bluuebunny/crossref_metadata_2025 huggingface dataset:
Minimal residual disease in acute myeloid leukemia: coming of age
Authors: Paietta Elisabeth
Published: October 2019

The achievement of complete hematologic remission (CR) is a prerequisite for cure in acute myeloid leukemia (AML). The conventional definition of CR, based on the morphologic recognition of ≤ 5% of leukemic blasts in the BM, does not provide sufficient insight into the quality of the response. Despite CR rates of 50%-80% (depending on age), the majority of patients with AML relapse within 3-5 years from diagnosis. Therefore, there is great need of more sensitive prognostic factors that can predict relapse. Minimal residual disease (MRD), defined as any measurable disease or leukemia detectable above a certain threshold (defined by the methodology applied), predicts failure to maintain a morphologic CR and affects survival negatively. AML is lagging behind acute lymphoblastic leukemia with respect to the implementation of MRD criteria for guidance during therapy. AML is particularly disadvantaged compared with acute lymphoblastic leukemia in that approximately half of AML patients lack a molecular target suitable for MRD monitoring. The detection of altered antigen (Ag) expression by leukemic myeloblasts is a valid alternative to DNA- or RNA-based MRD assays. Although associated with presenting prognostic factors (eg, cytogenetics and genotype), MRD represents the collective end result of all of the cellular mechanisms that determine a patient's response to a given therapy. Therefore, MRD has 2 potential roles in AML treatment: (1) as a posttherapy prognosticator used to assign patients to optimal postinduction/consolidation therapy, and (2) as an early surrogate end point for the evaluation of therapy efficacy.
Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma?
Authors: Rajkumar S. Vincent
Published: October 2019

The treatment of multiple myeloma is evolving rapidly. A plethora of doublet, triplet, and quadruplet combinations have been studied for the treatment of newly diagnosed myeloma. Although randomized trials have been conducted comparing older regimens such as melphalan-prednisone with newer regimens containing drugs such as thalidomide, lenalidomide, or bortezomib, there are few if any randomized trials that have compared modern combinations with each other. Even in the few trials that have done so, definitive overall survival or patient-reported quality-of-life differences have not been demonstrated. Therefore, there is marked heterogeneity in how newly diagnosed patients with myeloma are treated around the world. The choice of initial therapy is often dictated by availability of drugs, age and comorbidities of the patient, and assessment of prognosis and disease aggressiveness. This chapter reviews the current data on the most commonly used and tested doublet, triplet, and quadruplet combinations for the treatment of newly diagnosed myeloma and provides guidance on choosing the optimal initial treatment regimen.
When, how, and what cell source for hematopoietic cell transplantation in first complete remission adult acute lymphoblastic leukemia?
Authors: Lazarus Hillard M. , Advani Anjali S.
Published: October 2019

Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease affected by many patient- and disease-related factors, including age, immunologic subtype, and clinical, genetic, and molecular features. Allogeneic hematopoietic cell transplantation (HCT) has occupied an increasing therapeutic role as a result of significant improvements in supportive care and histocompatibility testing. ALL Philadelphia chromosome–negative patients formerly excluded now are considered HCT candidates and survival rates with alternative donors may approach those obtained with matched-related donors. Reduced-intensity conditioning rather than myeloablative conditioning appears to provide comparable patient outcome results although these observations have not been validated in prospective studies. Improved tools can identify patients thought to be in remission based on morphology but who have active disease at the molecular or immunophenotypic level (minimal residual disease). Using B-cell antigen panels, clone-specific immunoglobulins, or T-cell receptor rearrangements to detect positivity at thresholds of at least 1 in 104 cells, such patients may be taken to HCT. The ongoing advances in conventional therapy intensity, however, now yield improved results and ongoing reassessment of the place of HCT needs to be continued; every effort should be made to enroll eligible patients in clinical trials.
Thrombocytopenia and bleeding in pediatric oncology patients
Authors: Bercovitz Rachel S. , Josephson Cassandra D.
Published: October 2019

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

Strategies 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

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

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

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

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.
Older patients/older donors: choosing wisely
Authors: Artz Andrew S.
Published: October 2019

