, which interrupt the tunneling nanotubes used for mitochondrial transfer.
THE MEGAKARYOCYTES IN IDIOPATHIC THROMBOCYTOPENIC PURPURA, A FORM OF HYPERSPLENISM
Authors: DAMESHEK WILLIAM , MILLER EDWARD B. 
Published: October 2019

Abstract
1. The megakaryocytes of the sternal bone marrow at biopsy were studied in 11 cases of idiopathic thrombocytopenic purpura and compared with those of 10 normal cases, 5 of thrombocytopenic purpura associated with various types of splenomegaly, and of a large group of miscellaneous hematologic conditions, including leukemia, associated with a reduction in platelets.
2. Megakaryocyte counts expressed in terms of a million nucleated red cells and differential counts of megakaryocytes were performed. The megakaryocytes were classified as megakaryoblasts, promegakaryocytes, and mature forms, and were further subdivided into those showing granularity, platelet production, degenerated forms, and mitoses.
3. In the normal cases, not more than 300 megakaryocytes per million nucleated red cells were present, and an average of 68.6 per cent showed platelet production.
4. In acute idiopathic thrombocytopenic purpura, although the platelets in the circulating blood were rare, megakaryocytes were increased, being present in a proportion of 366 to 743 per million nucleated red cells. Platelet production was, however, greatly diminished and found in only 8 to 19 per cent of all megakaryocytes. Following splenectomy, there was a striking increase in platelet production, which was now present in 69 to 85 per cent of all cells; the large masses of new platelets in the marrow were often very striking.
5. In chronic idiopathic thrombocytopenic purpura, the megakaryocytes were considerably increased over normal values, but showed great diminution in platelet production; following splenectomy, extreme degrees of platelet production from megakaryocytes took place.
6. In splenomegaly of nonleukemic origin (cirrhosis, splenic vein thrombosis, Gaucher's disease, Felty's syndrome), the megakaryocytes were somewhat increased, but platelet production was normal.
7. In aplastic anemia, lymphosarcoma, acute leukemia, and other diseases invading or destroying the bone marrow, the megakaryocytes were conspicuously reduced, the few remaining cells present being of normal morphology.
8. The origin of the blood platelets from megakaryocytes, certain regulatory mechanisms for platelet production and delivery, and the possible relationship of the spleen to these mechanisms are discussed.
9. The findings of increased megakaryocytes and greatly diminished platelet production in the marrow before splenectomy and the striking increase in platelet production after splenectomy indicate a definite pathogenetic relationship of the spleen to the disease. Idiopathic thrombocytopenic purpura is probably a form of hypersplenism (splenic thrombopenia) in which, through a possible hormonal mechanism, the megakaryocytes of the bone marrow are inhibited from normal platelet production and delivery.
10. The marrow findings in idiopathic thrombocytopenic purpura are sufficiently characteristic to be of diagnostic value in differentiating the disease from leukemia and other conditions associated with a low blood platelet count.
RELATION OF CONTACTING SURFACE AND ANTICEPHALIN ACTIVITY TO THE MAINTENANCE OF THE FLUIDITY AND COAGULABILITY OF BLOOD
Authors: TOCANTINS LEANDRO M. 
Published: October 2019

Abstract
A review of the various factors in the blood that have to do with the promotion and the retardation of coagulation is presented.
Circulating blood seems to have within and about itself all the factors required to delay or to promote coagulation. The stability of blood (i.e., its tendency to remain fluid) depends on the extent of the dominance of the anticoagulant (fluidity-inducing) group of factors over the coagulant (coagulation-promoting) group.
Among the anticoagulant factors are the natural anticephalin activity of the plasma and the intact vascular endothelium; the latter is simulated by such contacting surfaces as collodion and paraffin films.
Alterations in the stability of blood result from uncompensated increases or decreases in one or more of the anticoagulant or coagulant factors.
The increased stability of hemophilic blood, due to an uncompensated excess of anticephalin activity, enables it to resist activation by cephalin or by contact with injured walls of blood vessels or with surfaces like glass. Blood obtained from normal individuals after severe hemorrhage has a decreased stability owing to an uncompensated diminution in anticephalin activity; such blood is readily clotted by cephalin and may not remain stable even when in contact with undamaged vascular endothelium or surfaces like collodion or paraffin.
SOME NEWER CONCEPTS OF THE NATURAL DERIVATIVES OF HEMOGLOBIN
Authors: WATSON CECIL JAMES 
Published: October 2019