Two lingering problems regarding transplantation in older adults have been how to select patients appropriately and whether to use older sibling donors. Allogeneic hematopoietic cell transplantation (HCT) of older patients may result in long-term survival due to GVL, but the data remain observational and mostly restricted to those 50 to 69 years of age. Patients with excellent performance status and low comorbidity have the best long-term survival after HCT. Novel measures of health status such as self-report or performance-based functional measures allow “staging the age” and may inform candidacy for less robust patients. Older matched sibling donors should be preferred over matched unrelated donors (MUDs) because outcomes are equivalent to superior for matched sibling donors compared with MUD. However, MUDs also achieve acceptable outcomes and long-term disease control. An alternative donor can be considered based on institutional protocols and expertise. Very limited information is available in patients or related donors 70 years of age and older. Future efforts to more completely characterize patient health status before transplantation will allow better application of HCT in older adults.
Clinically defining and managing high-risk pediatric patients with acute lymphoblastic leukemia
Authors: Alexander Sarah
Published: October 2019

For children with acute lymphoblastic leukemia, the identification of those at higher risk of disease recurrence and modifying therapy based on this risk is a critical component to the provision of optimal care. The specific definitions of high-risk ALL vary across cooperative groups, but the themes are consistent, being largely based on leukemia biology and disease response. Intensification of conventional chemotherapy for those with high-risk disease has led to improved outcomes. It is anticipated that the development of rational targeted therapy for specific biologically unique subsets of children with leukemia will contribute to ongoing progress in improving the outcomes for children with acute lymphoblastic anemia.
Intermediate-risk acute myeloid leukemia therapy: current and future
Authors: Döhner Konstanze , Paschka Peter
Published: October 2019

In 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

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

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.
Venetoclax and obinutuzumab for frontline treatment of chronic lymphocytic leukemia
Authors: Stephens Deborah M.
Published: October 2019

In a Blood Spotlight, Stephens reviews the evidence supporting the administration of venetoclax and obinotuzumab for frontline treatment of chronic lymphocytic leukemia and places the combination in the context of other accepted up-front therapies.
THE MEGAKARYOCYTES IN IDIOPATHIC THROMBOCYTOPENIC PURPURA, A FORM OF HYPERSPLENISM
Authors: DAMESHEK WILLIAM , MILLER EDWARD B.
Published: October 2019

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

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

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

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.
PLASMA CELL LEUKEMIA
Authors: MOSS WILLIAM T. , ACKERMAN LAUREN V.
Published: October 2019

A case of plasma cell leukemia is reported, together with a review of the literature, including a summary of the signs, symptoms, and laboratory findings usually present. The relationship of this leukemic state to ordinary plasmacytoma, a tumor of white cell origin, is discussed.
PSEUDOHEMOPHILIA
Authors: ESTREN S. , MÉDAL L. SANCHEZ , DAMESHEK WILLIAM
Published: October 2019

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

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.
Acute Intestinal Iron Intoxication
Authors: REISSMANN KURT R. , COLEMAN THOMAS J. , BUDAI BENEDICT S. , MORIARTY LAUREN R.
Published: October 2019

To simulate the fatal iron poisoning reported in children and to study the mechanism of the iron toxicity, dissociable iron salts were given by stomach or duodenal tube or by enema to rabbits and dogs. In either route of administration, the lethal dose was found to be approximately 150 to 200 mg. Fe per kilogram body weight.

Dissociable iron salts in toxic doses were rapidly absorbed through the histologically intact mucosa both from the small and from the large bowel. In the majority of the animals, no histological changes were seen in the intestinal mucosa, but intestinal bleeding occurred in some instances by diapedesis from the greatly congested capillaries.

Serum iron levels of several milligrams per cent developed within sixty minutes after ingestion of the iron salts, and with the exception of 300 to 400 micrograms per cent, the serum iron was non-beta1-globulin bound and in ferric state.

Although only a fraction of the total dose administered was found to be absorbed within nine hours, the observed serum iron rise was roughly proportional to the dose ingested, and the survival time varied inversely with the dose.

Acute intestinal iron poisoning must therefore be considered as a true absorptive intoxication. Any possibly occurring mucosal damage in stomach and intestines is of secondary importance.
Lymph Node Smears in the Diagnosis of Lymphadenopathy: A Review
Authors: LUCAS P. F.
Published: October 2019

1. A description of the cells of normal lymph nodes is presented, based on the examination and differential counts of smears from 15 nodes obtained at operation.

2. 95 per cent of the cells of normal nodes are lymphocytes. The most primitive cell is the multipotent hemohistioblast which gives rise to the histiocyte and the hemocytoblast the parent of three differentiated 'blast cells, the lymphoblast, monoblast and plasmoblast. 'Blast cells are rare in normal nodes but can be observed in inflammation.

3. The cytology of 85 pathologic nodes is described, the final diagnoses being confirmed histologically in most instances.

4. The features of inflammation are similar irrespective of the cause. Some types of inflammation result in excess of one series of cells more than another; it is rarely possible to distinguish them on these grounds, but the cytology may indicate those cases in which search for tubercle bacilli is likely to be rewarding.

5. Sternberg cells and their precursors are almost specific for Hodgkin’s disease. Diagnosis is possible if they are present together with a pleomorphic cytology.

6. A diagnosis of leukosis or primary or secondary neoplasm can be made if 80 per cent of the cells are abnormal. Distinction of these three groups from smears depends on the type and distribution of cells. The degree of abnormality bears no relation to prognosis.

7. Diagnosis depends on finding abnormal cells; differential counts are of little value.

8. Analysis of the few cases of reticulosis examined suggest that cytologic classification is unlikely to be useful.

9. Examination of one smear from each of 85 nodes for 15 minutes without clinical information enabled a diagnosis to be in 52 cases; the only error was that monocytic leukosis was called reticulosarcoma.

10. On two occasions, one of secondary carcinoma and one of reticulosis, the correct diagnosis was made from smears at a time when histology showed nonspecific changes only.

11. The method should find a useful place as a screening test in diagnosis of lymphadenopathy, excision of a node being carried out if aspiration fails or if the diagnosis cannot be made from smears.
Hemoglobin I: An Inherited Hemoglobin Anomaly
Authors: RUCKNAGEL D. L. , PAGE E. B. , JENSEN W. N.
Published: October 2019

A hitherto undescribed hemoglobin anomaly has been detected in a North Carolina Negro family. This new hemoglobin, designated type I, which has been electrophoretically characterized, was found in combination with normal adult A hemoglobin in 6 of 17 members of one family. In each, the ratio of normal to abnormal hemoglobin was similar. Hematologic abnormalities were not observed in any of the affected individuals. Ultracentrifugation sedimentation constants, absorption spectra, solubility and oxygen carrying capacity studies showed no differences from hemoglobin A.

It is proposed that the I hemoglobin gene is an allele of hemoglobin A and is transmitted as a simple dominant character in a manner similar to that of sickle cell hemoglobin. The homozygous form of I hemoglobin has not as yet been observed.
A Study of the Morphology of the Living Cells of Blood and Bone Marrow in Supravital Films with the Phase Contrast Microscope
Authors: ACKERMAN G. ADOLPH , BELLIOS NICHOLAS C.
Published: October 2019

The cells of the blood and bone marrow from various blood dyscrasias have been studied in the living state and compared with normal cells of the same lineage by means of vital films and phase contrast and bright field microscopes.

The precise morphology of the cells of the blood and bone marrow in a normal and diseased condition is most accurately obtained by an examination of the cells in a living condition. Such studies are possible with supravital staining and the phase contrast microscope. Since cellular structure and function are interdependent an alteration in one is necessarily reflected in the other. Further insight into the chemical structure and composition of cells of the blood and bone marrow in normal and diseased conditions may be obtained from cytochemical investigations. However, it is essential that cytochemical localization of substances within the cell must have its foundation in the morphology of the intact living cell.
Refractory Sideropenic Anemia in Childhood Due to an Error of Iron Metabolism
Authors: ZETTERSTRÖM ROLF , DELAVA SIMONE
Published: October 2019

Two cases of essential hypochronic anemia in childhood are reported. One of the cases which developed a mild Plummer-Vinson syndrome was completely refractory to peroral as well as intravenous iron therapy. In both cases the iron metabolism has been studied by means of radioiron.

The following characteristics were found: The serum iron level was extremely low but the iron binding capacity was normal. The absorption of iron from the alimentary tract was defective and intravenously injected radioiron was utilized for hemoglobin synthesis at a slow rate. There was a rapid plasma iron turnover.

The hypothesis is offered that the cause of the anemia resided in an abnormality in the regulation of iron metabolism.
Mediterranean Anemia in the Negro
Authors: SCHWARTZ STEVEN O. , HARTZ WILSON H.
Published: October 2019

1. Four Negro patients and their families previously reported in 1949 as examples of Mediterranean anemia were re-evaluated with regard to hemoglobin composition. The data have been presented.