Abstract
The transition of hemoglobin to bile pigment, at least under normal conditions, is believed to occur via an intermediate biliverdin-globin-iron (verdohemoglobin) and not over the stages of hematin and protoporphyrin. It is probable that the next step is a reduction to bilirubin with splitting off of iron. There is much reason to believe that the globin remains attached until the bilirubin passes through the liver cell, bilirubinglobin exhibiting a delayed or indirect van den Bergh reaction and not being excreted in the urine; the sodium bilirubinate of the bile exhibiting a prompt (1') van den Bergh reaction and being readily excreted in the urine. The former type is characteristic of retention, the latter of regurgitation jaundice.
The appearance of bilirubin in the urine is believed to be related to the concentration in the blood of the 1' or prompt bilirubin, rather than that of the total bilirubin. It is evident that the threshold may be considerably lower at the onset of jaundice, as, for example, in hepatitis, than during its defervescence. This undoubtedly accounts for the appearance of bilirubinuria prior to recognizable jaundice in certain instances, likewise for its presence in the cases of so-called "hepatitis without jaundice." In retention jaundice marked elevation of the total serum bilirubin is unassociated with bilirubinuria; in these cases the increase of bilirubin is mainly of the delayed or indirect reacting type. Further evidence is presented of the essential difference between the 1' or prompt, and the T minus 1', or delayed and indirect reacting bilirubins. This consists of a change of the order of reaction at one minute after adding the diazonium salt. The normal upper limit of the 1' bilirubin has been shown to be in the neighborhood of 0.2. mg. per 100 cc.; figures well below this value are usually obtained.
Further experience with the erythrocyte protoporphyrin in the anemias has revealed that this determination, quite apart from its fundamental interest, is at times of diagnostic value. Thus in several instances a significant elevation of the erythrocyte protoporphyrin has indicated that the initial impression of pernicious anemia was incorrect, and has led to the search for other information. Conversely, a low normal value in the presence of anemia has often correctly indicated or confirmed the diagnosis of pernicious anemia. Marked elevations have aided in confirming the presence of iron deficiency and have given some insight into the degree of its severity and chronicity. In certain cases, high values for the erythrocyte protoporphyrin have suggested the possibility of heavy metal toxicity, the existence of which has then been borne out by subsequent study.
MONOCYTIC LEUKEMIA AND TUBERCULOSIS
Authors: HELLER ELWYN L. , HILES CHARLES H. 
Published: October 2019

Abstract
A case of monocytic leukemia associated with active tuberculosis of pleura, pericardium, and lymph nodes is reported.
The criteria for the diagnosis of monocytic leukemia and the factors excluding a leukemoid reaction are presented.
The rarity of monocytic leukemia in contrast with the frequency of tuberculous infections and the rarity of active tuberculosis in the reported cases of monocytic leukemia indicate that the association of the two diseases is probably coincidental.
PSEUDOHEMOPHILIA
Authors: ESTREN S. , MÉDAL L. SANCHEZ , DAMESHEK WILLIAM 
Published: October 2019

Abstract
1. Eleven cases of a hemorrhagic diathesis are presented characterized by an increased bleeding time in the presence of a normal coagulation time, normal blood platelet count, and normal clot retraction. An analysis is made of 62 similar cases in the literature.
2. These cases, which have been designated as pseudohemophilia, probably represent a particular disorder of the capillaries, in which capillary retractility following trauma may be inherently defective.
3. The differential diagnosis of these cases from other types of hemorrhagic disease and the necessity for their recognition particularly from the prophylactic standpoint are stressed. Except for easily accessible local bleeding, therapy is at present ineffectual.
4. Standardized methods for the performance of hemorrhagic tests are suggested. The Lee-White method for the coagulation time may give normal values as high as 20 minutes or more.
Evaluation of the Quantitative Direct Antiglobulin Test in Hemolytic Disease of the Newborn Due to Anti-D
Authors: GREENWALT TIBOR J. , WAGNER JOYCE A. 
Published: October 2019

Abstract
1. 86 infants with hemolytic disease due to anti-D iso-immunization were studied by the quantitative direct antiglobulin test.
2. No regular correlation was found between this test and clinical severity.