2. Mediterranean anemia was confirmed in one entire family and in the index case of another family.

3. Two entire families and one member of another family were found to possess hemoglobin C.

4. Differential diagnostic points of Mediterranean anemia and hemoglobin C disease are presented.
Prevention of Neonatal Anemia in the Rat by the Pituitary Erythropoietic Factor
Authors: CONTOPOULOS A. N. , VAN DYKE D. C. , ELLIS S. , SIMPSON M. E. , LAWRENCE J. H. , EVANS H. M.
Published: October 2019

Of all the substances tested for the prevention of the neonatal anemia in the rat, only the pituitary preparations, erythropoietically active in the repair of post-hypophysectomy anemia, were able to prevent the development of neonatal anemia of the newborn rat.
Intracellular Protein Resembling Russell Bodies in Malignant Lymphomas Associated with Acquired Hemolytic Anemia
Authors: RAPPAPORT HENRY , JOHNSON FRANK B.
Published: October 2019

Large amounts of intracellular periodic acid-Schiff positive protein, closely resembling Russell bodies tinctorially and histochemically and, to varying degrees, morphologically, were found in the neoplastic cells of three patients with malignant lymphoma associated with acquired hemolytic anemia. Direct Coombs tests were positive in all three of these patients, and in two of them, immune autoantibodies against red cells were observed in unusually high titers. One of the latter also had abnormally high serum globulin levels with cryoglobulinemia.

A similar intracellular protein was present in the neoplastic tissue of seven of a control group of 65 unselected cases of malignant lymphoma. The serum globulin was elevated in four of the seven patients and one of these also had cryoglobulinemia. Definite evidence of hemolytic anemia was noted in one, and suggestive evidence in two of these four patients. A lymph node removed from a fifth patient, on whom no serum protein determinations had been made, showed hemosiderosis and marked erythrophagocytosis. This patient had not received blood transfusions or other treatment before biopsy was performed.

On the basis of our observations, it is suggested (1) that under certain conditions the neoplastic cells of malignant lymphomas are capable of synthesizing abnormal proteins; (2) that the presence of Russell body-like intracellular PAS-positive material in the neoplastic cells may be the morphologic manifestation of this protein synthesis; (3) that these abnormal proteins may play an important part in the immunological mechanisms responsible for the development of acquired hemolytic anemia in association with malignant lymphomas.
The Relationship of the Basophil to Blood Histamine in Man
Authors: VALENTINE WILLIAM N. , LAWRENCE JOHN S. , PEARCE MORTON LEE , BECK WILLIAM S.
Published: October 2019

Data are presented correlating 22 determinations of the histamine content of blood in patients with chronic granulocytic leukemia with (1) the basophils (2) the other myeloid granulocytes. Expressing the histamine in each case on the basis of the amount in 108 granulocytes, there is a readily evident positive correlation with the basophil percentage and a negative correlation with the percentage of other myeloid elements. This is strikingly apparent in instances where blood with a very high percentage of basophils was analyzed. The data indicate that in chronic granulocytic leukemia, the basophil is predominantly and, perhaps exclusively, responsible for the marked elevations in blood histamine. Inferentially, it appears probable that this cell type, though small in numbers, may be the principal carrier of histamine in non-leukemic blood.
Fundamental Observations on the Production of Compensatory Polycythemia in a Case of Patent Ductus Arteriosus With Reversed Blood Flow
Authors: SCHMID RUDI , GILBERTSEN A. S.
Published: October 2019

A proved case of patent ductus arteriosus occurring distal to the origin of the left subclavian artery with persistent reversal of flow through the shunt and compensatory polycythemia has been reported. Studies of cellular morphology and oxygen saturation of the bone marrow in the sternum and ilium were performed. The results indicated that the sternal marrow manifested the same marked degree of normoblastic hyperplasia as the iliac marrow, although the oxygen saturation of the iliac marrow was markedly decreased as compared to the normal saturation of the sternal marrow. This demonstrates that anoxia of the bone marrow could not have been the stimulus to the increased erythropoietic activity found in the sternal marrow. The study appears to support the belief that anoxemia of the blood stimulates the production or release of a humoral factor which in turn produces increased erythropoiesis.
Evidence Concerning the Inadequacy of Mutation as an Explanation of the Frequency of the Sickle Cell Gene in the Belgian Congo
Authors: VANDEPITTE J. M. , ZUELZER WOLF W. , NEEL JAMES V. , COLAERT J.
Published: October 2019

It is pointed out that there are two outstanding (and not mutually exclusive) possible explanations for the persistence of the sickle cell gene in the face of strong negative natural selection. These are (1) "balanced polymorphism," and (2) a high spontaneous mutation rate.

In Léopoldville, Belgian Congo, approximately 25 per cent of the natives exhibit the sickling phenomenon. Over a two and one-half year period 261 patients with sickle cell disease, distributed among 243 families, were seen at the Institute of Tropical Medicine in Léopoldville. A total of 233 of the 243 mothers of the patients in this series was tested for the sickling phenomenon. Only two failed to sickle. Hemoglobin from these two women was normal on paper electrophoresis.

The occurrence of these two exceptional mothers can be explained on the basis of mutation at some stage of oogenesis resulting in a sickle cell gene. Alternate possible explanations include (1) transmission by the mother of some other abnormal gene affecting hemoglobin synthesis, (2) occurrence in the mother of a genetic modifier of the effects of the sickle cell gene, (or its normal allele), and (3) unreported adoption.

These data make possible a preliminary calculation of the extent to which mutation may be responsible for maintaining the sickle cell gene. Calculations based on the assumption that both these exceptional mothers indicate the occurrence of a mutation will lead to maximal estimates of the rate of mutation of the sickle cell gene. This maximal estimate is 1.7 x 10-3 per gene per generation. This rate, although very high by the usual standards of human mutation rates, is only approximately one-tenth that necessary to offset natural selection in a population with 25 per cent sickling.
The Adrenal Cortex and Hemolysis
Authors: FELDMAN J. D. , RACHMILEWITZ M. , STEIN O.
Published: October 2019

Hemolysis was induced in rats by the intravenous administration of phenylhydrazine, immune hemolytic serum and Tween 80. During the period of red cell destruction, which lasted for three to four days, there was a marked leukocytosis, neutrophilia and eosinophilia which also persisted for three to four days. With phenylhydrazine and Tween 80 there was an initial transitory eosinopenia; with immune serum there was an immediate eosinophilia.

In contrast, anemia produced by cardiac hemorrhage was accompanied by a transient slight leukocytosis and eosinopenia. Within one day the white cell level returned to baseline levels, but eosinophilia appeared and persisted for two days. The injections of formaldehyde, ACTH, and saline, and cardiac puncture without bleeding caused a slight ephemeral leukocytosis and eosinopenia.

The peripheral blood cell response observed during hemolysis occurred in the presence or absence of the adrenals, and with or without the administration of ACTH.

It was concluded that hemolysis elicits a distinct pattern of cellular response in the peripheral blood which is not mediated through the adrenal cortex.
Distribution of Histamine among Leukocytes and Platelets
Authors: GRAHAM HELEN TREDWAY , LOWRY OLIVER H. , WHEELWRIGHT FRANCES , LENZ MIRIAM A. , PARISH HAVNER H.
Published: October 2019

1. Platelets and lymphocytes free of other white elements of blood have been analysed for histamine by a microchemical method. Platelets were found to contain 1280 µg. per liter or .009 µg. per 109 platelets, lymphocytes 2600 µg. per liter, or 0.6 µg. per 109 cells.

2. The histamine content of neutrophilic, eosinophilic and basophilic granulocytes has been calculated by multiple regression from histamine measurements on one series of blood samples from normal adults and another from subjects with chronic myelocytic leukemia. The normal values are 1080 µg. per l09 basophils and 160 µg. per 109 eosinophils or 2,400,000 and 360,000 µg. per liter respectively. The corresponding values for neutrophils are 3 µg. per 109 cells and 7000 µg. per liter. The values for the histamine concentration per cell are statistically significant for basophils and eosinophils, but not for neutrophils.

In the leukemia series, the values for neutrophils and basophils are respectively 69 and 305 µg. per 109 cells, and they are statistically significant. The difference from normal in the value for basophils was not statistically validated. There are, however, in chronic myelocytic leukemia, histological changes from the normal that are consonant with a decreased histamine content in basophils and an increased histamine content in eosinophils and neutrophils.

3. Although definite values for the histamine content of monocytes and the immature forms seen in chronic myelocytic leukemia have not been obtained, there is reason to believe that the histamine of these cell types does not exceed that of neutrophils.

4. By centrifuging white cells in a specific gravity gradient column, partial segregation of cell types was obtained. Peak concentrations were observed at the followihig specific gravities: lymphocytic leukemia lymphocytes, 1.063; myelocytes, normal lymphocytes and basophils, all near 1.070; neutrophils, 1.080, and eosinophils, 1.080 or higher. Although individual concentration peaks were usually quite sharp, there was considerable overlapping at intermediate specific gravities.

5. About half of the histamine of normal blood is in the basophils, one-third in the eosinophils and the remaining one-sixth in all the other blood elements combined. In blood samples from patients with chronic myelocytic leukemia, the fraction of blood histamine carried by each type of granulocyte varies widely.